The compound, its pharmaceutically acceptable salt, pharmaceutical composition

 

(57) Abstract:

Compounds of General formula I where at least one of R1, R2, R3or R4represents (CH2)m+1-C[(CH2)nCH3] -L-C(O)-(CH2)p-CH=CH-(CH2)qCH3,

where L Is O or CH2; m is an integer from 0 to 14 inclusive; n is an integer of 0 to 14; p and q are independently integers of 0-10, each of the remaining groups R1, R2, R3and R4independently represent-C(O)-(CH2)z-C(O)-(CH2)xCH3;

-(CH2)z+1-C(OH)H-(CH2)xCH3; -C(O)-(CH2)z-G-(CH2)xCH3where G is a group-S(O)-; x is an integer of 0 to 14; z is an integer 0-10; each A1and A2independently mean OH, OCH3, -OP(O)(OH)2, -O-(CH2)d+1-OPO(OH)2where d is independently an integer of 0-5; x is-CH2)tO(CH2)vCH3, -(CH2)tOPO(OH)2where t and v are integers 0-14; Y is OH; O(CH2)wCH3, halogen atom, -OC(O)-(CH2)wCH3where w is an integer 0-14, and their pharmaceutically acceptable salts. Compound 1 and its pharmaceutically acceptable salts possess antiviral activity. Described intermediate connection which has been created as medicines, with antiendotoxin activity, in particular analogs of lipid A.

The number of cases of infection with gram-negative bacteria in the United States is estimated from approximately 100,000 to 300,000 per year, with a mortality rate of 30-60 % (see Dudley, Am. J. Hosp. Pharm, 47, Supplement 3, 3, 1990). As primary chemotherapy for the treatment of these diseases usually use antibiotics, bactericidal effect leads to the destruction of bacteria and the associated allocation of endotoxin, i.e., lipopolysaccharide (LPS) of the remainder of the outer shell membrane of bacteria. The release of LPS causes a number of physiological effects in mammals, which all together are denoted by the terms "gram-negative endotoxemia" or "sepsis syndrome", including, for example, fever, General inflammation, diffuse coagulation of vessels (RCC), low blood pressure, acute renal failure, acute respiratory infections (ARI), destruction of liver cells and heart failure (see Dudley; Braunwald and others , "Harrison''s Priciples of Internal Medicine", II-nd edition, "McGraw-hill Beech company", New York, 1987).

Although endotoxin and initiates charging, he has little near outermost biological "intermediaries" (materials) which lead to infection and associated lesions. Endotoxin stimulates monocytes and macrophages to the production of the two main primary mediators - nekrose-tumor factor and interleukin-1. These mediators then cause the syndrome of sepsis by stimulating the inflammatory process or causing other types of cells, for example indoleamine cells to the selection of the sequence of secondary mediators, such as prostaglandins, leukotrienes, interferons, factors activate platelets, endorphins and factors that stimulate the formation of colonies. These inflammatory mediators actions affect vasomotor tone, microvascular permeability and on the aggregation of leukocytes and platelets. Although individual action and interaction of these products is quite complex, their negative effect on the initiation of septic shock is quite large (see the previously mentioned article by Braunwald and others).

As noted Di Piro (Am. J. Hosp. Pharm. 47, Supplement 3, 6, 1990), the molecule of bacterial lipopolysaccharide contains 3 main areas: the area of long-chain polysaccharide (O Antigen), the area of the core and lipid A. the Molecule lipopolysacharide obviously impacts can be attributed to the field of lipid A. The structure of the lipid A consists of a disaccharide and allerban long-chain fatty acids.

Therapy of diseases caused by endotoxin, usually aimed at controlling the inflammatory response. Similar alternative therapy includes treatment with corticosteroids in the hope to reduce damage to cell membranes caused by endotoxin as a mediator, and reduce the production of certain biological mediators (see Bown, N. Eng. J. Med. 317, 653, 1987; United group on the system radiation sepsis in the company of veterans, N. Eng. J. Med. 317, 659, 1987, Braunwald and others, noted earlier message); antibodies designed to neutralize bacterial lipopolysaccharide endotoxin (see, for example, Ziegler and others, N. Eng. J. Med. 307, 1225, 1982); the processing naloxone, which apparently blocks the effect of the pressure reduction associated with the syndrome of sepsis (see Sigrun and others, "Cecil Textbook of Medicine, 18th edition, Philadelphia, 1988, S. 1538-41) and processing of non-steroidal anti-inflammatory drugs aimed at blocking cyclooxygenase, resulting in reduced production of certain secondary mediators, such as prostaglandins and thromboxane (see the above work Di Piro).

Preferably at least one of the radicals R11, R2, R3or R4means

< / BR>
,

where each m independently is an integer lying in the range from 0 to 10 inclusive; each n independently is an integer lying in the range from 0 to 10, inclusive, for each of p and q independently observed the condition 0 (p + q) 12; each of the remaining radicals R1, R2, R3and R4independently represents a

,

where each X independently is an integer lying in the range from 0 to 10 inclusive; each Z independently is an integer lying in the range from 0 to 3 inclusive; each G independently represents SO or SO2; each of the A1and A2independently represents a

,

where each d independently represents an integer lying in the range from 0 to 2 inclusive; X represents H, (CH2)tOH, (CH2)tCH3, (CH2)tO(CH2)vCH3where t is an integer lying in the range from 0 to 6 inclusive, and v is an integer ranging from 0 to 6; Y represents OH or halogen.

More preferably, at least one of radially an integer, lying in the range from 6 to 10, inclusive, and most preferably equal to 6; provided that the condition 6 (p + q) 10, and most preferably q = 5; each of the remaining radicals R1, R2, R3and R4independently represents a

< / BR>
where each X independently is an integer lying in the range from 6 to 11 inclusive, and most preferably 6 or 10; each G independently represents SO or SO2; each of the A1and A2independently represents a

;

X represents CH2OH, CH2OCH3or CH2O(CH2)vCH3where v represents an integer ranging from 1 to 3 inclusive; Y represents OH.

Most preferably the above connection receive in the form of a salt of lysine, TRIS salt, ammonium salt or sodium salt. These include analogs of lipid A B-274, B-276, B-286 B-288 B-313 B-314 B-374, B-385 B-387 B-388, B-389 B-400, B-479 B-214, B-218, B-231, B-235, B-272 B-287 B-294 B-300, B-318, B-377, B-380, B-406 B-410, B-425 B-426 B-427 B-442 B-451 B-452, B-459, B-460, B-464 B-465, B-466 B-531 B-415 B-718, B-587, B-737, B-763, B-725 B-763 (contained in the description).

The least preferred according to the invention in the first aspect of the above compounds) s.

In accordance with the second aspect according to the invention provides compounds of General formula

< / BR>
where at least one of R1, R2, R3or R4represents a

< / BR>
where each L is an oxygen, nitrogen or carbon; each M represents oxygen or nitrogen; each m independently is an integer lying in the range from 0 to 14 inclusive; each n independently is an integer lying in the range from 0 to 14 inclusive; each p independently represents an integer lying in the range from 0 to 10 inclusive; each q independently represents an integer lying in the range from 0 to 10 inclusive; each X independently is an integer lying in the range from 0 to 14 inclusive; each Y independently is an integer lying in the range from 0 to 14 inclusive; each Z independently is an integer lying in the range from 0 to 10 inclusive; each of the remaining radicals R1, R2, R3and R4independently represents a

< / BR>
< / BR>
< / BR>
where each L is an oxygen, nitrogen or carbon; each of M Presto 14 inclusive; each m independently is an integer lying in the range from 0 to 14 inclusive; each n is independently from each other represents an integer lying in the range from 0 to 14 inclusive; each p independently represents an integer lying in the range from 0 to 10 inclusive; each o is independently represents an integer lying in the range from 0 to 10 inclusive; each X independently is an integer lying in the range from 0 to 14 inclusive; each Y independently is an integer lying in the range from 0 to 14 inclusive; each Z independently is an integer lying in the range from 0 to 10 inclusive; each G independently represents oxygen, nitrogen, sulfur, SO or SO2; each of the A1and A2independently represents H, OH,

,

where each d independently represents an integer lying in the range from 0 to 5 inclusive; each f is independently represents an integer lying in the range from 0 to 5 inclusive; each g independently represents an integer lying in the range from 0 to 5 inclusive; each of the A3independently represents a

< / BR>
where b is Oh, H, (CH2)tCH3, (CH2)tOH, (CH2)tO(CH2vCH3, (CH2)t-O-R5, (CH2)t-CH=CH-(CH2)vCH3,

where each of t and v independently represents an integer lying in the range from 0 to 14 inclusive; R5can have any of the above for R1-R4values; Y represents H, OH, O(CH2)wCH3, halogen,

< / BR>
where w is an integer ranging from 0 to 14 inclusive.

Preferably at least one of the radicals R1, R2, R3or R4represents a

< / BR>
where each m independently is an integer lying in the range from 0 to 10 inclusive; each n independently is an integer lying in the range from 0 to 10 inclusive, and most preferably equal to 6; each of p and q independently observed the condition 0 (p+q) 12, and most preferably q=5; each of the remaining radicals R1, R2, R3and R4independently represents a

< / BR>
where each X independently is an integer lying in the range from 0 to 10 inclusive; each Z independently predstavlyaet a

< / BR>
where each d independently represents an integer lying in the range from 0 to 2 inclusive; X represents H, (CH2)tCH3, (CH2)tOH, (CH2)tO(CH2)vCH3where t is an integer lying in the range from 0 to 6 inclusive; v is an integer ranging from 0 to 6; Y represents OH.

Most preferably the above connection receive in the form of a salt of lysine, TRIS salt, ammonium salt or sodium salt. These include analogs of lipid A B-415, B-459, B-460, B-465, B-466 B-477, B-510, B-427, D-464, and B-531 (contained in the description).

In accordance with a third aspect of the invention provides for therapeutic compositions comprising as an active ingredient the compound according to the invention together with suitable physiological media.

In accordance with the fourth aspect of the invention provides a compound of General formula

< / BR>
where R2means

,

< / BR>
< / BR>
< / BR>
where each J independently represents a hydroxyl or protected hydroxyl; each L is an oxygen, nitrogen or carbon; each M represents the sustained fashion; each m independently is an integer lying in the range from 0 to 14 inclusive; each n independently is an integer lying in the range from 0 to 14 inclusive; each p independently represents an integer lying in the range from 0 to 10 inclusive; each q independently represents an integer lying in the range from 0 to 10 inclusive; each X independently is an integer lying in the range from 0 to 14 inclusive; each Y independently represents an integer lying in the range from 0 to 14 inclusive; each Z independently is an integer lying in the range from 0 to 10 inclusive; each G independently represents oxygen, nitrogen, sulfur, SO or SO2; p1represents hydroxyl, protected hydroxyl or A protected group1where A1represents a

< / BR>
where each d independently represents an integer lying in the range from 0 to 5 inclusive; each f is independently represents an integer lying in the range from 0 to 5 inclusive; each g independently represents an integer lying in the range from 0 to 5 inclusive; each of the A3azederach from 0 to 14 inclusive; p2represents H, halogen, hydroxyl, protected hydroxyl, O(CH2)wCH3,

,

where w is an integer lying in the range from 0 to 14 inclusive.

Preferably R2represents a

< / BR>
< / BR>
where each J independently represents a hydroxyl or protected hydroxyl; each m independently is an integer lying in the range from 0 to 10 inclusive; each n independently is an integer lying in the range from 0 to 10 inclusive; each X independently is an integer lying in the range from 0 to 10 inclusive; each Z independently is an integer lying in the range from 0 to 3 inclusive; each G independently represents SO or SO2; for each p and q is independently a value of 0 (p+q) 12; p1represents hydroxyl, protected hydroxyl or A protected group1where A1represents a

< / BR>
where each d independently represents an integer lying in the range from 0 to 2 inclusive; p2represents H, hydroxyl, protected hydroxyl, O(CH2)wCH3where w represents a>represents a

< / BR>
where each J independently represents a hydroxyl or protected hydroxyl; each X independently is an integer lying in the range from 0 to 11 inclusive; each G independently represents SO or SO2; each n independently is an integer lying in the range from 6 to 10, inclusive, for each of p and q is the ratio 0 (p+q) 10; p1represents hydroxyl, protected hydroxyl or A protected group1where A1represents a

< / BR>
p2represents H, hydroxyl, protected hydroxyl or OCH3.

In accordance with the fifth aspect according to the invention provides compounds of General formula

< / BR>
where R4represents a

< / BR>
< / BR>
< / BR>
< / BR>
where each J independently represents a hydroxyl or protected hydroxyl; each L is an oxygen, nitrogen or carbon; each M represents oxygen or nitrogen; each E independently represents an integer lying in the range from 0 to 14 inclusive; each m independently is an integer lying in the range from 0 to 14 inclusive; Kadima is an integer, lying in the range from 0 to 10 inclusive; each q independently represents an integer lying in the range from 0 to 10 inclusive; each X independently is an integer lying in the range from 0 to 14 inclusive; each Y independently is an integer lying in the range from 0 to 14 inclusive; each Z independently is an integer lying in the range from 0 to 10 inclusive; each G independently represents oxygen, nitrogen, sulfur, SO or SO2; p3represents hydroxyl, protected hydroxyl, OCH group A2or A protected group2'where A2'provides a

< / BR>
where each d independently represents an integer lying in the range from 0 to 5 inclusive; each f is independently represents an integer lying in the range from 0 to 5 inclusive; each g independently represents an integer lying in the range from 0 to 5 inclusive; each of the A3independently represents a

< / BR>
where each j independently represents an integer lying in the range from 0 to 14 inclusive; Z is a hydroxyl, protected hydroxyl, an activated hydroxyl, or C istCH3, (CH2)tOH, (CH2)tO(CH2)vCH3, (CH2)tOPO(OH)2, (CH2)t-CH= CH-(CH2)vCH3, (CH2)t-O-R5,

< / BR>
where each of t and v independently represents an integer lying in the range from 0 to 14 inclusive; R5may have any of the values listed above for R1-R4.

Preferably R4represents a

< / BR>
< / BR>
where each J independently represents a hydroxyl or protected hydroxyl each m independently is an integer lying in the range from 0 to 10 inclusive; each n independently is an integer lying in the range from 0 to 10 inclusive; each X independently is an integer lying in the range from 0 to 10 inclusive; each Z independently is an integer lying in the range from 0 to 3 inclusive; each G independently represents SO or SO2; for each p and q is independently a value of 0 (p+q) 12; p3represents H, hydroxyl, protected hydroxyl, OCH, group A3'or A protected group2'where A2'represents a

< / BR>
DG is et a H, (CH2)tCH3, (CH2)tOH, (CH2)tO(CH2)vCH3where t is an integer lying in the range from 0 to 6 inclusive, and v is an integer lying in the range from 0 to 6, inclusive.

In the most preferred embodiment, R4represents a

,

where each J independently represents a hydroxyl or protected hydroxyl; each x independently is an integer lying in the range from 6 to 11 inclusive; each G independently represents SO or SO2; each n independently is an integer lying in the range from 6 to 10, inclusive, for each p and q is independently a value of 0 (p+q) 10; p3represents hydroxyl, protected hydroxyl, A group2'or A protected group2'where A2'represents a

;

X' represents CH2OH, CH2OCH3or CH2O(CH2)vCH3where v is an integer lying in the range from 1 to 3 inclusive.

In accordance with the sixth aspect according to the invention provides compounds of General formula

< / BR>
where each of R2and R hydroxyl or protected hydroxyl; each L represents oxygen, nitrogen or carbon; each M represents oxygen or nitrogen; each m independently is an integer lying in the range from 0 to 14 inclusive; each n independently is an integer lying in the range from 0 to 14 inclusive; each p independently represents an integer lying in the range from 0 to 10 inclusive; each q independently represents an integer lying in the range from 0 to 10 inclusive; each x independently is an integer lying in the range from 0 to 14 inclusive; each y independently is an integer lying in the range from 0 to 14 inclusive; each Z independently is an integer lying in the range from 0 to 10 inclusive; each G independently represents oxygen, nitrogen, sulfur, SO or SO2; p1represents hydroxyl, protected hydroxyl or A protected group1; p3represents hydroxyl, protected hydroxyl, A group2'or A protected group2'where each group A1and A2'independently from each other represents a

,

where each d independently represents an FDS is, lying in the range from 0 to 5 inclusive; each g independently represents an integer lying in the range from 0 to 5 inclusive; each of the A3independently represents a

,

where each j independently represents an integer lying in the range from 0 to 14 inclusive; p2represents H, hydroxyl, protected hydroxyl, O(CH2)wCH3,

< / BR>
where w is an integer from 0 to 14 inclusive; Q independently represents N3or NH2; X' represents X or a protected group X, where X represents H, (CH2)tCH3, (CH2)tOH, (CH2)tO(CH2)vCH3,

(CH2)t-CH=CH-(CH2)vCH3, (CH2)tO-R5< / BR>
< / BR>
where each of t and v independently represents an integer lying in the range from 0 to 14, inclusive, R5may have any of the values listed above for R1-R4.

Preferably each of R2and R4independently represents a

< / BR>
< / BR>
where each J independently represents a hydroxyl or protected hydroxyl; each m independently represents an integer cycloidal from 0 to 10 inclusive; each x independently is an integer lying in the range from 0 to 10 inclusive; each y independently is an integer lying in the range from 0 to 3 inclusive; each G independently represents SO or SO2for each p and q is independently a value of 0 (p+q) 12; p1represents hydroxyl, protected hydroxyl or A protected group1; p3represents hydroxyl, protected hydroxyl, A group2'or A protected group2'where each group A1and A2'independently represents a

< / BR>
where each d, independently, is an integer lying in the range from 0 to 2 inclusive; p2represents H, hydroxyl, protected hydroxyl, O(CH2)wCH3where w is an integer from 0 to 3 inclusive; X' represents H, (CH2)tCH3, (CH2)tOH, (CH2)tO(CH2)vCH3where t is an integer lying in the range from 0 to 6 inclusive; v is an integer lying in the range from o to 6, inclusive.

Most preferably each of R2and R4independently represents the x independently represents an integer lying in the range from 6 to 11 inclusive; each G independently represents SO or SO2; each n independently is an integer lying in the range from 6 to 10, inclusive, and is the ratio of 6 (p+q) 10; p1represents hydroxyl, protected hydroxyl or A protected group1; p3represents hydroxyl, protected hydroxyl, A group2'or A protected group2'where each group A1and A2'independently represents a

< / BR>
p2represents hydroxyl, X' represents H, (CH2)tCH3, (CH2)tOH, (CH2)tO(CH2)CH3where t is an integer lying in the range from 1 to 3 inclusive.

In accordance with the seventh aspect according to the invention provides compounds of General formula

< / BR>
where each of R1, R2, R3and R4independently represents a

< / BR>
< / BR>
< / BR>
< / BR>
where each J independently represents a hydroxyl or protected hydroxyl; each L is an oxygen, nitrogen or carbon; each M represents oxygen or nitrogen; each m is independently the number submitted, lying in the range from 0 to 14 inclusive; each p independently represents an integer lying in the range from 0 to 10 inclusive; each q independently represents an integer lying in the range from 0 to 10 inclusive; each x independently is an integer lying in the range from 0 to 14 inclusive; each y independently is an integer lying in the range from 0 to 14 inclusive; each z independently is an integer lying in the range from 0 to 10 inclusive; each G independently represents oxygen, nitrogen, sulfur, SO or SO2; p1represents hydroxyl, protected hydroxyl or A protected group1and p3represents hydroxyl, protected hydroxyl, A group2'or A protected group2'where each group A1and A2'independently represents a

< / BR>
where each d independently represents an integer lying in the range from 0 to 5 inclusive; each f is independently represents an integer lying in the range from 0 to 5 inclusive; each g independently represents an integer lying in the range from 0 to 5 inclusive; each of the A3azederach from 0 to 14 inclusive; p2represents H, halogen, hydroxyl, protected hydroxyl, O(CH2)wCH3,

,

where w is a number from 0 to 14 inclusive; X' represents X or a protected group X, where X represents H, (CH2)tCH3, (CH2)tOH, (CH2)tO(CH2)vCH3, (CH2)t-CH=CH-(CH2)vCH3, (CH2)t-O-R5, ,

where each of t and v independently represents an integer lying in the range from 0 to 14 inclusive; R5may have any of the values listed above for R1- R4.

Preferably each of R1, R2, R3and R4independently from each other represents a

< / BR>
< / BR>
where each J independently represents a hydroxyl or protected hydroxyl; each m independently is an integer lying in the range from 0 to 10 inclusive; each n independently is an integer lying in the range from 0 to 10 inclusive; each x independently is an integer lying in the range from 0 to 10 inclusive; each z is an integer lying in the range from 0 to 3 inclusive; each is1represents hydroxyl, protected hydroxyl or A protected group1; p3represents hydroxyl, protected hydroxyl, A group2'or A protected group2'where each group A1and A2'independently represents a

,

where each d, independently, is an integer lying in the range from 0 to 2 inclusive; p2represents H, hydroxyl, protected hydroxyl, or O(CH2)wCH3where w is an integer from 0 to 3 inclusive; X' represents H, (CH2)tCH3, (CH2)tOH, (CH2)tO(CH2)vCH3where t is an integer lying in the range from 0 to 6 inclusive, and v is an integer lying in the range from 0 to 6, inclusive.

Most preferably each of R1, R2, R3, R4independently represents a

,

where each J independently represents a hydroxyl or protected hydroxyl; each x independently is an integer lying in the range from 6 to 11 inclusive; each G independently represents SO or SO2; each n is independently predtstavlyaet a hydroxyl, protected hydroxyl or A protected group1; p3represents hydroxyl, protected hydroxyl, A group2'or A protected group2'where each group A1and A2'independently represents a

;

p2represents hydroxyl, X' represents H, (CH2)tCH3, (CH2)tOH, (CH2)t(CH2)vCH3where v is an integer lying in the range from 1 to 3 inclusive.

In accordance with the eighth aspect according to the invention provides a method of obtaining the compounds of formula

,

includes the following stages:

a) obtaining mannopyranoside formula

,

b) reaction of the specified mannopyranoside with a catalytic amount of naphthalene in the presence of lithium.

In accordance with the ninth aspect according to the invention provides a method of obtaining the compounds of formula

,

includes the following stages:

a) obtaining the compounds of formula

,

b) reaction of the compounds with ammoniarelated and salt alkali metal azide, preferably sodium azide.

In the preferred embodiment, this method kamuli

.

In accordance with the tenth aspect according to the invention provides a method of obtaining the compounds of formula

,

includes the following stages:

a) obtaining the compounds of formula

,

b) dissolving the compounds in trichloroacetonitrile;

b) the reaction between the specified dissolved substance and bis(trimethylsilyl)amidon lithium.

In accordance with the eleventh aspect according to the invention provides a method of carrying out the reaction of a combination of 3,4-dimethoxyaniline protective group with active azidoanilide, including first reaction azidoanilide with dimethoxybenzyl alcohol, and then efratom boron TRIFLUORIDE. In a preferred embodiment, asiasari is a compound of the formula

.

In accordance with the twelfth aspect according to the invention provides for the carrying out of the reaction combinations allyloxycarbonyl protective group of hydroxyl-containing side chain of a saccharide, comprising the reaction of a saccharide first with phosgene and then with allyl alcohol.

In a preferred embodiment, the saccharide is asiasari; the saccharide is a connection form the Association of the formula:

.

In accordance with the thirteenth aspect according to the invention provides a method for selective removal of the tert-butyldimethylsilyloxy group protected by acyl of saccharide, comprising the reaction of a saccharide with hydrofluoric acid.

In a preferred embodiment, the saccharide is a disaccharide; group protecting acyl moiety is allyloxycarbonyl group; protected acyl saccharide is a compound of the formula:

,

protected by acyl saccharide is a compound of the formula:

< / BR>
protected by acyl saccharide is a compound of the formula:

< / BR>
protected by acyl saccharide is a compound of the formula:

< / BR>
protected by acyl saccharide is a compound of the formula:

< / BR>
protected by acyl saccharide also contains 3,4-dimethoxybenzyl protective group; and protected by acyl saccharide is a compound of the formula:

< / BR>
In accordance with the fourteenth aspect according to the invention provides a method of carrying out the reaction of a combination of bis(alkoxy)postonline side chain with a saccharide comprising first reaction of the saccharide with Ariane bis(alkoxy)Gostilna side chain is a protected aryloxyalkyl phosphate group; the oxidizer is a m-chloroperbenzoic acid; the saccharide is a disaccharide, preferably asiasari; asiasari is a compound of the formula;

< / BR>
asiasari is a compound of the formula:

< / BR>
asiasari is a compound of the formula:

< / BR>
asiasari is a compound of the formula:

< / BR>
In accordance with the fifteenth aspect according to the invention provides a method of removing 3,4-dimethoxyaniline protective group from azidoanilide, including the reaction of azidoanilide with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in the dark under anaerobic conditions (in the absence of contact with air).

In accordance with the sixteenth aspect according to the invention provides a method of removing 3,4-dimethoxyaniline protective group from azidoanilide, including the reaction of azidoanilide with ammoniarelated.

In a preferred embodiment, the 15th and 16th aspects according to the invention asiasari is a compound of the formula:

< / BR>
In accordance with the seventeenth aspect according to the invention provides a method of performing selective reaction of a combination of alpha try and cesium carbonate.

In a preferred embodiment, aseoche is a compound of the formula:

< / BR>
In accordance with the eighteenth aspect according to the invention provides a method of obtaining a disaccharide, which includes stages: (a) receiving aidememoire containing 3,4-dimethoxybenzyl protective group, and (b) the reaction of the protected 3,4-dimethoxybenzyl group azidoanilide with the second activated aitomechanika in argon atmosphere in the presence of epirate of boron TRIFLUORIDE or trimethylsilyltrifluoromethane.

In the proposed version of aidememoire are compounds of the formula:

< / BR>
and aidememoire are compounds of the formula:

< / BR>
In accordance with a nineteenth aspect according to the invention provides a method of restoring azide side-chain saccharide without recovering the unsaturated side chain, comprising the reaction of azidoanilide with a complex of Tris-aristilde tin (II) trialkylamines in the dark under anaerobic conditions.

In a preferred embodiment, the complex of Tris-sensitivity tin (II) trialkylamine is a complex of Tris-sensitivity tin (II) with triethylamine; R>
< / BR>
In accordance with the twentieth aspect of the invention provides a method of removing allylacetate group from a molecule of saccharide, comprising the stage of: (a) receiving saccharide containing protected allyloxy-protective group of hydroxyl, and (b) the reaction of the protected saccharide with a complex of palladium.

In a preferred embodiment, the palladium complex is a tetrakis(triphenylphosphine)palladium (O); the saccharide is a compound of the formula:

< / BR>
and the saccharide is a compound of the formula:

< / BR>
In accordance with a twenty-first aspect according to the invention provides a method of alkylation C6-hydroxide of hexose without alkylation of the remaining free hydroxyl groups comprising the reaction hexose salt of silver and alkylhalogenide.

In a preferred embodiment, the silver salt is a silver oxide or silver carbonate: alkylhalogenide is methyliodide, and hexose is a compound of the formula:

< / BR>
In accordance with a twenty-second aspect according to the invention provides a method of phosphorylation of CI atom of the saccharide having amide side chain containing the conditions on the cold, and then reaction with dialkylphosphate.

In a preferred embodiment, the lithium base is a bis(trimethylsilyl)amide lithium; dialkylphosphate is diallylmalonate; and the saccharide is a compound of the formula:

< / BR>
In accordance with the twenty-third aspect according to the invention provides a method of obtaining CI dialkylphosphinate, which includes stages: (a) the reaction of a saccharide with trichloroacetonitrile and carbonate under anaerobic conditions and then (b) processing the Lewis acid and trialkylphosphites under anaerobic conditions.

In a preferred embodiment, the carbonate is a carbonate, cesium; trialkylphosphine is triarylphosphite; and the saccharide is a compound of the formula:

< / BR>
In accordance with a twenty-fourth aspect according to the invention provides a method of performing the reaction of a combination of alkyl side chain with azidoanilide containing free hydroxide, comprising the reaction of azidoanilide salt of an alkali metal and monoctyogenes sulfonium ALCALDIA under anaerobic conditions.

In a preferred embodiment, the salt of an alkali metal p is ldeal.

In accordance with a twenty-fifth aspect according to the invention provides a method of treating diseases in mammals, in which it is effective introduction receptor antagonist lipid A, which includes the introduction of a mammal a therapeutic composition according to the invention in a dose effective from the point of view of the binding of LPS to its receptor lipid A.

In accordance with a twenty-sixth aspect according to the invention provides a method of treating septic shock in a mammal, comprising the introduction of a mammal a therapeutic composition according to the invention in a dose effective from the point of view of counteracting the activation of LPS mediated activation of target cells.

In accordance with a twenty-seventh aspect according to the invention provides a method of treating LPS mediated activation of viral infections in mammals, including the introduction of a mammal a therapeutic composition according to the invention in a dose effective from the point of view of counteracting the activation of LPS mediated activation of target cells.

In a preferred embodiment, the virus comprises a binding site type NF - KB in the replication control placentas is hydrated virus is a herpes virus, for example, the Herpes simplex virus, and the virus is an influenza virus.

The term "protected group" in the sense in which it is used in this description, refers to a group (such as hydroxyl, associated with intermediate (intermediate derivative) according to the invention), protected from passing her a specific chemical reaction; specific reaction, subject to the lock, and the conditions under which the removal of the protective group, is individual for each of the intermediates and obvious to a person skilled in the implementation of the described synthetic methods. Examples of preferred protective groups include (but not limited to all possibilities) methyl, benzyl, substituted benzyl, silyl, alkylsilane, ethoxymethylene, alkylsilane, allyloxycarbonyl and aromatic acyl groups.

The term "activated connection" means that there is a carbon center, located next to the "displacement of the leaving group. The choice of an appropriate leaving groups are obvious to a person skilled in the area described in the invention of synthetic methods. Examples of preferred leaving groups are (not ogranicio-, aryloxy-, Se-alkyl groups and halogen atoms.

The term "monoactive connection" means the connection (for example intermediate connection according to the invention) has only one activated group in accordance with the above definition.

Described analogs of lipid A are especially effective therapeutic effect in the treatment or prevention of diseases, the course of which contribute mediators LPS; not associating themselves with a particular theory, it is possible to assume that these analogues obviously blocking access to the "target" for FSC places of mediator molecules, resulting directly "competition" with bacterial LPS. Due to the fact that such blocking occurs at a very early stage of the sequence of actions of mediators, a therapeutic effect is extraordinarily effective and is accompanied by minor side effects, or these effects are absent. In addition, since the analogues of lipid A according to the invention are synthesized by chemical means, they are relatively inexpensive to obtain and possess an unusually high degree of purity and a specific chemical composition, " of the invention are evident from the following preferred variants of the invention.

The following are examples of synthetic compounds, especially preferred for use according to the invention. These examples are intended to illustrate the invention and do not limit the limits of its formulas.

Below are the abbreviations used in the description:

Ac - acetate O < R

Sph - thiophenyl

DMB - 3,4-dimethoxybenzyl

AOC - allyloxycarbonyl

TBS is tert-butyldimethylsilyl

AllylO - allyloxy group

MPM - p-methoxybenzyl

Example 1. This example illustrates the synthesis contained in the description analogues of lipid A, as well as the synthesis of new intermediates, also claimed in the invention.

Part A. of the resulting monosaccharides and disaccharides

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It is located at 0oC to a solution of D-mannose (connection 1, 1.5 kg, with 8.33 moles, product form "Lancaster chemical company", Windham, new Hampshire), dissolved in anhydrous pyridine (3.5 kg, 126,0 of moles, the product of the firm "Aldrich chemical company, Milwaukee, Wisconsin) add at 5.6 kg (54,9 moles) of acetic anhydride (a product of the company "the Aldrich chemical company") for 4 h at such a speed that there is an opportunity to maintain the temperature of the reaction mixture in the range of 20-40oC. Obtained the o-pyridine (product of the company Aldrich chemical company); the resulting mixture is stirred for a further 48 hours, the Reaction mixture was poured into 14,0 l of a mixture of water with vigorous stirring and extracted with 12.0 l of dichloromethane (product company).T. Baker, Philipsburg, NJ).

The organic layer is washed first 1H hydrochloric acid (10,0 l, the product of the company Fisher scientific company, Pittsburgh, PA), then saturated aqueous bicarbonate sodium (20,0 l, a product of the company "Fisher scientific company") and finally in 5.0 l of a saturated aqueous solution of sodium chloride and dried over 3 kg of sodium sulfate (product of the company "Fisher scientific company"). The solution is filtered through a glass filter, and concentrate under reduced pressure at 40oC, receiving 3.5 kg compound 2 (Rf = 0,39 /ethyl acetate (the product of firm j.T. Baker"): hexane (product company).T. Baker"), 1: 1 by volume)/ in the form of a brown oil, which was used in the next stage without purification.

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Compound 2 (3.0 kg, 7,3 moles) is mixed with thiophenols (the product of the firm "Aldrich chemical company) (1.5 l, 11,0 moles) dissolved in 8.0 l of chloroform (product company).T. Baker") and add athirat of traktorid, boron (1.6 l, 12,9 moles, the product of the firm "Aldrich chemical company) with such speed, that temperatment data analysis by thin layer chromatography using a mixture of hexane: ethyl acetate 1: 1 by volume) mixture is cooled to room temperature and slowly poured with rapid mechanical stirring of 15.0 l of saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted 18,0 l dichloromethane, washed the organic layer first 15,0 l of saturated aqueous sodium bicarbonate solution, then 10,0 l of a saturated aqueous solution of sodium chloride and the resulting solution was dried over 3 kg of sodium sulfate, and then filtered through a glass filter. The filtrate is concentrated under reduced pressure at 40oC, receiving 4,99 kg compound 3 (Rf = 0,63 /ethyl acetate (the product of firm j. T. Baker"): hexane (product company).T. Baker"), 1:1, volume/ dark-brown oil, which was used in the next stage without purification.

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To mix by means of mechanical stirrers connection 3 (6,28 kg, 4.3 moles) dissolved in methyl alcohol (13,0 l product firm "Aldrich chemical company) gradually add 750,0 ml (or 3.28 moles) of 25% (weight/volume) solution of sodium methylate in methyl alcohol (product of the company Aldrich chemical company) maintaining the reaction temperature below 40oC. the resulting mixture was stirred at 40oC to complete the reaction, i.e., up until the thin layer chromatography using ethyl acetate will not indicate the presence of only product with Rf = 0,05.

The resulting mixture is cooled to on the l company"). The neutralized reaction mixture is filtered through a glass filter, and concentrate under reduced pressure at 40oC to obtain a brown oil. Specified oil partially purified by the addition with stirring of the two aliquot in a 10.0 l of a mixture of 5:1 by volume of ethyl acetate and hexane, discarding after each washing the top layer. The product, compound 4 (Rf = 0,05 (ethyl acetate)), obtained as a brown oil after drying in vacuum.

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Compound 4 (3.0 kg) dissolved in anhydrous N,N-dimethylformamide (6,0 HP product firm "Aldrich chemical company) at room temperature. To the resulting solution was added initially 1.0 kg (4.3 moles) ()-10-camphorsulfonic acid (the product of the firm "Aldrich chemical company), and then slowly, within 48 hours, add 8,0 l 2.2-dimethoxypropane (the product of the firm "Aldrich chemical company). Data analysis by thin layer chromatography (using a mixture of hexane : ethyl acetate 1:4 by volume) indicate the completion of the reaction. After completion of the reaction the mixture is then poured into a 10.0 l of saturated aqueous sodium bicarbonate solution and extracted with 12.0 l of dichloromethane. The organic layer is washed first with 5.0 litres of water, then of 10.0 l of a saturated aqueous solution of sodium chloride and dried the unity 5 in the form of a black oil. The crude oil was dissolved in 10.0 l of boiling ethyl acetate, cooled to room temperature and left to crystallize overnight. The crystalline mass is then cooled to 5oC, filtered and washed with 5.0 l of hexane at 0oC, receiving 2.0kg partial compound 5 as a pale brown needle-shaped crystals. The remainder of the filtrate is concentrated under reduced pressure at 40oC, the oil obtained is dissolved in 2.0 l of dichloromethane and injected the solution into which a column of silica gel (2.0 kg, the product of firm j. T. Baker"), elwira a mixture of ethyl acetate : hexane 1:4 by volume. Filter and concentrate kristallisera of ethyl acetate, receiving additional 1.5 kg of crystalline product. The combined crystals are recrystallized from ethyl acetate, receiving only 2.9 kg compound 5 (Rf = 0,60 /ethyl acetate: hexane, 1:4 volume/ total yield of 66% compared to compound 1.

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Compound 5 (1.98 kg, of 6.0 moles) dissolved in anhydrous tetrahydrofuran (6.0 liters, the product of the firm "Aldrich chemical company) and added at room temperature of 40.0 g (0.31 in moles) of naphthalene (product of the company Aldrich chemical company) in an atmosphere of nitrogen. To the resulting solution was then added to 20.0 grams (2.9 moles) of lithium wire (3.2 mm in diameter, amerivault by means of mechanical stirrers. After data analysis by thin layer chromatography (using a mixture of hexane : ethyl acetate 1:1 by volume) indicate the completion of the reaction, the excess of lithium is removed and poured the reaction mixture at 10.0 l of a saturated aqueous solution of ammonium chloride (the product of the company "Fisher scientific company"). The mixture is extracted with 10.0 l of dichloromethane, the organic layer was washed with 7.0 l of a saturated aqueous solution of sodium chloride, dried over 2 kg of sodium sulfate, filtered through a glass filter, and concentrate under reduced pressure at room temperature, receiving 1.4 kg of the crude compound 6 (Rf = 0.50 in /ethyl acetate:hexane, 1:1 by volume).

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Compound 6 (3.5 kg) is added slowly under stirring with a mechanical stirrer for 0.5 l of acetic anhydride and 4.5 l of anhydrous pyridine. The introduction is carried out in a bath of a mixture of ice water, maintaining the reaction temperature below 25oC. After 48 h the reaction mixture is concentrated to dryness at room temperature and reduced pressure, getting syrupy crystalline mass which was filtered through a glass filter and washed with 1.0 l of hexane at 0oC, receiving 2.25 kg of compound 7 (Rf = 0.50 in /ethyl acetate:hexane, 1:4 by volume) as white goldust firm Aldrich chemical company") and add at -30oC using a funnel for introducing solids mixture powder americanidiot (550,0 g, 1.0 mol, product of the company Aldrich chemical company) and sodium azide (40,0 g, of 0.62 mol, product of the company Aldrich chemical company). In the process of introduction of the reagents, the temperature rises to -26oC. After stirring at -28oC for 4 h, the reaction mixture was slowly poured in 4.0 l of ice water; when this occurs the gas. Then the reaction mixture was diluted with 4% ethyl acetate and separate the two layers. The organic layer is washed first with 1.0 l of water, and then 1.0 l of a saturated aqueous solution of sodium chloride, filtered through a glass filter and concentrate to dryness under reduced pressure at room temperature, receiving approximately 70 g of the crude product as a pale yellow oil. The specified oil is passed through a short column with silica gel (1.0 kg), elwira a mixture of ethyl acetate:hexane 1:2 by volume. After distillation under reduced pressure at room temperature of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) and dried overnight under vacuum at room temperature get 56,0 g (0,169 moles) of compound 8 is seen in a mixture of dioxane (1,47 l, the product of the firm "Aldrich chemical company) and water (600 ml) and add 64,5 g (0,93 moles) of sodium nitrate (product of the company Aldrich chemical company). The reaction mixture is heated at the boil under reflux for 1 h, cooled at room temperature and diluted with ethyl acetate (2.0 l). Both layers are separated and the aqueous layer was extracted with 2.0 l of ethyl acetate. The combined organic layer is washed first with 1.0 l of water, then 1.0 l saturated aqueous sodium bicarbonate solution and finally 1.0 l of a saturated aqueous solution of sodium chloride; the resulting solution was dried over 500 g of sodium sulfate, filtered through a glass filter, and concentrate under reduced pressure at room temperature, receiving a yellow oil. The oil obtained is passed through a short column with silica gel (1.0 kg), elwira a mixture of ethyl acetate: hexane 1: 1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature get 55,0 g (has 0.168 moles) of compound 9 as a colorless foamy substance with access, close to quantitative (Rf = 0,14 /ethyl acetate : GE is on and 14 ml (about 0.14 moles) of trichloroacetonitrile (the product of the firm "Aldrich chemical company). To the resulting solution was added at 0oC for 4 h in 0.1 M solution of bis (trimethylsilyl) amide lithium (product of the company Aldrich chemical company) in hexane. The reaction is quenched by 10 ml of a saturated aqueous solution of ammonium chloride and extracted with 200 ml of ethyl acetate. The organic layer was washed with 100 ml saturated aqueous solution of sodium chloride; the resulting solution was dried over 50 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The crude product is passed through a column of silica gel (150 g), elwira mixture of ethyl acetate: hexane 1:3 by volume, receiving 1.40 g (3.2 mmol) of alpha-trichloromethane (compound 10A, Rf = 0,37 /ethyl acetate : hexane 1:3 by volume/) in the form of a syrup with the release of 67% and 0.47 g (1.09 mmol) of beta-trichloromethane (compound 10b, Rf = 0.45 in /ethyl acetate:hexane, 1:3 volume/) in the form of needle-shaped crystals with a yield of 25%.

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Compound 10A (130 mg, 0.30 mmol) is mixed with 3,4-dimethoxybenzyl alcohol (0,65 ml, 0.45 moles) of the product of the firm "Aldrich chemical company) and anhydrous dichloromethane (5.0 ml). To the obtained mixture is added 200 mg of fine powder molecular sieves AW-300. The mixture was stirred at 0oC for 1 h, cooled to -78oC and add 1.0 ml of 0.02 M RA is sodium carbonate and extracted with 50 ml dichloromethane. The organic layer is dried over 25,0 g sodium sulfate, filtered through a glass filter, and concentrate under reduced pressure at room temperature. After purification on a column of silica gel with elution with a mixture of ethyl acetate: hexane 1: 6 by volume, receiving a mixture of compound 11a (Rf = 0.28 in /ethyl acetate:hexane, 1:3 by volume) and the compound 11b (Rf = 0.31 in /ethyl acetate : hexane, 1:3 volume/) in the form of a solid crystalline substance. Specified crystalline substance is recrystallized from a mixture of ethyl acetate:hexane 1: 2 by volume as described above. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature get 91,9 g (of 0.21 moles) of pure compound 11b yield 70%.

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To a solution of compound 11b (18,48 g to 0.04 moles) in methyl alcohol (200 ml) is added 2.0 ml of 25% (weight/ volume) solution of sodium methylate in methyl alcohol; the mixture is stirred at room temperature for 4 h, the Reaction mixture was neutralized with 10 ml of a saturated aqueous solution of ammonium chloride and extracted with 500 ml of ethyl acetate. The organic layer is washed first with 100 ml of water, and sale under reduced pressure at room temperature, receiving the crude product, which is passed through a column of silica gel (2.0 kg), elwira a mixture of ethyl acetate: hexane 1:2 by volume, receiving of 15.1 g (of 0.038 moles) of compound 12 (Rf = 0,19 /ethyl acetate:hexane, 1:2 volume/ output to 90%.

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Compound 12 (15,1 g of 0.038 moles) dissolved in 200 ml of anhydrous dichloromethane. To the resulting solution was successively added at 0oC and stirring with a magnetic stirrer 12.4 g (of 0.038 moles) of 4-dimethylaminopyridine. After 30 min the mixture is dissolved in 100 ml of hexane and filtered through 100 g Celite-545 (product firm "Aldrich chemical company). The filtrate is dispersed under reduced pressure at room temperature and pass the remainder through a column of silica gel (2.0 kg), elwira a mixture of ethyl acetate:hexane 1:4 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure and room temperature to obtain 22.1 g (0,034 moles) of compound 13 (Rf = 0,41/ethyl acetate:hexane, 1:2 by volume) to yield 89%.

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Compound 13 (22,0 g 0,034 moles) is dissolved in 90 ml of glacial acetic acid (product of the company "Fisher scientific company") and 10 ml of water and stirred with a magnetic stirrer at room t three times subjected to azeotropic rectification, using each time 50 ml of toluene (product company).T. Baker"). The residue was subjected to purification on a column of silica gel (2.0 kg), elwira linear gradient from 1:99 by volume to 5: 95 by volume mixtures of methyl alcohol:chloroform, receiving an increase of 22.7 g (0,037 moles) of compound 14 (Rf = 0,151/methyl alcohol:chloroform, 98:2 by volume/) with a quantitative yield. The connection 14 is used without further purification.

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Compound 14 (20.6 g, 0,034 moles) is dissolved in N,N-dimethylformamide (33.9 ml) at 0oC in nitrogen atmosphere. To the resulting solution was added at the beginning of 11.5 g (to 0.17 moles) of imidazole (product of the company Aldrich chemical company), and then 5.5 g (0,037 moles) of tert-butyldimethylsilyloxy (product firm "Lido Corporation of America, Gastonia, North America. Carolina). The resulting mixture is stirred for one hour, diluted with 500 ml ethyl acetate and poured into 500 ml of saturated aqueous sodium bicarbonate solution. The organic layer is washed first with 200 ml saturated aqueous sodium bicarbonate solution, then 200 ml of water and, finally, 100 ml of a saturated aqueous solution of sodium chloride, filtered through a cotton filter and subjected to distillation under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (2, is (as evidenced by the data analysis by thin layer chromatography) to obtain 24.2 g (0,033 moles) of compound 15 (Rf = 0,76/ethyl acetate:hexane, 1:1 by volume/ output to 98%.

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Compound 15 (24,1 g 0,033 moles) dissolved in anhydrous toluene (300,0 ml) and anhydrous pyridine (20,0 ml) at 0oC in nitrogen atmosphere. To the resulting solution was added for 10 min at 24.1 ml (0,046 moles) of 1.93 M solution of phosgene in toluene (product company "Fluka chemical Corporation, Ronkonkoma, new York). After 30 min for 5 min add 24,0 ml (0,353 moles) allyl alcohol (product of the company "Fluka chemical Corporation, Ronkonkoma, new York, and the resulting reaction mixture is stirred for an additional 10 minutes the Reaction is quenched by adding 100 ml of a saturated aqueous solution of sodium bicarbonate and dissolved in 1 l of ethyl acetate.

The organic layer is washed first with 500 ml of water, and then 500 ml of a saturated aqueous solution of sodium chloride, dried over 500 g of sodium sulfate, filtered through a cotton filter and subjected to distillation under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (2.0 kg), elwira a mixture of ethyl acetate: hexane 1:4 by volume, getting to 25.3 g (0,031 moles) of compound 16 (Rf = 0,60 /ethyl acetate:hexane, 1:2 volume/ output to 94%.

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Compound 16 (25,3 g 0,031 moles) is dissolved in a test tube made of polypropylene per 250 ml of 100 m is th 100 ml of a 4M solution of hydrochloric acid (the product of the firm "Aldrich chemical company) in acetonitrile. After 30 min the reaction is quenched by adding 100 ml of saturated aqueous sodium bicarbonate solution and extracted with 500 ml of chloroform. The organic layer is washed first with 100 ml of water, then 100 ml of a saturated aqueous solution of sodium chloride, dried over 100 g of sodium sulfate, filtered through a cotton filter and subjected to distillation under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (2.0 kg), elwira a mixture of ethyl acetate:hexane 2:3 by volume, getting to 19.9 g (0,029 moles) of compound 17 (Rf = 0,53 /ethyl acetate:hexane, 1:1, volume/ output to 91%.

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Compound 12 (20,0 g, 50.1 mmol) dissolved in anhydrous dichloromethane (500,0 ml) at 0oC and successively added to the resulting solution of 19.4 g (52.7 mmol) of compound 86 (see below), to 20.8 g (100,9 mmol) of 1,3-dicyclohexylcarbodiimide and 120 ml (0.98 mmol) of 4-dimethylaminopyridine. After stirring at room temperature for 20 min, the reaction mixture was diluted with 500 ml of hexane, filtered through a glass filter through 100 g Celite-545 and washed solid residue 100 ml of hexane. The combined filtrate is concentrated under reduced pressure at room temperature and the obtained residue was subjected to purification on a column of silica gel is the UCC (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature get 35,0 g (47,0 mmol) compounds 18 (Rf = 0,54/ ethyl acetate:hexane, 1:4 by volume/ output to 93%.

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A solution of compound 18 (35,0 g, and 47.0 mmol) in a mixture of 240 ml of glacial acetic acid and 60 ml of water is stirred with a magnetic stirrer for 14 h at room temperature. Then the reaction mixture was concentrated under reduced pressure at room temperature, and the crude product is subjected to azeotropic distillation with three portions of 50 ml of toluene. The product was subjected to purification on a chromatographic column with silica gel (3.0 kg), elwira first with a mixture of hexane:diethyl ether (product of the company "Mallinckrodt chemical company, St. Louis, Missouri), 1:1 by volume) and then with ethyl acetate, receiving of 29.3 g (41.6 mmol) of compound 19 (Rf = 0,62 /dichloromethane:methyl alcohol, 95:5 by volume/ output to 89%.

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Compound 19 (4.9 g, 6,94 mmol) dissolved in anhydrous toluene (50,0 ml) and anhydrous pyridine (12.0 ml) at 0oC in nitrogen atmosphere. To the resulting solution was added 1.31 ml (12.3 mmol) of allylchloroformate (the product of the firm "Aldrich chemical company). Later 7.5 h the mixture is diluted with 100 ml ethyl acetate and washed successively with 100 ml saturated aqueous sodium bicarbonate solution, 100 ml of water and 100 ml saturated aqueous solution of sodium chloride. The mixture is dried over 50.0 g sodium sulfate and powerpocket through a column of silica gel (500 g), elwira a mixture of ethyl acetate: hexane 1: 2 by volume. After removal of the solvent from fractions containing the product ( as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature gain of 4.2 g (5.32 mmol) of compound 20 (Rf = 0.70 and /ethyl acetate:hexane, 1:1 by volume)/) c output 77%.

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To stir magnetic stirrer, the solution 18,26 g (0.02 mmol) of compound 20 in 200 ml of anhydrous tetrahydrofuran add 17,02 ml (0,069 mmol) of bis(allyloxy)-(diisopropylamino) phosphine (obtained in accordance with the method described by Brennercom and king, Tetraheron Lett, 30, 4219, 1989) and 14,58 g (0,208 moles ) 1H-tetrazole (product firm "Amresco chemical company, Solon, Ohio) at room temperature under nitrogen atmosphere. After 1 hour the mixture is cooled to -78oC and add a solution 11,95 g of 3-chloroperbenzoic acid (the product of the firm "Aldrich chemical company) in 80 ml of anhydrous dichloromethane. The temperature of the reaction mixture is brought to 0oC and stirred for 20 minutes the Reaction is quenched with 50 ml of 10% aqueous sodium thiosulfate solution and stirred for further 10 min at room temperature. Then the reaction mixture is poured into 200 ml saturated aqueous sodium bicarbonate solution and EXT the range of sodium chloride, dried over 200 mg of sodium sulfate, distilled off the solvent under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (2.0 kg), elwira a mixture of ethyl acetate:hexane 1:2 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature get 17,64 g (0,0186 moles) of compound 21 (Rf = 0,32 /ethyl acetate:hexane 1:2 by volume/) c output 80,5%.

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Compound 21 (35,0 g, 0,0369 moles) dissolved in 40 ml of tert-butyl alcohol (product of the company Aldrich chemical company) and 40 ml of concentrate fosfatnogo buffer with pH=7.0 (product firm "Fisher scientific company") and 200 ml of dichloromethane. To the resulting solution was added at room temperature in a nitrogen atmosphere 33 g (0,145 moles) of 2,3-dichloro-5,6-dicyan-1,4-benzoquinone (product of the company Aldrich chemical company). The reaction mixture was stirred in the dark at room temperature for 14 hours the Reaction is quenched with 200 ml of 10% aqueous sodium thiosulfate solution (product firm "Fisher scientific company"), poured into 100 ml saturated aqueous sodium bicarbonate solution and extracted with 1 l of chloroform. The organic layer is washed with onaut solvents under reduced pressure at room temperature. The mixture was subjected to purification on a column of silica gel (3.0 kg), elwira a mixture of dichloromethane:methyl alcohol, 90:2 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by the method of thin-layer chromatographie) under reduced pressure at room temperature receive 27.5 (0,0344 moles) of compound 22 (Rf = 0,57 /dichloromethane:methyl alcohol, 95:5 by volume/ output to 94%.

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To a solution of compound 22 (of 52.8 g of 0.066 moles) 1.32 l of trichloroacetonitrile added under stirring with a mechanical stirrer to 53.0 g (0,163 moles) of cesium carbonate (product of the company Aldrich chemical company) at room temperature under nitrogen atmosphere. After 8 h the mixture is filtered through Celite-545", washed with 500 ml of dichloromethane and the solvent is distilled off under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (3.0 kg), elwira a mixture of dichloromethane:diethyl ether 95:5 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature to obtain 30.0 g (of 0.03 moles) of compound 23A (alpha-isomer) (Rf = 0,79 /dichloromethane:diethyl ether, 9:1 by volume of the Yat in the above reaction, and after cleaning they receive the second connection part 23A. Both parts combine, getting just 32,2 (0,034 moles) of pure compound 23A with the release of 52%.

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A mixture of compound 23A (6.0 g, 6.3 mmol) and compound 17 (4.5 g, 6.5 mmol) is dried in vacuum for 14 h and dissolved in 100 ml of anhydrous dichloromethane. To the resulting mixture are added 10 g of powder molecular sieves AW-300 (dried by annealing in vacuum) and the resulting mixture was stirred at room temperature in argon atmosphere. The mixture is then cooled to -23oC and add to 9.45 ml (1.89 mmol) of a 0.2 M solution epirate boron TRIFLUORIDE in dichloromethane (obtained by dissolving 0.25 ml (2,03 mmol) epirate boron TRIFLUORIDE in 10 ml of anhydrous dichloromethane and stirring with 200 mg of powder molecular sieves AW-300 for 1 h at room temperature) for 6 h using a syringe. The reaction is quenched by 30 ml of saturated aqueous sodium bicarbonate, diluted with 500 ml of dichloromethane and filtered through 50 g Celite-545". The filtrate is washed first with 200 ml saturated aqueous sodium bicarbonate solution, then 200 ml of water and finally with 200 ml of a saturated aqueous solution of sodium chloride; the filtrate 300g dried over sodium sulfate, filtered through a cotton filter, the column with silica gel (1.0 kg), when elution with a mixture of ethyl acetate: hexane 1: 3 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data of analogues by thin layer chromatography) under reduced pressure at room temperature get 5,42 g (3.67 mol) of compound 24 (Rf = 0.34 in /ethyl acetate : hexane 1:2 by volume/ output to 59%.

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Compound 24 (2,11 g, 1.43 mmol) was dissolved in anhydrous dichloromethane (22,0 ml) and added to 1.9 g of the complex tribenzoate tin (II) with triethylamine (obtained according to the method of Bart with labour). The resulting mixture is stirred for 8 hours at room temperature in a nitrogen atmosphere in the absence of light. The results of the analysis by thin-layer chromatography (hexane: ethyl acetate, 1:1 by volume) indicate that the magazine is empty original product. The reaction mixture was loaded directly on a column of silica gel (200 g), elwira first with a mixture of hexane:ethyl acetate 4:1 by volume) to remove by-products, and then 200 ml of ethyl acetate. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature gain of 0.91 g (1.34 mmol) connect varaut in anhydrous dichloromethane (10.0 ml) and added dropwise at room temperature, 1.7 g (4,65 mmol) of compound C6 (see below) and 1.98 g (9.60 mmol) of 1,3-dicyclohexylcarbodiimide. After 14 h the results of the analysis by thin-layer chromatography (hexane: ethyl acetate, 1:1 by volume) indicate the completion of the reaction. The reaction mixture is diluted with 50 ml ethyl acetate and filtered through 10 g Celite-545", the solid product is washed with 20 ml of ethyl acetate and subjected to rectification of the filtrate under reduced pressure at room temperature, obtaining the resulting syrupy residue. The syrup was dissolved in 5 ml dichloromethane, loaded into a column of silica gel (100 g), elwira first with a mixture of hexane:ethyl acetate 2:1 by volume) and then with a mixture of hexane: ethyl acetate 1: 1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature to obtain 2.0 g (0.95 mmol) of compound 26 (Rf = 0,5/ ethyl acetate:hexane, 1:1, volume/) with 71% yield.

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Compound 26 (817,0 mg, 0,386 mmol) is mixed with 13.5 ml of dichloromethane, 1,4 ml tert-butyl alcohol and 1.4 ml of the concentrate of phosphate buffer with pH= 7.0. To the resulting mixture 439 mg (1.9 mmol) of 2,3-dichloro-5,5 km ditzian-1,4-benzoquinone. The resulting mixture is stirred with a magnetic stirrer in a nitrogen atmosphere in them by volume) do not indicate the full expenditure of the original product (which is approximately 4.5 hours). The reaction is quenched by 10 ml of 10% aqueous sodium thiosulfate solution, diluted with 100 ml dichloromethane and poured into 50 ml saturated aqueous sodium bicarbonate solution. The organic layer is separated, washed with 50 ml saturated aqueous solution of sodium chloride, dried over sodium sulfate and filtered through a cotton filter. The crude reaction mixture was loaded directly on a column of silica gel (100 g), elwira a mixture of dichloromethane: methyl alcohol, 95:5 by volume, getting 606 mg (0.35 mmol) of compound 27 (Rf = 0,42 / dichloromethane:methyl alcohol, 95:5 by volume/ output to 91%.

With the aim of obtaining an analogue of lipid A B-274-32 carry out the removal of protection from connection 27 in accordance with the method described below for compounds 31 and the free acid is introduced into the reaction with 1 - lysine in accordance with the method described below for similar B-214-32.

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To a solution of compound 27 (408,4 mg, 0,237 mmol) in anhydrous tetrahydrofuran (5.0 ml) is added slowly at -78oC in nitrogen atmosphere with stirring 0,256 ml (0,262 mmol) 0,99 M solution of n-utility (the product of the firm "Aldrich chemical company) in hexane. After 5 min to the mixture of 0.71 ml (0,355 mmol) of 0.5 M solution of diallylmalonate (obtained according to sposo quench the reaction by 1 ml of glacial acetic acid. The reaction mixture was poured into 20 ml saturated aqueous sodium bicarbonate solution and extracted with 100 ml dichloromethane. The organic layer is washed first with 20 ml saturated aqueous sodium bicarbonate, then with 20 ml of a saturated aqueous solution of sodium chloride, dried over 50 g of sodium sulfate, filtered through a cotton filter and the solvent is distilled off under reduced pressure at room temperature. The obtained residue was subjected to purification on a column of silica gel (100 g), elwira a mixture of dichloromethane:ethyl acetate 1: 1 by volume, receiving 298,2 mg (0,158 mmol) of compound 28 (Rf = 0,38 /dichloromethane:methyl alcohol, 95:5 by volume/ output 66,8%.

With the aim of obtaining analogues of lipid A B-231-31 and B-231-32 carry out the removal of protection from the connection 28 in accordance with the method described below for compound 31. Similar lipid A B-231-32 get through reaction of the free acid with L-lysine in accordance with the method described below for similar B-214-32. Similar lipid A B-214-32. Similar lipid A B-231-31 get through reaction of the free acid with TRIS in accordance with the method described below for similar B-214-31.

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Method (a). 389,0 mg (0.92 mmol) of 1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benzodioxol-3(IH)-she received sorochka molecular sieves 4A (a product of the company "the Aldrich chemical company"), dried by calcination. To the reaction mixture is added slowly at 0oC in argon atmosphere a solution of 287,2 mg (0.15 mmol) of compound 28, dissolved in 2.9 ml of dichloromethane. After 2 h to the reaction mixture slowly add 5 ml (0.50 mmol) of a 0.1 M solution of 1,1,1-Tris(acetoxy)-1,1-dihydro-1,2-benzodioxol-3(1H)-it is in dichloromethane and stirred the reaction mixture for an additional 2 hours and Then the resulting mixture was diluted with 10 ml of diethyl ether and add to it 20 ml of a mixture 1:1 by volume of 10% aqueous sodium thiosulfate solution and add saturated aqueous sodium bicarbonate solution. The resulting mixture was extracted with 100 ml dichloromethane, the organic layer washed with 50 ml saturated aqueous solution of sodium chloride, dried over 50 g of sodium sulfate, and the solvent is distilled off under reduced pressure at room temperature. The remainder will podvergaetsya cleaning on 6 plates of 0.5 mm for preparative thin-layer chromatography (product of the company "E. M. science, Gibbstown, PCs, new Jersey, using for elution of a mixture of dichloromethane: methyl alcohol, 95:5 by volume. Strip product elute from the silica gel with ethyl acetate, getting to 110.0 mg (0,058 moles) of the compound 29 (Rf = 0,59 /dichloromethane:methyl alcohol, 95:5 by volume/)CLASS="ptx2">

With the aim of obtaining an analogue of lipid A B-218-31 and B-218-32 carry out the removal of protection at connection 29 in accordance with the method described below for compound 31. Similar lipid A B-218-32 get through reaction of the free acid with 1-lisinop in accordance with the method described below for similar B-214-32. Similar lipid A B-218-31 get through reaction of the free acid with TRIS in accordance with the method described below for similar B-214-31.

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Compound 30 (332,0 mg, 0,176 mmol) dissolved in 40 ml of a mixture of anhydrous tetrahydrofuran with 96% formic acid (a product of the company "the Aldrich chemical company, a 10: 1 by volume) in nitrogen atmosphere in the dark. To the resulting solution was added tetrakis(triphenylphosphine)palladium (O) (2,07 g, 1.76 mmol) (product of the company Aldrich chemical company) and triphenylphosphine (1.45 g, 5,28 mmol, the product of the firm "Aldrich chemical company). The reaction mixture was stirred at room temperature for 2 h, the solvent is distilled off under reduced pressure at room temperature and the obtained residue is subjected to three azeotropic distillation with 5 ml of toluene. The residue is again dissolved in 10 ml of methanol and passed through a solution of gaseous hydrogen sulfide in the Solvent for 5 minutes the e column with DE cellulose (100 g, the product of the company Sigma chemical company, St. Louis, PCs Missouri), elwira salt gradient from 0 to 0.1 M solution of ammonium acetate in a mixture with methyl alcohol and chloroform 3:2:1 by volume. The fractions containing the product (as evidenced by the data analysis by thin layer chromatography), combine and add an equal volume of chloroform. The organic layer is separated and concentrated under reduced pressure at room temperature, obtaining the product in the form of ammonium salts. The specified product is dissolved in 100 ml of water and removed by lyophilization excess of ammonium acetate. The resulting product represents the analogue of lipid A B-214-33.

Dried product is transferred to the free acid in the transmission through the column with a mixture of cellulose (a product of the company Sigma chemical company, St. Louis, PCs Missouri), elwira a mixture of methyl alcohol : chloroform: water 3:2:1 by volume. A solution of the product in the form of the free acid dispersed to dryness under reduced pressure at room temperature to constant weight.

Then the obtained product is dissolved in 5 ml of methyl alcohol and add to it 73 mg (0.49 mmol) of 1-lysine (product of the company "Sigma" brand "for cell cultures") in 5.0 ml of water. The resulting mixture is 300 ml does not contain pyrogenic additives demensional water, filtered through a Teflon filter for jhud with pore size of 0.2 μm (firm Rainin instruments", Woburn Massachusetts,) and lyophilizers obtaining 256,7 mg (0,124 mmol) salt pickles tetraline (i.e., compound 31; Rf = 0.64 in /chloroform: methyl alcohol: glacial acetic acid:water, 125:75:10:20 by volume) as a white hygroscopic foam substances with 71% yield. This product (compound 31) represents the analogues of lipid A B-214-32.

Analogues of lipid A B-215-31 receive as a result of the previously obtained free acid with Tris(oxymethyl)aminomethane (the product of the company "Sigma"). The resulting mixture is subjected to distillation to dryness under reduced pressure at room temperature; the resulting product is again dissolved in not containing pyrogenic additives and deionized water, filtered through a Teflon filter for jhud with pore size of 0.2 μm (firm Rainin instruments", Woburn, mA) and lyophilizers obtaining salt of Tris(oxymethyl)aminomethane, B-214-31.

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Compound 25 (3,90 g, is 2.74 mmol) was dissolved in 40 ml of anhydrous dichloromethane at room temperature. To the resulting solution was added 3.6 g (10.9 mmol) of compound C8 (see below) and 4.50 g (21.9 mmol) of 1,3-dicyclohexylcarbodiimide. The reaction Splatt, 1:1 by volume) indicate the completion of the reaction. The reaction mixture is diluted with 100 ml of hexane and filtered through 20 g Celite-545"; the solid product was washed with 100 ml of ethyl acetate and subjected to rectification of the filtrate under reduced pressure at room temperature, obtaining the resulting syrupy residue. The syrup was dissolved in 5 ml dichloromethane, loaded into a column of silica gel (400 g), elwira first with a mixture of hexane:ethyl acetate 4:1 by volume) and then with a mixture of hexane: ethyl acetate 1:1 by volume, to deliver to 3.36 g (1.64 mmol) of compound 32 (Rf = 0,51 /ethyl acetate:hexane, 1:1, volume/ output to 60%.

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Compound 32 (of 3.46 g, 1.69 mmol) was dissolved in 35 ml of dichloromethane and 3.5 Il tert-butyl alcohol. To the resulting solution was added initially to 3.5 ml of the concentrate of phosphate buffer with pH = 7.0, and then 957,0 mg (4.2 mmol) of 2,3-dichloro-5,6-dicyan-1,4-benzoquinone. The resulting heterogeneous mixture is stirred with a magnetic stirrer in a nitrogen atmosphere in the dark for about 12 hours, or until until the results of the analysis by thin layer chromatography (dichloromethane:methyl alcohol, 19:1 by volume) do not indicate the full expenditure of the original product. The reaction is quenched by 30 ml of 10% aqueous solution of thiosulfate on the strategic layer is separated, washed with 100 ml saturated aqueous solution of sodium chloride, dried over 100 g of sodium sulfate and filtered through a cotton filter. The crude reaction mixture was loaded directly on a column of silica gel (400 g), elwira gradient mixtures of dichloromethane:methyl alcohol, 99: 1 - 50:1 - 19:1 - 4:1 in volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature gain of 2.8 g (1.47 mmol) of compound 33 (Rf = 0,32/ dichloromethane:methyl alcohol, 19:1 by volume/ output to 87%.

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To a solution of compound 33 (716,4 mg, 0,377 mmol) in anhydrous tetrahydrofuran (71,0 ml) is added slowly at -78oC in nitrogen atmosphere with stirring 377 μl (0,415 mmol) of 1.1 M solution of n-utility (the product of the firm "Aldrich chemical company) in hexane. After 5 min to the mixture of 1.13 ml (0,566 mmol) of 0.5 M solution of diallylmalonate in anhydrous toluene. The resulting mixture was heated to 0oC, stirred for an additional 10 min and quenched the reaction by 716,0 μl of glacial acetic acid. The reaction mixture was poured into 100 ml saturated aqueous sodium bicarbonate solution and extracted with 500 ml DIC ml of a saturated aqueous solution of sodium chloride, dried over 300 g of sodium sulfate, filtered through a cotton filter and the solvent is distilled off under reduced pressure at room temperature. The obtained residue was subjected to purification on a column of silica gel (100 g), elwira mixture of toluene:ethyl acetate 3:1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature get 450,4 mg (0,219 mmol) of compound 34 (Rf = 50 / dichloromethane:methyl alcohol, 19:1 by volume/ output 58%.

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Method (b). Compound 34 (810.0 mg, 0.40 mmol) dissolved in anhydrous acetonitrile (10.0 ml) and add 1 ml of water. To the resulting solution was added first 693,0 mg (3,20 mmol) of the red oxide of mercury (II) (a product of the company "Aldrich chemical company), then 434,4 mg (1.60 mmol) of mercury chloride (II) (a product of the company "the Aldrich chemical company"), and the resulting mixture was stirred at room temperature under nitrogen atmosphere W for 1 h Then the reaction mixture was diluted with 20 ml of methyl alcohol; pass through it for 5 min gaseous hydrogen sulfide and filter the solution through silica gel (10 g), pre-treated with a mixture of dichloromethane:methyl alcohol, 4,1 purification on a column of silica gel (100 g), elwira first hexane diethyl ether 7:4 by volume, and then a mixture of dichloromethane: methyl alcohol 4: 1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature get 539,0 mg (0,287 mmol) of compound 30 (Rf = 0,53 /dichloromethane: methyl alcohol, 95:5 by volume/ output to 72%.

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To stir magnetic stirrer, a solution of compound 9 (380,0 g to 1.3 mol) dissolved in N,N-dimethylformamide (1.5 l) first add 227,0 g (3.25 mol) of imidazole at 0oC in nitrogen atmosphere, and then 263,0 g (1,7 mol) tert-butyldimethylsilyloxy. The solution is stirred for 1.5 hours, diluted with 2 l of ethyl acetate and poured into 2 l of saturated aqueous sodium bicarbonate solution. The organic layer is separated and washed first with 2.0 l of a saturated aqueous solution of sodium bicarbonate, then 2.0 liters of water, and, finally, 1.0 l of a saturated aqueous solution of sodium chloride. The organic layer is dried over 500 g of sodium sulfate, filtered through a glass filter and subjected to distillation under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (4.0 kg), elwira mixture E. the comfort data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature get 411,0 g (1.0 mol) of compound 36 /ethyl acetate:hexane, 1,4 volume/ yield 78%.

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To a solution of compound 36 (411,0 g, and 1.0 mole), dissolved in methyl alcohol (8.0 l) is added to 50.0 ml of 25% (weight/volume) solution of sodium methylate in methyl alcohol and the resulting mixture was stirred at room temperature for 6 hours Then the reaction mixture was neutralized with 1.0 saturated aqueous solution of sodium chloride 8.0 and extracted with ethyl acetate. The organic layer is separated and washed first with 1.0 l of water, then 1.0 l of a saturated aqueous solution of sodium chloride, dried over 1.5 kg of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The crude product is purified on a column of silica gel (4.0 kg), elwira gradient mixtures of hexane:ethyl acetate, sodium from 5.1, then taking a 4: 1, 3: 1 and finally 2:1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography), under reduced pressure at room temperature and drying overnight under vacuum at room temperature get 339,8 g of (0.95 moles) of compound 37 /ethyl acetate:hexane, 1:2 volume/ yield 93%.

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To a solution of compound 37 (0.5 g, 1.4 mmole), dissolved in anhydrous dichlo the carbodiimide and 1.8 g (0.02 mmole) of 4-dimethylaminopyridine under stirring with a magnetic stirrer at 0oC. the Reaction mixture is additionally stirred for 3 hours, diluted to 20.0 ml of hexane and filtered through 5 g Celite-545". The filtrate is concentrated under reduced pressure at room temperature and the residue is purified on a column of silica gel (100 g), elwira a mixture of ethyl acetate:hexane 1:7 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature get to 0.63 g (of 1.02 mmole) of compound 38 (Rf = 0.64 in /ethyl acetate:hexane, 1:4 by volume/ output to 73%.

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Compound 38 (0,63 g of 1.02 mmole) was dissolved in 8.0 ml of glacial acetic acid and 2.0 ml of water under stirring with a magnetic stirrer at room temperature for 12 hours. The mixture is concentrated under reduced pressure at room temperature and subjected to three azeotropic distillation with 10 ml of toluene. The residue was subjected to purification column with silica gel (100 g), elwira a mixture of ethyl acetate: hexane 1:2 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) when p is less of 0.57 g (0.99 mmole) of compound 39 (Rf = 0,22 /ethyl acetate: hexane, 1,2, volume/ output to 98%.

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A mixture of compound 23A (to 113.4 mg, 0,134 mmol) and compound 39 (321,5 mg, and 0.61 mmol) is dried under vacuum for 14 hours, and dissolve in 10.0 ml of anhydrous toluene. To the resulting mixture of 300.0 mg powder molecular sieves AW-300 (dried by annealing in vacuum) and the resulting mixture was stirred at room temperature for 1 hour in an argon atmosphere on a magnetic stirrer. The mixture is then cooled to -35oC and added to 8.0 ml (0.32 mmol), 0.04 M solution epirate boron TRIFLUORIDE in toluene (obtained by dissolving 200 μl (1.6 mmol) of epirate boron TRIFLUORIDE in 40 ml anhydrous and stirring with 200 ml of powder molecular sieves AW-300 for 1 h at room temperature) for 2.5 h using a syringe. The reaction is quenched by 10 ml of saturated aqueous sodium bicarbonate, diluted with 100 ml dichloromethane and filtered through 20 g Celite-545". The filtrate is washed first with 100 ml saturated aqueous sodium bicarbonate solution, then with 100 ml of water and finally with 100 ml saturated aqueous solution of sodium chloride; dried over 50 g sodium sulfate, filtered through a glass filter, and concentrate under reduced pressure at room temperature. The remainder of podathey of the solvent from the fractions, containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature get 119,1 mg (0,094 moles) of compound 40 (Rf = 0,44 /ethyl acetate:hexane, 1:2 volume/ output to 70%.

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To stir magnetic stirrer, a solution of compound 40 (110,0 mg, 0.09 mmol) dissolved in 1.0 ml anhydrous toluene and 33.0 μl (0.34 mmol) of anhydrous pyridine, was added when 0oC dropwise to 68.0 μl (0.13 mmol) of 1.93 M solution of phosgene in toluene, and stirred the reaction mixture for an additional 15 minutes To the resulting solution was added dropwise 100 μl (1.47 mmol) of allyl alcohol, the reaction mixture is stirred for a further 30 min, then the reaction quenched by introducing at 0oC ml saturated aqueous sodium bicarbonate solution. The reaction mixture is extracted with 100 ml of ethyl acetate, the organic layer was washed with 10.0 ml of a saturated aqueous solution of sodium chloride, dried over 25 g of sodium sulfate, filtered through a glass filter, and concentrate under reduced pressure at room temperature. The obtained residue was subjected to purification on a column of silica gel (100 g), elovedates.com data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature get 75,0 mg (0.06 mmol) of compound 41 (Rf = 0.75 in /ethyl acetate: hexane, 1:3 volume/ output 64%.

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To stir magnetic stirrer, a solution of compound 41 (75,0 mg, 0,056 mmol) dissolved in 4.0 ml of anhydrous dichloromethane add 250.0 mg (0.45 mmol) of complex tribenzoate tin (II) with triethylamine and the resulting mixture was stirred at room temperature in a nitrogen atmosphere in the absence of light until, until the results of the analysis by thin-layer chromatography (hexane:ethyl acetate, 1:1 volume) do not evidence the magazine is empty, the original product (i.e., within 2 hours). The reaction mixture was loaded directly on a column of silica gel (10.0 g), elwira first with a mixture of hexane:ethyl acetate 4:1 by volume) and then with ethyl acetate. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) for 30 min, under reduced pressure at room temperature, drying in vacuum at room temperature for 30 minutes, get up 64.4 mg (0.05 mmol) of compound 42 (Rf = 0,57 /ethyl acetate:hexane, 1:1, volume/ output to 90%.

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To stir with the magnetic stirrer at 0oC to a solution of compound 42 (64.4 mg, 0.05 mmol) in anhydrous dichloromethane (3.0 ml) is added 67,0 mg (0.28 mmol) of shoedini chromatography (hexane: ethyl acetate, 1: 1 by volume) indicate the completion of the reaction, the reaction mixture is diluted with 50 ml ethyl acetate and filtered through 10 g Celite-545; the resulting solid product is washed with 20 ml of ethyl acetate and concentrate the filtrate under reduced pressure at room temperature, obtaining the resulting syrupy residue. The syrup was dissolved in 1 ml dichloromethane, loaded into a column of silica gel (10.0 g), elwira first with a mixture of hexane: ethyl acetate 9: 1 by volume) and then with a mixture of hexane:ethyl acetate 1:1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data by thin layer chromatography) under reduced pressure at room temperature produces a 87.0 mg (0.04 mmol) of compound 43 (Rf = 0,95 / ethyl acetate:hexane, 1:1, volume/ output to 85%.

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To stir magnetic stirrer 2 M solution of hydrogen fluoride in acetonitrile (12.0 ml), placed in a Teflon reactor, add at room temperature 70.0 mg (0.036 mmol) of compound 43, dissolved in 5.0 ml of dichloromethane. The resulting mixture was stirred for another 14 h, dilute to 20.0 ml of saturated aqueous sodium bicarbonate solution and extracted to 100.0 ml dichloromethane. The organic layer is separated and washed first with sodium, filtered through a glass filter, and concentrate under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (10 g), elwira a mixture of dichloromethane: methyl alcohol 98oC2 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis at room temperature and drying overnight under vacuum at room temperature gain of 60.3 mg (0.035 mmol) of compound 44 (Rf = 0,78, dichloromethane:methyl alcohol 98:2 by volume) to yield 97%.

With the aim of obtaining an analogue of lipid A-276-32 carry out the removal of protection at connection 44 in accordance with the method described above for compounds 31 and the free acid is introduced into the reaction with L-lissom in accordance with the method described above for analog In-214-32.

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To stir magnetic stirrer, the solution of 65.0 mg (0,038 mmol) of compound 44 5.0 anhydrous dichloromethane add 70.0 mg (0.28 mmol) BIZ(allyloxy) (diisopropylamino) phosphine and 70.0 mg (1.0 mmol) IH-tetrazole at 0oC in nitrogen atmosphere. The mixture is heated to room temperature and stirred for 1 h Then the mixture is cooled to -78oC and add a solution 11,95 mg (0.12 mmol) 3-chloroperbenzoic acid, RA is for an additional 20 min, then add 10.0 ml of a saturated aqueous solution of sodium bicarbonate. The reaction mixture is extracted with 100 ml of dichloromethane; the organic layer is separated and washed first with 10.0 ml of water, then over to 25.0 g of sodium sulfate. From the dried product is distilled off the solvent under reduced pressure at room temperature and the residue is purified on a column of silica gel (10.0 g), elwira a mixture of ethyl acetate:hexane 1:1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under reduced pressure at room temperature get to 53.0 mg (0,028 mmol) of compound 30 (Rf = 0,29 /ethyl acetate: hexane, 1:1, volume/ output to 74%.

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To stir magnetic stirrer, the solution 19,0 g (0.05 mmol) of compound 37 in 65 ml of anhydrous dichloromethane was added when 0oC in nitrogen atmosphere of 2.75 g (of 0.11 mol) of a 60% dispersion of sodium hydride in oil (the product of the firm "Aldrich chemical company). The mixture is stirred first 5 minutes at 0oC, then 15 min at room temperature. To the reaction mixture in an argon atmosphere is added dropwise via SPR is armeana. After stirring for 30 min the reaction mixture was cooled to 0oC and added dropwise to 5.0 ml of methyl alcohol, excess unreacted sodium hydride; the mixture is diluted with 300 ml of dichloromethane and washed first of 300.0 ml of a saturated aqueous solution of ammonium chloride, then of 300.0 ml of a saturated aqueous solution of sodium chloride. The organic layer is separated, dried over 100.0 g of sodium sulfate and concentrate under reduced pressure, getting syrupy product. The syrup was subjected to purification on a column with silica gel (2.0 kg), elwira gradient mixtures of ethyl acetate : hexane 1:12, then 1:9, 1:8 and 1:5 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under reduced pressure at room temperature gain of 20.1 g (0.04 mmol) of compound 45 (Rf = 0,53 / ethyl acetate : hexane, 1:4 by volume/ output to 68%.

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To stir magnetic stirrer, a solution of compound 45 (13,69 g, 26.5 mmol) and compound B4 (see below, 6.3 g, of 31.8 mmol) dissolved in anhydrous dichloromethane (76,0 ml), add at room temperature in a nitrogen atmosphere 11,0 g is aminopyridine in anhydrous dichloromethane for 1 h The reaction mixture is stirred for 9 h at room temperature, filtered through a 100.0 g Celite-545"; the resulting solid product is washed with 20 ml of ethyl acetate. The combined filtrate and wash solution of ethyl acetate, concentrated under reduced pressure at room temperature, after which the crude product is purified on a column of silica gel (2.0 kg), elwira a mixture of hexane:ethyl acetate 9:1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis at room temperature and drying overnight under reduced pressure at room temperature gain of 17.4 mg (25.1 mmol) of compound 46 (Rf = 0,80 /ethyl acetate:hexane, 1:4 by volume/ output to 94%.

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A solution of compound 46 (17,4 g 25,0 mmole), dissolved in 100.0 ml of a mixture of 8:1 by volume glacial acetic acid and water, for example, heated at 60oC under stirring with a magnetic stirrer for 12 hours the Mixture is concentrated under reduced pressure at 40oC and the crude product is purified on a column of silica gel (2.0 kg), elwira gradient mixtures of ethyl acetate : hexane 1:6 to 1:2 by volume. After removal of the solvent from fractions containing the product (as evidenced by Dan the overnight under vacuum at room temperature to obtain 15.0 g (22.9 mmole) of compound 47 (Rf = 0,13 /ethyl acetate:hexane, 1:4 by volume/ yield 91%.

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To the stirring by the magnetic stirrer connection 47 (8, 85 g, 12.7 mmol) dissolved in a mixture of anhydrous toluene and anhydrous pyridine added at 0oC in nitrogen atmosphere is added dropwise within 30 min of 1.75 ml (16.5 mmol) of allylchloroformate. The reaction mixture is diluted with 300 ml ethyl acetate, washed first with 100 ml saturated aqueous sodium bicarbonate solution, then with 100 ml of water and then 100 ml of a saturated aqueous solution of sodium chloride, dried over 100 g of sodium sulfate and concentrate under reduced pressure at room temperature. The residue is dissolved in 10 ml of dichloromethane, loaded into a column of silica gel (1.0 kg), elwira a mixture of ethyl acetate:hexane 1:9 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature gain of 8.1 g (10.9 mmole) of compound 48.

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To stir magnetic stirrer, a solution of 1.6 g (of 2.06 mmol) of compound 48 in 10.0 ml of anhydrous dichloromethane add first 757,0 mg (3.1 mmol) of bis(allyloxy)(diisopropylamino) phosphine, and then adut to -78oC and added dropwise over 10 min a solution of 550,0 mg (2.2 mmol) of 55% 3-chloroperbenzoic acid dissolved in 5.0 anhydrous dichloromethane. The reaction is quenched at -78oC by the addition of 50.0 ml of a saturated aqueous solution of sodium bicarbonate. The reaction mixture is extracted with 200 ml of dichloromethane; the organic layer and washed first to 50.0 ml of water, then to 50.0 ml of a saturated aqueous solution of sodium chloride and dried over 50.0 g sodium sulfate. After concentration under reduced pressure at room temperature to obtain the crude product, which was subjected to purification on a column of silica gel (300,0 g), elwira a mixture of ethyl acetate: hexane 1:4 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight get 1.7 g (1.8 mmol) of compound 49.

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To stir magnetic stirrer 6M solution of hydrogen fluoride in acetonitrile (70,0 ml), placed in a Teflon reactor, add at room temperature of 10.5 g (11.6 mmol) of compound 49, dissolved in 10.0 ml of dichloromethane. The resulting mixture was stirred for domoraud of 500.0 ml of dichloromethane. The organic layer is washed first with 100 ml of water, then 100 ml of a saturated aqueous solution of sodium chloride. The organic layer is then dried over 250,0 g sodium sulfate, filtered through a glass filter, and concentrate under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (1.0 kg), elwira a mixture of hexane:ethyl acetate 3:1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) reduced pressure at room temperature and drying overnight under vacuum at room temperature to obtain 7.9 g (10.1 mmol) of compound 50.

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To a solution of compound 50 (1.1 g, 1.4 mmol) in 10.0 ml of trichloroacetonitrile added under stirring with a mechanical stirrer 2.6 g (8.0 mmol) of cesium carbonate at room temperature in a nitrogen atmosphere. After 2 h the mixture is filtered through a glass filter through 25,0 g Celite-545", filtered, the solid residue was washed with 100 ml of dichloromethane and concentrate the combined filtrate and wash solution under reduced pressure at room temperature. The crude product is purified on a column of silica gel (20,0 g), elwira mixture dichloro Tvout data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature get 600,7 mg (0.65 mmol) of the compound 51A (alpha-isomer) and 500.0 mg of the compound 51B (beta-isomer) with a total yield of 85%.

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To stir magnetic stirrer, a solution of compound 45 (13.8 g, 26.8 mmol), dissolved in 100.0 ml of a mixture of anhydrous toluene and anhydrous pyridine added at room temperature under nitrogen atmosphere is added dropwise within 30 min to 21.0 ml (40.2 mmol) of 1.93 M e RA phosgene in toluene, the reaction mixture is stirred for an additional 15 min, add 16,1 ml (214,4 mmol) allyl alcohol and stirred the mixture for a further 1 h the reaction mixture is diluted with 100 ml saturated aqueous sodium bicarbonate solution and extracted with 300 ml of ethyl acetate. The organic extract washed first with 200 ml of water, then 100 ml of a saturated aqueous solution of sodium chloride and dried over 200 g of sodium sulfate. The dried organic layer was filtered through a glass filter, and concentrate under reduced pressure at room temperature. The crude product is dissolved in 10 ml of dichloromethane and loaded into a column of silica gel (1.0 kg), elwira a mixture of ethyl acetate:hexane 1:9 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight in a vacuum is of 52 (15.6 g, of 26.1 mmole), dissolved in a 50.0 ml of glacial acetic acid and 2.0 ml of water, stirred with a magnetic stirrer at room temperature for 12 hours the Mixture is concentrated under reduced pressure at room temperature and subjected to three azeotropic distillation with 10 ml of toluene. The residue was subjected to purification on a column of silica gel (1.0 kg), elwira two gradient mixtures: the first ethyl acetate: hexane 1:2 by volume, then with ethyl acetate. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature get 12,1 (21.6 mmole) of compound 53 with the release of 83%.

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To stir magnetic stirrer, a solution of compound 53 (10.3 g, 18.5 mmole) dissolved in anhydrous dichloromethane (400 ml) at 0oC in nitrogen atmosphere, first add a 2.9 (42,6 mmole) of imidazole, and then 3.6 g (24,1 mmole) of tert-butyldimethylsilyloxy. The solution is heated to room temperature and stirred for 13 h, the Reaction mixture was poured into 1 l of saturated aqueous solution of ammonium chloride and extracted with 1 dichloromethane. Organizes ml of a saturated aqueous solution of sodium chloride. The washed organic layer is dried over 300 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The crude product is purified on a column of silica gel (1.0 kg), elwira a mixture of ethyl acetate: hexane 1:8 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature to obtain 10.6 g (15.8 mmol) of compound 54 (Rf = 0.70 and /ethyl acetate: hexane, 1:4 by volume/ yield 85%.

< / BR>
To stir with a mechanical stirrer a solution of compound 54 (8,9 g, 13.2 mmol), dissolved in 270,0 ml of anhydrous toluene and 4.2 ml of anhydrous pyridine, is added slowly at 0oC in nitrogen atmosphere for 10 minutes to 10.2 ml (26.4 mmol) of 1.93 M solution of phosgene in toluene and stirred the reaction mixture for an additional 15 minutes Later 20 min to the resulting solution was added within 5 min to 8.0 ml (105,6 mmol) allyl alcohol, the reaction mixture is stirred for a further 15 minutes the Reaction is quenched by introducing 200 ml of saturated aqueous sodium bicarbonate solution, dilute 1.0 ethylacetate sodium, dried over 500 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The obtained residue was subjected to purification on a column of silica gel (1.0 kg), elwira a mixture of ethyl acetate:hexane 1:9 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by the method of thin-layer temperature and drying overnight under vacuum at room temperature to obtain 9.5 g (12.5 mmol) of compound 55 (Rf = 0,68 /ethyl acetate:hexane, 1:9 by volume/ output to 95%.

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In a Teflon reactor at 1.0 l dissolve compound 55 (5.8 g, 7.6 mmol) in 200 ml of dichloromethane. To the resulting solution was mixed with a magnetic stirrer, add at room temperature, 150 ml of 1 M solution of hydrofluoric acid in acetonitrile (12.0 ml). After 7 hours the reaction mixture is quenched, pouring it into 200 ml of saturated aqueous sodium bicarbonate solution at 0oC and shaken out of 500.0 ml of dichloromethane. The organic layer is separated and washed first with 100 ml of water, then 100 ml of a saturated aqueous solution of sodium chloride, dried over 300,0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The obtained residue was subjected to purification on to the s, containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature produces 4.5 mg (6.7 mmol) of compound 56 (Rf = 0.33 in ethyl acetate:hexane, 1:4 by volume) to yield 88%.

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A heterogeneous mixture of 8.0 g (12.2 mmole) of compound 47, 11.3 g (48.8 mmol) of silver oxide (1) (a product of the company "Aldrich chemical company) and 120,0 ml (1,92 mole) under the conditions (the product of the firm "Aldrich chemical company) is stirred in the dark mechanical stirrer at 39oC for 12 h under nitrogen atmosphere. The reaction mixture is cooled, filtered through a 100.0 g Celite-545": the solid product is washed with 200 ml of ethyl acetate. The combined filtrate and wash solution concentrate under reduced pressure at 4oC, receiving the crude product, which is then dissolved in a 50.0 ml dichloromethane and cooled to 0oC. To the cooled reaction mixture is added immediately first, 1.0 g (14,69 mmol) of imidazole, and then for 5 min, tert-butylchloroformate. The reaction mixture is heated to room temperature, stirred for another 1 h, quenched with 100 ml saturated aqueous sodium bicarbonate solution and extracted with 500 ml dig the Tria, dried over 300 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The obtained residue was subjected to purification on a column of silica gel (100 g), elwira a mixture of ethyl acetate:hexane 1: 9 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature get 6.85 g (10.2 mmol) of compound 57A (Rf = 0,63 /dichloromethane: diethyl ether, 19:1 by volume/ output 84% of 1.11 g (1,22 mmol) of the compound 57B (Rf = 0,90 /dichloromethane:diethyl ether, 19:1 by volume/ output 10%.

< / BR>
To stir magnetic stirrer, a solution of 8.7 g (of 0.013 mmol) of compound 57A dissolved in 46 ml of anhydrous dichloromethane added 4.8 ml (0.02 mmol) bis(allyloxy)-(diisopropylamino) phosphine and 4.1 g (to 0.06 moles) IH-tetrazole at room temperature in a nitrogen atmosphere. After 5 minutes the mixture is cooled to -78oC and add the solution to 3.35 g (0,02 mol) of a 55% solution of 3-chlorbenzoyl acid in 37 ml of anhydrous dichloromethane is added dropwise within 10 minutes the Reaction is quenched at -78oC add 100 ml of saturated aqueous bicarbonate is Ala 200 ml of water, then 200 ml of a saturated aqueous solution of sodium chloride, and dried over 300 g of sodium sulfate. After concentration under reduced pressure at room temperature to obtain the crude product, which was subjected to purification on a column of silica gel (1.0 kg), elwira a mixture of ethyl acetate:hexane 1:6 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying in vacuum overnight at room temperature to obtain 8.8 g (to 0.011 moles) of compound 58 (Rf = 0.28 in /ethyl acetate:hexane, 1:4 by volume/ output to 85%.

< / BR>
To 80 ml of stirred with a magnetic stirrer 6 M solution of hydrogen fluoride in acetonitrile, placed in a Teflon reactor, add at room temperature of 8.8 g (10.6 mmol) of compound 58 dissolved for another 9 hours, poured into 200.0 ml saturated aqueous sodium bicarbonate solution at 0oC and shaken out of 300.0 ml of dichloromethane. The organic layer was washed with a 100.0 ml saturated aqueous sodium chloride, dried over 100.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature. The residue is subjected to the indicator of fractions, containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature to obtain 5.7 g (7.95 mmol) of compound 59 (Rf = 0,37, dichloromethane:methyl alcohol, 95:5 by volume) with a yield of 75%.

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To stir with a mechanical stirrer a solution of compound 59 (10,32 g, 14.5 mmol) in 200.0 ml of trichloroacetonitrile add 8,80 g (63.7 mmole) of potassium carbonate at room temperature in a nitrogen atmosphere. After 20 minutes the mixture is filtered through 100 g Celite-545 and washed with filtered the solid residue 100 ml of dichloromethane; the combined filtrate concentrated under reduced pressure at room temperature. The crude product is purified on a column of silica gel (10.0 g), elwira a mixture of ethyl acetate:hexane 1: 1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature to obtain 11.1 g (12.9 mmol) of compound 60 B (beta-isomer) and compound 60A (alpha-isomer) (Rf = 0,61 and 0,53 /ethyl acetate: hexane, 1:1 to about what lei) is dried under vacuum for 14 hours, and dissolve in 10.0 ml of anhydrous dichloromethane. To the resulting mixture of 800.0 mg powder molecular sieves AW-300, dried by annealing in vacuum. The resulting mixture was stirred on a magnetic stirrer at room temperature in an argon atmosphere, cooled to -23oC and slowly add 740 μl (0,147 mmol) of a 0.2 M solution epirate boron TRIFLUORIDE in anhydrous dichloromethane (obtained by dissolving 250 ál (2,03 mmol) epirate boron TRIFLUORIDE in 10 ml of anhydrous dichloromethane and stirred with 200 mg of powder molecular sieves AW-300 for 1 h at room temperature) for 1 h the Reaction is quenched by 5.0 ml of a saturated aqueous sodium bicarbonate, diluted with 100 ml dichloromethane and filtered through 10 g Celite-545". The filtrate is washed first with 50 ml saturated aqueous sodium bicarbonate solution, then with 50 ml water and finally with 50 ml of a saturated aqueous solution of sodium chloride, the filtrate is dried over 25,0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The obtained residue was subjected to purification on a column of silica gel (100 g), elution with a mixture of ethyl acetate:hexane 1:3 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis method tongolo atoi temperature produces 430 mg (0,292 mmol) of compound 62 (Rf = 0,2 /ethyl acetate:hexane, 1:2 volume/ output to 60%.

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A mixture of compound 23 (A (250.0 mg, 0,265 mmol) and compound 14 (205,0 mg, 0,265 mmol) is dried in vacuum for 14 h and dissolved in 15.0 ml of anhydrous dichloromethane. To the resulting mixture of 600.0 mg powder molecular sieves AW-300, dried by annealing in vacuum and the resulting mixture was stirred on a magnetic stirrer for 1 h at room temperature in argon atmosphere. The mixture is then cooled to -23oC and added slowly to 400 microns (0,265 mmol) of a 0.2 M solution epirate boron TRIFLUORIDE in anhydrous dichloromethane (obtained by dissolving 250 ál (2,03 mmol) epirate boron TRIFLUORIDE in 10 ml of anhydrous dichloromethane and stirring with 200 mg of powder molecular sieves AW-300 for 1 h at room temperature) for 30 minutes the Reaction is quenched by 5.0 ml of a saturated aqueous sodium bicarbonate, diluted with 100 ml dichloromethane and filtered through 10 g Celite-545". The filtrate is washed first with 50 ml saturated aqueous sodium bicarbonate solution, then with 50 ml water and finally with 50 ml of a saturated aqueous solution of sodium chloride; the filter is dried over 25,0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The remainder of padonki of the solvent from the fractions, containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying for wear in vacuum get 210 ml (0,152 mmol) of compound 63 (Rf = 0,23 /ethyl acetate:hexane, 1:2 volume/ output 62%.

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A mixture of compound 51 A (601,4 mg, 0,636 mmol) and compound 39 (769,3 mg, 1.38 mmol) is dried in vacuum for 14 h and dissolved in 40.0 ml of anhydrous dichloromethane. To the obtained mixture is added 1.0 powder molecular sieves AW-300, dried by annealing in vacuum. The resulting mixture was stirred for 1 h on a magnetic stirrer at room temperature in an argon atmosphere, then cooled to -35oC and slowly add 10.0 ml (0,190 mmol) of 0.02 M solution epirate boron TRIFLUORIDE in anhydrous dichloromethane (obtained by dissolving 250 ál (2,03 mmol) epirate boron TRIFLUORIDE in 10 ml of anhydrous dichloromethane, diluting the resulting mixture of 91.5 ml of anhydrous toluene and stirring with 200 mg of powder molecular sieves AW-300 for 1 h at room temperature) for 1.5 hours the Reaction is quenched by 10,0 saturated aqueous sodium bicarbonate, diluted with 200 ml of dichloromethane and filtered through 10 g Celite-545". The filtrate is washed is one solution of sodium chloride; the filtrate is dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature. The obtained residue was subjected to purification on a column of silica gel (100 g), elution with a mixture of ethyl acetate: hexane 1: 2 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and dried overnight in vacuum at room temperature get 297,5 mg (0,152 mmol) of compound 64 (Rf = 0,42 /dichloromethane:diethyl ether, 9:1, volume/ output to 34%.

< / BR>
A mixture of compound 60 (a mixture of alpha - and beta-isomers) (7,35 g, 8.5 mmol) and compound 56 (5.0 g, 7.4 mmol) is dried in vacuum for 14 h and dissolved in 200.0 ml of anhydrous dichloromethane. To the resulting mixture of 8.2 g of powder molecular sieves AW-300, previously dried by annealing in vacuum. The resulting mixture was stirred on a magnetic stirrer for 1 h at room temperature in an argon atmosphere, then cooled to -35oC and added slowly to 8.7 ml (0.50 mmol) of 0.05 M solution trimethylsilyltrifluoromethane (the product of the firm "Aldrich chemical company) (obtained by dissolving otka molecular sieves AW-300 for 1 h at room temperature) for 8 hours The reaction is quenched by a 100.0 ml saturated aqueous sodium bicarbonate, diluted with 500 ml of dichloromethane and filtered through 50 g Celite-545". The filtrate is washed first with 100 ml saturated aqueous sodium bicarbonate solution, then with 100 ml of water and finally with 100 ml saturated aqueous solution of sodium chloride; dried over 100.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature. The obtained residue was subjected to purification on a column of silica gel (200 g), elution with a mixture of ethyl acetate: hexane 1: 4 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying overnight under vacuum at room temperature gain of 8.1 g (0,006 mmol) of compound 65 (Rf = 0,42 /ethyl acetate:hexane, 1:2 volume/ output to 82%.

< / BR>
To stir magnetic stirrer, a solution of compound 65 (1,99 g, 1.48 mmol) dissolved in 10.0 ml of anhydrous dichloromethane, add 250.0 mg (0.45 mmol) of complex tribenzoate tin (II) with triethylamine and the resulting mixture was stirred at room temperature in a nitrogen atmosphere in the absence of light for 30 min, imetelstat about the magazine is empty original product. The reaction mixture was loaded directly on a column of silica gel (10.0 g), elwira at the beginning of a mixture of hexane:ethyl acetate 4:1 by volume) to remove by-products, and then with ethyl acetate. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) for 30 min under reduced pressure at room temperature and drying in vacuum at room temperature for 30 min get partially purified compound 66 (1,72 g; 1.33 mmol; Rf = 0,48 /dichloromethane:methyl alcohol, 95:5 by volume), suitable for subsequent use in the reaction, with the release of 90%.

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To stir magnetic stirrer connection 66 (1,72 g, 1.33 mmol) in anhydrous dichloromethane (10.0 ml) is added at 0oC 1.1 g (of 4.44 mmol) of compound D2 (see below) and 1.83 g (8.80 mmol) of 1,3-dicyclohexylcarbodiimide. After 30 minutes, when the results of the analysis by thin layer chromatography (dichloromethane : methyl alcohol, 95:5 by volume) indicate the completion of the reaction, the reaction mixture is diluted with 50 ml ethyl acetate, filtered through 10 g Celite-545", the solid product is washed with 20 ml of ethyl acetate and concentrate the filtrate under reduced pressure at room temperature is in a column with silica gel (100 g), elwira first with a mixture of hexane:ethyl acetate 4:1 by volume) to remove residues of the initial reagents, and then with a mixture of hexane:ethyl acetate 1:2 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature over night get 1,82 g (1.04 mmol) of compound 67 (Rf = 0,54 /dichloromethane:methyl alcohol, 95:5 by volume/) with 71% yield.

< / BR>
To stir magnetic stirrer 6M solution of hydrogen fluoride in acetonitrile (0.8 ml), placed in a Teflon reactor, add at room temperature 390,0 mg (0,224 mmol) of compound 67, dissolved in 0.5 ml dichloromethane. The resulting mixture was stirred for 1.5 h, dilute to 20.0 ml of saturated aqueous sodium bicarbonate solution and extracted to 100.0 ml dichloromethane. The organic layer is washed first of 20.0 ml of water, then 10.0 ml of a saturated aqueous solution of sodium chloride, dried over 25,0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (50.0 g), elwira a mixture of dichloromethane:methyl alcohol, 98:2 by volume. After distillation, rastvoriteli reduced pressure at room temperature and drying in vacuum overnight at room temperature get 325,0 mg (0.20 mmol) of compound 68 (Rf = 0.52 in, dichloromethane:methyl alcohol, 95:5 by volume) with a yield of 89%.

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To stir magnetic stirrer, a solution of 50.0 mg (0.03 mmol) of compound 68, dissolved in 1.0 ml anhydrous dichloromethane added at the beginning of 11.3 mg (0.045 mmol) of bis(allyloxy) (diisopropylamino) phosphine, and then to 9.4 mg (is 0.135 mmol) 1H-tetrazole at 0oC in nitrogen atmosphere. The reaction mixture was warmed to room temperature, stirred for 30 min, cooled to -78oC and add a solution of 9.4 mg (being 0.036 mmole) of 3-chloroperbenzoic acid in 100 μl of dichloromethane is added dropwise and stirred the mixture for an additional 20 minutes To the reaction mixture is added 0.5 ml of saturated aqueous sodium bicarbonate solution and extracted with 10.0 ml of dichloromethane. The organic layer was separated and stirred first 10.0 ml of water, and then 5.0 ml of a saturated aqueous solution of sodium chloride, and dried over 5,0 g of sodium sulfate. After concentration under reduced pressure at room temperature to obtain the crude product, which was subjected to purification on a column of silica gel (10.0 g), elwira a mixture of ethyl acetate:chloroform 1:1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis method tanksley is based temperature gain of 41.7 mg (0,023 mmol) of compound 69 (Rf = 0.40 in /dichloromethane:methyl alcohol, 95:5 by volume/ output to 78%.

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To a solution of compound 69 (130,0 mg, 0,072 mmol) dissolved in 10.0 ml of a mixture of tetrahydrofuran with 96% formic acid (10:1 by volume) in nitrogen atmosphere in the absence of light add tetrakis(triphenylphosphine)palladium (O) (843,0 g to 0.72 mmol) and triphenylphosphine (575,0 g, 2.19 mmol). The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure at room temperature. The resulting residue is mixed with 5.0 ml of toluene and dispersed under reduced pressure at room temperature to obtain a thick paste, which was transferred to a suspension of 10.0 ml of methanol, and passed through her gaseous hydrogen sulfide in a few minutes. The solvent is removed by distillation under reduced pressure at room temperature, and the crude product extracted 10.0 ml of a mixture of methyl alcohol:chloroform:water, 3:2:1 by volume, and filtered through a Teflon filter for ghvd (0.2 micron) (firm Rainin Tool"). The filtrate is purified on a column of DE-cellulose (100 g, product of Sigma chemical company), elwira 2.0 l of a mixture of methyl alcohol:chloroform:water, 3:2:1 by volume using a linear salt gradient from 0 to 0.1 M solutions of acetate of am is ecografia) combine and add an equal volume of chloroform. The organic layer is separated and concentrated under reduced pressure at room temperature, obtaining the product in the form of ammonium salts. The specified product is dissolved in 100 ml of water and lyophilizer to remove excess ammonium acetate. The lyophilized product was transferred to a suspension of 40.0 ml of water, mixed with 6.0 g of the resin")-100" (sodium form, the product of the company Bio-Rad Laboratries", Hercules, California), is passed through a column of 10.0 g of the resin")-100" (sodium form) and elute 20,0 ml of water. The solution is filtered through a Teflon filter for ghvd (0.2 micron) (firm Rainin Tool"), receiving 98,0 mg (0,063 mmole) of Tetra-ammonium salts, i.e. compounds 70 Rf = 0,60 (chloroform:methyl alcohol: glacial acetic acid:water, 125:75:10:20 by volume) as a white hygroscopic foam substances with the release of 87%.

The connection 70 is an analog of lipid A-531-35. The analogue of lipid A-531-32 receive as a result of the reaction of the received analogue in the form of the free acid with L-lysine in accordance with the previously described method for the connection 31 and analogue In-214-32.

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To stir magnetic stirrer, a solution of compound 66 (510,0 mg, 0,358 mmol) in anhydrous dichloromethane (6.0 ml) is added at 0oC 245,0 mg (0,895 the analysis by thin layer chromatography (dichloromethane: methyl alcohol, 95:5 by volume) indicate the completion of the reaction, the reaction mixture is diluted with 50 ml ethyl acetate, filtered through 10 g Celite-545", the solid product is washed with 20 ml ethyl acetate and concentrate the filtrate under reduced pressure at room temperature, obtaining the resulting syrupy residue. The crude syrup was dissolved in 5 ml dichloromethane, loaded into a column of silica gel (100 g), elwira first with a mixture of hexane: ethyl acetate 3:1 by volume) to remove residues of the initial reagents, and then with a mixture of hexane:ethyl acetate 1:2 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying in vacuum at room temperature over night get 447,0 mg (0.24 mmol) of compound 71 (Rf = 0.40 in /dichloromethane:methyl alcohol, 95:5 by volume/ output to 67%.

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To stir magnetic stirrer 6M solution of hydrogen fluoride in acetonitrile (6.0 ml), placed in a Teflon reactor, add at room temperature 447,0 mg (0.24 mmol) of compound 71, dissolved in 2.3 ml of dichloromethane. The resulting mixture was stirred for 2 h, dilute to 20.0 ml of saturated odml water, then 10.0 g of a saturated aqueous solution of sodium chloride, dried over 25,0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The residue was subjected to purification on a column of silica gel (100.0 g), elwira a mixture of dichloromethane:methyl alcohol, 100:4 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis method, thin-layer chromatography) under reduced pressure at room temperature get 404,0 mg (0.23 mmol) of compound 72 (Rf = 0,37, dichloromethane:methyl alcohol, 95:5 by volume) with a yield of 96%.

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To a solution of compound 72 (20,0 ml, to 0.011 mmol) in 1.0 ml of anhydrous tetrahydrofuran is added slowly at -78oC under stirring in nitrogen atmosphere to 12.5 ál (0,012 mmol) of 1.0 M solution of bis(trimethylsilyl)amide lithium in tetrahydrofuran. After 5 min to the mixture 34,0 ál (0.017 mmol) of 0.5 M solution of diallylmalonate in anhydrous toluene and stirred for 10 minutes the Mixture is heated to 0oC, stirred for 10 minutes the Mixture is heated to 0oC, stirred for an additional 10 min and quenched by 40 μl of glacial acetic acid. The reaction mixture is poured into 10.0 ml of a saturated aqueous solution of bi is the target of sodium bicarbonate: dried over 30.0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. The obtained residue product is passed through a column of silica gel (10.0 g) elwira a mixture of dichloromethane: methyl alcohol 100:4 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data by thin layer chromatography) under reduced pressure at room temperature gain of 15.0 mg (0.008 mmol) of compound 73 (Rf = 0,29, dichloromethane: methyl alcohol, 95:5 by volume) to yield 69%.

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Compound 24 (51,5 mg, 0.035 mmol) was dissolved in 1.0 ml of dichloromethane, 1.0 ml of tert-butyl alcohol and 1.0 ml of the concentrate of phosphate buffer with pH = 7.0. To the resulting heterogeneous mixture is added to 100.0 mg (0.43 mmol) of 2,3-dichloro-5,6-dicyan-1,4-benzoquinone. The resulting mixture is stirred with a magnetic stirrer in a nitrogen atmosphere in the dark up until the results of the analysis by thin-layer chromatography (hexane: ethyl acetate, 1:2 by volume) do not indicate the full expenditure of the original product (after about 4 hours). At this point the reaction is quenched with 2 ml of 10% aqueous sodium thiosulfate solution, dilute 10.0 ml of dichloromethane and poured into 5.0 ml of a saturated aqueous solution of sodium bicarbonate. Organize and filtered. The crude reaction mixture was loaded directly on a column of silica gel (10.0 g), elwira a mixture of dichloromethane: methyl alcohol, 98:2 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) under reduced pressure at room temperature and drying in vacuum at room temperature over night get 40,0 mg (0.03 mmol) of compound 74 (Rf = 0.36 and /hexane:ethyl acetate, 2:1, volume/ output to 87%.

< / BR>
To a solution of compound 74 (93,6 mg, 0.07 mmol) in 1.0 ml of trichloroacetonitrile added under stirring with a mechanical stirrer 58,0 mg (0,175 mmol) of cesium carbonate at room temperature in a nitrogen atmosphere. After 1 h the mixture is filtered through 5.0 g "Celite-545", filtered, the solid residue washed with 10 ml dichloromethane and concentrate the combined filtrate under reduced pressure at room temperature. The crude product is purified on a column of silica gel (10.0 g), elwira first with a mixture of dichloromethane: diethyl ether, 9:1 by volume) to remove impurities associated with the reagents, and then ethyl acetate. After removal of the solvent from fractions containing the product (what evidence drying overnight under vacuum at room temperature get to 43.2 mg (0,029 mmol) of compound 75 (Rf = 0,29, dichloromethane:diethyl ether 9:1 by volume) to yield 42%.

.

To a solution of compound 75 (68,2 mg, 0,046 mmol) and 19.0 ál (0,092 mmol) triarylphosphine (product of Alfa products) dissolved in 2.0 ml of anhydrous dichloromethane was added when 0oC in nitrogen atmosphere for 11.0 ál trimethylsilyltrifluoromethane. After stirring for 1 hour the reaction mixture was quenched with 1.0 ml of saturated aqueous sodium bicarbonate solution and extracted to 50.0 ml of dechlorinate. The organic layer is dried over 30.0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The remainder of the product was subjected to purification on a column of silica gel (25,0 g), elwira a mixture of hexane:ethyl acetate 4:1 by volume. After removal of the solvent from fractions containing the product (as evidenced by the data analysis method of thin-walled chromatography), get 37,0 mg (0,025 mmol) of compound 76 (Rf = 0.45, and hexane:ethyl acetate 2:1 by volume) with 30% yield.

.

To stir magnetic stirrer, a solution of compound 76(37,0 mg of 0.025 mmol), dissolved in 0.5 ml of anhydrous dichloromethane, add to 42.0 mg (0,076 mmol) complex of Tris-benzothioate tin (II) with triethylamine and stirred polularity analysis by the method of thin-walled chromatography (dichloromethane: methyl ether, 95:5 by volume) suggest using the original product. The reaction mixture was loaded into a column of silica gel (5.0 g), elwira first with a mixture of hexane: ethyl acetate 4: 1 by volume) to remove by-products, and then 100% ethyl acetate. After removal of the solvent from fractions containing the product (as evidenced by the data analysis method of thin-walled chromatography) under reduced pressure at room temperature and drying in vacuum at room temperature for 30 min get to 31.9 mg (0,023 mmol) of partially purified compound 77 (Rf = 0,42 /dichloromethane:methyl alcohol, 95:5 by volume/), suitable for subsequent use in the synthesis, with the release of 90%.

.

To stir magnetic stirrer, a solution of compound 77 (31,9 mg, 0.23 mmol) in anhydrous dichloromethane (0.5 ml) is added at 0oC 18,0 mg (0.92 mmol) of compound D2 (see below) and 23.0 mg (1.38 mmol) of 1,3-dicyclohexylcarbodiimide. After 30 min, when the results of the analysis by thin layer chromatography (dichloromethane:methyl alcohol, 95:5 by volume) indicates the completion of the reaction, the reaction mixture is diluted with 10 ml ethyl acetate, filtered through a 1.0 g Celite-545", the obtained solid product was washed with 5.0 ml ethylacetate balance. The crude syrup was dissolved in 1.0 ml of dichloromethane, loaded into a column of silica gel (10.0 g), elwira first with a mixture of hexane:ethyl acetate 4:1 by volume) to remove residues of the initial reagents, and then hexane:ethyl acetate 1:2 by volume. After removal of the solvent and their fractions, containing the product (as evidenced by the data analysis thin-layer chromatography) under reduced pressure at room temperature and drying at room temperature during the night of 15.1 g (1.04 mmol) of compound 78 (Rf = 0,48 /dichloromethane:methyl alcohol, 95:5 by volume/ output to 32%.

With the aim of obtaining analysis of lipid A B-380-32 carry out the removal of protection in connection 78 in accordance with the method described above for compounds 31 and the free acid is introduced into the reaction with L-lysine in accordance with the method described above for analogue B-214-32.

.

To a mixture of compound 10b (1.13 g, 2.58 mmol) and 500 μl (0.45 mmol) of allyl alcohol, dissolved in 1.0 g of finely ground powder in molecular sieves AW-300. After stirring for 1 h at room temperature the mixture is cooled to -78oC and added dropwise within 1 h of 15.0 ml of 0.02 M solution trimethylsilyltrifluoromethane in dichloromethane. The reaction is quenched by 10,0 m the t over to 25.0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature. After purification on a column of silica gel (100 g), elution with a mixture of ethyl acetate: hexane 1:4 by volume, and removal of the solvent from fractions containing the product (as evidenced by the data analysis by thin layer chromatography) to obtain 380 mg (0.85 mmol) of the compound 79b(j=0,58 /ethyl acetate: hexane, 1: 3 volume/ output 33% and 143 mg (0.34 mmol) of compound 79a (Rf = 0,54 /ethyl acetate:hexane, 1:3 volume/ output to 13%.

.

To a solution of 3.25 g (17.2 mmol) of compound 79 and 220,0 ml of a mixture of acetone: water (10:1 by volume) is added 6.0 g (51.2 mmol) of 4-methylmorpholine-N-oxide (product of the company Aldrich chemical company), and then 20.0 mg (0.08 mmol) of tetrakis OS (product of the company Aldrich chemical company). The reaction mixture is stirred for 2.5 days at room temperature in absence of light. The reaction is then quenched by adding a 100.0 ml saturated aqueous solution of sodium thiosulfate, stirred for another 1 h and extracted with 200.0 ml of dichloromethane. The organic layer is washed first with a 100.0 ml of water, then to 100.0 ml saturated aqueous sodium chloride, dried over 50.0 g sodium sulfate, filtered and concentrated under panigoro in 200.0 ml of a mixture of methyl alcohol and water (1: 1 by volume). To the resulting solution was added 6.0 g (28.1 mmol) of periodate sodium (product of the company Aldrich chemical company) at 0oC and vigorous stirring. After 1 h the reaction mixture was diluted with dichloromethane. The organic layer is washed first with a 100.0 ml unsaturated aqueous solution of sodium chloride, dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature, again receiving the crude product as a yellowish oil.

The crude product is dissolved in a 50.0 ml of methyl alcohol, cooled to 0oC and add 1.5 g (39.7 mmol) sodium borohydride (the product of the firm "Aldrich chemical company) in the form of individual portions. After 1 h the reaction mixture was quenched by the addition of 50.0 ml of a saturated aqueous solution of ammonium chloride and extracted with 200.0 ml of dichloromethane. The organic layer was washed with a 50.0 ml of a saturated aqueous solution of sodium chloride, dried over 20,0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature, obtaining the crude product as a yellowish brown oil.

The crude product is dissolved in a 50.0 ml of methyl alcohol and add 100 ál (25% weight. %) of sodium methylate, sodium borohydride. After 2.5 with the t 200.0 ml of dichloromethane. The organic layer is washed 50,0 ml unsaturated aqueous solution of sodium chloride, dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature, obtaining the crude product. In the cleaning product on a column of silica gel (100 g), elution mixture of ethyl acetate: hexane 1:1 by volume, obtain 3.0 g (9,06 mmol) of compound 80 (Rf = 0,27 /ethyl acetate:hexane, 1:1, volume/) with a total yield of 53%.

.

To a solution of compound 80(1.0 g, to 3.02 mmole) dissolved in 10.0 ml of anhydrous dichloromethane at first add 411 mg (6,04 mmole) of imidazole at 0oC, and then 0.55 g (3,62 mmole) of tert-butyldimethylsilyloxy. After stirring for 30 min the reaction mixture was quenched with 10.0 g of a saturated aqueous solution of ammonium chloride and extracted to 100.0 ml of ethyl acetate. The organic layer is dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature to obtain the crude product as a colourless oil.

The crude product is dissolved 30.0 ml of anhydrous dichloromethane, cooled to 0oC and added 0.97 g (3.63 mmol) of compound 46, and then injected 0.75 g (3.63 mmol) of 1,3-dicyclohexylcarbodiimide and 20 mg (of 163.7 IMO for an additional 2 h, quenched by the addition of 50.0 ml of a saturated aqueous solution of ammonium chloride and extracted to 100.0 ml dichloromethane. The organic layer is dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature, obtaining oil. The result of purification oil on a column of silica gel (100.0 g), elution with a mixture of ethyl acetate:hexane 1:6 by volume, and removal of the solvent from fractions containing the product earn 1.25 g (1.90 mmol) of compound 81 (Rf = 0,88 /ethyl acetate: hexane, 1:2 volume/) with a total yield of 63%.

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To a solution of compound 81 (11.2 mg, 17.0 mmol), dissolved in 4.0 ml of anhydrous tetrahydrofuran at first, add at room temperature, 10 ml (173 mmol) of acetic acid, and then 20 mg (76.5 mmol) of solid tetrabutylammonium (the product of the firm "Aldrich chemical company). The reaction mixture is stirred for a further 1 h, and then quenched with 2.0 ml of a saturated aqueous solution of ammonium chloride and extracted with T50,0 ml of ethyl acetate. Organic layer washed 20,0 ml of a saturated aqueous solution of sodium chloride, dried over 10.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature to obtain 8,1 mg (14.9 mcmole) connection 82 (Rf = 0.28 in /ethyl acetate (1.0 ml anhydrous dichloromethane was added when 0oC first, 7.4 mg (20.2 mcmole) bis(allyloxy)(diisopropylamino)phosphine, and then to 6.5 mg (92,8 of mcmole) 1H-tetrazole. After 30 min the reaction mixture is heated at room temperature and add the additional amount to 7.4 mg (30.2 mcmole) bis(allyloxy)(diisopropylamino)phosphine, and the reaction mixture is stirred for an additional 30 minutes the mixture is Then cooled to -78oC and add a solution of 6.6 mg (38,2 mcmole) 3-chloroperbenzoic acid dissolved in 300,0 μl of anhydrous dichloromethane. The reaction mixture was quenched by adding 2.0 ml of a mixture 1:1 by volume of a saturated aqueous solution of sodium bicarbonate. The resulting reaction mixture is heated at room temperature and extracted with 10.0 ml of dichloromethane. The organic extract was washed with 5.0 ml of a saturated aqueous solution of sodium chloride and dried over 5.0 g of sodium sulfate. After filtration and concentration of the dried extract under reduced pressure at room temperature gain of 8.9 mg (12.6 mcmole) of compound 83 (Rf = 0.28 in /ethyl acetate:hexane, 1:1 by volume/ yield 85%.

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A solution of compound 83 (0,82 g, 1,165 mmole) dissolved in 100 ml of a mixture of glacial acetic acid and water 1:1 by volume), stirred for 8 h at room temp is e oil is dissolved in a 50.0 ml of toluene and dried by azeotropic distillation added toluene under reduced pressure at room temperature.

The crude oil was dissolved in 20,0 ml of anhydrous dichloromethane, cooled to 0oC and add 1.0 g (14.7 mmol) of imidazole, and then injected 0.2 g (1.3 mmole) of tert-butyldimethylsilyloxy. After stirring for 30 min the reaction mixture was quenched by the addition of 20.0 ml of a saturated aqueous solution of ammonium chloride and extracted to 100.0 ml of ethyl acetate. The organic layer is dried over 20,0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature, obtaining the crude product as oil. The result of purification oil on a column of silica gel (100.0 g), elution with a mixture of ethyl acetate: hexane 1:2 by volume, and distillation under reduced pressure at room temperature of the solvent from fractions containing the product, obtain 0.65 g (0,835 mmol) of compound 84 with the release of 72%.

A solution of compound 84 (0,58 g, 0,764 mmol) dissolved in 10.0 ml of anhydrous toluene is cooled to 0oC and consistently add 10 ml (12.4 mmol) of anhydrous pyridine and 1.0 ml (1.93 mmol) of 1.93 M solution of phosgene in toluene. The reaction mixture was stirred for 30 min and add 400,0 ál (5,88 mmol) allyl alcohol. After additional stirring for 30 min at room temperature to reactio smetana, the organic layer is washed first with 10.0 ml of a saturated aqueous solution of sodium chloride, dried over 10.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature, receiving 0.7 g (0.81 mmol) of compound 55 (Rf = 0,85 /dichloromethane:diethyl ether, 4:1, volume/).

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To a solution of compound 85 (0,60 g, 0,696 mmol) dissolved in 5.0 ml anhydrous dichloromethane, add 0.5 g (1.1 mmol) of the complex Tris-benzothioate tin (II) with triethylamine. After stirring for 5 min add an additional amount of 0.5 g (1.1 mmol) of the complex Tris-benzothioate tin (II) with triethylamine and stirred for an additional 5 minutes, the Reaction mixture was loaded directly on a column of silica gel (20,0 g), elwira first with a mixture of hexane:ethyl acetate 4:1 by volume, and then a mixture of methyl alcohol:dichloromethane, 1:19 by volume, obtaining the crude amine.

The crude amine was dissolved in 3.0 ml of anhydrous dichloromethane, cooled to 0oC and add 290,0 mg (0,872 mmol) of compound C8, and then injected 200.0 mg (0,969 mmole) of 1,3-dicyclohexylcarbodiimide. After 1 h the reaction mixture is allowed to warm to room temperature, stirred for additional 2 h, dilute to 10.0 IDE oil. The result of purification oil on a column of silica gel (100.0 g), elution with a mixture of ethyl acetate: hexane 1:8 by volume, obtain 380 mg (0,330 mmol) of compound 86.

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To a solution of 3.0 ml of 6M hydrogen fluoride in 30 ml of acetonitrile contained in the reactor of Teflon, at 0oC added dropwise a solution to 300.5 mg (0,261 mmol) of compound 86 in 2.0 ml of acetonitrile. After stirring for 1 h the reaction mixture was poured in 100) ml of saturated aqueous sodium bicarbonate solution and extracted with 100,) ml dichloromethane. The organic layers are washed to 50.0 ml saturated aqueous sodium bicarbonate solution, dried over 10.0 g sodium sulfate, filtered and concentrated under reduced pressure at room temperature until an oily residue. Cleaning chromatographytandem on silikagelevye column with elution by the mixture hexane:ethyl acetate (1:1 by volume) to give 200 mg (0,193 mmol) of compound 87.

Connections 88 and 89 are synthesized in accordance with the General methods described above for the synthesis of compounds 33 and 34.

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To stir at room temperature suspension of compound 89 (102,5 mg, 48.6 per µmol) in a mixture of acetonitrile (1.5 ml) and water (100 ml) was added mercuric oxide (11) and 96 mg, 443 μmol) and dujarie precipitation. The mixture is filtered through Celit e 545, collect the filtrate, and within 1 h bubbled through the hydrogen sulfide. The mixture is again filtered, the United filtrates are washed with saturated aqueous sodium bicarbonate, dried with saturated aqueous sodium chloride, then with sodium sulfate, filtered and concentrated under reduced pressure to an oil. This oil is purified directly by passing it through a column of silica gel (10.0 g) with elution with a mixture of methanol:chloroform (1:19 by volume), and then chromatographia in the second column of silica gel (10.0 g) with elution by the mixture hexane:ethyl acetate (1:4 by volume). Get to 54.5 mg (28.3 mmol) of compound 90.

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Compound 90 (37.5 mg, of 19.5 mmol) is dissolved in the dark, in argon atmosphere, in a mixture of tetrahydrofuran: 96% formic acid (10:1 by volume), and added dropwise to the obtained solution of tetrakis(triphenylphosphine)palladium (O) and triphenylphosphine. The reaction is performed as described above for compound 30 (procedure a), receiving 15,0 mg (to 9.91 mmol) of compound 91 in the form of the free acid. To obtain similar V-34 lipid A, according to the method described above for similar V-32 conduct the reaction of the compound 91 with L-lysine.

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First, in standard conditions providesto 4-dimethylamino-pyridine, the reaction is carried out at room temperature. After evaporation of excess alleluya reagents in vacuum at room temperature to obtain the crude product, acylated in position 4. This product is used in subsequent transformations without further purification.

The crude product acylated in position 4, is subjected to synthetic transformations and purification as described above for converting compounds 55 and 56, and get a connection 92 (Rf : 0,23 hexane:ethyl acetate, 4:1 by volume).

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Compound 47 was identified in and processed, as described above, except that as cilleruelo reagent using tert-BUTYLCARBAMATE. Then 2.2 g (2.8 mmol) of selected 4-etilirovannogo 6-similarvideo product is dissolved in 20,0 ml of a mixture of acetone-water (9oC1) by volume). To this mixture is added 0.7 g (5.7 mmol) of 4-methylmorpholine-N-oxide and 10.0 mg (0.04 mmol) of tetrakis osmium, and the resulting reaction mixture is stirred for 2.5 hours the Reaction is stopped by adding a 100.0 ml saturated aqueous sodium thiosulfate solution, and extracted with the mixture of 100.0 ml of dichloromethane. The organic layer is dried over 20,0 g of sodium sulphate and evaporated at room temperature under reduced is astonaut in 20,0 ml of methanol and stirred with 2.0 potassium carbonate for 25 minutes Then the reaction mixture is diluted to 100.0 ml dichloromethane, filtered through 10.0 g Celite and washed to 100.0 ml of 0.1 N hydrochloric acid. The organic layer is washed 25,0 ml of saturated solution of sodium chloride, dried over 30.0 sodium sulfate and concentrated at room temperature under reduced pressure, obtaining the crude product. This product was then purified on 200,0 g silica gel, elwira a mixture of hexane:ethyl acetate (9:1). The target product is obtained with a yield of 80% (Rf: 0,46 hexane:ethyl acetate, 4:1 by volume). The obtained intermediate product is subjected to the synthetic transformations described above for the conversion of compounds 45 and 52, and then the synthetic transformations described above for converting compounds 55 and 56 receive the final target intermediate connection 93 (Rf:0,33 hexane:ethyl acetate, 4:1 by volume).

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3,4,6-triacetoneamine (Pfanstiehl Labza., Inc.), subjected to the synthetic procedures described above for the conversion of compound 7 to 9. Then the obtained product is protected by anomeric position as described above for compound 36. Treatment of this compound for the removal of the protective acetate groups from positions 3, 4 and 6 and subsequent protection regulations 4 and 6 acetonide carried out as described above for the synthesis of the secondary school to obtain compounds 37-45, and then the synthetic transformations described for producing compounds 45-54.

of 10.5 g (15.6 mmol) of the obtained product is dissolved in 500 ml of anhydrous dichloromethane at room temperature in a nitrogen atmosphere, and added 18.6 ml (140,7 mmol) of 2,4,6-collidine (Aldrich chemical Co). Then to the mixture for 1.5 hours added dropwise a solution of 4.8 ml (36,3 mmol) diethylaminoacetate (Aldrich chemical Co) in 120,0 ml of anhydrous dichloromethane. The resulting mixture was stirred for further 2 hours, then "quenched" by adding 100 ml of anhydrous methanol. The reaction mixture is poured into 200 ml saturated aqueous sodium bicarbonate solution and extracted with 500 ml of dichloromethane. Then the organic extract was washed with 200 ml saturated aqueous solution of sodium chloride and dried over 100 g of sodium sulfate. The crude product is purified on 500 g of silica gel, elwira a mixture of hexane:ethyl acetate (10:1 by volume), get target product, fluorinated in position 4, with the release of 65% (Rf:0,77 hexane: ethyl acetate, 10:1 by volume).

Then this product is subjected to the synthetic transformations described above to produce compounds 55-56, receiving the connection 94 (Rf:0,78 Hexane:ethyl acetate, 2:1 by volume) with a good yield.

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Connection 95 produces what melirovanie side chain a10 (see below) under the conditions described above for the synthesis of compound 45. The product is then subjected to alkylation reactions described above to produce compounds 80-85, and then the transformations described above to produce compounds 87 and 86, and receive the intermediate compound 95 (Rf:0,09 hexane:ethyl acetate, 1:1 by volume).

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Compound 47 was identified in and processed, as described above, except that as cilleruelo reagent using tert-BUTYLCARBAMATE. Then the selected 4-methylated 6-sililirovany product is subjected to the transformations described above to obtain compound 56 of 55, after which phosphorylate in free position 6 in the manner described above for the synthesis of compound 49. This product is converted into the target intermediate compound 96 (mixture of alpha and beta isomers) using a two-stage procedure described above for the synthesis of compounds 51A and 51B (from compound 49 through the connection 50). Compound 96 (a mixture of alpha - and beta-isomers): Rf:0.50 0,83 (hexane:ethyl acetate, 1:1 by volume).

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Intermediate compound 97 was synthesized from compound 47 as follows. A mixture of 2.0 g (3.1 mmol) of compound 47, 1.0 g of powdered molecular sieves 300A, 300,0 mg (1,29 mmol) ()-10-temperature in nitrogen atmosphere for 45 minutes Then the reaction mixture is diluted to 50.0 ml dichloromethane, washed first of 20.0 ml of saturated aqueous sodium bicarbonate solution, and then 20 ml of a saturated aqueous solution of sodium chloride. The organic layer is dried over 30.0 g of sodium sulfate, the solvent is removed at room temperature under reduced pressure, and the crude product was then purified according to 200.0 g of silica gel, elwira first 1.0 l of hexane, then 1.0 l of a mixture of hexane:ethyl acetate (99:1 by volume), and finally 1 l of a mixture of hexane:ethyl acetate composition of 97:3 (by volume). The target product is obtained with a yield of 85%. (1,96 g, 2.6 mmol) Rf:to 0.47 (hexane: ethyl acetate, 19:1 by volume).

The above product is dried in vacuum overnight, then dissolved in 10.0 ml of anhydrous dichloromethane. To this mixture is added first 625,0 μl (3.9 mmol) of triethylsilane (Aldrich chemical Co.), and then of 2.8 ml (2.8 mmol) of 1.0 M solution of titanium chloride (IV) in dichloromethane (Aldrich chemical Co) for 5 min at room temperature in a nitrogen atmosphere. Then the reaction mixture is diluted to 50.0 ml dichloromethane and washed first with 50 ml saturated aqueous sodium bicarbonate solution, and then about 20 ml of a saturated aqueous solution of sodium chloride. The organic layer is dried over 10,0 g of sodium sulfate, ponie the 200 g of silica gel, elwira a mixture of hexane: ethyl acetate 19:1 by volume). The yield of the desired product in 74% (1.4 g, 1.9 mmol). Rf:of 0.14 (hexane:ethyl acetate, 19:1 by volume).

This alkilirovanny in position 6, the product is subjected to a series of transformations described above for three-stage synthesis of compounds 60A and 60B of 57A (through 58 and 59) to give compound 97 (in the form of a mixture of alpha and beta forms). Rf:of 0.55 and 0.67 (hexane:ethyl acetate, 2:1 by volume) with comparable outputs.

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First conduct the reaction of the compound 12 from compound A25 (as described above for the synthesis of compound 13) and the product received is sequentially subjected to the synthetic transformations described above to produce compounds 13-23. This is followed by a response received - isomeric product with compound 17 (as described above for the synthesis of compound 24), and the resulting product is subjected to a series of transformations described above to produce compounds 25, 32-34, 30 (method b), and 31. Similar lipid W-32 is produced by reaction of the obtained free acid with L-lysine as described above for analog V-32. Similar V-31 is produced by reaction of the free acid with Tris as described above for W-31.

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Conducting the reaction of the compound 12 from compound A6 (as described above for the synthesis of compound 18) and received FTUS received alpha-Samarovo product with compound 17 (as described above for the synthesis of compound 24), and the resulting product is subjected to a series of transformations, described above to produce compounds 25-30 (method a) with the only difference that first made by the reaction of compound 26 with one equivalent of protected allylcarbamate side chain (obtained as described above for the side chains A4-A6 using C4 as source material), and then carry out the condensation with C6. The resulting product deprotected as described above for the synthesis of compound 31. Similar V-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog V-32.

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Spend the reaction of compound 25 with E-2-tetradecenoic acid (described by Mimuro etc. in J. Pharmacolio-Dyn 1938 6(8):527, 1983), as described above for the synthesis of compounds 26, and the resulting product is subjected to a sequence of transformations described above to produce compounds 27, 28 and 31. Similar B286-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Spend the reaction of compound 25 with the beginning of the connection C6, and then with the compound H1 (see below) selective condensation as described above to obtain compound 26, and the resulting product is successively subjected to the transformations described above to produce compounds 27-31 (method a), 31. Similar B287-32 Lipe get H1, as described for B6, condensing the compound C4 with Z-7-tetradecenoic acid, which is obtained according to the General methodology used for connection B4.

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Conduct the reaction between H2 (see below) with compound 17 (as described above for the synthesis of compound 24), and the resulting product is subjected to a series of synthetic transformations described above to produce compounds 25-31. Similar B288-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

Connection H2 is identical in its structure to the connection 23A, except that allyloxy-protected phosphate group (23A) is replaced by allyloxycarbonyl-protected hydroxyl group (H2), the connection H2 receive essentially the same as described above for compounds 23A.

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Conducting the reaction of the compound 12 from compound A17 (see below) as described above to obtain compound 18, and the resulting product is successively subjected to the transformations described above to produce compounds 19-23. Conducting the reaction of the obtained alpha-isomer of the product with the compound 17 as described above to obtain compound 24), and the resulting product is subjected to a sequence of transformations described above for the La analog B214-32.

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Conducting the reaction of the compound 12 from compound A17 (see below), as described for the synthesis of compound 18. The product received is sequentially subjected to the transformations described above to produce compounds N 19-29, then deprotection as described above for compound 31. Similar B300-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 25 first with E-2-tetradecenoic acid (described by Mimuro etc. in J. Pharmacoli o-Dyn 6(8):527, 1983), and then with the compound C5 selective condensation (as described above for compounds 26) and the product received is sequentially subjected to the transformations described above to produce compounds 27, 28 and 31. Similar B313-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 25 first connection H3 (selective condensation), and then with the compound C6 (see below) selective condensation, as described above for the synthesis of compound 26, and the resulting product is subjected to successive transformations described above for compounds 27-31. Similar B314-32 lipid A obtained by reaction of the free acid with L-lysine as described above for annenia C4 condense with decanoas acid (Aldrich chemical Co.).

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Spend the reaction of compound 25 with a racemic mixture E3 and E5, as described above for the synthesis of compound 26, and the resulting product is successively subjected to the transformations described above to produce compounds 27, 28, 31. Similar B318-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 23A connection 87, as described above for the synthesis of compound 24. Then the obtained product is subjected first to the transformations described above to produce compounds 32-34, 30 (method b), and 31 (in that order), and then deprotection as described above for compound 31. Similar B377-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32, with the only difference that receive delizioso salt (not TetraSociology).

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Conducting the reaction of the compound 12 from compound A23 (see below), as described above for the synthesis of compound 18, and the resulting product is successively subjected to the transformations described above to produce compounds 19-23. Conducting the reaction of the obtained alpha-isomer of the product with the connection 17, as described above for the synthesis of compound 24, and the product of this reaction is subjected to a series of prolipid get A reaction of the free acid with L-lysine, as described above for analog B214-32.

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Spend the reaction of compound 25 with connection A30 (see below), as described above for compound 26. The resulting product is first subjected to a series of consecutive transformations described above to produce compounds 27 and 28, and then deprotected as described above to obtain compound 31. Similar B385-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Spend the reaction of compound 25 with connection A31 (see below), as described above for compound 26. The resulting product is subjected to successive transformations described above to produce compounds 27 and 28, after which deprotection as described above to obtain compound 31. Similar B387-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 25 first connection C8, and then E-tetradecenoic acid (described by Mimuro etc. in J. Pharmacoli o-Dyn 6(8): 527, 1983), as described above for the synthesis of compound 26. The product received is sequentially subjected to the transformations described for producing compounds 27, 28, 30 (method b) and 31. Similar B388-32 lipid A obtained by reaction of the free acid described above for the synthesis of compound 32. The product received is sequentially subjected to the transformations described above to produce compounds 33 and 34, after which deprotection oxathiolane group in the manner described to obtain compound 30 (method b), and the phosphate and hydroxyl groups in the manner described for compound 31. Similar B398-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-327

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Spend the reaction of compound 12 with TRANS-2-decanoas acid (Lancaster Synthesis Inc. as described above for the synthesis of compound 18, and the resulting product is successively subjected to the transformations described above to produce compounds 19-23. Then carry out the reaction of the obtained alpha-isomer of the product with the compound 17 as described above to obtain compound 24), and the product of this reaction is subjected to the transformation described above for the synthesis of compound 25. The resulting product is subjected to the transformation described above for the synthesis of compound 32, the resulting product is subjected to a series of transformations described above to produce compounds 33, 34 and 30 (method b) (in this sequence), and deprotection phosphate and hydroxyl groups as described above to obtain compound 31. Similar B400-32 l avodat the reaction of the compound 12 from compound A6 (as described above for the synthesis of compound 18), and the product received is sequentially subjected to the transformations described above to produce compounds 19-23. The obtained alpha-isomer product given designation H12A.

Spend the reaction of compounds 12 H1 (see connection B287), as described above for the synthesis of compounds 13, and the resulting product is subjected first to the transformations described above to obtain compound 19, and then the transformations described above to produce compounds 15-17 (in that order). Received the product given designation H13.

Conduct the reaction between the H12A and H13 as described above to obtain compound 24, and the resulting product is subjected first to the transformation described above to obtain compound 25, and then a series of transformations described above to produce compounds 32-34 (in specified order). Diciannove group received product deprotection as described above for compound 30 (method b), and the phosphate and hydroxyl groups as described above for the synthesis of compound 31. Similar B406-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Check the reaction of the compound 53 compound 23A (as described above for the synthesis of compound 40), and obtained the product phosphorylate, as described above to obtain compound 30 (method b), and deprotection phosphate and hydroxyl groups as described above to obtain compound 31. Similar B410-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 51A with compound 39 (as described above for the synthesis of compound 40), and the resulting product is successively subjected to the transformations described above to produce compounds 41-44. Then the product obtained fastreroute as described above to obtain compound 30 (method b), and deprotection phosphate and hydroxyl groups, as described for connection 31. Similar lipid A B415-32 is produced by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 42 with 1,3-dicyclohexylcarbodiimide and E7, as described above to obtain compound 43, and the resulting product is first subjected to the transformation described above to obtain compound 44, then phosphorylate as described above to obtain compound 30 (method b), and finally, deprotection as described above for the synthesis of compound 31. Similar lipid A B425-32 is produced by reaction of the free acid with L-linobrowser in the reaction of synthesis of compound 40 (above), sequentially subjected to the transformations described above to produce compounds 41-44. Then phosphorylate, as described above for compound 30 (method b), and, finally, deprotection as described above for compound 31. Similar B426-32 is produced by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 51A with compound 56 (as described above for the synthesis of compound 65), and the resulting product is successively subjected to the transformations described above to produce compounds 66-69. The resulting product deprotected as described for connection 31. Similar lipid A B427-32 is produced by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 56 with the connection 23A (as described above for the synthesis of compound 24), and the resulting product is subjected to synthetic transformation described above to obtain compound 25. This is followed by reaction of the resulting product with a mixture of compounds E3 and E5 (see below), as described above for compound 43. The resulting product is subjected to the synthetic transformations described above to obtain compound 44, phosphorylate, as described above to obtain compound 28, and the notes with L-lysine, as described above for analog B214-32.

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Compounds 19 and subjected to the same transformations that are carried out for the synthesis of compound 58 of the connection 47. The resulting product deprotected as described above for compounds 22, then activate as described above for the synthesis of compounds 23A. Conducting the reaction of the obtained compound with compound 56 (as described above for the synthesis of compound 65), and the resulting product is subjected to the transformation described above to obtain compound 66. This is followed by a reaction with a compound E3 (see below) as described above to obtain compound 67, and the resulting product is subjected to the transformations described above to produce compounds 68, 69, 31 (in that order). Similar B451-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 25 compound E3 (as described above for the synthesis of compound 26), and the resulting product is subjected to a series of transformations described above to produce compounds 27, 28, 31 (in that order). Similar B452-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 51A with the tion, described above for connection 66. Then spend the reaction product of this transformation with a mixture of compounds E3 and E5, as described above for the synthesis of compound 67, and the resulting product is subjected to a series of transformations described above to produce compounds 68, 69, 31 (in that order). Similar B459-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 51A with compound 56 (as described above for the synthesis of compound 65), and the resulting product is subjected to synthetic transformation described above to obtain compound 66. The product obtained in this transformation, is introduced into reaction with the compound E3 (see below), as described for the synthesis of compound 67, and the resulting product is successively subjected to the transformations described above to produce compounds 68 and 69. The resulting product deprotected as described for connection 31. Similar B460-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conducting the reaction of the compound 51A with compound 56 (as described above for the synthesis of compound 62), and the resulting reaction product is subjected to synthetic TA is E5 (see below), as described for the synthesis of compound 67, and the result of this reaction product is successively subjected to the transformations described above to produce compounds 68 and 69. The resulting product deprotected as described for connection 31. Similar B465-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conduct the reaction mixture compounds 60A and 60B with compound 56 (as described above for the synthesis of compound 65), and obtained in this reaction product is subjected to the transformation described above for the connection 66. Conducting the reaction of the obtained product with a compound E3 (see below), as described for the synthesis of compound 67, and obtained in this reaction product is subjected to a series of transformations described above to produce compounds 68, 69 and 31 (in that order). Similar B466-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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Conduct the reaction mixture compounds 60A and 60B with compound 56 (as described above for the synthesis of compound 65), and the product of this reaction is subjected to synthetic transformation, described the obtained product with a compound 67, and the product of this reaction is subjected to a series of transformations, opican the lots with L-lysine, as described above for analog B 214-32.

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Conduct the reaction mixture compounds 60A and 60B with compound 56 (as described above for the synthesis of compound 65), and the resulting product is successively subjected to the transformations described above to produce compounds 66-68. The resulting product (corresponding to the connection 68 above) deprotection as described for the synthesis of compound 31. Similar B479-32 lipid A obtained by reaction of the free acid with L-lysine as described above for analog B214-32.

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The connection 52 is first sequentially subjected to the transformations described above to produce compounds 46 and 47, and then is subjected to the transformations described above to produce compounds 57-60. Resulting from the implementation of these transformations the product is introduced into the reaction with compound 56 (as described above for the synthesis of compound 65) obtained in this reaction the product is successively subjected to the transformations described above to produce compounds 66-70, receiving similar B510-35.

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Similar B464 identical in structure to the connection 70, with the only difference that when the connection 45 use a side chain containing one carbon atom more than the A10 modificar the synthesis of compound 65). The product received is sequentially subjected to the synthetic transformations described above to produce compounds 66-70, receiving similar B718-35.

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Conducting the reaction of the compound 93 connection 60 (as described above for the synthesis of compound 65). The product received is sequentially subjected to the transformations described above to produce compounds 66-70, receiving similar B718-35.

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Conducting the reaction of the compound 94 connection 60 (as described above for the synthesis of compound 65). The product received is sequentially subjected to the transformations described above to produce compounds 66-70, receiving similar B737-35.

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Conducting the reaction of the compound 96 connection 60 (as described above for the synthesis of compound 65). The product received is sequentially subjected to the transformations described above to produce compounds 66-70, receiving similar B736-35.

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Conducting the reaction of the compound 96 connection 56 (as described above for the synthesis of compound 65). The product received is sequentially subjected to the transformations described above to produce compounds 66-70, receiving similar B725-35.

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Conducting the reaction of the compound 97, compound 56 (as described above for the synthesis of compound 65). Received the dialogue B763-35.

Part B. Synthesis of the side chains.

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To dry tetrahydrofuran (500,0 ml) by boiling under reflux successively added activated zinc (101.0 g, 1.54 mol, Fisher scientific), ethylbromoacetate (3.0 ml, Aldrich chemical Co.) and heptylene (47,4 ml, 0,308 mol, Aldrich chemical Co.) one portion. To the mixture is added dropwise within 3 h add 134,0 ml (1.232 metric mol) ethylbromoacetate). The mixture is refluxed for another 10 min, cooled to room temperature, and quenched by slow addition of a saturated aqueous solution of potassium carbonate (160,0 ml). After a 30-min intensive stirring of the solution is filtered through 500.0 g Celite 545, getting a clear yellow solution of the crude raminosoa of ester. The solution is acidified with 1.0 N hydrochloric acid (300,0 ml), stirred for 3 h, diluted with 2.0 l of hexane, and neutralized by adding of 300.0 ml of a saturated aqueous solution of sodium bicarbonate. The organic layer was washed with saturated aqueous sodium chloride (400,0 ml), dried over 500.0 g of sodium sulphate, filtered and evaporated. The residue is purified on silikagelevye column (1.0 kg), elwira a mixture of hexane: ethyl acetate (6: 1 by volume). Evaporation of the solvent from fractions containing the product (oprating (0,298 mol) of the compound A1 (Rf:0.7 to hexane:ethyl acetate, 4:1 by volume) to yield 97%.

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[R] -(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (653,5 mg, 1.05 mmol, Aldrich chemical Co.) and cyclooctatetraene (279,8 mg, 1.0 mmol, Alfa chemical Co. Ward hill, Massachusetts) is combined in a round bottom flask with a volume of 125 ml, equipped with a shutoff valve with a lateral arm, a magnetic stirrer and water fridge, and placed in the dry box. Then the flask was removed from the box and placed in an atmosphere of argon. Into the flask is injected anhydrous toluene (40,0 ml) and triethylamine (1.7 ml, 10.0 mmol, Aldrich chemical Co.), purged with nitrogen to remove oxygen, and the resulting mixture was refluxed with stirring in an argon atmosphere for 15 hours to Give a dark red solution to cool to 20oC and form a red jelly-like precipitate. The excess solvent is removed from the mixture using a 12-inch needle gauge 22, and remove any traces of volatile components under vacuum for several hours (taking special precautions against air penetration). Solid red-black residue is dissolved in anhydrous, containing no oxygen tetrahydrofuran under stirring in nitrogen atmosphere at 25oC for 1 h Obtained transparent orange-brown solution politieacademie.

Connection A1 (334,2 g, 1.15 mol) is dissolved in anhydrous methanol (330,0 ml) and removed from the obtained solution by triple oxygen freezing and thawing under vacuum using liquid nitrogen and a nitrogen atmosphere. To the reaction solution in the syringe to add the above solution of the catalyst - polytrimethylene kit [R]-2,2'-bis(diphenylphosphino)-1,1'- unaffiliated. The reaction mixture is injected into purged with argon 2-liter bomb for hydrogenation containing washed with methanol and ion-exchange resin Dowex H-200 H+(3.0 g, Aldrich chemical Co.), using injection catheter, in an argon atmosphere. The bomb is filled with gaseous hydrogen (Liquid Carbonic, Tewskbury, Massachusetts) to a pressure of 100 ATM, and the reaction mixture is stirred at 25oC for 66 hours When the pressure in the bomb drops to 20 atmospheres, a hydrogen excess release of the bomb, the reaction mixture is filtered under vacuum to remove volatiles, and get 334,0 g (1.15 mol) of the compound A2 (Rf: 0,31 hexane: ethyl acetate, 4:1 by volume) with a yield of 99%.

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Compound A2 (89,6 g, 0,347 mmol) dissolved in tetrahydrofuran (800,0 ml). To this solution was added a 2.5 M aqueous solution of sodium hydroxide (300,0 ml, 0.75 mol) and the resultant mixture and diethyl ether:hexane (1:1 by volume) and the aqueous layer was separated. The organic phase is extracted further 200.0 ml of water and the combined aqueous phases are acidified with 67 ml of concentrated hydrochloric acid. The acidified mixture is extracted with 2.0 l of diethyl ether, the extract washed first with 1.0 l of water, then 1.0 l of a saturated aqueous solution of sodium chloride, and dried over 500.0 g of magnesium sulfate. The solvent is removed under reduced pressure and the resulting grey solid was dissolved in 2.0 ml of acetonitrile at 80oC. To the resulting solution at 80oC add dicyclohexylamine a (80.0 ml, 0.40 mol), Aldrich chemical Co. ). The mixture is cooled to -20oC, receiving 104,7 g (0.24 mol) of the compound A3 (Rf: 0,38, hexane:ethyl acetate:glacial acetic acid, 1:1:0.1 volume) in the form of whitish fine needles, with 71% yield.

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Compound A3 (104,7 g, 246,0 mol) is suspended in ethyl acetate (2.0 l) to this suspension is added first triethylamine (37,2 g, 369,0 mmol) and then 2-bromoacetophenone (48,9 g, 246,0 mmol, in one piece, Aldrich chemical Co.): the addition is carried out at 0oC in nitrogen atmosphere. After 3 h the reaction mixture is heated to room temperature, stirred for 6 h, filtered under vacuum. The residue is washed 400,0 ml of ethyl acetate, the filtrate is washed first of 500.0 ml of 0.8 M hydrochloric acid, and then 500 ml of evaporated at 50oC under reduced pressure, getting frozen grey solid, which is recrystallized from 1.1 l of hexane and dried in a vacuum drying Cabinet at 50oC, receiving 81,05 g (223,9 mmol) of compound A4 (Rf: 0,65, chloroform:methanol 95:5 by volume) in the form of a whitish solid, with a yield of 91%.

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Compound A4 (20.2 g, 65,9 mmol) at 0oC dissolved in anhydrous toluene (300,0 ml) and anhydrous pyridine (30,0 ml) and to this solution is added dropwise, of 1.93 M solution of phosgene in toluene (50,0 ml of 96.5 mmol). The reaction mixture was stirred 10 min, then added dropwise allyl alcohol (20.2 ml, 297,0 mmol). Stirred for another 10 minutes, then at 0oC stop the reaction by adding to 100.0 ml saturated sodium bicarbonate solution. Then the solution is warmed up to the 25oC and extracted with 1.0 l of ethyl acetate. The organic layer is washed of 500.0 ml of a saturated aqueous solution of sodium chloride, dried over 500.0 g of sodium sulphate, filtered and evaporated. The residue is purified on a column of silica gel (2.0 kg) elwira a mixture of ethyl acetate: hexane (1: 9 by volume). Evaporation of the solvent from fractions containing the product (determined by thin layer chromatographic analysis) under reduced pressure at room temperature, d is e A5 (16,07 g, 41,17 mmol) is dissolved at 0oC in flask Morton in glacial acetic acid (150,0 ml) and added to a solution of zinc dust (24.2 g, 371,0 mmol). The solution is heated to 25oC, stirred for 1 h, and then filtered through a 50.0 g of Celite 545 and evaporated. The residue is purified on silikagelevye column, elwira first with a mixture of ethyl acetate:hexane (4:1 by volume) and then with a mixture of methanol:chloroform:acetic acid (10:40:1 by volume). Evaporation of the solvent from fractions containing the product (determined by thin layer chromatographic analysis) under reduced pressure at room temperature, gives A6 (10.8 g, 39,65 mmol, Rf: 0,34, hexane:ethyl acetate, 2:1 by volume) to yield 96%.

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To stir with a mechanical stirrer suspension 1000,3 g (15,33 mol) of activated zinc powder in 2.5 l of anhydrous tetrahydrofuran is added dropwise within 10 minutes, in a nitrogen atmosphere, at room temperature add 56,0 ml (0.59 mol) of methylpropanoate (Lancaster chemical Co., Windham, New Hampshire). The reaction mixture is heated to boiling point (reflux), dropwise over 5 min add 496,3 g (3,96 mol) of n-gibellina, and then dropwise within 4 hours, add another 700,0 ml (7,39 mol) of methylpropanoate. The mixture is boiled with obratimogo aqueous solution of potassium carbonate, and add 1.0 kg Celite 545. The heterogeneous mixture is filtered through 200,0 g Celite 545 and washed his four 1-l portions of ethyl acetate. The filtrate is separated and the aqueous layer was extracted with two portions of ethyl acetate in 500,0 ml combined organic layers are washed of 500.0 ml of a saturated aqueous solution of sodium chloride, dried over 2.0 kg of sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The crude oily product orange intensively stirred at room temperature in two-phase system consisting of 1.5 l of hexane and of 500.0 ml of 1.0 N aqueous solution of hydrochloric acid, dropwise adding to it for 40 min 250 ml of concentrated hydrochloric acid. After stirring the obtained heterogeneous system for another 20 minutes, the layers separated and the aqueous layer was extracted with 200 ml portions of hexane. The combined organic layers are washed of 500.0 ml of a saturated aqueous solution of sodium bicarbonate, dried over 500.0 g of sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The crude orange liquid is distilled, using brush rotary evaporator with a bath temperature of 110oC and a pressure of 1.0 mm RT. Art. Partially purified PR C /0.4 mm RT. Art.) compound A7 (Rf : 0,65, hexane:ethyl acetate, 4:1 by volume) as a transparent colorless liquid.

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In obeskislorozhennuju dry box, 250-ml vessel Slanka, equipped with a magnetic stir bar and refrigerator, in a 100.0 ml of degassed toluene and 4.0 ml, containing no oxygen triethylamine, suspended 1.54 g (2,47 mmol) of [R] -(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 662,0 mg (2.36 mmol) of the polymer dichloro(cycloocta-1,5-diene)ruthenium (II). The reaction vessel is sealed in an inert atmosphere, removed from the dry box, and refluxed in an argon atmosphere until then, until it forms an orange solid (approximately 24 hours). The reaction mixture is slowly cooled to 0oC (within 2 hours), after which the gel-like semi-product of the red color suspended in a 50.0 ml of dry dehairing toluene. The suspension is shaken with light circular movements to flush crystal-like plates, allow it to settle for 10 min, and decanted from the solid product, the excess solvent, using a 50 ml syringe with needle gauge 20. The above procedure was repeated once more, and then evaporated the resulting catalyst to dryness under a pressure of 1 mm RT.article within 2 hours of Red-orange solid is the area of argon for 1 h, for which the mixture turned into a clear red solution. This catalyst solution via a cannula in an argon atmosphere is transferred to a degassed solution of the above compounds A7.

A 2-liter three-neck flask in an argon atmosphere, dissolve the compound A7 (365,3 g, 1,824 mol) of 500.0 ml of methyl alcohol brand "For liquid chromatography high pressure", taken from the open bottle. The flask is sealed with a vacuum adapter and two rubber gaskets, and cool the flask with liquid nitrogen prior to the formation of a white solid substance during freezing flask pumped. Then the solid is placed in an atmosphere of argon and heated to room temperature with a hair dryer. These procedures cooling, pumping and heating was repeated three times. After the last cycle of digitize add chiral catalyst in a 100.0 ml anhydrous not containing oxygen of tetrahydrofuran, as described above. The resulting mixture using a Teflon cannula in an argon atmosphere transfer in the reaction bomb with a capacity of 2 liters, containing 1.0 g, (a total of 5.21 mmol) of the monohydrate of paratoluenesulfonyl (Aldrich chemical Co.), purged for 2 h in argon, the reaction Sosa and twice rinsed with hydrogen under a pressure of 7 ATM. In the bomb serves hydrogen to a pressure of 105 MPa and stirred the reaction mixture for 72 h, after the first 15 min of stirring again filled with hydrogen to an initial pressure. After absorbing 25 ATM of hydrogen from the system slowly release hydrogen and purge with argon (three times). The methanol solution is evaporated under reduced pressure, the obtained residue is dissolved in ethyl acetate and stirred for 15 min with 300,0 ml saturated aqueous sodium bicarbonate solution. The layers separated, the organic layer washed to 100.0 ml saturated aqueous sodium chloride, dried over 100.0 g sodium sulfate, filtered and concentrated in vacuo at room temperature. The residue is purified by 2.5 kg of silica gel, elwira first mixture of 32.0 liters of hexane, then with 8.0 l of a mixture of hexane:ethyl acetate (19:1 by volume), then 16,0 l mixture of hexane:ethyl acetate (9:1 by volume) and, finally, an 8.0 litre of a mixture of hexane:ethyl acetate (3:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and drying in vacuum at room temperature over night give 325,0 g (1,61 mol, the yield of 88.1 percent, the enantiomeric excess of 98%) of compound A8 (Rf: 0,46, hexane:ethyl acetate) sociallyengaged (Aldrich) in 500.0 g of anhydrous diethyl ether, at 0oC in nitrogen atmosphere is added dropwise over 3.5 hours add 159,0 g (0.78 mol) of the compound A8 of 200.0 g of anhydrous diethyl ether. After stirring for another 15 min at room temperature, the fully reacted reaction mixture is cooled to 0oC and quenched by adding dropwise 1.0 l of 1.0 N aqueous hydrochloric acid, then add 200.0 ml of concentrated hydrochloric acid. The formed transparent layers separated, and the aqueous layer was extracted three times with 300 ml portions of diethyl ether. The combined extracts washed first with 200.0 ml of water, and then 200.0 ml saturated aqueous solution of sodium chloride. Water layers again extracted three times with 300-ml portions of chloroform. The combined organic layers dried over 500.0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature, obtaining a transparent yellow oil. The crude product is distilled in 500.0 g of silica gel, elwira first of 5.0 l of a mixture of hexane:ethyl acetate (9:1 by volume) then 20,0 l mixture of hexane:ethyl acetate (4:1 by volume), then an 8.0 litre of a mixture of hexane:ethyl acetate (3:1 by volume), then 1.0 l of chloroform, then 6.0 liters of a mixture of chloroform:methanol (9:1 by volume), and, finally, 4.0 l of a mixture of chloroform: methanol (4: 1 by volume). You is), under reduced pressure at room temperature and drying overnight under vacuum at room temperature to give a 94.2 g (0.54 mol, yield 69%) of compound A9 (Rf: 0,33, ethyl acetate: hexane, 1:1 by volume) as a colorless transparent oil.

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To mix the solution 114,1 g (of 0.65 mol) of the compound A9 3.6 l of anhydrous pyridine, 2oC in nitrogen atmosphere for 15 min chunks 10.0 g add 136,6 g(to 0.72 mol) of para-toluensulfonate (99+%, Aldrich chemical Co.). The reaction mixture is allowed to slowly warm to room temperature, stirred her 8 hours in nitrogen atmosphere, concentrated by evaporation in a vacuum, and subjected to azeotropic distillation to dryness with three 500-ml portions of toluene, using a vacuum. The crude syrupy product is dissolved in 2.5 l of ethyl acetate and of 500.0 ml of a saturated aqueous solution of sodium chloride. The layers are separated, and washed the organic layer of 500.0 ml of a saturated aqueous solution of sodium chloride. Combined aqueous layers are extracted twice with 500-ml portions of chloroform. The combined organic layers dried over 500.0 g of sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on 1.5 kg of silica gel, elwira first 12,0 l mixture of hexane:this is the amount of then 4,0 l dichloromethane and finally, 16,0 l mixture of dichloromethane:methanol (9: 1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and drying in vacuum at room temperature overnight to give a 96.9 g (0.29 mol) of the compound A10 (Rf:0,45 hexane: ethyl acetate (4: 1 by volume), then 4,0 l dichloromethane and finally, 16,0 l mixture of dichloromethane: methanol (9: 1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and drying in vacuum at room temperature overnight to give a 96.9 g (0.29 mol) of the compound, A10 (Rf: 0,45 hexane:ethyl acetate, 2:1 by volume) as a yellow oil with a yield of 45%.

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To a stirred solution of 20.0 ml (0,136 mol) octene-1 (Aldrich chemical Co. in 300,0 ml of anhydrous tetrahydrofuran at 0oC in argon atmosphere is added dropwise over 30 min add 70,5 ml (0,177 mol) of a 2.5 M solution of n-utility in hexane (Aldrich chemical Co.). Mixture is allowed to warm to room temperature over 1 h, then cool it to 0oC and added dropwise within 20 min add 35,9 ml (0,272 mol) of 1,4-diiodobutane Older is more to 400.0Hz in units of g of ice and divide the resulting layers. The organic layer is washed of 300.0 ml of a saturated aqueous solution of sodium chloride, dried over 150,0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. From the crude product by distillation at 0.1 mm RT.article and 70-80oC remove excess diiodobutane, the obtained residue is purified on a 500.0 g of silica gel, elwira 2.0 l of hexane. Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and drying in vacuum at room temperature over night give 23,0 g (0,078 mmol) of compound A11 (Rf: 0,6 hexane) to yield 58%.

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To mix the solution 6,53 g (37.5 mmol) of compound A9 and 45.0 ml of anhydrous pyridine at room temperature under nitrogen atmosphere add 11,58 g (37.5 mmol) of 4-methoxy-triphenylmethylchloride (Aldrich chemical Co). The reaction mixture was stirred at room temperature for 4.5 h, diluted with 200.0 ml of dichloromethane, washed the organic layer to 100.0 ml of water, dried over 150,0 g sodium sulfate, filtered concentrated under reduced pressure at room temperature and subjected to azeotropic distillation to dryness with three 100 ml portions of toluene, using a vacuum. Neotia of the solvent from the fractions, containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, the product is dissolved in 200 ml of hexane, filtered, and the filtrate concentrated under reduced pressure at room temperature and dried in vacuum at room temperature over night, getting 16.5 g (36,9 mmol) of compound A12 (Rf: 0,49, hexane:ethyl acetate, 4:1 by volume) to yield 98%.

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To a stirred solution of 17.1 g (of 0.038 mmol) of the compound A12 in 60,0 ml of anhydrous N, N-dimethylformamide at 0oC in an atmosphere of nitrogen added in small portions to 2.94 g (0,076 mmol) of sodium hydride (60% in oil, Aldrich chemical Co., washed with hexane). The mixture is stirred 15 min at 0oC, for 30 min added dropwise 12.3 g (0,042 mmol) of compound A11, allow the reaction mixture to warm to room temperature, stirred her for another 16 h and quenched by slow addition of 10.0 ml of methanol at 0oC. the resulting mixture was stirred for further 30 min, diluted with 300,0 ml of dichloromethane and washed the resulting organic solution of 200.0 ml saturated aqueous sodium chloride, dried over 150,0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on 500,0 g selectorates of fractions, containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and dried in vacuum at room temperature overnight to give 2.5 g (4.1 mmol) of the compound A13 (Rf: 0,5, hexane:ethyl acetate, 10:1 by volume) with a yield of 11%.

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To a stirred solution of 2.6 g (4.26 deaths mmol) of compound A13 in 80,0 ml dichloromethane add 1.0 ml of concentrated hydrochloric acid. The solution is stirred for 1 h at room temperature, diluted with 400,0 ml of ethyl acetate, washed four times the organic solution 100 ml portions of a saturated aqueous solution of sodium chloride, dried over 60,0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on of 300.0 g of silica gel, elwira 2.0 l of a mixture of hexane:ethyl acetate (5:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis under reduced pressure at room temperature, and dried in vacuum at room temperature overnight to give 1.69 in (4.26 deaths mmol) of compound A14 (Rf:0,4, hexane:ethyl acetate, 4:1 by volume), which contains a small amount of 4-methoxycarbonylmethylene. In the subsequent syntheses this product espolea A14 50,0 ml of anhydrous dichloromethane under nitrogen atmosphere add 3.0 g of calcined in a flame of molecular sieves 3A (Aldrich chemical Co.), stirred the reaction mixture for another 40 min, diluted suspension of 50.0 ml of dichloromethane, washed with an organic suspension first, 50 ml of 10% (weight:volume) aqueous solution of sodium thiosulfate, then, 50 ml of a saturated aqueous solution of sodium chloride, dried over 60,0 g sodium sulfate, filtered through 20,0 g Celite 545 and concentrated under reduced pressure and room temperature. The residue is purified by 50.0 g of silica gel, elwira 300 ml of a mixture of hexane:ethyl acetate (7:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and dried in vacuum at room temperature for 30 min give 0,46 g (1.37 mmol) of the compound A15 (Rf: 0,88, hexane:ethyl acetate, 2: 1 by volume) to yield 84%, which is directly used in the next reaction.

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To mix the solution and 0.46 g (1.37 mmol) of the compound A15 12.0 ml of tert-butanol and 3.0 ml (28.3 mmol) of 2-methylbutan - 2 (Aldrich chemical Co) at 0oC added dropwise 10.0 ml of an aqueous solution containing 1.04 g (by 8.22 mmol) of the dihydrate of sodium chlorite (Eastman Kodak Co., Rochester, new York) and 1,11 g (8,04 mmol) of monobasic sodium phosphate (Fisher scientific Co.). Suspension per the sodium, dilute it to 100.0 ml diethyl ether and separate the formed layers. The organic layer is washed with 50 ml saturated aqueous solution of sodium chloride, dried over 60 g of sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified by 100.0 g of silica gel, elwira first, 300 ml of a mixture of hexane:ethyl acetate composition 4:1 (by volume), followed by 300 ml of a mixture of hexane: ethyl acetate composition 2:1 (by volume) and, finally, 500 ml of a mixture of hexane:ethyl acetate (1:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, and dried in vacuum at room temperature over night give 342,0 mg (0.97 mmol) of the compound A16 (Rf: 0,28, hexane:ethyl acetate, 2:1 by volume) with the yield of 70.8%.

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To mix the solution 0,342 g (0.97 mmol) of the compound A16 in 16.0 ml of methanol and 0.5 ml (to 4.23 mmol) of quinoline (Aldrich chemical Co.) at room temperature in a nitrogen atmosphere add to 100.0 mg of 5% (by weight) of palladium on calcium carbonate containing an admixture of lead (Aldrich chemical Co.). The reaction mixture is pumped, rinsed three times with hydrogen, and stirred under hydrogen atmosphere (atmospheric pressure) nitrogen is the t room temperature, and dilute to 100.0 ml dichloromethane. The organic solution is washed twice with 60 ml portions of 1.0% aqueous solution of hydrochloric acid and one of 50.0 ml of a saturated aqueous solution of sodium chloride, dried over 60,0 g sodium sulfate, filtered, concentrated under reduced pressure at room temperature and dried in vacuum at room temperature over night, getting 340,0 mg (0.96 mmol) of the crude compound A17 (Rf:0.50 to hexane:ethyl acetate, 2:1 by volume), with a yield of 99%. Connection A17 used in the next reaction without further purification.

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To a stirred solution of 10.0 g (64.8 mmol) decen-1-ol (Farchan chemical Co. Gainesville, Florida) in 10 ml of anhydrous pyridine at 0oC in nitrogen atmosphere slowly over 5 min add 18,5 g (97,0 mmol) para-toluensulfonate (99-% Aldrich chemical Co.). The reaction mixture is allowed to slowly warm to room temperature, stirred her 4 h and diluted with 200.0 ml of ethyl acetate. The organic solution is washed to 50.0 ml of a saturated aqueous solution of sodium chloride, dried over 50.0 g sodium sulfate, filtered, concentrated under reduced pressure and room temperature, and heated azeotropic distillation in vacuum to dryness with three portions of toluene, receive the work without additional purification.

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To a stirred solution of 18.0 g (50,7 mmol) of the compound A18 in 420,0 ml of anhydrous dimethyl sulfoxide (Fisher scientific Co) at room temperature under nitrogen atmosphere add to 36.0 g (to 194.6 mmol) phthalimide potassium (Aldrich chemical Co.). The reaction mixture is heated to 50oC, stirred for 3 h and diluted with 1.0 l of ethyl acetate. The resulting organic solution is washed first with 200.0 ml saturated aqueous sodium bicarbonate solution, then 200.0 ml saturated aqueous sodium chloride, dried over 150,0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on of 300.0 g of silica gel, elwira 3.0 l of a mixture of hexane:ethyl acetate (6:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and drying in vacuum at room temperature over night give 13,0 g (45,8 mmol) of compound A19 (Rf : 0,39, hexane:ethyl acetate, 6:1 by volume) to yield 84%.

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To a stirred solution of 13.0 g (45,8 mmol) of compound A19 in 200.0 ml of methanol and 8.1 ml (68,5 mmol) of quinoline at room temperature in a nitrogen atmosphere add 1.0 g of 5% (by weight) of palladium on the carbonate calamospora hydrogen (at atmospheric pressure) for 1 h The reaction mixture is blown with nitrogen and filtered through a 100.0 g of Celite 545, elwira three 50-ml portions of methanol. The filtrate is concentrated under reduced pressure at room temperature and diluted with of 500.0 ml of dichloromethane. The organic solution was washed with two 100-ml portions of 1.0 hydrochloric acid, and then to 100.0 ml saturated aqueous sodium chloride, dried over 150,0 g sodium sulfate, filtered, concentrated under reduced pressure at room temperature and dried in vacuum at room temperature over night, getting 13,0 g (of 45.6 mmol) of the crude compound A20 (Rf : 0,39, hexane:ethyl acetate, 6:1 by volume) with access to 99.6%. Connection A20 is used in the next reaction without further purification.

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A 21. To a stirred solution of 6.0 g (21,0 mmol) of the compound A20 in 200.0 ml of absolute ethanol (quantum chemical Co., Cincinnati, Ohio) at room temperature add to 5.1 ml (105,0 mmol) hydrazinehydrate (98%, Lancaster Chemical Co.). The reaction mixture is heated to 75oC, stirred for 75 min, cooled to room temperature and diluted with 300,0 ml of dichloromethane and 100 ml of water. The resulting salts are separated and the aqueous layer was extracted with two 50-ml portions of dichloromethane. The combined organic layers is the best 3.2 g of the crude compound A21 (Rf : 0.08 chloroform:methanol, 10:1 by volume) to yield 100%. The crude product used in the next reaction without further purification.

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To a mechanically stirred solution of 4.8 g (15.6 mmol) of compound A4 60,0 ml of anhydrous toluene at 0oC in nitrogen atmosphere add to 6.0 ml (74,2 mmol) of anhydrous pyridine, and then dropwise within 20 min type of 8.9 ml (17,2 mmol) of 1.93 M solution of phosgene in toluene. The mixture was stirred at 0oC for another 15 min, then added dropwise within 5 min add 2.7 g (17,2 mmol) of the compound A21 and 30.0 ml of anhydrous toluene. The reaction mixture is stirred for another 25 minutes, put 30,0 unsaturated aqueous sodium bicarbonate solution, and dilute to 100.0 ml of ethyl acetate. The organic suspension was washed with a 50.0 ml of a saturated aqueous solution of sodium chloride, dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on 200,0 g silica gel, elwira 3.0 l of a mixture of hexane:ethyl acetate (6:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and dried in vacuum at room temperature overnight to give 5.2 g (10.6 mmol) of the compound A22 (rloi Morton flask to a solution of 5.2 g (of 10.7 mmol) of the compound A22 in 200 ml of glacial acetic acid under nitrogen atmosphere, at room temperature add 14.0 g (214,1 mmol), activated powdered zinc. The reaction mixture is stirred for 30 min and filter the suspension through a layer 60,0 g Celite 545, elwira four 50-ml portions of methyl alcohol. The filtrate is concentrated under reduced pressure and room temperature, and heated azeotropic vacuum distillation to dryness with three 50-ml portions of toluene. The crude oily product yellow clear on 200,0 g silica gel, elwira 2.0 l of a mixture of hexane:ethyl acetate structure of 6:1 (by volume) and then a 5.0 l of a mixture of hexane:ethyl acetate 1:1 (by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, and dried in vacuum at room temperature overnight to give 3.55 g (9,63 mmol) of the compound A23 (Rf : 0,08 hexane:ethyl acetate, 2:1 by volume) to yield 90%.

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To a stirred solution of 23.7 g (amount of 0.118 mmol) dodecanol acid (Aldrich chemical Co. ) and 32.9 g (0,107 mmol) of compound A4 of 250.0 ml of anhydrous dichloromethane at 0oC add 0.03 g (0.2 mmol) 4-dimethylaminopyridine, and then 29,2 g (0,143 mol) of 1,3-dicyclohexylcarbodiimide. After stirring at 25oC for 2.5 h teperature. The obtained residue is purified on silica gel (2.0 kg) mixture of ethyl acetate: hexane (1:9 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and dried in vacuum at room temperature over night give of 48.7 g (0.10 mol) of the compound A24 (Rf : 0,6, hexane:ethyl acetate, 4:1 by volume) to yield 84%.

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To mechanically stir in the Morton flask to a solution of compound A24 (16.07 g, 32,99 mmol) of 150.0 ml of glacial acetic acid at 0oC added 24.2 g (371,0 mmol) of zinc dust. After warming to 25oC and stirring for 1 h, the reaction mixture was filtered through a 50.0 g of Celite 545 and concentrated under reduced pressure and room temperature. The obtained residue is purified on silica gel (1.0 kg) elwira first with a mixture of ethyl acetate:hexane (4:1 by volume) and then with a mixture of methanol:chloroform:acetic acid (10:40oC1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, and dried in vacuum at room temperature overnight to give 10.8 g (39,35 mmol) of the compound A25 (Rf : 0,34, hexane: e is ancaster Synthesis) of 20.0 ml of anhydrous tetrahydrofuran at 0oC in nitrogen atmosphere are added dropwise 1.5 ml (3.73 mmol) of 2.51 M solution of n-utility in hexane (5 minutes). The reaction mixture was stirred 1 h at 0oC, after which the solution is transferred via cannula to stir at room temperature and under nitrogen atmosphere a solution and 0.46 ml (6,74 mmol) methylchloroform (Aldrich chemical Co.), in 10.0 ml of anhydrous tetrahydrofuran. The resulting reaction mixture is stirred for further 30 minutes , then extinguish its 10.0 ml of a saturated solution of ammonium chloride. The resulting mixture is extracted with three 20-ml portions of ethyl acetate, the combined organic layers are washed with 10 ml saturated sodium chloride, dried over 20,0 g of anhydrous sodium sulfate, filtered and concentrated at room temperature. The crude product to 0.69 g (2.89 mmol) of the compound A26 (output 85,4%) - used in the next stage without additional purification after drying in vacuum at room temperature overnight (Rf : 0,78, hexane:ethyl acetate, 4:1 by volume).

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To a stirred suspension 4,349 g (23.07 mmol) of copper iodide (1) (to 99.9%, Aldrich chemical Co) in 40.0 ml of anhydrous diethyl ether at 0oC in nitrogen atmosphere is added dropwise within 15 minutes add 30,0 ml (46.2 mmol) of 1.5 M solution metallice in diethyl ether (what omashu cannula quickly transferred to stir at room temperature under nitrogen atmosphere a solution of 5.0 g (20,97 mmol) of the compound A26 50,0 ml of anhydrous diethyl ether. After stirred for a further 5 minutes the reaction mixture is quenched by 60.0 ml of a saturated solution of ammonium chloride and stirred for further 1 h the mixture is diluted to 50.0 ml of hexane, filtered through 50 g of Celite 545, elwira 50 ml of hexane, and separate the layers. The aqueous layer two 50-ml portions of hexane, the combined organic layers washed with 50 ml saturated sodium chloride solution, dried over 100.0 g of anhydrous sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on two series connected ammo Prep PAK (500/silica (waters associated), elwira of 10.0 l of a mixture of diethyl ether; hexane with gradient from 98,5 to 2.5 (by volume) at a flow rate of eluent 200 lhs/min, using as a system for pumping and detection liquid chromatography device Prep LC/System 500 (waters associates). The lifting of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, and drying in vacuum at room temperature overnight to give 1.25 g (is 4.93 mmol) of the compound A27 (Rf : 0,28, diethyl ether:hexane, 1:19 by volume) with the output of 23.5% and 2.55 g (10,08 mmol) of the compound A28 (Rf : 0,22, di is soedineniya A27 8.0 ml of anhydrous dichloromethane at 0oC in nitrogen atmosphere is added dropwise over 15 minutes add to 18.1 ml (to 18.1 mmol) of 1.0 M solution of diisobutylaluminium in hexane (Aldrich chemical Co).

The reaction mixture was quenched by 60.0 ml of a saturated solution of ammonium chloride and stirred for further 45 minutes. The resulting mixture was extracted with three 50-ml portions of ethyl acetate, the combined organic layers washed with 50 ml saturated dissolved, filtered and concentrated under reduced pressure and room temperature. The residue is purified on 150,0 g of silica gel, elwira 2,0 mixture of hexane: diethyl ether (7/5 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, and drying in vacuum at room temperature overnight to give 1.29 g (5,70 mmol) of the compound A29 (Rf : 0,19, diethyl ether:hexane, 3:7 by volume) with a yield of 62.8%.

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To a stirred solution of 1.20 g (and 5.30 mmol) of the compound A28 6.0 ml of chloroform at room temperature in a nitrogen atmosphere one portion added 4.6 g (53,00 mmol) of activated manganese dioxide (Aldrich chemical Co. ). The reaction suspension boil for 30 minutes under reflux, then cooled to room temperature, the research Institute at room temperature. The crude intermediate was dissolved in 50 ml of tetrahydrofuran and cooled to 0oC, then one portion added to 4.0 ml of 2-methylbutan-2. To the reaction solution dropwise over 5 minutes add 10,0 mixtures containing dibasic sodium phosphate (Fisher scientific Co.), the sodium chlorite (Eastman Kodak Co) and water according 1:0, 09: 1 (weight: weight:volume). The reaction mixture was stirred at 0oC for another 30 minutes, then extinguish it 50,0 ml of 10% aqueous sodium thiosulfate solution and stirred for further 10 minutes the mixture is acidified to pH 3.0 with 1.0 N hydrochloric acid and extracted with three 50-ml portions of ethyl acetate. The combined organic layers washed with 50 ml saturated sodium chloride solution, dried over 100.0 g of anhydrous sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on 200,0 g silica gel, elwira 2.0 l of a mixture of hexane:diethyl ether (3:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, and drying in vacuum at room temperature overnight to give 1.01 g (4,22 mmol) of the compound A30 (Rf: 0,21, diethyl ether:hexane, 3:7 by volume) with access 79,60oC in nitrogen atmosphere is added dropwise over 2 minutes add a 15.7 μl (0.18 mmol) of oxalicacid (Aldrich chemical Co.). The reaction mixture is stirred for 40 minutes at 0oC, then concentrate it under reduced pressure, moisture, and dried for 1 hour in vacuum at room temperature, receiving the connection A31 in the form of crude syrupy product which is used without further purification.

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To mix the solution octene-1 (31,6, 0,287 mol, Aldrich chemical Co) in anhydrous tetrahydrofuran (250,0 ml) at 0oC in nitrogen atmosphere is added dropwise over 40 minutes add n-motility (163,5 ml, 0,315 mol). The solution is stirred for 1 h at 25oC, dropwise over 10 minutes add 1,3 - diiodopropane (103,0 g, 0,349 mol, Aldrich chemical Co.) and the resulting mixture is stirred for 20 hours of the Reacted mixture is diluted with of 250.0 ml of hexane and poured into 400,0 ml of ice water. The product is washed twice with 300 ml portions of a saturated aqueous solution of sodium chloride, dried over 500.0 g of sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on a column of silica gel (1.0 kg), elwira hexane. Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis.

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To a stirred solution of potassium cyanide (55,0 g,0,8456 mol, Aldrich chemical Co.) in dimethyl sulfoxide (750,0 ml) dropwise over 30 minutes add 135,0 g (0,485 mol) of the compound B1. Then the solution is stirred for 5 hours at 50oC, diluted of 250.0 ml of hexane, and mix of 250.0 ml of water. The organic layer is dried over 50.0 g of magnesium sulfate, filter and concentrate under reduced pressure at room temperature. The residue is purified on silica gel (2.0 kg) elwira a mixture of hexane:ethyl acetate (95:5 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, gives 51,4 g (0.29 mol) of the compound B2 (Rf:0.3, the ethyl acetate:hexane, 5:95 by volume) with a yield of 81%.

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Connection B2 (9,36 g, 0,053 mol) is dissolved in ethylene glycol (90,0 ml, Aldrich chemical Co.) to the resulting solution was added 8,89 g (0,158 mol) of potassium hydroxide (Fisher scientific). After 4 hour of stirring at 140oC and subsequent cooling to 25oC, the reaction mixture was diluted to 90.0 ml of water, and washed twice with 90 ml portions of dichloromethane. The aqueous layer was acidified with 200.0 ml of 1.0 hydrochloric acid, and extracted the product with hexane (250,0 ml). The extract is dried over 50 g of sulfasalizine B3 (Rf:0,2, hexane:ethyl acetate, 4:1 by volume) to yield 82%.

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To a solution of quinoline (10.0 ml, 0,084 mol) in hexane (190,0 ml) is added the compound B3 (20,0 g, is 0.102 mol) and Lindlar catalyst (i.e. 5% palladium on calcium carbonate mixed with lead, 86,0 g). The reaction mixture is stirred for 5 h in an atmosphere of hydrogen, filtered and evaporated. The residue was diluted with 10.0 ml of dichloromethane, alkalinized of 150.0 ml of IN sodium hydroxide solution and washed with water layer of 50.0 ml of dichloromethane. Then the aqueous layer was acidified to 20.0 ml of 6N hydrochloric acid and extracted with ethyl acetate (200.0 ml). The extract was washed with 200.0 ml saturated aqueous sodium chloride, dried over 100.0 g sodium sulfate, filtered and concentrated under reduced pressure, getting to 19.8 g (0.1 mol) of the compound B4 (Rf: 0,2, hexane:ethyl acetate, 4:1 by volume) to yield 98%.

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Compound B4 (23.7 g, B mol) and compound A4 (32,9 g, 0,107 mol) at 0oC dissolved in of 250.0 ml of anhydrous dichloromethane, and the resulting solution was added first, 0.03 g (0.2 mmol) 4-dimethylaminopyridine, and then 29,2 g (0,143 mol) of 1,3-dicyclohexylcarbodiimide. The solution was stirred at 25oC for 2.5 h, diluted (100 ml) with hexane, filtered and concentrate under reduced pressure at room temperature. OST is the solvent of the fractions, containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, gives of 48.7 g (0.10 mol) of the compound B5 (Rf:0,6 hexane:ethyl acetate, 4:1 by volume) to yield 84%.

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Compound B5 (16,1 g, 0,412 mol dissolved in 150,0 ml of glacial acetic acid and to this solution at 0oC added 24.2 g (0,370 mol) of a powder of metallic zinc. The reaction mixture is intensively stirred at 25oC for 40 min, diluted with 150,0 ml of ethyl acetate, filtered and concentrated under reduced pressure and room temperature. The residue is purified on a column of silica gel (1.0 kg) elwira a mixture of hexane:ethyl acetate (9:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, gives 10.8 g (0.04 mol) of the compound B6 (Rf:0,3, hexane:ethyl acetate, 4:1 by volume), with a yield of 96%.

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To 101.0 g (1.54 mol) of activated zinc, suspended in boiling under reflux in anhydrous tetrahydrofuran (500 ml) add 3.0 ml of ethylbromoacetate and 67.5 ml (0,308 mol) of undecylenic (one portion, Aldrich chemical Co. ). To the mixture is added dropwise within 3 h add 134,0 atory and stop the reaction by slow addition of 160,0 ml of a saturated aqueous solution of potassium carbonate. The resulting heterogeneous mixture was intensively stirred for 30 min, and then filtered through 500.0 g Celite 545, getting a clear yellow solution of the crude complex raminosoa ether. The solution is acidified 300,0 ml of 1.0 N hydrochloric acid, stirred for 3 h, saturated aqueous sodium hydrogen carbonate solution. Then the organic layer was washed with 400,0 ml of a saturated aqueous solution of sodium chloride, dried over 1.0 kg of sodium sulfate, filter and concentrate under reduced pressure. The residue is purified on silica gel (1.0 kg), elwira a mixture of hexane: ethyl acetate (6:1 by volume) and receive of 80.6 g (0,298 mol) of the compound C1 (Rf: 0.7 to hexane:ethyl acetate, 4:1 by volume) to yield 97%.

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Polytrimethylene complex [R] -2,2'-bis(diphenylphosphino)-1,1'-unaffiliated receive, in the form of a clear orange-brown solution of [R]-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and cyclooctatetraene, as described above.

The solution 311,0 g (1.15 mol) of the compound C1 in 330,0 ml of anhydrous methanol obzharivayut from dissolved oxygen by using three freeze - thawing with liquid nitrogen in the atmosphere of nitrogen gas. To the solution containing the compound C1, using a syringe add rest is lsua catheter, the reaction mixture in an argon atmosphere into purged with argon bomb hydrogenation containing 3.0 g washed with methanol and ion-exchange resin Dowex 50X8-200 H+. In the bomb serves hydrogen to a pressure of 100 ATM, and the reaction mixture is stirred at 25oC for 66 hours When the pressure drops to 20 ATM, the excess hydrogen produced, the reaction mixture is filtered, and vacuum to remove volatile components, receiving 310,2 g (1,14 mol) of the compound C2 with a yield of 99%.

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Connection C2 (94,4 g, 0,347 mol) is dissolved in tetrahydrofuran (800,0 ml) and to this solution was added a 2.5 M aqueous solution of sodium hydroxide (300,0 ml, 0.75 mol). The resulting mixture was intensively stirred at 25oC in nitrogen atmosphere for 1.5 hours. The reaction mixture was diluted with 1.0 l of a mixture of diethyl ether:hexane composition of 1:1 (by volume) and the aqueous layer was separated. The organic phase is then extracted with 200.0 ml of water, the aqueous phases are combined and acidified to 20.0 ml of hydrochloric acid. Then the acidified mixture is extracted with 2.0 l of diethyl ether, washed first extract 1.0 l of water, then of 500.0 ml of a saturated aqueous solution of sodium chloride and dried over 200,0 g of magnesium sulfate. Under reduced pressure at room temperature to remove the solvent, and the resulting Serov is dobavlaut dicyclohexylamine a (80.0 ml, 0.40 mol) and cooled the mixture to -20oC, receiving 102,1 g (0.24 mol) of the compound C3 (Rf: 0,38, hexane:ethyl acetate:glacial acetic acid, 1:1:0.1 volume), in the form of fine white needles, with 71% yield.

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At 0oC in nitrogen atmosphere suspended in 2.0 l of ethyl acetate connection C3 (102,0 g, 0.24 mol). To the suspension is added first to 37.2 g (369,0 mmol) of triethylamine, then 48,9 g (246,0 mmol) of 2-bromoacetophenone (one portion). After 3 h the reaction mixture was warmed to room temperature and stirred for further 6 hours Then the reaction mixture was subjected to vacuum filtration. The residue is washed 400,0 ml of ethyl acetate. The filtrate is washed first of 500.0 ml of 0.8 M hydrochloric acid, then of 500.0 ml of water and, finally, 200.0 ml saturated aqueous sodium chloride solution and dried over 300,0 g of magnesium sulfate. In vacuum at 50oC the solvent is evaporated, getting gray frozen solid, which is recrystallized from 1.1 l of hexane and dried in vacuum at 50oC, receiving 81,09 g (223,9 mmol) of compound C5 (Rf: 0,65, chloroform: methanol, 95:5 by volume), in the form of a whitish solid with a yield of 91%.

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To a suspension of 2.5 g (9,18 mmol) C4 and 1.0 g of molecular sieves 4A of 28.0 ml of a mixture of hexane:dichloromethane composition 3:1 (by volume) in atmospheres J. Org. Chem. 1989 54:3738). The reaction mixture was cooled to 0oC and added dropwise 63,0 μl (0.51 mmol) of epirate boron TRIFLUORIDE. After 5 min the reaction is stopped by 2.0 ml of saturated aqueous sodium bicarbonate solution, and heated the reaction mixture to 25oC. the mixture is Then extracted to 100.0 ml of ethyl acetate, washed with a 50.0 ml of a saturated aqueous solution of floridante, dried over 50.0 g sodium sulfate, filtered, and removed solvent under reduced pressure at room temperature. The residue is purified on a column of silica gel (300,0 g), elwira a mixture of ethyl acetate: hexane (1: 9 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, gives 3.1 g (of 7.97 mmol) of compound C5 (Rf:0,7, ethyl acetate:hexane, 3:17 by volume) with the release of 87%.

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Compound C5 (3.1 g) was dissolved in tetrahydrofuran (30,0 ml) and to this solution was added to 16.0 ml (40.0 mmol) of a 2.5 M solution of sodium hydroxide. The reaction mixture was stirred at 25oC for 6 days, dilute to 100.0 ml of hexane and bring the pH to 5.0 to 40.0 ml of 1N hydrochloric acid. Then the reaction mixture is shaken out of 300.0 ml of ethyl acetate, washed with a 100.0 ml saturated aqueous raii and room temperature. The residue is purified on a column of silica gel (300,0 g), elwira a mixture of methanol: chloroform with a gradient from 3:17 (by volume) to 1:6 (by volume). Each gradient mixture also contains 2 drops of glacial acetic acid in 100.0 ml of solvent. Gain of 1.46 g (4.0 mmol) of the compound C6 (Rf:0,14, hexane: ethyl acetate, 2:1 by volume) to yield 50%.

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Connection C1 (2,04 g of 7.96 mmol) was dissolved in 25,0 ml of dry diethyl ether. To this solution at 0oC in nitrogen atmosphere add 1,3-propanedithiol (10,8 ml of 7.97 mmol, in one piece, Aldrich chemical Co.). Then dropwise over 2 min add 1.0 ml (8,13 mmol) epirate boron TRIFLUORIDE. The reaction mixture was stirred at 0oC for 30 min at room temperature for 48 h, poured into saturated aqueous sodium bicarbonate solution (200.0 ml) and stirred for further 30 minutes the Solution is shaken out three times with 50 ml portions of hexane. The combined organic fractions washed to 50.0 ml of a saturated aqueous solution of sodium chloride, dried over 50.0 g of Sultana magnesium, filtered and concentrated under reduced pressure and room temperature. The product was then purified on a column of silica gel (200,0 g) elwira 2.0 l of a mixture of ethyl acetate:hexane gradient from 0:100 to 5-95 by volume). Fractions containing the PTS is P CLASS="ptx2">

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Compound C7 (2,88 g, 8,01 mmol) dissolved in tetrahydrofuran (20,0 ml) and to this solution was added 10.0 ml of 2.5 M aqueous solution of sodium hydroxide. The reaction mixture is heated to 100oC, stirred for 16 h, cooled to room temperature, the pH adjusted to 2.0 10.0 ml of 1.0 N hydrochloric acid and extracted with 200.0 ml of ethyl acetate. The organic layer was washed with a 50.0 ml of a saturated aqueous solution of sodium chloride, dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. Clean finish on a column of silica gel (300,0,), elwira first 1.0 l of a mixture of hexane:ethyl acetate (4:1 by volume), and then 1.0 l of a mixture of chloroform: methanol: glacial acetic acid (9:1:0.1). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, give 2.10 g (6,33 mmol) of compound C8 (Rf:0,20, hexane:ethyl acetate, 2:1 by volume) to yield 79%.

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To a mechanically stirred suspension 1004,0 g (15,4 mol) of activated powdered zinc in 2.5 l of anhydrous tetrahydrofuran under nitrogen atmosphere at room temperature dropwise within 10 min add 30,0 ml (0,1,25 mol) of n-undecylenic (Aldrich chemical Co.) and within 4 hours add a 1.00 l (6.3 mol) of benzylbromide (Aldrich chemical Co.). After boiling under reflux for a further 1 h the reaction mixture was cooled to room temperature and slowly poured into 3.0 l of stirred saturated aqueous solution of potassium carbonate. To the resulting solution was added to 1.0 kg of Celite 545 and the filtered heterogeneous mixture through 200,0 g Celite 545, elwira four 1-l portions of ethyl acetate. The filtrate is separated and the aqueous layer was extracted with two 500-ml portions of ethyl acetate. The combined organic layers are washed of 500.0 ml of a saturated aqueous solution of sodium chloride, dried over 100 g of Sultana sodium, filtered and concentrated to dryness in vacuo. The crude orange oil intensively stirred for 3 h at room temperature in two-phase system consisting of 1.0 l of hexane and 1.0 l of 1.0 N hydrochloric acid, dropwise adding to the system 80 ml of concentrated hydrochloric acid. After stirring the obtained heterogeneous solution for 20 min, the layers separated and the aqueous layer was extracted with two 200-ml portions of hexane. The combined organic layers washed first of 500.0 ml of a saturated aqueous solution of sodium bicarbonate, then of 500.0 ml of a saturated aqueous solution of sodium chloride, dried over 100 g of sodium sulfate, filter and concentrate Dosh is 9:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature and drying in vacuum at room temperature over night give 884,7 g (2,66 mmol) of compound D1 (Rf:0,67, hexane:ethyl acetate, 4:1 by volume) as a yellow solid with a yield of 82%.

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To a stirred solution of 17.9 g (53,9 mmol) of the compound D1 in 110,0 ml of methanol in an atmosphere of argon added 20% palladium hydroxide on coal (Aldrich chemical Co. ). The resulting suspension is rinsed three times with hydrogen and pumped, and then stirred for 1 h at room temperature under atmospheric pressure of hydrogen. The reacted reaction mixture is diluted with 100 ml dichloromethane, filtered through a 50.0 g of Celite 545 and the filtered solid residue is washed with two 50-ml proportions dichloromethane. The United filtrates are concentrated under reduced pressure and room temperature. The crude product quick clean on 200,0 g silica gel, elwira 2.0 l of a mixture of chloroform: methanol (9:1 by volume). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature the ethanol:acetic acid, 9:1:0.1) as a white solid with a yield of 85%. In order to avoid decomposition of the compound D2 was immediately used in the next reaction.

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To intensively mix the solution 1000,0 g (9,42 mol) methylthiopyridine (Aldrich chemical Co.) in 2.0 l of anhydrous tetrahydrofuran at 0oC in nitrogen atmosphere add 1312,0 ml (9,14 mol) of triethylamine, and then dropwise within 12 h add 2138,0 ml (9,42 mol) 1-iododecane (Aldrich chemical Co). The reaction mixture is heated to room temperature, stirred for further 24 h, diluted with 2.0 l of ethyl acetate, and washed first with 1.0 l of 1.0 N hydrochloric acid, then 1.0 l of a saturated aqueous solution of sodium bicarbonate and, finally, 1.0 l of a saturated aqueous solution of sodium chloride. The organic layer is dried over 500.0 g of sodium sulfate, filter and concentrate under reduced pressure at room temperature, receiving 2230,0 g of compound E1 (Rf: 0,69, hexane:ethyl acetate, 4:1 by volume), which is used in the next stage without additional purification.

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To mix the solution 2100,0 g (8,07 mol) of the crude compound E1 5.2 l of acetone and 5.2 l of water at -10oC portions over 3 hours add 5,0 kg (8,13 mol) peroxymonosulfate potassium (OXO E, is slowly quenched at 0oC 3,0 l 3,0 OHM aqueous solution of sodium thiosulfate. The mixture was diluted with 8.0 l of dichloromethane and 4.0 l of water, filtered through 500.0 g Celite 545 and the filtered solid is washed with three 500 ml portions of chloroform. The United filtrates washed first with 10.0 l of a saturated aqueous solution of sodium bicarbonate, then 20,0 l of a saturated aqueous solution of sodium chloride, dried the organic layer over 2.5 kg of sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The crude product is obtained by washing the obtained solid with 8.0 l of hexane and get 1541,0 g (5,58 mol) of the compound E2 (so pl. 62,6 - 63,5oC, Rf: 0,2, hexane: ethyl acetate, 1:1 by volume) as a white solid with a yield of 69:.

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To stir the mixture 1644,0 g (5,95 mol) of the compound E2 in 6.0 liters of toluene and 48.0 l aqueous solution of 0.05 M phosphate buffer at room temperature add 12,0 lipase (PS-800, Amano was INTL. Enzyme Co., Troy, Virginia). The reaction mixture was stirred 24 h at room temperature, add another 11.9 Gipsy (PS-800), and the resulting suspension stirred for 96 hours the resulting mixture was acidified with 6.0 liters of chloroform and separated layers. The aqueous layer was extracted with five 1 liter portions of chloroform, the United organomercury. The crude product is suspended in 6.0 liters of ethyl acetate, heated to 60oC, cooled to room temperature, filtered and the resulting solid product is washed with two 500-ml portions of ethyl acetate. The crude solid product is recrystallized twice from 10,0 l of ethyl acetate, getting 305,0 g (1,16 mol, so pl. 80,4 - 81,8o(C) E3 connection with the release of 19.5%. United uterine fluid is concentrated under reduced pressure at room temperature and purified by 2.0 kg of silica gel, elwira first 4,0 l of hexane, then 6.0 liters of a mixture of hexane:ethyl acetate (4:1 by volume), then 4,0 l of chloroform and, finally, of 10.0 l of a mixture of chloroform:methanol:acetic acid (9:1:0.1). Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure at room temperature, and dried in vacuum at room temperature over night give 90.0 g (0.34 mol, the yield of 5.8%) of compound E3 (Rf: 0,12, chloroform: methanol:acetic acid, 9:1:0.1 volume), of 300.0 g of a mixture of E3 and E4, and 500.0 g (1,81 mol, the yield of 30.4%) E4 (Rf:0,63, Chloroform:methanol:acetic acid, 9:1:of 0.1 by volume).

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To a solution of 500.0 g (1,81 mol) of the compound E4 5.0 l of methanol PI room temperature was added dropwise a 2.0 l 2.0 N aqueous rostislaw to pH 2.0 to 3,0 2,0 l 2,0 N hydrochloric acid and diluted with 4.0 l of chloroform. The layers are separated and the aqueous layer was extracted with three 1 liter portions of chloroform. The combined organic layers dried over 500.0 g of sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The crude solid product is recrystallized four times from 6.0 liters of ethyl acetate, getting 167,0 g (0.64 mol, so pl. 81,2 - 82,1oC) pure compound E5 (Rf:0,12, chloroform:methanol:acetic acid, 9:1:0.1 volume) with the release of 35.2%. The concentration of the fallopian solutions at reduced pressure and room temperature get more of 250.0 g of the crude E5.

.

To a stirred solution of 1.07 g (of 3.85 mmol) of the crude compound E1 20,1 ml of anhydrous dichloromethane at 0oC portions over 10 min add 2.86 g (7.7 mmol) of 3-chloroperoxybenzoic acid. The mixture is stirred for 1 h slowly quenched at 0oC 10.0 ml of 3.0 M aqueous solution of sodium thiosulfate. The mixture is then diluted to 100.0 ml dichloromethane, the organic layer washed to 100.0 ml saturated aqueous sodium bicarbonate solution, and 100.0 ml of a saturated aqueous solution of sodium chloride, the organic layer dried over 100.0 g sodium sulfate, filtered and concentrated under reduced dmol) connection E6 (Rf:0,67, hexane:ethyl acetate, 1:1 by volume).

.

To a solution of 970,0 mg (3:32 mmol) of compound E6 in 15.0 ml of methanol at room temperature, add 4.0 ml of 1.0 N aqueous solution of sodium hydroxide. The mixture is stirred for 1 h, then acidified with her 4,0 ml of 2.0 N hydrochloric acid. The final mixture is diluted to 100.0 ml of chloroform, the layers separated and the aqueous layer was extracted with three 100-ml portions of chloroform. The combined organic layers dried over 100.0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The crude solid connection E7 used without further purification.

.

To a mechanically stirred, boiling under reflux the suspension of 5.5 g (84,1 mmol), activated powdered zinc in 50 ml of anhydrous tetrahydrofuran is added dropwise within 1 min in nitrogen atmosphere add 1.0 ml (9.0 mmol) of ethylbromoacetate. Then one portion add 3.0 g (to 16.9 mmol) of the compound B2, then drop by drop in techeye 45 min type of 7.4 ml (66,7 mmol) ethylbromoacetate. After 10 min of boiling under reflux, the reaction mixture was cooled to room temperature, diluted with 170,0 ml tetrahydrofuran and quenched by adding dropwise within 10 min of 22.0 ml of a 50% identification cease, decanted tertrahydrofuran ring solid solution with zinc, and washed solid zinc four 50-ml portions of tetrahydrofuran. Received containing product solutions are combined and intensively stirred from 17.0 ml of 1.0 N hydrochloric acid for 2 hours , and concentrated in vacuo at room temperature. The residue is dissolved in a 50.0 ml saturated aqueous sodium bicarbonate solution, dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The crude product is purified on 200,0 g silica gel, elwira 3.0 l 10:1 (by volume) mixture of hexane:ethyl acetate. Evaporation of the solvent from fractions containing the product (identified by thin layer chromatographic analysis) under reduced pressure and room temperature, and drying in vacuum at room temperature overnight to give to 3.52 g (13,2 mmol) G1 (Rf: 0,65, hexane:ethyl acetate, 4:1 by volume) as a clear colorless oil with a yield of 78.2%.

.

To a stirred solution of 1.5 g (5,64 mmol) G1 7.0 ml of anhydrous diethyl ether and 434,0 ál (from 6.22 mmol), mercaptoethanol (Aldrich chemical Co.) at 0oC in nitrogen atmosphere is added dropwise over 5 min add 762,0 ál (6.20 mmol) of epirate TRIFLUORIDE Bo the n aqueous solution of sodium bicarbonate, and stirred for further 5 minutes the mixture is extracted with three 50-ml portions of ethyl ether, the combined organic layers mix of 50.0 ml of a saturated aqueous solution of sodium chloride, dried over 50.0 g sodium sulfate, filtered and concentrated under reduced pressure and room temperature. The crude product is dissolved in of 14.0 ml of tetrahydrofuran, mixed with 7.0 ml of 2.5 M aqueous solution of sodium hydroxide and 16 hours stirred at 80oC. the Final reaction mixture is cooled to room temperature, extracted with three 10-ml portions of diethyl ether and acidified aqueous layer to pH of 2.0 and 1.0 N hydrochloric acid. The resulting aqueous suspension is extracted with three 10-ml portions of diethyl ether, the combined organic layers washed with 10.0 ml of a saturated aqueous solution of sodium chloride, dried over 20,0 g sodium sulfate, filtered, concentrated under reduced pressure at room temperature and dried in vacuum at low temperature during the night, getting 1.40 g (to 4.68 mmol) of the crude compound G2 (Rf:0,6 hexane) to yield 83%. The product is used without further purification.

The following is a characterization of the described compounds and a description of the analyses used to test oharakterizoval connections.

Connection 2.

1H NMR (CDCl3) Delta: between 6.08 M. D. (1Halphad, J=1,71 Hz), and 5.8 (1Hbeta, d, J=1,22 Hz), 5,48-5,10 (3H, m), 4,32-of 3.80 (3H, m), 2,33-1,92 (15H, m C.).

Connection 3.

1H NMR (CDCl3) Delta: 7,52-7,30 M. D. (5H, m), 5,52 (2H, d), 5,32 (2H, m), br4.61 (1H, m) to 4.33 (1H, DD), of 4.12 (1H, DD), to 2.18 (3H, s), is 2.09 (3H, s), is 2.05 (3H, s) 2,03 (3H, s).

Connection 4.

1H NMR (CD3D) Delta: of 7.48-7,12 M. D. (5H, m), the 5.51 (1H, s), 4,20 (1H, s), was 4.02 (1H, s), 3,97-3,68 (4H, m).

Connection 5.

1H NMR (CDCl3) Delta: 7,49-7,39 M. D. (5H, m), 5,78 (1H, s), 4,39 (1H, d), 4.26 deaths (1H, DD), to 4.01 (1H, DDD), 3,81 (1H, DD), of 3.77 (2H, m), of 1.52 (3H, s) of 1.50 (3H, s) of 1.43 (3H, s) to 1.37 (3H, s).

Connection 6.

1H NMR (CDCl3) Delta: 6,30 m D. (1H, DD, J=1,50, 6,11 Hz), 4.72 in (H, DD, J= 1,79, 6,07 Hz), 4,34 (1H, d, J=7,39 Hz), of 3.94 (1H, DD, J=5,48, 10,92 Hz), 3,84-3,71 (3H, m) of 1.53 (3H, s) of 1.43 (3H, s).

Connection 7.

1H NMR (CDCl3) Delta: 6,33 M. D. (1H, DD, J=1,46, 6,1 Hz), 5,32 (1H, dt, J= 1,7, 1,7, 7,8 Hz), was 4.76 (1H, DD, J=2.0 a, 6,1 Hz), a 4.03 (1H, DD, J=1,71, 7,81 Hz), of 3.97 (1H, m), a 3.87 is 3.76 (2H, m), is 2.09 (3H, s), of 1.52 (3H, s) of 1.41 (3H, s).

Connection 8.

Rf0.21 methanol : chloroform, 5:95 (about./vol.).

1H NMR (CDCl3) Delta: 5,61 M. D. (1H, d, J=8,79 Hz), 5,13 (1H, t, J=9.5 Hz), 3,91 (1H, DD, J=lower than the 5.37, 10,98 Hz in), 3.75 (1H, t, J=9.5 Hz), 3,91 (1H, DD, J=9,76 Hz), of 3.56 (1H, DD, J=8,79, 9,52 Hz), 3,49 (Nata, t, J=10.0 Hz), of 5.34 (1Halpha, t) 5,00 (1Hbeta, t, J=9.7 Hz), 4,78 (1Halpha, DD, J=5,1, 7,8 Hz), 4.04 the-to 3.64 (m), 3,41-3,23 (m) a 2.12 (3H, s) of 1.45 (3Halphawith), the 1.44 (3Halpha, C) of 1.39 (1Hbeta, C) of 1.35 (3Hbetawith).

Compound 10A.

1H NMR (CDCl3) Delta: 8,78 ppm (1H, d, J=3,9 Hz), of 5.48 (1H, t, J=9,52 Hz), 3.95 to 3,86 (2H, m), 3,82-with 3.79 (2H, m) and 3.59 (1H, DD, J=3,67, with 10.3 Hz), of 2.15 (3H, s) of 1.47 (3H, s) of 1.39 (3H, s).

Compound 10b.

1H NMR (CDCl3) Delta: 8,80 m D. (1H, s), 5,88 (1H, d, J=7,09 Hz), 5,09 (1H, t, J=10.0 Hz), 3,95 (1H, DD), of 3.75 (2H, m), 3,48 (1H, DDD), was 2.05 (3H, s), by 1.68 (3H, s) of 1.39 (3H, s).

Compound 11a.

1H NMR (CDCl3) Delta: 7,43 M. D. (1H, m), 6,76 (2H, m), 5,46 (1H, t), at 4.99 (1H, d), and 4.75 (1H, d), 4,70 (1H, d), 4,51 (1H, t), of 3.97 (3H, s) of 3.94 (3H, s), 3,81 (1H, m), 3,76 (1H, m), 3,10 (1H, DD), 2,10 (3H, s) of 1.46 (3H, C) to 1.35 (3H, s).

Compound 11b.

1H NMR (CDCl3) Delta: 6,95-6,80 m D. (3H, m), of 5.92 (1H, t, J=10.0 Hz), is 4.85 (1H, d), br4.61 (1H, d), 4,50 (1H, d, J=8.0 Hz), 3,95 (1H, DD), 3,88 (1H, t, J=10.4 Hz), 3,80 (1H, t, J=9,3 Hz), 3,63 (1H, t, J=9.0 Hz), of 3.46 (1H, DD, J=9,0, 10,0 Hz), 3,29 (1H, m), 2,11 (3H, s) of 1.46 (3H, s) of 1.35 (3H, s).

The connection 12.

1H NMR (CDCl3) Delta: 6,98-6,84 M. D. (3H, m), a 4.86 (1H, d), to 4.62 (1H, d), to 4.46 (1H, d), of 3.96 (1H, DD), 3,90 (6H, s), 3,83 (1H, t), of 3.60 (1H, t), 3,50 is 3.40 (2H, m), 3,23 (1H, m), of 1.52 (3H, s) of 1.42 (3H, s).

The connection 13.

1H NMR (CDCl3)50 (1H, d, J=7,81 Hz), 3,95 (1H, DD, J=5,35, 10,99 Hz), 3,88 (3H, s), a 3.87 (3H, s), with 3.79 (1H, t, J=4,88 Hz), 3,62 (1H, t, J= 9,77 Hz), 3,21 (1H, m), 2,78 (1H, m), 2,62 (1H, m), 1,7-1,56 (m) of 1.45 (3H, s) of 1.35 (3H, C), 1,27-1,24 (m) 0,86 (3H, t).

The connection 14.

1H NMR (CDCl3) Delta: 6,98-6,82 M. D. (3H, m), 5,91 (1H, m), lower than the 5.37 (1H, DD), from 5.29 (1H, d), 5,10 (1H, m), 4,88-rate 4.79 (2H, m), 4,68-4,60 (2H, m), 4,50 (1H, d), of 3.94 (1H, m) to 3.89 (3H, s), 3,88 (3H, s), a-3.84 (1H, m) to 3.64 (1H, m), 3,48-to 3.35 (2H, m), 2,75-2,62 (2H, m), 1,80-of 1.62 (2H, m), 1,42-1,20 (m) 0,86 (3H, t).

The connection 15.

1H NMR (CDCl3) Delta: 6,95-for 6.81 M. D. (3H, m), 5,90 (1H, m), to 5.35 (1H, DD, J= 1,46, 17,33 Hz), and 5.30 (1H, DD, J=1,22, 10,49 Hz), to 5.08 (1H, m) a 4.86 (1H, d, J=11,47 Hz), 4,82 (1H, t, J=9.1 Hz), 4,60 (3H, m), 4,43 (1H, d, J= 7,65 Hz), 3,91 (1H, m), 3,88 (3H, s), a 3.87 (3H, s), 3,52 (1H, dt, J=2,0, 9.28 are, 9.28 are Hz), 3,42 (1H, DD, J=8,05, 10.5 Hz), the 3.35 (1H, m) of 2.75 (1H, DD, J=EUR 7.57, 15,39 Hz) to 2.66 (1H, DD, J=4,88, 15,38 Hz), 1,78-of 1.62 (m), 1,40-1,20 (m), of 0.91 (9H, s) 0,86 (3H, t), of 0.10 (3H, s), and 0.09 (3H, s).

The connection 16.

1H NMR (CDCl3) Delta: 6,94-6,82 M. D. (3H, m), 5,99 of 5.84 (2H, m), 5,33 (2H, m), 5,26 (2H, m), is 5.06 (1H, m) 5,00 (1H, t), 5,88 (1H, d), of 5.81 (1H, t), 4,66-4,56 (5H, m), of 4.44 (1H, d, J=8,05 Hz), 3,88 (3H, s), a 3.87 (3H, s), of 3.80 (1H, m), 3,56-of 3.48 (2H, m), 2,71 at 2.59 (2H, m), 1,65(m), 1,49-1,29(m) of 0.90 (9H, s), 0,89 is 0.86 (3H, m) 0,86 (6H, s).

Connection 17.

1H NMR (CDCl3) Delta: 6,94-6,82 M. D. (3H, m), 5,95 and 5.86 (2H, m), are 5.36 (2H, d), a 5.25 (2H, t), 5,04 (2H, m), 4,62 (5H, m), 4,50 (1H, d, J=8,05 Hz), 3,88 (3H, s), a 3.87 (3H, s), a-3.84 (1H, m) to 3.67 (1H, DD, J=4,15, a 12.7 Hz), of 3.48 (1H, m), 2,72-2,60 (2H. 3H, m), of 5.39 (1H, m), and 5.30 (1H, m), 5,20 (1H, m), the 4.90 (1H, t), 4,84 (1H, d), br4.61 (1H, d), 4,51 (1H, d), of 3.96 (1H, DD), to 3.89 (3H, s), 3,88 (3H, s), 3,80 (1H, t), the 3.65 (1H, t), of 3.46 (1H, DD), 3,29 (1H, m), 2,69 (1H, DD), 2,58 (1H, DD), 2,28 (1H, t), 2,10 is 1.96 (2H, m), 1,72 is 1.58 (2H, m) of 1.42 (3H, s) of 1.35 (3H, s), 1.32 to-1,18 (m), 0,89-of 0.82 (6H, m).

Connection 19.

1H NMR (CDCl3) Delta: 6,98-6,82 M. D. (3H, m), 5,42 (1H, m), and 5.30 (1H, m), 5,12 (1H, m), 4,88 (1H, d), 4,82 (1H, t) and 4.65 (1H, d), of 4.49 (1H, d), of 3.94 (1H, m), 3,90 (3H, s) to 3.89 (3H, s), 3,83 (1H, m), 3,60 (1H, t), of 3.46-to 3.35 (2H, m), is 2.30 (2H, t), 2,09-to 1.98 (4H, m), 1,67(m), 1,40-1,22(m), 0,91-of 0.85 (6H, m).

The connection 20.

1H NMR (CDCl3) Delta: 6,94-for 6.81 M. D. (3H, m) 5,94 (1H, m), 5,39-of 5.26 (4H, m), 5,13 (1H, m), a 4.86 (1H, d), 4,79 (1H, m), 4,68-4,59 (m) to 4.52 (1H, d), 4,42 (2H, m), 3,88 (3H, s), a 3.87 (3H, s), 3,52 (2H, m), of 3.45 (1H, t, J= 8,06 Hz), 2,60 (2H, m), is 2.30 (2H, t), 2,10-of 1.95 (4H, m), 1.70 to 1,53 (m), 1,40-1.27mm (m), 0,88-0,84 (6H, m).

Connection 21.

1H NMR (CDCl3) Delta: 6,94-6,80 m D. (3H, m), 5,97-of 5.83 (3H, m), 5.40 to-5,22(8H, m), 4,96 (1H, DD, J=9.28 are, 10,26 Hz), 4,84 (1H, d, J=11,48 Hz), 4,68-4,29 (11H, m) a 3.87 (3H, s), 3,86 (3H, s), of 3.60 (1H, m), 3,49 (1H, DD, J= 8,06, 10,26 Hz), of 2.68 (2H, t), and 2.26 (2H, K), 2,08-1,90 (4H, m), 1.70 to 1,65 (m), 1,32-1,18 (m) is 0.84 (6H, m).

The connection 22.

1H NMR (CDCl3) Delta: 5,95 of 5.84 M. D. (3H, m), 5,59 (1HBetat), 5,40-to 5.21 (9H, m), of 5.03 (1Ht), 4,76-4,22 (10H, m), 3,42 (1HBeta, DD, J= 8,05, 10.5 Hz), 3,20 (1HAlpha, DD, J=3,17, 10.5 Hz), was 2.76-2,62 (2H, m), 2,30-of 2.23 (2H, m), 2,09-of 1.95 (4H, m), 1.70 to 1,65(m), 1,35-1,18(), 5,96 of 5.84 (3H, m), to 5.57 (1H, DD, J=9,03, a 10.74 Hz), 5,41-5,22 (9H, m), 4,60 was 4.42 (8H, m), 4,32 (1H, DD, J=3,91, of $ 11.97 Hz), 4,18 (1H, d, J=8,79 Hz) to 3.58 (1H, DD, J=3,0, 10,0 Hz), 2,80-to 2.67 (2H, m) to 2.29 (2H, t), 2.06 to 1,95 (4H, m), 1.70 to 1,59 (m), 1,35-1,25 (m), 1,81-1,90 (6H, m).

Compound 23B.

1H NMR (CDCl3) Delta: 8,80 m D. (1H, s), 5,98-of 5.82 (3H, m), 5,72 (1H, d), 5,42-5,22 (9H, m), of 5.15 (1H, t), 4,62-to 4.41 (8H, m) to 4.23 (2H, m), and 3.72 (1H, t), 2,81 of 2.68 (2H, m), is 2.30 (2H, m), 2,10 is 1.96 (4H, m), 1,71-of 1.52 (m), 1,37-1,15 (m) to 0.88 (6H, m).

The connection 24.

1H NMR (CDCl3) Delta: 5,95-5,86 M. D. (3H, m), 5,99-of 5.83 (5H, m), 5.40 to-5,22 (12H, m), 5,10-5,22 (2H, m), 4,91 (H, d, J=10,7 Hz), and 4.68 (1H, DD), with 4.64-4,43 (10H, m) 4,333 (1H, K), 4,27 (H, DD, J=4,9, to 12.8 Hz), 4,00 (1H, d, J=9.9 Hz), with 3.89 (3H, s), 3,88 (3H, in), 3.75 (2H, m), of 3.60 (1H, m), of 3.54 (1H, DD, J=7,9,9,8 Hz), 3,47 (1H, DD, J=8,6, and 11.0 Hz), 2,78-of 2.58 (4H, m), 2,30-of 2.23 (2H, t), 2,03-of 1.95 (4H, m), 1.70 to to 1.59 (2H, m), 1,39-1,25(m), 0,90-of 0.82 (9H, m).

The connection 25.

1H NMR (CDCl3) Delta: 7.23 percent, M. D. (1H, m), 6,92-PC 6.82 (2H, m), 5,98-5,85 (5H, m), 5.40 to-to 5.21 (12H, m), 5.08 to 4,99 (2H, m), is 4.85 (1H, m), 4,62 was 4.42 (10H, m), of 4.38-to 4.23 (2H, m) to 3.89 (6H, s), 3.75 to 3,61 (2H, m), 2,96 (1H, DD), of 2.72 (1H, DD), 2,61 (2H, m), 2,29-of 2.15 (2H, m), 2,02-of 1.94 (4H, m), 1.70 to 1.52m (m), 1,38-1,20 (m), 0,91-of 0.82 (9H, m).

The connection 26.

1H NMR (CDCl3) Delta: 7,29 M. D. (2H, d), 7,16 (2H, d), 6,91-6,85 (7H, m), 6,40 (1H, d), between 6.08 (1H, d), 5,98-5,85 (5H, m), 5.40 to-5,15 (13H, m), 5,07 (1H, t), to 4.98 (1H, m), 4,76-to 4.23 (m), 3,98 (1H, K), of 3.84 (3H, s), 3,83 (2H, m), 3,82 (3H, s), with 3.79 (3H, s), of 3.77 (3H, s), 3,82 (3H, m), 3,60-3,50 (2H, m), 2,70-to 2.42 (4H, m), a 2.36-2,22 (4H, m),6,35 M. D. (1H, d), 5,98-of 5.82 (5H, m), 5,44-to 5.21 (13H, m) 5,00 (1H, m), 4,94 (1H, d), 4,68-4,48 (m), 4,32 (1H, DD), 4.26 deaths-to 4.15 (2H, m) 4,00 (1H, m), 3,92-3,82 (2H, m), 3,79-the 3.65 (2H, m) to 3.58 (1H, DD), 2,68-2,49 (4H, m), 2,41-2,22 (6H, m), 2,09-of 1.97 (4H, m), 1.70 to 1,19 (m), 0,91-0,80 (15H, m).

The connection 28.

1H NMR (CDCl3) Delta: 6,80 m D. (1H, d, J=8,2 Hz), of 6.52 (1H, d, J=7,6 Hz), 6,01 of 5.84 (5H, m) 5,72 (1H, DD, J=2.7, and 5.4 Hz), the 5.45-5,17 (13H, m), 5,02-of 4.90 (2H, m), 4,94 (1H, d, J=8.1 Hz), 4,67-4,33 (m), 4,39-to 4.28 (3H, m), of 4.12 (1H, m), 3,99-of 3.85 (3H, m), 3,89-3,68 (4H, m), 2,64-2,52 (4H, m), a 2.36-2,12 (6H, m), 2,10-of 1.95 (4H, m), 1.70 to 1,15 (m), 0,91-0,81 (15H, m).

The connection 29.

1H NMR (CDCl3) Delta: 7,30 m D. (1H, d), 6,55 (1H, d), 6,00-5,85 (5H, m), 5,78 (1H, DD), 5,44-5,19 (13H, m), 5,10-4,82 (3H, m), 4,67-4,46(m) of 4.38-to 4.28 (2H, m), is 4.15 (1H, m), 4,00-3,86 (2H, m), 3,86-of 3.60 (m), 3,40-33,34 (4H, m), 2,66-to 2.42 (6H, m), 2,37-2,22 (6H, m), 2,08 is 1.96 (4H, m), 1,69-1,20(m), 0,87(15H, m).

The connection 30.

1H NMR (CDCl3) Delta: 7,38 M. D. (1H, d), to 7.09 (1H, d), 6,00-of 5.83 (5H, m), 5,71 (1H, m), 5,43-5,19 (13H, m), free 5.01 (1H, m), to 4.87 (2H, m), 4,68-of 4.44 (m), 4,40-4,36 (m) 4,18 (1H, m), 3,93 (1H, DD), 3,76 (1H, K), 3,71-3,62 (2H, m) to 3.38 (2H, K), of 3.32 (2H, K), 2,68-to 2.41 (8H, m), 2,28-of 2.20 (2H, t), 2,07-of 1.95 (4H, m), 1,68 is 1.48 (m), 1,35-1,12 (m), 0,90-0,81(15H, m).

Analog B214 (Compound 31).

Rf0,43, chloroform : methanol : acetic acid : water, 125:75:10:20 (vol./about./vol.).

Retention time (ghvd) 12,22 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 5,40 m D. (1H, m) to 5.17 (1H, m), 5,09 (1H, SUB>:CD3OD, 33:1, vol/about.) Delta: 205,26 M. D. 205,16, 173,71, 172,57, 170,52, 168,10, 167,45, 130,63, 127,93, 100,63, 94,55, 74,64, 72,74, 72,42, 71,60, 69,82, 67,95, 67,64, 59,95, 53,57, 43,03, 42,79, 41,74, 38,26, 36,78, 34,63, 33,91, 33,47, 31,51, 31,46, 31,43, 31,38, 29,25, 29,21, 29,15, 29,12, 29,08, 29,06, 28,96, 28,93, 28,86, 28,74, 28,65, 28,56, 26,79, 26,12, 25,15, 24,78, 24,53, 23,00, 22,91, 22,24, 22,22, 13,51.

31P NMR (CDCl3:CD3OD 3:1, vol/about.) Delta: 1,31 memorial plaques - 1,40.

The connection 32.

1H NMR (CDCl3) Delta: 6,89-6,80 m D. (3H, m), of 6.68 (1H, d, J=8,79 Hz), 6,56 (1H, d, J=8,05 Hz), 5,95-5,86 (5H, m), 5,41-5,28 (13H, m), equal to 4.97 (1H, m), 4,80 (1H, t, J=9.7 Hz), 4.72 in(H, d, J=8.5 Hz), 4,60 (m), 4,48 (2H, m), 4,30 (2H, m), of 3.97 (2H, t), with 3.89 (3H, s), 3,85 (3H, s), of 3.77-3,74 (2H, m), 3,68-of 3.60 (2H, m), 3.00 and-2,56 (m), and 2.26 (2H, t), 2,09 of-1.04 (m), 0,88-0,84 (15H, m).

The connection 33.

1H NMR (CDCl3) Delta: 6,83 M. D. (1H, d, 7,33), 6,59 (1H, d, J=9,03 Hz), 5,94 and 5.86 (5H, m), vs. 5.47 (1H, t, J=7,1 Hz), 5.40 to-5,30 (12H, m) 5,00 (1H, m), 4,68 is 4.45 (m), to 4.38 (1H, K), 4,32-4,20 (2H, m), 3,83 at 3.69 (2H, m) to 3.41 (1H, K), 2,98-of 2.56 (8H, m), and 2.27 (2H, t), 2,07-1,90 (m), 1,67-of 1.52(m), 1,35-1,15(m), 0,89-0,85(15H, m).

The connection 34.

1H NMR (CDCl3) Delta: 7,39 M. D. (1H, d), was 7.08 (1H, d), 6,00-of 5.83 (7H, m), 5,70 (1H, DD), 5,43-5,20 (13H, m), free 5.01 (1H, m), 4,88 (1H, m), 4,65 is 4.45 (m), 4,40-of 4.25 (2H, m), 4,18 (1H, m) to 3.92 (1H, DD), of 3.75 (1H, K) to 3.67 (1H, m), 3,39 (2H, d), of 3.32 (2H, K), 2,67-to 2.42 (4H, m), 2,24 (2H, t), 2,07-of 1.92 (2H, m), 1,74 of 1.46 (m), 1,35-1,24(m), 0,91-0,82 (15H, m).

The connection 36.

Rf0,77, hexane : ethyl acetate, 1:1 vol./about.

(3H, C) to 1.35 (3H, s) to 0.89 (9H, s), 0,12 (3H, s) of 0.11 (3H, s).

The connection 37.

Rf0,37, hexane : ethyl acetate, 3:1, vol/about.

1H NMR (CDCl3) Delta: 4,70 m D. (1H, d, J=7.5 Hz), 33,86 (1H, d, J= 3,0,8,35 Hz), of 3.77 (1H, t, J=10.3 Hz), 3,57 (1H, t, J=9,29 Hz), of 3.45 (1H, m), 3,30 (1H, m), 1,50 (3H, s) of 1.42 (3H, s) of 0.91 (9H, s) of 0.14 (3H, s), 0,13 (3H, C).

The connection 38.

1H NMR (CDCl3) Delta: 5,90 m D. (1H, m), to 5.35 (1H, DD, J=1,46, 17,36 Hz), 5,23 (1H, d, J=10,49 Hz), to 5.08 (1H, m), the 4.90 (1H, t, J=10,01 Hz), 4,60 (3H, m), 3,86 (1H, DD, J=5,61, 10,98 Hz), 3,74 (1H, t, J=10.5 Hz), 3,62 (1H, t, J=9,52 Hz), 3,30 (2H, m) of 2.75 (1H, DD, J=7,0, to 15.8 Hz), 2,63 (1H, DD, J= 6,33, 5,15,53 Hz), 1,65 (m) of 1.42 (3H, s), 1,32 (3H, s), 1,24 (m) to 0.89 (9H, s) 0,86 (3H, t), of 0.12 (3H, s) of 0.10 (3H, s).

The connection 39.

1H NMR (CDCl3) Delta: 5,90 m D. (1H, m), 5,38 (1H, DD), from 5.29 (1H, d), 5,07 (1H, m), to 4.81 (1H, t), to 4.62 (2H, m), 33,88 (1H, m), 3,80 (1H, m), 3,62 (1H, m), 3,40 (1H, m), and 3.31 (1H, DD), and 2.79 (2H, m) to 1.98 (1H, t), 1,72 (1H, m) of 1.65 (1H, m), 1.27mm(m) of 0.91 (9H, s) to 0.88 (3H, t), of 0.18 (3H, s), 0,17 (3H, s).

The connection 40.

1H NMR (CDCl3) Delta: 5,96-5,85 M. D. (4H, m), 5,42-5,22 (11H, m), of 5.05 (1H, m) 5,00 (1H, t), 4,80 (1H, DD), 4,66 was 4.42 (m), 4,35-4,22 (2H, m), 4,10 (1H, d), 3,61 (1H, m), 3,52 (1H, m), 3,42 (1H, DD), and 3.31 (1H, DD), 2,78-2,62 (4H, m), 2,28 (2H, t), 2,09-of 1.95 (4H, m), 1,69-to 1.87 (4H, m), 1,38-1,19 (m) to 0.92 (9H, s), 0,85 (15H, m), 0,16 (6H, s).

The connection 41.

1H NMR (CDCl3) Delta: 5,94-5,86 M. D. (5H, m), 5,38-to 5.21 (12H, m), 5,19 is equal to 4.97 (2H, m), 4,72 was 4.42 (m (9H, C), 0,87-0,86 (15H, m), 0,17 (3H, s), 0,16 (3H, s).

The connection 42.

1H NMR (CDCl3) Delta: 7,20 m D. (1H, d), of 7.00 (1H, d), 5,95 (5H, m), and 5.30 (m) of 4.95 (1H, K), and 4.75 (1H, t), 4,55(m) 4,30 (m), 33,90 (1H, DD), 3,70 (m) of 3.45 (m), at 3.35 (2H, s), or 3.28 (2H, s), 2,60 (1H, DD), 2,45 (m), of 2.25 (2H, t), 1,95 (m) 1,65(m) 1,50 (m) 1,20 (m) 0,85 (15H, m) to 0.80 (9H, s), and 0.08 (6H, s).

The connection 44.

1H NMR (CDCl3) Delta: 7,20 m D. (1H, d), PC 6.82 (1H, d), 5,95 (5H, m), and 5.30(m), 5,10 (m), 4,58 (m), 4,47 (m) 4,30 (m), 3,70 (m) 3,35 (m) 2,50 (m in), 2.25 (2H, t), 2,00 (m) 1,50 (m), 1,25 (m) 0,85 (15H, m).

The connection 45.

Rf0,53, hexane : ethyl acetate, 4:1 vol./about.

1H NMR (CDCl3) Delta: 4,53 M. D. (1H, d, J=7,42 Hz) to 3.99 (1H, m), a 3.87-to 3.73 (2H, m), 3,60 (1H, t, J=9,2 Hz), 3,26-3,14 (2H, m), 1.70 to and 1.63 (2H, m) to 1.48 (3H, s) of 1.40 (3H, s), 1.27mm (mH, sh.C) of 0.91 (9H, s), 0,90-of 0.85 (3H, m), 0,13 (3H, s) of 0.21 (3H, s).

The connection 46.

Rf0,80, hexane : ethyl acetate, 4:1 vol./about.

1H NMR (CDCl3) Delta: 5,43-5,28 M. D. (2H, m), of 5.03 (1H, m), 4,49 (1H, d, J= 7,46 Hz), 3,86-to 3.73 (2H, m), 3,66 of 3.56 (2H, m), 3,22-3,10 (2H, m), 2,30-of 2.26 (2H, t), 2,09-of 1.97 (m), 1,83-1,54 (m) to 1.48 (3H, s) to 1.38 (3H, s), of 1.26 (m, sh.C) of 0.91 (9H, s), 0,89-0,85 (6H, m), 0,13 (3H, s), 0,12 (3H, s).

Connection 47.

Rf0,13, hexane : ethyl acetate, 4:1 vol./about.

1H NMR (CDCl3) Delta: 5,44-5,28 M. D. (2H, m), 5,10-5,04 (1H, m), a 4.53 (1H, d, J=7,6 Hz), 3,91-of 3.85 (2H, m), of 3.77-3,66 (2H, m), of 3.43 (1H, m) to 3.33 (1H, m), 3,18 (1H, dinnie 48.

Rf0,45, hexane : ethyl acetate, 4:1 vol./about.

1H NMR (CDCl3) Delta: 5,95 m D. (1H, m), 5,33 (2H, m), and 5.30 (2H, m), 5,07 (1H, m), to 4.62 (2H, d), 4,48 (1H, d, J=7.8 Hz), of 4.44 (1H, DD, J=2,2, 11.3 Hz), 4,33 (1H, DD, J=6,1, 11.7 Hz), 3,85 (1H, m), 3,68 (1H, m), TO 3.58 (1HOH, d, J= 3.2 Hz), of 3.45 (1H, m), 3,37 (1H, m), 3,18 (1H, t, J=9.1 Hz), 2,98 (1H, t, J=10.1 Hz), 2,28 (2H, t), to 2.06 (m), 1,82 (m) of 1.65 (m), 1,25 (m) of 0.91 (9H, s) of 0.85 (6H, m) of 0.13 (6H, s).

The connection 49.

Rf0,29, hexane : ethyl acetate, 4:1 vol./about.

1H NMR (CDCl3) Delta: 5,95 m D. (3H, m), 5,41-5,26 (8H, m) 5,00 (1H, m), 4.63 to-4,47 (m) 4,30 (1H, DD, J=6,6, 11.7 Hz), 4,18 (1H, K), and 3.72 (1H, m), 3,55 (1H, m) of 3.25 (2H, t, J=7,9, or 10.3 Hz) and 3.15 (1H, t, J=8,8, to 10.8 Hz), of 2.25 (2H, t), from 2.00 (4H, m), 1,65(m) 1,50(m), 1,25(m) of 0.91 (9H, s) of 0.85 (6H, m), of 0.01 (6H, 2s).

The connection 50.

Rfof 0.25 and 0.20, diethyl ether : dichloromethane, 1:9.about.

1H NMR (CDCl3) Delta: 5,95 m D. (3H, m), 5,35 (m in), 5.25 (m), of 4.95 (m), 4,59 (m) 4,30 (m in), 3.75 (m), 3,60 (m) to 3.35 (m in), 2.25 (2H, t), 2,00 (m) of 1.65 (m), 1,25 (m) of 0.85 (6H, m).

Compound 51A.

Rf0,50, diethyl ether : dichloromethane, 1:9.about.

1H NMR (CDCl3) Delta: 8,77 M. D. (1H, s) 6,38 (1H, d, J=2,41 Hz), 5,95 (3H, m), and 5.30(m), to 4.98 (1H, m), 4,55 (m), and 4.40 (m), of 4.05 (1H, m), 3,85 (1H, m in), 3.75 (1H, m), 3,60 (1H, DD, J=3,42, 9.5 Hz), and 2.27 (2H, t), 2,00 (m), of 1.65 (m), 1,25 (m) of 0.85 (6H, m).

Connection 51B.

Rf0,37, diethyl ether : di is, is), 4,50 (m), 4,32 (1H, DD), 3,80 (1H, m), 3,70 (1H, t), 2,70 (2H, t), of 2.25 (2H, t), 1,95 (m), 1,60 (m), 1,25 (m) of 0.85 (6H, m).

The connection 52.

Rf0.38 (ethyl acetate : hexane, 1:9.about.

1H NMR (CDCl3) Delta: 5,98-5,88 M. D. (1H, m), 5,32 (1H, m), 5.25-inch (1H, m), 4,88 (1H, m), to 4.62 (2H, d), 4,48 (1H, d, J=7,46 Hz), 3,86-3,66 (m) and 3.59 (1H, t, J=9.4 Hz), 3,23-3,10 (m), 1,87 and 1.80 (2H, m), 1,64-of 1.56 (2H, m), to 1.48 (3H, s) to 1.38 (3H, s) of 0.91 (9H, s), 0,90 is 0.86 (3H, t), of 0.13 (3H, s), 0,12 (3H, s).

The connection 53.

Rf0,12, ethyl acetate : hexane, 1:4.about.

1H NMR (CDCl3) Delta: 5,93 M. D. (1H, m), lower than the 5.37 (1H, m), 5,27 (1H, m), the 4.90 (1H, m), 4,67-4,58 (2H, m), of 4.54 (1H, d, J=7.5 Hz), 4,12 (1H, K), of 3.94 (1H, m), a 3.87 (1H, DD, J=3,4, and 11.5 Hz), 3,78 at 3.69 (2H, m), 3,50-of 3.43 (2H, m), 3,34-3,30 (1H, m), 3,21 (1H, DD, J=7,6, 10,0 Hz), 3,03 (1H, t, J=9,2 Hz), 2.05 is for 2.01 (1H, m), 1,96-1,50 (m), 1,36-1,23 (m) to 0.92 (9H, s), from 0.88 to 0.85 (3H, m), and 0.15 (3H, s) of 0.14 (3H, s).

The connection 54.

1H NMR (CDCl3) Delta: 5,91 M. D. (1H, m), lower than the 5.37-5,32 (1H, m), 5,26-5,23 (1H, m), 4.92 in-to 4.87 (1H, m), 4,65-4,55 (2H, m), 4,47 (1H, d, J=of 7.64 Hz), 3,90-3,74 (m) of 3.48 (1H, DD, J=2.1 a, 9,3, 11.2 Hz), 3,42 (1HOH, d, J=2.1 Hz), or 3.28 (1H, m), 3,18 (1H, DD, J=7,6,9,9 Hz) of 3.00 (1H, DD, J=8,7,9,8 Hz), 1,89(m), 1,60-1,20(m) of 0.91(18H, s), 0,90-0,84 (3H, m), 0,065 (6H, s) 0,059 (6H, s).

The connection 55.

1H NMR (CDCl3) Delta: 5,97-by 5.87 M. D. (2H, m), lower than the 5.37-5,31 (2H, m), 5,28-5,23 (2H, m), to 4.81 (1H, m), 4,69 (1H, t, J=10.0 Hz), 4,68-of 4.57 (2H, m), 4,48 (1H, d, J=7.5 Hz), 33,79 (1H, in), 3.75-of 3.65 (2H, d), 3,64-to 3.58 (1H, m), to 3.36 (1H, m), 3.27 to inania 56.

1H NMR (CDCl3) Delta: 5,96-by 5.87 M. D. (2H, m), 5,38-5,20 (4H, m), 4,80 (1H, m), 4,69-4,56 (m) to 4.52 (1H, d, J=7,4 Hz), 3,81-3,59 (3H, m) to 3.36 (1H, m), 3,30-3,26 (1H, DD, J= of 7.64, 9,88 Hz), 3,20 (1H, t, J=9,25 Hz), 2,19 (1HOH, t, J=5.71 in Hz), is 1.82 (2H, K), 1,68-1,50(m), 1,24 (mH, sh.C) to 0.92 (9H, s) of 0.85 (3H, m) of 0.14 (6H, s).

Connection 57A.

1H NMR (CDCl3) Delta: 5,43-5,28 M. D. (2H, m), is 5.06 (1H, m), 4,47 (1H, d, J=7.68 per Hz), 3,83 (1H, m), of 3.73 (1H, m), 3,66 of 3.56 (2H, m), 3,47 (1H, m) to 3.38 (3H, s) to 3.34 (1H, m), 3,20 (1H, t, J= 7.9 Hz), 2,98 (1H, t, J=8,9 Hz), to 2.29 (2H, t), 2,09-1,50 (m), 1,34-1,25 (m) to 0.92 (9H, s), 0,91-of 0.85 (6H, m) of 0.14 (6H, s).

Connection 57B.

1H NMR (CDCl3) Delta: 7,89-7,34 M. D. (10H, m), 5,43-of 5.29 (2H, m) 5,00 (1H, m), of 4.44 (1H, d, J=7,74 Hz), 3,84-3,70 (3H, m), of 3.46 (3H, s), or 3.28 (1H, K) 3,18 (2H, m), 3.04 from (1H, t, J=9.5 Hz), 2,30 (2H, t), 2,11 is 2.00 (4H, m), 1,89 (2H, m) to 1.70 (2H, m), 1,58 (2H, m), 1.27mm(m) of 1.07 (9H, s) of 0.95 (9H, s) of 0.87 (6H, m), 0,16 (3H, s), and 0.15 (3H, s).

The connection 58.

1H NMR (CDCl3) Delta: 5,96-by 5.87 M. D. (2H, m), 5,41-5,23 (m) 5,00 (1H, m), 4,58 (4H, m), 4,46 (1H, d, J=7,50 Hz) to 4.23 (1H, K), of 3.77-3,68 (m) of 3.57 (1H, DD, J=5,13, 10,91 Hz) to 3.41 (1H, m) to 3.35 (3H, s), 3,24 (1H, DD, J=7,7, the 10.1 Hz), of 3.12 (1H, DD, J=8,8, 9.7 Hz), 2,28-of 2.26 (2H, t), 2,07-of 1.52 (m), 1,32-1,12 (m) of 0.91 (9H, s), 0,90-of 0.85 (6H, m) of 0.13 (6H, s).

The connection 59.

1H NMR (CDCl3) Delta: 5,97-5,90 M. D. (2H, m), 5,41-a 5.25 (4H, m), equal to 4.97 (1H, m), br4.61-of 4.54 (4H, m), 4,27-4,07 (2H, m), 3,81 is 3.40 (m), to 3.38 (3H, s), 3,32 (2H, m), up 3.22 (1H, t, J=9.9 Hz), 2,29-of 2.24 (2H, m), 2,08-of 1.52 (m), 1,33-1,23 (m), 0,88-0,84 (6H, m).

1H NMR (CDCl3) Delta: total of 8.74 M. D. (1Halphabeta, 2C), to 6.39 (1Halpha, d, J= 3.46 in Hz), 6,00-5,91 (2H, m), to 5.58 (1Hbeta, d, J=8,46 Hz), 5,42-5,25 (m) 5,00 (1H, m), 4,63 is 4.36 (m), 3,99-3,50 (m) 3,37 (3Hbetawith), to 3.36 (3Halphawith), 3,34-33,30 (m), 2,35 was 2.25 (2H, m), 2,08-1,80 (m), 1.70 to 1,54 (m), 1,27-1,23 (m), 0,89-0,85 (6H, m).

The connection 62.

1H NMR (CDCl3) Delta: of 6.96 M. D. (1H, s), 6,85 (2H, m), 5,95 (5H, m), and 5.30 (m) 5,00 (m) 4,60 (m), 4,35 (1H, d), 4,27 (1H, DD), 4,20 (1H, K), 3,98 (1H, d), 3,85 (6H, 2s), 3,75 (m) to 3.52 (2H, m) to 3.35 (1H, t), 3,15 (1H, t) 2,60 (2H, m), of 2.25 (2H, t), from 2.00 (4H, m), 1,60 (m), 1,25 (m) of 0.85 (9H, m).

Connection 63.

1H NMR (CDCl3) Delta: 6,98 m D. (1H, d, J=1,71 Hz), make 6.90 (1H, d, J=8,30 Hz), 6,85 (1H, d, J=8,30 Hz), 5,95 (4H, m), and 5.30 (m) 5,00 (1H, t, J=9,03 Hz), 4,90 (m) 4,55 (m) 4,30 (m), 3,85 (6H, 2s), 3,70 (m), 3,62 (1H, m), 3,50 (m) 3,35 (m) of 3.00 (1H, t, J=9.8 Hz), 2,69 (2H, t), of 2.25 (2H, t), 2,00 (m), 1,60 (m), 1,25 (m) of 0.85 (9H, m).

The connection 64.

1H NMR (CDCl3) Delta: 5,95 m D. (4H, m), 5.40 to-5,22 (10H, m), 4,96 (1H, m), the 4.90 (1H, m), 4,55 (m), 4,32 (1H, d), 4,30-4,22 (2H, m), 4,18 (1H, K), 4,10 (1H, DD), 3,90 (m in), 3.75 (m) 3,50 (m) to 3.33 (2H, m), 3,20 (m), of 3.00 (1H, t), of 2.25 (2H, t), from 2.00 (4H, m) 1,80 (m) 1,50 (m) of 0.91 (9H, s) of 0.85 (9H, m), and 0.15 (6H, s).

The connection 65.

1H NMR (CDCl3) Delta: 5,98-by 5.87 M. D. (4H, m), 5,42-5,23 (m) of 4.95 (1H, m), 4,80 (2H, m), 4,65-4,50 (m) of 4.49 (1H, d, J=7,6 Hz), 4,27 (1H, d, J=8.1 Hz), 4.26 deaths (1H, m), a 3.87 (1H, d, J=9,95 Hz), 3,83-3,54 (m) to 3.36 (3H, s), 3,30-3,13 (4H,/SUP>H NMR (CDCl3) Delta: 7,32 M. D. (1H, d, J=8,2 Hz), 7,24 (1H, d, J=9.8 Hz), 5,97-of 5.89 (4H, m), lower than the 5.37-5,23 (m), 4,91 (2H, m), to 4.81 (1H, m), 4,71 (1H, m), 4.63 to-4,54 (m), 4,24 (1H, K), 3,88-33,43 (m), 3,39 (3H, s), 2,53-of 2.50 (4H, m), and 2.26-of 2.23 (2H, t), 2.06 to 1,54 (m), 1,2 (m), 0.88 to 0,83 (m), and 0.08 (3H, s), 0,05 (3H, s).

The connection 68.

Rf0,52, dichloromethane : methanol, 95:5 vol./about.

1H NMR (CDCl3) Delta: 7,25 M. D. (1H, d, J=7,6 Hz), 7,22 (1H, d, J=8,4 Hz), 5,97-5,85 (4H, m), 5,41-5,20 (m) of 5.05 (1H, d, J=8.0 Hz), is 4.93 (1H, m), 4,78 (1H, m), 4,65-4,51 (m), 4,28 (1H, K), 4,11 (1H, m), 3,79 is 3.57 (m), 3,52-3,39 (m) 3,337 (3H, s) of 2.50 (4H, t), of 2.25 (2H, t), 2,07 is 1.96 (4H, m), 1,78 is 1.48 (m), 1,24 (m) 0,86 (15H, m).

Connection 69.

1H NMR (CDCl3) Delta: 7,55 M. D. (1H, d), 7,05 (1H, d), 6,00-5,86 (6H, m), 5,79 (1H, m), 5,42-5,20 (m), 4,91 (1H, m), 4,84 (2H, m), and 4.75 (1H, t), 4,67-to 4.52 (m), 4,28 (1H, K), of 4.13 (1H, m), of 4.05 (1H, m), 3,91 (1H, d), 3,80 is 3.40 (m), 3,39 (3H, s), 2,52 (4H, m), and 2.26 (2H, t), 2,10-of 1.95 (4H, m), 1,82 was 1.43 (m, 1,38-1,24 (m), 0,87(15H, m).

Similar B531 (compound 70).

Retention time (ghvd) 13,87 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: from 5.29 M. D. (1H, DD, J=3,3, 6,3 Hz), 5,20 (1H, m), 5,10 (1H, m), 4,70 (1H, m), 4,46 (1H, d, J=8,2 Hz), 3,86 (2H, m), 3.72 points-3,30 (m) 3,20 (3H, s) 3,18 (1H, t), of 2.38 (4H, m), 2,10 (2H, t), equal to 1.82 (4H, m), 1,72-0,95 (m) of 0.68(15H, t).

13C NMR (CDCl3: CD3OD, 3:1, vol/about.) Delta: 205,9 M. D., 174,1, 168,0, 167,6, 130,6, 127,8, 100,3, 94,6, 80,1, 78,9, 74,6, 73,6, 72,8, 71,1, 70,6, 69,7, 69,2, 69,08, 67,3, 58,3, 54,9, 52,2, 52,1, 48,8, 47,5, 43,0, 42,9 DCl3:CD3OD, 3:1, vol/about.) Delta: 0,58 m D. - 1,24.

Connection 71.

1H NMR (CDCl3) Delta: 7,10 M. D. (1H, d), to 6.95 (1H, d), 5,95 (4H, m), 5.25-inch (m) to 4.92 (1H, d), 4,82 (1H, d), and 4.75 (1H, m) and 4.65 (m) 4,50 (m) to 4.38 (1H, K), 3,85 (1H, m), 3.45 points (m) at 3.35 (3H, s), 2,80 (4H, m), 2.63 in (2H, m) of 2.20 (2H, t), 1,95 (m) 1,65 (m) 1,20 (m) 0,80(24H, m), of 0.05 (6H, s).

The connection 72.

1H NMR (CDCl3) Delta: 7,22 M. D. (1H, m), of 6.65 (1H, d), 5,90 (4H, m), 5.40 to-5,23 (m) of 4.90 (1H, m), a 4.83 (1H, m), 4,70 (1H, d), 4,60-4,50 (m), and 4.40 (1H, K), 4,10 (1H, m), was 4.02 (1H, m), 3,95 (1H, K), 3,80-3,62 (m), 3,47 (3H, m), 3,39 (3H, s) to 3.36 (1H, t), 2,98-and 2.83 (4H, m), 2,24 (2H, t), from 2.00 (4H, m), 1,80-1,20 (m) 0,85(15H, m).

Connection 73.

1H NMR (CDCl3) Delta: 7,55 M. D. (2H, m), 5,95 (6H, m), 5,80 (1H, m), 5,35 (m) of 4.90 (1H, m), 4,60 (m), 4,32 (1H, K) to 4.15 (1H, m), 3,65 (m) of 3.45 (1H, m) to 3.35 (3H, s), 2,85 (4H, m), of 2.25 (2H, t), from 2.00 (4H, m), 1,80 (m), 1,25 (m) 0,85 (15H, m).

The connection 74.

1H NMR (CDCl3) Delta: 5,95 m D. (5H, m), the ceiling of 5.60 (1H, t), and 5.30 (m) of 5.05 (3H, m), and 4.75 (2H, m), 4,60 (m) 4,50 (m), and 4.40 (m), 4,30 (m), 3,90 (1H, m), 3.75 to (m), 33,60 (m), 3,47 (m), or 3.28 (1H, DD), 2,68 (4H, m), of 2.25 (2H, t), a 2.00 (4H, m), 1,60 (m), 1,25 (m) of 0.85 (9H, m).

Connection 75.

1H NMR (CDCl3) Delta: cent to 8.85 M. D. (1H, s), of 6.45 (1H, d, J=3.6 Hz), of 5.92 (5H, m), the ceiling of 5.60 (1H, t, J=10,2 Hz), and 5.30 (m), 5,10 (m) 5,033 (1H, dt, J=4,3, 10.1 Hz), 4,62 (m) 4,50 (m) 4,30 (1H, K), 4,25 (1H, m) 4,00 (1H, d, J= 10,8 Hz in), 3.75 (1H, DD, J=4,3, and 11.5 Hz), 3,70 (1H, DD, J=3,6, and 11.0 Hz), 3,61 (1H, m), 3,40 (1H, DD, J=7,9, 9.7 Hz), 2 the TA: 5,98 m D. (7H, m), of 5.75 (1H, t, J=8,2 Hz), 5,35 (m) 5,07 (1H, m), 5,04 (1H, DD, J=9,2, 10.1 Hz), of 4.95 (1H, t, J=9.8 Hz), 4,62 (m) 4,50 (m), 4,47 (1H, d, J=7.5 Hz), 4,30 (m) 4,00 (2H, m), 3,70 (1H, DD, J=3,9, of 11.4 Hz), 3,60 (1H, m), 3,42 (1H, DD, J=7,5, 9.8 Hz), 2,70 (4H, m), of 2.25 (2H, t), from 2.00 (4H, m), 1,62 (m) of 1.30 (m) of 0.85 (9H, t).

Connection 77.

1H NMR (CDCl3) Delta: 5,95 m D. (7H, m), of 5.55 (1H, t), 5,35 (m) of 5.05 (m) of 4.90 (1H, t), 4,62 (m) 4,50 (m), 4,28 (m) 4,20 (m) of 4.05 (m), the 3.65 (m), at 3.35 (1H, K), of 2.92 (1H, t), 2,70 (m) 2,60 (2H, d), of 2.25 (2H, t), 2,00 (m) 1,75 (m), 1,60 (m) of 1.30 (m) of 0.85 (9H, t).

The connection 78.

1H NMR (CDCl3) Delta: of 7.36 M. D. (1H, d, J=8.5 Hz), 7,28 (1H, d), 5,90(7H, m), the ceiling of 5.60 (1H, DD, J=10,6, and 11.6 Hz), and 5.30 (m) of 5.05 (1H, m), the 4.90 (2H, m), and 4.75 (1H, t, J=9.5 Hz), 4,55 (m) 4,30 (m) 4,08 (2H, m), 3,85 (m), 3,68 (m) 3,35 (m), 2,65 (m) of 2.50 (2H, t), of 2.45 (2H, t), of 2.25 (2H, t), 2,00 (m), 1,60 (m) of 1.30 (m), 0,85 (15H, m).

Connection 79a.

1H NMR (CDCl3) Delta: 5,94 M. D. (1H, m), the 5.45 (1H, d, J=9.5 Hz), to 5.35 (1H, DD, J=1,47, and 17.1 Hz), a 5.25 (1H, d, J=10.0 Hz), to 4.98 (1H, d, J=3,66 Hz), equal to 4.97 (1H, m), 4,25 (1H, DD, J=5,2, a 12.7 Hz), 4,06 (1H, DD, J=1,2, of 14.7 Hz), 3,90-of 3.60 (m), 3,14 (1H, DD, J=3,4, 10,2 Hz), 2,12 (3H, s) of 1.45 (3H, s) to 1.37 (3H, s).

Compound 79b.

1H NMR (CDCl3) Delta: 5,94 M. D. (1H, m), to 5.35 (1H, DD, J=1,5, and 17.1 Hz), a 5.25 (1H, DD, J=1,2, and 17.1 Hz), of 4.95 (2H, t, J=9,76 Hz), 4,47 (1H, d, J=7,81 Hz), and 4.40 (1H, DD, J=5,1, 11.7 Hz), 4,16 (1H, DD, J=6,5, and 12.4 Hz), 3,95 (1H, DD, J=5,4, and 10.8 Hz), 3,80 (1H, t, J=10,7 Hz), the 3.65 (1H, t, J=9,76 Hz), 3,43 (1H, DD, J= 8,1, 10,0 Hz), with 3.27 (1H, m), 2,12 (3H, s) of 1.45 (3H, s), 1,360 (m), of 3.28 (1H, DD, J=3,66, 10,0 Hz), 2,62 (1H, d, J=2,44 Hz), 2,22 (1HOHt) and 1.51 (3H, s) of 1.44 (3H, s).

Connection 81.

1H NMR (CDCl3) Delta: of 5.92 M. D. (1H, m), 5,44 (1H, t, J=9,52 Hz), lower than the 5.37 (1H, DD, J= 1,46, to 17.4 Hz), 5,27 (1H, DD, J=1,2, 10.5 Hz), 5,11 (m) 5,02 (1H, d, J=3.42 Hz), br4.61 (2H, m), 3,85 (m), the 3.65 (m), 3,05 (1H, DD, J=3,66, 10.5 Hz), and 2.79 (1H, DD, J=7,08, 14,5 Hz), 2,65 (1H, DD, J=6.35mm, to 15.4 Hz), 1,65 (m) of 1.45 (3H, s) of 1.36 (3H, s), 1,25 (m) of 0.90(12H, m), and 0.08 (6H, s).

The connection 82.

1H NMR (CDCl3) Delta: 5,95 m D. (1H, m), the 5.45 (1H, t, J=9,3 Hz), lower than the 5.37 (1H, DD, J= 1,47, to 15.8 Hz), 5,27 (1H, DD, J=1,22, 10.5 Hz), 5,12 (1H, m), 4,99 (1H, d, J=3,66 Hz), to 4.62 (2H, m), 3,80 (m), the 3.65 (m), and 3.16 (1H, DD, J= 3,62, the 10.5 Hz), 2,78 (1H, DD, J=7,02, to 15.4 Hz), 2,63 (1H, DD, J=6,30, the 15.6 Hz), 1,65 (m) of 1.46 (3H, s) to 1.37 (3H, s), 1.26 in (m) 0,86 (3H, t).

Connection 83.

1H NMR (CDCl3) Delta: 5,95 m D. (3H, m), 5,41 (m), 5,27 (m), 5,12 (1H, m), 5,02 (1H, d, J=3,4 Hz), 4,55 (m), 4,25 (m), 3,90 (m), the 3.65 (1H, t, J=8,8 Hz), 3,10 (1H, DD, J=3,67, 10.5 Hz), and 2.79 (1H, DD, J=5,4, 14.4 Hz), 2,63 (1H, DD, J= 6,6, 15.6 Hz), 1,65 (m) of 1.45 (3H, s) of 1.36 (3H, s), 1.26 in (m) 0,86 (3H, t).

The connection 84.

Rf0.6 methylene chloride : diethyl ether, 4:1 vol./about.

1H NMR (CDCl3) Delta: 5,95 m D. (3H, m), of 5.40 (m in), 5.25 (1H, DD), 5,13 (1H, m), to 4.98 (1H, d, J=3,4 Hz), 4,55 (m), 4,25 (m), 3,80 (m), the 3.65 (1H, t), 3,38 (m) of 3.13 (1H, DD), a 2.75 (1H, DD), 2,65 (1H, DD), 1,68 (m) to 1.45 (2H, K), 1,25 (m) of 0.85(12H, m) of 0.10 (6H, s).

Connection 85.

1H NMR (CDC(1H, DD), 2,68 (1H, DD), 2,58 (1H, DD), of 2.15 (2H, K), 1,25 (m) 0,85 (m) of 0.10 (6H, s).

Connection 86.

Rf0,80, methylene chloride : diethyl ether, 4:1 vol./about.

1H NMR (CDCl3) Delta: 7,55 M. D. (1H, d, J=8,8 Hz), 5,95 (4H, m), 5,80 (m) of 4.95 (m), is 4.85 (1H, t, J=10.0 Hz), 4,78 (1H, d, J=3.6 Hz), 4,55 (m), 4,35 (1H, m), 4,25 (m), 3,85 (m), 3,71 (2H, d), 3,62 (1H, m), 3,20 (1H, d, J= a 13.9 Hz), and 3.16 (1H, m), 2,85 (1H, d, J=a 13.9 Hz), 2,60 (2H, m), a 2.01 (2H, m), 1.55V (m) 1,20 (m) 0,85 (m) of 0.10 (6H, 2s).

Connection 87.

Rf0,08, hexane : ethyl acetate, 1:1 vol./about.

1H NMR (CDCl3) Delta: 7,51 M. D. (1H, d, J=9,52 Hz), 5,95 (4H, m), and 5.30 (m) of 4.95 (1H, m), 4,82 (2H, m), 4,55 (m), 4,35 (1H, m), 4,25 (2H, m), 3,85 (m), the 3.65 (m), and 3.16 (m) 2,84 (1H, d, J=14,41 Hz), 2,55 (m) 2,01 (m), 1.55V (m) 1,20 (m) of 0.85 (6H, t).

The connection 90.

Rf0,39, methylene chloride : methanol, 95:5 vol./about.

1H NMR (CDCl3) Delta: 7,62 m D. (1H, d, J=8.0 Hz), 7,20 (1H, d, J=8.1 Hz), 5,90 (7H, m), 5,46 (1H, t, J=10.0 Hz), 5.40 to-5,15 (m) of 5.05 (1H, m), 4,85 (m) 4,50 (m) 4,30 (m), 4,25 (m) to 4.15 (m), 3,90 (m), 3,70 (1H, m), of 3.60 (1H, m), 3,53 (1H, DD), 3,35 (m), 2,70-2,42 (8H, m), of 2.25 (2H, t), 2,00 (m) 1,80-1,45 (m), 1,37-1,07 (m) 0,85 (15H, m).

Similar B235.

Rfto 0.47, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,43 minutes

1H NMR (CDCl3:CD3OD, 1:1, vol/about.) Delta: 5,15 M. D. (2H, m), 5,00-4,80 (3H, m), 3 is a: of 208.3 M. D. 207,8, 175,6, 174,1, 172,4, 170,0, 169,4, 102,8, 95,2, 76,8, 74,8, 74,3, 72,6, 71,8, 70,0, 61,5, 55,0, 52,2, 43,8, 43,5, 43,0, 40,2, 38,5, 35,7, 33,2, 30,8, 30,6, 30,4, 30,2, 26,9, 26,5, 26,4, 26,3, 24,8, 23,9, 23,7, 15,0.

Similar B235 (fully protected).

Rf0,39, methylene chloride : methanol, 19:1 vol./about.

1H NMR (CDCl3) Delta: 7,40 m D. (1H, d), 7,13 (1H, d), 5,93 (7H, m), 5,70 (1H, m), 5,46-5,16 (m) 5,00 (1H, m), a 4.86 (2H, m), 4,67-4,46 (m) of 4.38-4,27 (m) 4,18 (1H, m), 3,93 (1H, d), 3,80-of 3.60 (m), 3,40-3,30 (m), 2,68-2,42 (m), 2,22 (2H, t), 1,80-0,80 (m).

Similar B272.

Rfof 0.48, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd): 14,13 minutes

Similar B272 (fully protected).

Rf0,66, methylene chloride : methanol, 19:1 vol./about.

1H NMR (CDCl3) Delta: 7,13 M. D. (1H, d), 7,05 (1H, d), of 5.92 (8H, m) 5,69 (1H, DD), 5,32 (m) 5,09 (1H, m), 4,88 (1H, d), 4,80 (1H, t), 4,65 is 4.45 (m), to 4.38-4,20 (m), 3,88-3,62 (m) of 3.32 (2H, K), 2,58 (m) 2,43 (2H, m), of 2.25 (2H, t), from 2.00 (4H, m), 1,58 (m) of 1.23 (m), 0,85(15H, m).

Similar B286.

Rf0,43, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 14,70 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 6,58 M. D. (2H, m), 5,61 (2H, d, J= 15.3 Hz), 5,28 (1H, DD, J=2,9, 5.7 Hz), 5,20 is 5.07 (2H, m), 5,00-4,88 (3H, m) to 4.52 (1H, d, J=8,2 Hz), 4,20-of 4.05 (m), 3,85-3,20 (m), 2,48 is 1.75 (m), 1,40 (m), 1,20-186 (fully protected).

Rf0,60, methylene chloride : methanol, 95:5 vol./about.

1H NMR (CDCl3) Delta: 6,88-of 6.73 M. D. (4H, m), 5,98-5,85 (7H, m), of 5.83 (1H, d), 5,71 (2H, m), 5,42-5,20 (16H, m), 5,16 (1H, t), to 4.98 (1H, m), is 4.85 (2H, DD), 4,67 is 4.45 (m), to 4.41-the 4.29 (2H, m), 4,18 (1H, m), of 3.95 (1H, DD), 3,88 (1H, d), of 3.75 (1H, m) to 3.67 (1H, m), 2,63 is 2.46 (3H, m), 2,22 (2H, t), 2,12 (2H, t), from 2.00 (2H, m), 1,78-1,15 (m) 0,84 (15H, m).

Similar B287.

Rfof 0.49, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,70 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 5,28 m D. (1H, DD, J=3,6, 6,0 Hz), 5,12 (2H, m), 4,96 (2H, m), to 4.87 (1H, m), 4,50 (1H, d, J=8.7 Hz), 4,05 (m), 3,80 (m), 3,60-3,24 (m), 2,40-2,10 (m) 1,80 (m) 0,65(15H, m).

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 0,31 m D. - 1,66.

Similar B287 (fully protected).

Rf0,68, methylene chloride : methanol, 95:5 vol./about.

1H NMR (CDCl3) Delta: 7,14 M. D. (1H, d, J=7.9 Hz), to 6.80 (1H, d, J=8.0 Hz), of 5.92 (8H, m), 5,70 (1H, m), the 5.45 5.17 to (m) of 5.05 (1H, m), 5,02 (1H, m), is 4.93 (1H, d, J= 7.9 Hz), a 4.86 (1H, t), 4,67-4,47 (m), 4,32 (m), 4,19 (1H, DD), a 3.87 (1H, d), 3,66 (m) of 3.32 (2H, K), 2,70-2,24 (m) 2,00 (m) of 1.55 (m), 1,25 (m) 0,85 (15H, m).

Similar B288.

Rf0,82, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,48 minutes

1H NMR (CDCl3

13C NMR (CDCl3: CD3OD, 3: 1, vol/about.) Delta: 205,02, 173,56, 172,44, 170,78, 167,76, 167,32, 130,64, 130,54, 100,68, 94,57, 75,75, 74,65, 72,58, 72,26, 70,10, 68,01, 67,83, 67,55, 60,74, 53,24, 51,04, 42,87, 41,62, 38,46, 38,31, 36,64, 33,74, 33,60, 33,33, 33,18, 32,02, 31,71, 31,63, 31,37, 31,32, 31,27, 31,20, 31,04, 30,86, 29,15, 29,11, 29,08, 29,00, 28,97, 28,93, 28,88, 28,83, 28,80, 28,70, 28,59, 28,51, 28,43, 28,30, 26,67, 25,00, 24,59, 24,37, 22,85, 22,78, 22,11, 21,97, 13,37.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 1,49 m D.

Similar B294.

Rf0,69, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Similar B294 (fully protected).

Rf0,40 methylene chloride : methanol, 95:5 vol./about.

Retention time (ghvd) 15,07 minutes

1H NMR (CDCl3) Delta: 7,41 M. D. (1H, d, J=8,2 Hz), to 7.09 (1H, d, J=8.5 Hz), 6,00-of 5.82 (7H, m), 5,70 (1H, m), 5,43-5,20 (m) 5,02 (1H, m), to 4.87 (2H, m), 4,69-of 4.44 (m), 4,40-to 4.28 (3H, m), 4,18 (1H, DD), of 3.94 (1H, d), 3,78-3,61 (4H, m), of 3.46 (2H, m), 3,38 of 3.28 (5H, m), 2,65-2,42 (m) 2,00 (5H, m), 1,64-1,25 (m) 0,86 (15H, m).

Similar B300.

Rfof 0.51, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,65 minutes

Similar B300 (fully protected).

Rf0,36, methylene chloride : methanol, 95:5 vol./about.

1H NMR (CDCl3)), to 3.99 (1H, d), 3,90 (1H, m), 3.75 to of 3.60 (3H, m), 3,47 (1H, m), 3,38-3,30 (2H, m), 2,65 is 2.43 (6H, m), 2,30 (1H, DD), to 2.18 (1H, DD), from 2.00 (2H, t), 1,60-1,20 (m), 0,87 (15H, m).

Similar B313.

Rf0,57, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 11,75 minutes

Similar B313 (fully protected).

Rf0,71, methylene chloride : methanol, 19:1 vol./about.

1H NMR (CDCl3) Delta: 7,37 M. D. (1H, d), PC 6.82 (2H, m), 5,91(7H, m), of 5.75 (1H, t), 5,7 (1H, d), 5,41-5,19 (m), 4,96-to 4.87 (2H, m), 4.63 to-4,48 (m), 4,45-4,30 (m) 4,18 (1H, m), 3,95 (1H, d), 3,80-3,60 (m) to 3.38 (2H, K), 2,65-2,48 (6H, m), 2,24 (2H, t), 2,17-of 1.95 (6H, m), 1.70 to 1,10 (m) 0,85(15H, m).

Similar B314.

Rfof 0.48, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 27,93 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 5,266 M. D. (1H, m) to 5.17 (1H, m) 5,08 (1H, m) 5,00 (1H, m), is 4.93 (2H, m), 4,48 (1H, d, J=7.9 Hz), 4.00 points (m), 3,85-3,20 (m) of 1.80 (4H, m), 1,40-1,00 (m) 0,70 (18H, m).

Similar B314 (fully protected).

Rf0.46 methylene chloride : methanol, 19:1 vol./about.

1H NMR (CDCl3) Delta: 7,38 M. D. (1H, d, J=7.8 Hz), 6,14 (1H, d, J=8.0 Hz), 6,05-of 5.82 (7H, m), 5,70 (1H, t), the 5.45 5,20 (m), 5,11-to 4.98 (1H, m), 4,90-4,82 (2H, m), 4,67 was 4.42 (m), 4,39-4,22 (m), 4,10 (1H, DD), 3,98-of 3.85 (2H, m), 3,83-3,62 (m) to 3.38 (2H, K), 2,68-2,30 (m) 2,25 (m) a 2.00 (4H, m), 1.55V (m), 1,25 (about. /about./about./about.

Retention time (ghvd) 14,05 minutes

Similar B318 (fully protected).

Rf0,44, methylene chloride : methanol, 19:1 vol./about.

1H NMR (CDCl3) Delta: 7,40 m D. (1H, d), of 6.99 (1H, d), 6,05-of 5.82(7H, m), 5,78 (1H, K), 5,46-5,15 (m) 5,02 (1H, m), 4,91-4,80 (3H, m), 4,70 was 4.42 (m), to 4.38-4,20 (m), 3,90-3,25 (m), 2,93-2,50 (m in), 2.25 (2H, t), 2,00 (m), 1,90-1,10 (m) 0,85(15H, m).

Similar B377.

Rf0.52 chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Similar B377 (fully protected).

Rf0,39, methylene chloride : methanol, 19:1 vol./about.

1H NMR (CDCl3) Delta: 7,62 m D. (1H, d, J=8.0 Hz), 7,20 (1H, d, J=8.1 Hz), 5,90 (7H, m), 5,46 (1H, t, J=10.0 Hz), 5.40 to-5,15 (m) of 5.05 (1H, m), 4,85 (m) 4,50 (m) 4,30 (m), 4,25 (m), 4,16 (m), 3,90 (m), 3,70 (1H, m), of 3.60 (1H, m), 3,53 (1H, DD), 3,35 (m), 2,70-2,42 (8H, m), of 2.25 (2H, t), 2,00 (m) 1,80-1,45 (m), 1,37-1,07 (m) 0,85 (15H, m).

Similar B379.

Rf0,55, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 9,12 minutes

1H NMR (CDCl3:CD3OD, 3:2, vol/about.) Delta: 5,14 M. D. (2H, m), of 5.05 (1H, m) to 4.92 (1H, t), 4,78 (2H, m), 4,43 (2H, m), 3,92-3,44 (m) of 3.13 (2H, m), with 2.93 (1H, m), 2,70 (1H, m), 2,35 (3H, m), 2,22 (4H, m), 2,12 (1H, DD), was 1.94 (2H, m), 1,74 (2H, m), 1.30 and 0.90 or (m) of 0.58 (15H, t).

Similar B379 (fully protected).

R

Similar B385.

Rf0,85, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 18,35 minutes

Similar B385 (fully protected).

Rf0,40, methylene chloride : methanol, 97:3.about.

1H NMR (CDCl3) Delta: 6,52 M. D. (1H, d), 5,93-5,85 (7H, m), 5,71 (1H, m), 5,59 (1H, sh.C) the 5.45 to 5.21 (m), is 5.18 (1H, m), 4,99 (1H, m), a 4.83 (2H, m), 4,66 is 4.45 (m), and 4.40-4.25 in (m), 4,18 (1H, m), 3.95 to the 3.65 (m), 2,70 is 2.46 (m in), 2.25 (2H, t), 2,15-1,99 (m) 0,85 (15H, m).

Similar B387.

Rf0,50, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 19,05 minutes

Similar B387 (fully protected).

Rf0,50, methylene chloride : methanol, 95:5 vol./about.

1H NMR (CDCl3) Delta: 6,60 m D. (1H, d), of 5.99 and 5.86 (7H, m), 5,70 (1H, m), 5,44 (1H, m), 5,42-to 5.21 (m), 5,12 (1H, d), 4,65-of 4.44 (m), of 4.35-4.26 deaths (m) of 4.05 (m), 3,90 (m), 2,72-2,48 (m) to 2.35 (m in), 2.25 (m), 2,14-1,94 (m), 1,58-1,18 (m) 0,89(15H, m).

Similar B388.

Rf0,70, chloroform : acetic acid : water, 125:75:10:20./about./about. /about.

Retention time (ghvd) 13,92 minutes

Similar B398.

Rfof 0.49, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 7,12 minutes

1H NMR (CD3OD) Delta: 5,42 m D. (1H, m), lower than the 5.37 (1H, t), 5,38 (1H, m), of 5.26 (1H, m), is 5.18 (1H, m), 4,70 (1H, d, J=8.6 Hz), 4,22-3,82 (m) 3,76 (1H, d, J= 11,4 Hz), 3,55 (1H, t, J=11,0 Hz), 3,42 (1H, d, J=10.3 Hz), 2,72-2,60 (5H, m), 2,42 (1H, DD, J=8,6, and 17.1 Hz), 2,31 (2H, t), 2,18 is 2.00 (6H, m), 1.77 in is 1.58 (4H, m), 1,50 is 1.23 (m), 0,87(15H, m).

13C NMR (CD3OD) Delta: 207,2 M. D. 206,8, 176,0, 174,7, 173,0, 170,8, 170,2, 133,0, 130,8, 103,6, 96,2, 82,5, 82,4, 81,0, 80,8, 78,0, 77,9, 77,8, 75,7, 75,6, 75,5, 74,8, 74,7, 73,3, 72,4, 72,1, 70,4, 70,2, 69,9, 62,4, 56,8, 54,2, 44,5, 44,2, 44,0, 41,0, 39,7, 36,4, 35,6, 33,8, 33,5, 32,0, 31,7, 31,2, 30,8, 29,0, 28,5, 27,8, 27,4, 27,3, 25,3, 25,1, 24,8, 20,3, 20,0, 19,9, 15,5.

Similar B400.

Rf0,36, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 14,27 minutes

Similar B400 (fully protected).

Rf0,21, methylene chloride : methanol, 98:2 vol./about.

1H NMR (CDCl3) Delta: 7,43,82 (1H, K), 3,70 (2H, m) to 3.33 (4H, m), 2,58 (2H, m), 2,46 (4H, K) 2,17 (2H, K), 1,64-1,20 (m) of 0.85 (12H, t).

Similar B406.

Rfof 0.35, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,95 minutes

Similar B406 (fully protected).

Rf0,33, methylene chloride : methanol, 19:1 vol./about.

1H NMR (CDCl3) Delta: 7,32 M. D. (1H, d), 7,17 (1H, t), 6,05-5,85 (7H, m), 5,73 (1H, m), the 5.45 5,20 (m), with 5.22 (1H, m), 4,91 of 4.8 (2H, m), 4,68-4,43 (m), 4,40-4,28 (m) 4,20 (1H, m), 3,91 (1H, DD), 3,82 of 3.75 (m) and 3.59 (1H, K), 3,42-3,29 (m) of 2.72 (2H, d), 2,35-2,20 (m in), 2.25 (2H, t), 2,10-1,91 (m) of 1.65 (2H, t), 1,50 (m), 1,25 (m) 0,85( 15H, m).

Similar B410.

Rfof 0.51, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,70 minutes

1H NMR (CDCl3: CD3OD, 3:1, vol/about.) Delta: 5,28 m D. (1H, sh.d) to 5.17 (1H, m), 5,09 (1H, m) 5,00 (1H, m), of 4.95 (1H, t, J=9.6 Hz), 4,46 (1H, d, J= 8.1 Hz), 4.09 to (1H, m), 3,85-of 3.46 (m) of 3.25 (3H, m), 2,45 was 2.25 (6H, m) to 2.06 (2H, t), of 1.80 (4H, m) 0,65 (15H, m).

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 1,32 m D. 1,12.

Similar B410 (fully protected).

Rf0,41, methylene chloride : methanol, 97:3.about.

1H NMR (CDCl3) Delta: 7,50 m D. (2H, DD), of 5.92(7H, m), 5,80 (1H, m), 5,12-5,23 (17H, m), 4,80 (2H, m), 4,74 (1H, t), 4,62-5,00 (15H, m) to 4.33 (2H, m), 4.1 Analog B415.

Rf0,50, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) br12.62 minutes

Similar B415 (fully protected).

Rf0.20 methylene chloride : methanol, 98:2 vol./about.

1H NMR (CDCl3) Delta: 7,53 M. D. (1H, d),? 7.04 baby mortality (1H, d), 5,94 (7H, m), 5,73 (1H, m), 5,43-5,20(17H, m), 5,02 (1H, m), 4,88 (2H, m), 4,58(15H, m), 4,37 (1H, m), 4,28 (1H, DD), 4,18 (1H, t), of 4.12 (1H, t), of 3.95 (1H, DD), 3,86 (1H, t), of 3.78 (1H, DD), to 3.67 (1H, m) and 3.59 (1H, m), 3,44 (3H, m), 3,32 (2H, K) to 2.55 (4H, m), of 2.45 (2H, t), 2,02 (4H, m), of 1.78 (2H, m), 1,68-1,20 (m), 0,87 (15H, m).

Similar B425.

Rf0,62, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 14,05 minutes

1H NMR (CD3OD:CDCl3, 2:1, vol/about.) Delta: 5,40-5,12 M. D. (m), 4,18-3,70 (m), 3,45-3,19 (m) 2,60 (m in), 2.25 (2H, t), 2,00 (m) 1,80 (m), 1,65-1,15 (m) 0,85(15H, m).

Similar B425 (fully protected).

Rf0.75, methylene chloride : methanol, 95:5 vol./about.

1H NMR (CDCl3) Delta: 7,45 M. D. (1H, d), at 6.84 (1H, d), 5,95 (7H, m), 5,80 (1H, m), 5,46-5,22 (m) of 5.05 (1H, m), 4,85 (m), 4,67-4,48 (m) 4,30 (m), 3.95 to of 3.80 (m in), 3.75 (2H, d), the 3.65 (1H, m), 3,25 (m) and 3.15 (2H, t), to 2.65 (m) 2,60 (1H, d), to 2.55 (1H, d), of 2.25 (2H, t), 2,00 (m) 1,80 (m), 1,65-1,20 (m) 0,85 (15H, m).

Similar B426.

Rf0,44, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /P>Rf0,50, methylene chloride : methanol, 95:5 vol./about.

1H NMR (CDCl3) Delta: 7,38 M. D. (1H, d), 7,11 (1H, d), 5,95 (7H, m) 5,72 (1H, m), 5,65 (m), 5,42-5,18 (m) of 5.05 (m) of 4.95 (1H, t), is 4.85 (1H, d), 4,68-4,25 (m) of 3.95 (1H, m), 3,79 (m), 3,55-3,30 (m) of 2.68 (2H, t), of 2.58 (2H, t), of 2.45 (m in), 2.25 (2H, t), 2,00 (m), 1,69-1,45 (m), 1,30-1,15 (m) 0,85(15H, m).

Similar B427.

Rf0,62, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 14,17 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: lower than the 5.37 M. D. (1H, m), 5,27 (1H, m) to 5.17 (1H, m), 4,78 (1H, m), a 4.53 (1H, d, J=6.3 Hz), 4.04 the-3,20 (m) 2,43 (4H, m), of 2.15 (2H, t), 1,95 of-1.83 (4H, m), 1.70 to 0,95 (m) 0,75 (15H, t).

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 1,24 m D. - 1,40.

Similar B442.

1H NMR (CDCl3:CD3OD, 2:1, vol/about.) Delta: 5,20 M. D. (m), 5,13 (m) of 4.95 (m), and 4.75 (m), 3,85 of 3.28 (m), 2,68 (m), 2.40 a (m) of 2.10 (2H, t), 1,80 (m) of 1.65 to 1.00 (m) 0,70 (15H, m).

Similar B442 (fully protected).

1H NMR (CDCl3) Delta: 7,60-7,50 M. D. (2H, d), 5,95 (7H, m), 4,88 (1H, m), 4,70 is 4.45 (m), 4,35 (2H, m), 4,15 (m), 3,85 is-3.45 (m), 2,88 (m) to 2.65 (2H, t), of 2.25 (2H, t), 2,00 (m), 1,78 is 1.23 (m), 0,85 (15H, m).

Similar B451.

Rf0,45, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 12,37 minutes

1H NMR (CD), of 4.00 (2H, m), 3,80-3,20 (m) 3,18 (3H, s), 3,17 (1H, t), 2,68 (4H, m), a 2.36 (2H, ABX, J=4,5, 8,4, 16.1 Hz), 2,10 (2H, t), of 1.80 (4H, m), 1,55-1,05 (m) 0,67 (15H, m).

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 0,51 m D. - 1,41.

Similar B451 (fully protected).

Rf0,19, methylene chloride : methanol, 95:5 vol./about.

1H NMR (CDCl3) Delta: 7,74 M. D. (1H, d), 7,54 (1H, d), of 5.92 (6H, m), of 5.85 (1H, m), 5,44-5,20(16H, m), a 4.86 (2H, m), 4,70 (1H, t), 4,63 (9H, m), 4,50 (4H, m), to 4.38 (1H, K) to 4.17 (1H, m), 4,08 (1H, m), 3,82-of 3.46 (8H, m), to 3.38 (3H, s), 2,96-by 2.73 (4H, m), 2,62 (2H, m), and 2.26 (2H, m), from 2.00 (4H, m), 1,80-1,18 (m) 0,85(15H, m).

Similar B452.

Rf0,44, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 10,30 min

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 5,34 m D. (1H, m), is 5.18 (1H, m), of 4.95 (1H, t, J=9.6 Hz), is 4.93 (1H, m), 4,50 (1H, d, J=8,3 Hz), of 4.05 (1H, m), 3,92-of 3.60 (m), 3,50-3,20 (m) to 2.65 (2H, m), 2.40 a-2,10 (m) of 1.85 (4H, m), 1,55-1,00 (m), 0,70 (15H, m).

13C NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 173,52 M. D. 172,22, 170,24, 164,80, 164,62, 130,71, 127,87, 100,08, 94,05, 74,49, 73,09, 72,26, 71,68, 69,72, 68,01, 67,49, 66,94, 59,99, 57,58, 56,96, 55,94, 53,83, 51,80, 42,15, 38,61, 36,90, 34,07, 33,43, 32,03, 31,49, 31,40, 29,25, 29,20, 28,93, 28,83, 28,58, 28,37, 28,27, 26,81, 26,12, 25,20, 24,70, 24,54, 23,68, 22,24, 21,37, 13,52.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 1,24 m D. - 1,65.

Similar B452 (fully zaa: of 7.48 m D. (1H, d), 7,03 (1H, d), 5,95 (7H, m), 5,79 (1H, m), the 5.45 is 5.18 (m) of 5.03 (1H, m), 4,85 (m), 4,75-4,50 (m) 4,30 (m), 4,25 (1H, m), 3,91 (1H, DD), 3,78-of 3.60 (m), 3,55 (m), 3,30 (2H, d), 2,90-2,50 (m), of 2.25 (2H, t), 2,00 (m) 1,80-1,15 (m) 0,85 (15H, m).

Similar B459.

Rfof 0.49, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

1H NMR (CDCl3: CD3OD, 3:1, vol/about.) Delta: 5,42 m D. (1H, sh.C) a 5.25 (1H, m) to 5.17 (1H, m), and 4.75 (1H, m), with 4.64 (1H, d, J=7,7 Hz), of 2.15 (2H, t), 1,90 and 1.80 (4H, m), 1.70 to 1.00 and (m) 0,75 (15H, sh.C).

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 1,39 memorial plaques - 1,51.

Similar B459 (fully protected).

Rf0,43, methylene chloride, 95:5 vol./about.

1H NMR (CDCl3) Delta: 7,68-7,50 M. D. (2H, m), 5,95 (7H, m), of 5.85 (1H, m), 5,42-5,23 (12H, m), is 4.93 (1H, m), 4,82 (1H, m), was 4.76 (1H, m), 4,66-4,55 (m), or 4.31 (1H, m), 4.26 deaths (1H, K), of 4.12 (2H, m), 3,83-3,42 (m), 2,95-2,84 (4H, m), and 2.26 (2H, t), from 2.00 (4H, m), 1,80-1,18 (m) 0,85 (15H, m).

Similar B460.

Rf0,63, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 14,52 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 5,34 m D. (1H, m), 5,19 (1H, m), 5,11 (1H, m), and 4.68 (1H, m) to 4.41 (1H, d, J=8.1 Hz), 3,90 (1H, m), 3,81-3,12 (m) 2,70 (4H, K) of 2.10 (2H, t), of 1.80 (4H, m), 1,58-0,90 (m) 0,65 (15H, t).

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 1,38 m D. - 1,30.

EN who (m), of 4.95 (1H, m), 4,82 (m), 4,72 (2H, K) 4,55 (m), 4,28 (m), 4,10 (m) of 3.80 (1H, d), 3,70-3,55 (m), 3,51 is-3.45 (m), 2,95-of 2.81 (m in), 2.25 (2H, t), 2,00 (m) 1,75 (m) of 1.45 (m), 1,25 (m) 0,85 (15H, m).

Similar B465.

Rf0,83, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,53 minutes

1H NMR (CDCl3:CD3OD, 2:1, vol/about.) Delta: 5,34 m D. (1H, DD, J=3.3, which is 6.7 Hz), 5,19 (1H, m), 5,11 (1H, m), 4,69 (1H, m), of 4.54 (1H, d, J=7.9 Hz), of 1.80 (4H, m), 1.60-to 0,95 (m) 0,65 (15H, m).

31P NMR (CDCl3:CD3OD, 2:1, vol/about.) Delta: 1,32 m D. - 1,40.

Similar B465 (fully protected).

1H NMR (CDCl3) Delta: 7,55 M. D. (2H, m), 5,93(7H, m), 5,80 (1H, m), 5,50-5,25 (m) of 4.90 (2H, m), 4.75 V-4,50 (m) 4,30 (2H, m), 4,13 (1H, m), 3,85 is 3.40 (m), 2.95 and is 2.80 (4H, m), and 2.26 (2H, t), from 2.00 (4H, m), 1,80-0,80 (m).

Similar B466.

Rfof 0.51, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Retention time (ghvd) accounted for 14.45 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: memorial plaques are 5.36 (1H, DD, J=3.2, and a 6.7 Hz), 5,18 (1H, m), 5,09 (1H, m) and 4.65 (1H, m), 4,48 (1H, d, J=8,3 Hz), 3,90-3,24 (m), 3,17 (3H, s), 2,70 (4H, K) of 2.10 (2H, t), 1,8- (4H, m), 1,55-1,00 (m) 0,65(15H, t).

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: -0,67 memorial plaques of 1.50.

Similar B466 (fully protected).

1H NMR (CDCl3) deltas), of 2.30 (2H, t), 2,10-1,25 (m) 0,85(15H, m).

Similar B477.

Rfof 0.53, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,48 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: memorial plaques are 5.36 (1H, DD, J=3.3, then the 6.8 Hz), 5,18 (1H, m), 5,10 (1H, m), 4,70 (1H, m), of 4.57 (1H, d, J=8,2 Hz), 3,90-3,25 (m) 3,20 (3H, s), 2,73 (4H, m), 2,10 (2H, t), of 1.80 (4H, m), 1,65-0,90 (m) 0,70 (15H, t).

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: -0,64 memorial plaques - 1,44.

Similar B477 (completely replaced).

Rf0,41, methylene chloride : methanol 95:5 vol./about.

1H NMR (CDCl3) Delta: 7,56 M. D. (2H, m), 5,93 (6H, m), of 5.82 (1H, m), 5,44-5,24 (12H, m), the 4.90 (1H, m), 4,70 (1H, t), of 4.66-4.53-in (m), 4,32 (1H, K), of 4.12 (1H, m), 3,85-3,42 (m) to 3.38 (3H, s), 2,93-2,82 (m), and 2.26 (2H, t), a 2.00 (4H, m), 1,80-1,20 (m) 0,85 (15H, m).

Similar B479.

Rf0,97, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Similar B510.

Rfto 0.47, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 6,37 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: memorial plaques are 5.36 (1H,sh.C) 4,55 (1H, d, J=8,2 Hz), 4,00-3,20 (m), 3,23 (3H, s), 2.40 a (4H,sh.C) 1,60-0,70 (m).

13C NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 205,96 M. D. 205,80, 167,85, 165, 28,78, 28,57, 28,51, 25,20, 25,10, 22,79, 22,09, 13,25.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: -0,72 memorial plaques - 1,49.

Similar B464.

Rfof 0.51, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 17,62 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: from 5.29 memorial plaques by 5.18 (1H, m), 5,09 (1H, m), 4,70 (1H, m), of 4.44 (m), 3,88 (2H, m), 3.72 points-of 3.12 (m), and 3.16 (3H, s), a 2.36 (4H, m) 2,07 (2H, t), 1,87 to 1.76 (4H, m), 1.60-to 0,92 (m) 0,65 (15H, m).

13C NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 206,07 M. D. 206,00, 174,15, 167,99, 167,15, 130,69, 127,82, 100,22, 94,98, 80,12, 78,86, 74,88, 74,82, 73,72, 72,84, 71,81, 70,70, 69,74, 69,17, 67,28, 58,38, 55,12, 54,21, 52,12, 43,08, 42,98, 42,78, 37,37, 36,65, 34,47, 34,19, 33,63, 32,14, 31,48, 31,35, 29,41, 29,25, 29,22, 29,14, 29,08, 29,05, 28,93, 28,91, 28,87, 28,72, 28,62, 28,54, 26,78, 26,13, 25,32, 24,82, 24,63, 22,94, 22,88, 22,22, 13,47.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: -0,629 memorial plaques - 1,431.

Similar B587.

Rf0,62, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 14,80 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 5,26 M. D. (1H, m) to 5.17 (1H, m), 5,10 (1H, m), 4,70 (1H, m), 4,49 (1H, d, J=8,10 Hz), 3,91-3,29 (m), 3,26 (3H, s), 3,24-3,20 (m), 3,17 (3H, s), 3,12 (m), 2,89 (1H, t, J=of 9.30 Hz), 2,34 (4H, m), of 2.08 (2H, t), 1,89 is 1.75 (4H, m), 1,62-0,92 (m) 0,64 (15H, m).

13C NMR (CDCl3:C27, 67,88, 66,93, 64,48, 61,86, 59,96, 58,49, 54,98, 52,53, 50,60, 43,15, 42,89, 37,30, 36,99, 34,44, 34,17, 33,64, 31,48, 31,40, 31,35, 29,34, 29,22, 29,13, 29,08, 28,93, 28,84, 28,70, 28,61, 28,54, 26,79, 26,14, 25,29, 24,81, 24,62, 22,92, 22,86, 22,22, 13,49.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: -0,673 memorial plaques - 1,509.

Similar B718.

Rf0,40, chloroform : methanol : acetic acid : water 125:75510:about 20. /about./about./about.

Retention time (ghvd) 13,65 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 5,34 m D. (1H,sh.C) 5,20 (1H, m), 5,12 (1H, m), 4,70 (2H, m), 4,32 (1H, d, J=8.0 Hz), 4,0-of 3.85 (m), 3,70-3,20 (m) 3,18 (3H, s), 3,22-3,13 (m) 2,35 (m) of 2.08 (2H, t), 1,90 (3H, s), 1,90-to 1.77 (4H, m), 1,63-1,00 (m), of 0.67(m, t).

13C NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 206,35 M. D. 205,88, 174,23, 169,94, 168,25, 167,20, 130,80, 127,94, 100,45, 94,44, 80,48, 74,68, 74,38, 73,93, 71,89, 70,65, 69,70, 69,28, 69,20, 68,39, 67,02, 58,59, 54,85, 52,19, 43,23, 43,07, 37,31, 36,97, 34,50, 34,26, 33,74, 31,50, 31,45, 31,08, 29,43, 29,37, 29,32, 29,28, 29,20, 29,17, 29,14, 29,04, 29,01, 28,94, 28,84, 28,71, 28,64, 26,89, 26,25, 25,37, 24,89, 24,72, 23,03, 22,97, 22,33, 22,30, 20,43, 13,78, 11,98.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: -0,63 memorial plaques - 1,59.

Similar B725.

Rf0,58, chloroform : methanol : acetic acid : water 125:75510:about 20. /about./about./about.

Retention time (ghvd) 17,58 minutes

1H NMR (CDCl3: CD3OD, 3:1, vol/about.) Delta: 5,32 M. D. (1H, sh.C) of 5.24 (1H, m), 5,12 (1H, m), 4,78 (1H, 3
OD, 3:1, vol/about.) Delta: 296,06 M. D. 205,94, 174,02, 167,82, 167,20, 130,87, 127,82, 101,11, 94,88, 81,24, 79,45, 78,93, 77,30, 73,69, 72,58, 71,53, 70,04, 69,82, 69,40, 69,01, 68,02, 64,72, 59,95, 55,31, 52,30, 49,00, 48,78, 48,57, 48,36, 48,14, 47,93, 47,72, 43,15, 43,07, 37,39, 36,67, 34,89, 34,21, 33,75, 31,54, 31,45, 31,42, 29,41, 29,27, 29,20, 29,15, 28,99, 28,88, 28,77, 28,70, 28,61, 26,87, 26,22, 25,37, 24,89, 24,74, 23,03, 22,96, 22,29, 22,26, 13,57.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 0,74 m D. - 1,27.

Similar B736.

Rf0,57, chloroform : methanol : acetic acid : water, 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 12,57 minutes

1H NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 5,20 m D. (1H, m), 5,10 (1H, m), 4,70 (1H, m), a 4.53 (1H, d, J=3.5 Hz), and 4.40 (1H, d, J=7,7 Hz), 3,90-3,20 (m) 3,18 (3H, s), 2,34 (4H, K) of 2.10 (2H, t), of 1.85 (4H, m), 1.70 to 0,90 (m) 0,65 (15H, m).

13C NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 206,00 M. D. 205,81, 174,05, 167,52, 167,01, 130,62, 127,71, 100,47, 97,33, 80,00, 79,66, 74,71, 73,69, 71,67, 70,67, 70,56, 69,42, 69,24, 69,12, 67,84, 66,51, 65,00, 58,35, 58,34, 55,21, 52,02, 43,05, 42,88, 37,23, 36,60, 34,42, 34,10, 33,55, 31,39, 31,37, 31,30, 31,25, 29,26, 29,17, 29,12, 29,08, 29,03, 28,99, 28,95, 28,86, 28,84, 28,81, 28,74, 28,63, 28,55, 28,45, 26,70, 26,04, 25,23, 24,74, 22,88, 22,80, 22,13, 22,10, 13,38.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 0,99 memorial plaques - 0,48.

Similar B737.

Rf0,71, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 12,45 mi is J=8.0 Hz), 4,20 (1H, t) 4,07 (1H, t, J= 4,14 Hz), 3,98-3,81 (m), and 3.72-of 3.27 (m), 3,17 (3H, s), 3,12 (m) of 2.33 (4H, m) 2,07 (2H, t), 1,90-1,78 (m), 1.60-to 0,98 (m) 0,65(15H, m).

13C NMR (CDCl3: CD3OD, 3:1, vol/about.) Delta: 206,1 M. D. 179,7, 174,1, 168,0, 167,2, 130,7, 127,8, 100,3, 94,2, 90,3, 84,0, 80,1, 74,8, 73,8, 71,8, 70,6, 70,4, 70,1, 69,5, 69,1, 68,1, 66,9, 66,7, 64,7, 58,2, 55,1, 51,9, 43,0, 42,9, 37,3, 36,7, 34,4, 34,2, 33,6, 32,5, 31,5, 31,4, 31,3, 29,3, 29,2, 29,1, 29,0, 28,9, 28,8, 28,7, 28,6, 28,5, 28,4, 26,8, 26,1, 25,3, 24,8, 24,6, 22,9, 22,2, 13,5.

31P NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: -0,635 memorial plaques - 1,634.

19F NMR (CDCl3:CD3OD, 3:1, vol/about.) Delta: 1,62 m D.

Similar B763.

Rf0,92, chloroform : methanol : acetic acid : water 125:75:10:20 on. /about./about./about.

Retention time (ghvd) 13,70 minutes

The connection 92.

Rf0,26, hexane : ethyl acetate, 4:1 vol./about.

1H NMR (CDCl3) Delta: 5,95 m D. (1H, m), 5,32 (1H, d, J=and 17.2 Hz), 5,28 (1H, d, J= 10.4 Hz), 4,80 (m), 4,58 (2H, d), 4,50 (1H, d, J=7,40 Hz), 4,08 (1H, K), 3,78-3,49 (m), 3,30-3,13 (m) 2,30 (1HOHwith), to 2.06 (3H, s), 1,80 (m) of 1.55 (m), 1,25 (m) to 0.89 (9H, s), or 0.83 (3H, t), of 0.11 (6H, s).

Connection 93.

1H NMR (CDCl3) Delta: of 5.92 M. D. (1H, m), are 5.36 (1H, DD, J=1,4, and 17.3 Hz), 5,28 (1H, DD, J=1,2, 10.5 Hz), 4,88 (1H, m), to 4.62 (2H, m), 4,48 (1H, d, J= 7,6 Hz), a 3.87-to 3.67 (m) 3,50 (3H, s), 3,22-3,13 (3H, m), of 3.07 (1H, DD, J= 8,3, the 9.7 Hz), 1,90 (3H, m) to 1.60 (2H, m), 1,23 (m) of 0.90 (9H, s) of 0.85 (3H, t), of 0.12 (6H,2s).

5,94 (1H, m) to 5.35 (1H, d, J=15,5 Hz in), 5.25 (1H, d, J=9.3 Hz), 4,89 (1H, m), to 4.62 (2H, m), of 4.54 (1H, d, J=7,4 Hz), 4,46-to 4.28 (1H, DDD, J=7,7, 10,1, 50.0 Hz), 3,90-3,68 (m) of 3.43 (1H, m), 3.33 and-3,19 (2H, m), a 1.88 (2H, m)that is 1.77 (1H, t), 1.26 in (mH, sh.C) to 0.88 (9H, s) 0,86 (3H, t), and 0.15 (6H,2s).

Connection 95.

Rf0,06, hexane : ethyl acetate, 1:1 vol./about.

1H NMR (CDCl3) Delta: 5,93 M. D. (4H, m), 5,27(8H, m) to 4.92 (1H, d, J= 3.5 Hz), 4,78 (1H, m), 4,70-4,55(8H, m), is 4.21 (1H, m), 3,88-3,60 (m) and 3.59 (1H, DD, J=4,6, 13,0 Hz), 3,30 (1H, DD, J=3,5, 10.1 Hz) and 1.83 (2H, m), and 1.54 (2H, m), 1.26 in (m) of 0.85 (3H, m).

The connection 96.

Rfalpha0,52, hexane : ethyl acetate, 1:1 vol./about.

Rfbeta, 0,30 hexane : ethyl acetate, 1:1 vol./about.

1H NMR (CDCl3) Delta: 8,69 M. D. (1H, s), 6,33 (1Halpha, d, J=3,4 Hz), of 5.92 (2H, m) to 5.56 (1Hbeta, d, J=8.5 Hz), and 5.30 (6H, m), 5,02 (1H, m), 4,53 (4H, m), or 4.31 (1H, m), 4,22 (2H, m), 3,82 (3H, m), and 3.72 (1H, t, J=8.5 Hz), 3,57 (3Halpha, (C), of 3.56 (3Hbetawith), to 3.49 (2H, m) of 3.25 (3H, m), 2,10 (2H, m), 2,04 (4H, m), a 1.88 (2H, m), of 1.65 (2H, m), and 1.56 (1H, s), 1,25 (m) 0,86 (6H, m).

Connection 97.

1H NMR (CDCl3) Delta: total of 8.74 M. D. (1H, s) 6,40 (1H1-alpha, D., 5,59 (1Hbeta, d, J= 8.5 Hz), 5.40 to-5,23 (6H, m) 5,0 (1H, m), of 4.57 (4H, m), 4,50 (1HAlphato), 4,36 (1HBetato), 3,80 (3H, m), 3,63 (3H, m), 3,42 (2H, m), 3,30 (1H, t, J= 9,3 Hz), 2,28 (2H, t), 2,08-1,82 (m), 1.70 to 1,20 (m), or 0.83 (9H, m).

Connection A1.

1H NMR (CD IS), 1,68-is 1.51 (2H, m), 1,37-of 1.18 (9H, m) to 0.88 (3H, t).

Connection A2.

1H NMR (CDCl3) Delta: 4,16 M. D. (2H, K), 3,98 (1H, m), 2,95 (1H, d), 2,52 (1H, DD, J=2,9, 5.8 Hz), 2.49 USD (2H, DD), 1,55-is 1.51 (2H, m), 1,47 to 1.37 (2H, m), 1,30-1,11 (10H, m) of 0.87 (3H, t).

Compound A3.

1H NMR (CDCl3) Delta: 3,86-3,78 M. D. (1H, m), 2,96-of 2.86 (2H, m), 2,33, of 2.16 (2H, ABX, J=2,4, 9,5, 15.6 Hz), 2,03-of 1.94 (4H, sh.d) and 1.83-of 1.74 (4H,sh. d), 1,66-to 1.60 (2H, sh.d), 1,54-1,10 (22H, m) 0,86 (3H, t).

Compound A4.

1H NMR (CDCl3) Delta: 7,92 m D. (2H, DD, J=1,1, 7,7 Hz), 7,63 (1H, t of d, Jt= 7,6 Hz, Jd=1.2 Hz), 7,50 (H, J=7,7 Hz), 5,49, 5,38 (2H, AB, J=16.5 Hz), 4,14 (1H, m), 3,50 (1H, sh.C), 2,69-of 2.58 (2H, ABX, J=2,9, 9,4, 15.1 Hz), 1,65-to 1.45 (2H, m), 1,4-1,2 (10H, m) to 0.88 (3H, t).

Compound A5.

1H NMR (CDCl3) Delta: to $ 7.91 M. D. (2H, DD, J=1,2, 6.4 Hz), to 7.61 (1H, t of d, Jt=7,6 Hz, Jd=1.2 Hz), 7,50 (2H, t, J=7.8 Hz), 5,99-of 5.89 (1H, m), 5,42, 5,38 (2H, AB, J= 15.1 Hz), 5,27 (2H, d), of 5.24 (1H, m), 4,6 (2H, DD), 2,83, was 2.76 (2H, ABX, J= lower than the 5.37, 7,56, and 21.7 Hz), 1,75-of 1.65 (2H, m), 1.41 to of 1.26 (10H, m), of 0.87 (3H, t).

Compound A6.

1H NMR (CDCl3: CD3OD, 15:1) Delta: 5,90 m D. (1H, m), 5,32 (2H, DD), 5,19-free 5.01 (1H, m), of 4.57 (2H, dt), 2,61-of 2.56 (2H, ABX, J=lower than the 5.37, EUR 7.57, 19,7 Hz), 1,65-of 1.55 (2H, m), 1,31-1,21(10H, m) of 0.82 (3H, t).

Compound A7.

1H NMR (CDCl3) Delta: 4,90 m D. (1Hnorthward-Hwith), 3,74 (3H, s), of 3.45 (2H, s), 2,52 (2H, t), to 2.18 (2HAnanovaformt), 1,62-1,52 (, is), is 2.88 (1H, d, J= 3.8 Hz), 2.49 USD (1H, DD, J= 3,1, and 16.4 Hz), is 2.41 (1H, DD, J=9,1, of 16.5 Hz), 1,58 to 1.47 (2H, m), 1,44-to 1.38 (2H, m), 1,37 is 1.23(10H, m) of 0.87 (3H, t).

Compound A9.

1H NMR (CDCl3) Delta: 3,91-3.75 M. D. (3H, m), 2,62-of 2.38 (2HOH, m) 1,75-to 1.61 (2H, m), 1,55-of 1.36 (2H, m), 1,35 is 1.23(10H, m) of 0.87 (3H, t).

The A10 Connection.

1H NMR (CDCl3) Delta: 7,86 M. D. (2H, s, J=8,3 Hz), 7,34 (2H, d, J=8.1 Hz), 4,27 (1H, m), 4,13 (1H, m), and 3.72 (1H, m), is 2.44 (3H, s), 1,89-of 1.81 (1H, m), 1,68-of 1.62 (2H, m), 1,39-1,25(12H, m) of 0.87 (3H, t),

13C NMR (CDCl3) Delta: 144,44 M. D. 132,59, 129,49, 127,49, 67,60, 37,14, 35,86, 31,39, 29,11, 28,83, 25,11, 22,25, 21,26, 13,70.

Connection A11.

1H NMR (CDCl3) Delta: 3,21 M. D. (2H, t), 2,20-2,10 (4H, m) of 1.93 (2H, m), 1,58 (2H, m) of 1.46 (2H, m), 1,40-1,22 (6H, m) to 0.88 (3H, t).

Connection A12.

1H NMR (CDCl3) Delta: 7,43 M. D. (2H, d), 7,33-7,20(10H, m), at 6.84 (2H, d), with 3.79 (3H, s), 3,74 (1H, sh.C) to 3.38 (1H, m), up 3.22 (1H, m), 2,98 (1H, d, J=2,9 Hz), 1,72 (1H, m), 1.56 to 1,24(10H, m) of 0.87 (3H, t).

Connection A13.

1H NMR (CDCl3) Delta: 7,44 M. D. (2H, d), 7,33-7,19(10H, m), PC 6.82 (2H, d), with 3.79 (3H, s), 3,40 (2H, m), or 3.28 (1H, m) and 3.15 (2H, t), 2,11 (4H, K) of 1.75 (2H, K), 1,55-1,25 (29H, m) to 0.88 (6H, t).

Connection A14.

1H NMR (CDCl3) Delta: 3,80 m D. (2H, m), 3,52 (2H, m), 3,42 (1H, m), of 2.72 (1H, m), 2,17 (4H, m), 1,80-to 1.25(26H, m) to 0.88 (6H, t).

Connection A16.

1H NMR (CDCl3) Delta: 3,68 3) Delta: 5,33 m D. (2H, m), 3,68 (1H, m), 3,52 (2H, m), of 2.56 (2H, m), 2,02 (2H, m), 1,98-1.27mm (27H, m) to 0.88 (6H, t).

Connection A18.

1H NMR (CDCl3) Delta: 7,80 m D. (2H, d), of 4.05 (2H, t), of 2.51 (2H, m), of 2.45 (2H, s) to 2.06 (2H, m) of 1.41 (2H, m) of 1.27 (6H, m) to 0.88 (3H, t).

Connection A19.

1H NMR (CDCl3) Delta: 7,84 M. D. (2H, m), 7,72 (2H, m), 3,83 (2H, t), of 2.56 (2H, m) to 2.06 (2H, m) of 1.34 (2H, m) of 1.20 (6H, m), is 0.84 (3H, t).

Connection A20.

1H NMR (CDCl3) Delta: 7,82 M. D. (2H, m), 7,71 (2H, m), 5,44 (1H, m), lower than the 5.37 (1H, m), and 3.72 (2H, t), is 2.44 (2H, K), of 1.95 (2H, m), 1,18 (8H, m), or 0.83 (3H, t).

Connection A21.

1H NMR (CDCl3) Delta: 5,48 m D. (1H, m), of 5.34 (1H, m), a 2.71 (2H, t), to 2.18 (2H, K) 2,03 (2H, m) of 1.27(8H, m) of 0.87 (3H, t).

Connection A22.

1H NMR (CDCl3) Delta: to $ 7.91 M. D. (2H, d), to 7.61 (1H, t, J=7,3 Hz), 7,56 (2H, t), of 5.50 (1H, m), to 5.35 (2H, s), and 5.30 (1H, m), of 5.15 (1H, t), 4,78 (1H, t), 3,17 (2H, m), is 2.74 (2H, t), 2,24 (2H, t), a 2.01 (2H, K), was 1.58 (2H, m), of 1.57 (2H, d), of 1.26(16H, m) of 0.87 (6H, t).

Connection A23.

1H NMR (CDCl3) Delta: 6,85 M. D. (1H, m), the 5.45 (1H, m), 5,32 (1H, m), is 5.06 (2H, m) to 4.92 (1H, d), 3,15-3,00 (m) of 2.45 (2H, t), 2,32 (1H, d), 2,20 (m) 2,03 (m) to 1.59 (m), 1.28 (in m) of 0.85 (6H, m).

Connection A24.

1H NMR (CDCl3) Delta: of 7.90 m D. (2H, d), to 7.61 (1H, t), 7,49 (2H, t), of 5.34 (2H, s), and 5.30 (1H, m), is 2.74 (2H, m), 2,31 (2H, t), 1,69-of 1.57 (4H, m), 1,37-1,20(28H, m) to 0.88 (6H, t).

Connection A25.

1H NMR (CDCl3) Delta: 3,76 m D. (3H, s), 2,32 (2H, t), and 1.56 (2H, m), of 1.40 and 1.35 (m), 1,30-1,22 (m) to 0.88 (3H, t).

Connection A27.

1H NMR (CDCl3) Delta: 5,65 M. D. (1H, s) to 3.67 (3H, s), 2,61 (2H, t), of 1.88 (3H, s), 1,50-1,40 (m), 1,35-1,20 (m) to 0.88 (3H, t).

Connection A28.

1H NMR (CDCl3) Delta: 5,66 m D. (1H, s), 3,68 (3H, s), of 2.15 (2H, t), 1,50-1,40 (m), 1,34-1,20 (m) to 0.88 (3H, t).

Connection A29.

1H NMR (CDCl3) Delta: 5,40 m D. (1H, t, J=7,1 Hz) to 4.15 (2H, t), from 2.00 (2H, t), of 1.66 (3H, s), 1,40-of 1.20(18H, m) to 0.88 (3H, t).

Connection A30.

1H NMR (CDCl3) Delta: 5,64 m D. (1H, s), 4,91 (1H,sh.C) to 2.15 (2H, t), 2,11 (3H, s) to 1.48 (4H, m), 1,29(14H, m) to 0.89 (3H, t).

Connection A31.

Rf0,76, hexane : ethyl acetate, 3:2 vol./about.

1H NMR (CDCl3) Delta: 6,02 M. D. (1H, s), 2,19 (2H, m) to 2.13 (3H, s) to 1.48 (2H, m) of 1.26(16H, m) to 0.88 (3H, t).

Connection B1.

1H NMR (CDCl3) Delta: 3,30 m D. (2H, m), and 2.26 (2H, m) to 2.13 (1H, m), of 1.95 (1H, m), 1,47 (m), 1.28 (in m) to 0.88 (3H, t).

Connection B2.

1H NMR (CDCl3) Delta: 2,50 M. D. (2H, t), of 2.33 (2H, m) to 2.13 (2H, m) and 1.83 (2H, m) to 1.45 (2H, m), 1.30 and 1,25 (6H, m) to 0.89 (3H, t).

Compound B3.

1H NMR (CDCl3) Delta: 2,49 m D. (2H, t), 2,24 (2H, m) to 2.13 (2H, m), of 1.80 (2H, m) to 1.45 (2H, m), 1,37-of 1.26 (6H, m) to 0.88 (3H, t).

Compound B4.

Compound B5.

1H NMR (CDCl3) Delta: of 7.90 m D. (2H, d), to 7.61 (1H, t), 7,49 (2H, m), 5,38 (1H, m), and 5.30 (2H, m) of 2.75 (2H, m), 2,31 (2H, m) to 2.06 (2H, m) to 1.99 (2H, m), by 1.68 (2H, m), 1.27mm (m) to 0.88 (6H, t).

Connection B6.

1H NMR (CDCl3) Delta: 5,38 M. D. (1H, m), a total of 5.21 (1H, m), 2,61 (2H, m) to 2.29 (2H, t), is 2.05 (2H, m) to 1.99 (2H, m) to 1.67 (2H, m) of 1.62 (2H, m), 1.26 in(15H, m) of 0.87 (6H, t).

Connection C1.

1H NMR (CDCl3) Delta: 4,19 m D. (2H, K), of 3.43 (2H, s), 2,52 (2H, m) to 1.60 (3H, m) of 1.29(18H, m) of 0.87 (3H, t).

Connection C2.

Rf0,35, hexane : ethyl acetate, 4:1 vol./about.

1H NMR (CDCl3) Delta: 4,16 M. D. (2H, K), of 3.97 (1H, m), 2,46 (1H, DD, J= 3.2, and a 16.4 Hz), of 2.38 (1H, DD, J=9,0, 16.4 Hz), 1,54-1,10 (23H, m) 0,86 (3H, t).

The Connection C3.

1H NMR (CDCl3) Delta: 3,84 m D. (1H, m), 2,96 (2H, m), a 2.36 (1H, DD, J= 2,7, or 15.9 Hz), 2,17 (1H, DD, J=9,3, the 15.6 Hz), 2,02 (4H, m), of 1.78 (4H, m) of 1.66 (2H, m), 1.41 to (m), 1,25 (m) of 0.87 (3H, t).

Connection C4.

1H NMR (CDCl3) Delta: 7,93 M. D. (2H, d), 7,63 (1H, t, J=7,3 Hz), 7,50 (2H, t), 5,43 (2H, K), 4,14 (1H, m), 2,70 (1H, DD, J=2,9, and 14.9 Hz), 2,53 (1H, DD, J=9,3, 15.1 Hz), 1,40-1,20(20H, m) to 0.88 (3H, t).

Connection C5.

1H NMR (CDCl3) Delta: to $ 7.91 M. D. (2H,2D), to 7.59 (1H, t, J=6.5 Hz), 7,49 (2H, t), 7,27 (2H, d), 6,86 (2H, d), 5,33 (2H, K), 4,51 (2H, K), of 3.94 (1H, m), with 3.79 (3H, s), and 2.79 (1H, DD, J=7,0, 15.2 Hz), to 2.66 (1H, DD, J=5,5,15,3 Hz), of 1.62 (2H, m), 1,40-of 1.26 (16H, m), 0.88 to (3, ,79 (3H, s), 2,60 is 2.55 (2H, m), 1,69 is 1.60 (1H, m), 1,59 of 1.50 (1H, m), 1,40-1,18 (18H, m) to 0.88 (3H, t).

Connection C7.

1H NMR (CDCl3) Delta: 4,15 M. D. (2H, K), of 3.05 (4H, m), 2,70 (2H, m), 2,04 (3H, m) to 1.87 (1H, m), 1,31-1,21(21H, m) of 0.87 (3H, t).

Connection C8.

1H NMR (CDCl3) Delta: 3,12 M. D. (2H, s), 3,03 (2H, t), was 2.76 (2H, t), 2,13-2,01 (m) 1,89 (m), and 1.54 (m), 1,26 (m) to 0.88 (3H, t).

Connection D1.

1H NMR (CDCl3) Delta: of 7.36 M. D. (5H, s) to 5.17 (2H, s), of 3.48 (2H, s) of 2.50 (2H, t), and 1.56 (6H, s) of 1.24 (12H, m) to 0.88 (3H, t).

Compound D2.

1H NMR (CDCl3) Delta: 3,52 m D. (2H, s), of 2.56 (2H, t), of 1.16 (2H, m), 1,25 (14H, m) to 0.88 (3H, t).

The E1 Connection.

1H NMR (CDCl3) Delta: 3,74 m D. (3H, s), up 3.22 (2H, s), 2,62 (2H, t) to 1.59 (2H, m) of 1.35 (2H, m), 1,25 (14H, m) to 0.88 (3H, t).

Compound E2.

1H NMR (CDCl3) Delta: 3,80 m D. (3H, s), 3,68 (2H, m), 2,82 (2H, m), 1.77 in (2H, m), 1,50-of 1.40 (2H, m), 1.26 in (14H, m) to 0.88 (3H, t).

The E3 Connection.

1H NMR (CDCl3) Delta: 3,84 m D. (1H, d, J=14,5 Hz), 3,49 (1H, d, J=14.4 Hz), is 3.08-3,03 (1H, m), 2,89-of 2.81 (1H, m), 1,79-of 1.74 (2H, m) and 1.51-of 1.40 (2H, m), 1,35-1,25 (14H, m) to 0.88 (3H, t).

Connection E4.

1H NMR (CDCl3) Delta: 3,80 m D. (3H, s), 3,68 (2H, m), 2,84 (2H, m), 1.77 in (2H, m), 1,50-of 1.40 (2H, m), 1.26 in (14H, m) to 0.88 (3H, t).

Connection E5.

1H NMR (CDCl3) l3) Delta: 3,96 m D. (2H, s), 3,82 (3H, s), 3,24 (2H, m) to 1.86 (2H, m), 1,44 (m), 1,25 (m) of 0.87 (3H, t).

Connection E7.

Rf0,33, methylene chloride : methanol, 19:1 vol./about.

1H NMR (CDCl3) Delta: 4,01 m D. (2H, s), with 3.27 (2H, m) to 1.87 (2H, m), 1,47-of 1.26 (16H, m) to 0.88 (3H, t).

Connection G1.

1H NMR (CDCl3) Delta: 4,19 m D. (2H, K), of 3.45 (2H, s) to 2.67 (2H, t), of 2.20 (2H, m), 2,12 (2H, m) of 1.76 (2H, m) to 1.45 (2H, m), 1,35-1,25 (9H, m) to 0.88 (3H, t).

Connection G2.

1H NMR (CDCl3) Delta: 4,21 M. D. (2H, m), 3,06 (2H, m) to 2.94 (2H, K), 2,20-2,01 (m) 1,80-1,50 (m), 1,48 was 1.43 (m, 1,39-1,22 (m) to 0.88 (3H, t).

Example 3. Inhibition of LPS induced production of tumor necrosis factor (TNF) and IL-Beta in vitro.

And LPS and bacterial lipid A induce the production of tumor necrosis factor (TNF) and IL-Beta in cultures of human monocytes (J. Immunol 139:429, 1987). As specified in the following experiments described in the invention analogues of lipid And inhibit it mediated LPS and/or lipid a induces.

Monocytes isolated from human blood by centrifugation with a gradient of density Percoll placed in 48-cell Cup with a density of approximately 1106cell 1 cell in the environment PPMI 1640 (Article IBCO, Grand island, NY) containing 10 % serum cheloveka-Louis, Missouri) concentration of 10 ng/ml or lipid A (Daiichi chemicals, Tokyo, Japan) concentration of 1.0 ng/ml in the medium RPMI 1640 combine with 0.45 ml of medium RPMI 1640 containing 1 % human plasma, and add to cultivated monocytes. In experiments using similar lipid And it is added in variable concentrations, for example 0-100 μm on the sample volume of 50 ál, and analyze it for the presence of TNF and Il-Beta. Analysis of TNF and IL-Beta carried out using a kit from IFU R & D Systems (Minneapolis, Minnesota) and the recipes, however, can be used by any other standard sets for IFU, for example the set supplied by the company "Gensim, Cambridge, Massachusetts. Each experiment was repeated three times.

The degree of inhibition of LPS induced production of TNF analogues of lipid A depends on the concentration of analogue. From all tested analogs of lipid A of the most effective in the inhibition of LPS induced production of TNF was similar In 531-35, for which the value of the ED50approximately 0,02 nm. Found that other analogs of lipid A, any abscopal LPS induced production of TNF are V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, W-34, B-35, B-32, B-32, B-32, B-35, F-35, F-35, Gino analogues of lipid A inhibit LPS induced production of IL-Beta in monocytes. LPS added at a concentration of 10 ng/ml, analogs of lipid A - at concentrations of 0-10 μm. Found that the degree of inhibition of production of IL-Beta also depends on the concentration of analogue.

In another series of experiments was studied analogues of lipid A LPS induced production of TNF by macrophages of Guinea pigs and mice. Macrophages of Guinea pigs Hartley-white (elm hill Breeders, Chelmsford, Massachusetts) of C57BL/6 mice (Jackson Labza, Bar Harbor, Maine) were isolated from the abdominal cavities initiated animals. The initiation was performed by intraperitoneal injection of 2 mg of Guerin Bacillus calmette (BCG; RIBI Immunochemical Research. Inc., Hamilton, Montana) at a concentration of 10 mg/ml in saline solution for mice and 2 mg BBG at a concentration of 2 mg/7 ml in mineral oil for Guinea pigs. Three days after the introduction of the abdominal cavity of animals by standard methods was isolated macrophages. The cells were allowed to adhesives to the cups for crops for 2-3 h, and then brought into contact with the medium RPMI 1640 containing 10 % calf serum embryo and LPS at a concentration of 10 ng/ml To test the inhibitory capacity of the culture medium immediately before addition of LPS was added analogues of lipid A (at a concentration of 0-100 μm). After 3 CAS, 1981. Analogues of lipid W-32, W-32, W-32, W-32, W-32, W-32, W-32, W-34, B-35, 465-32, V-32, V-32, V-35 and F-35 (just tested to date analogues) inhibit LPS induced production of TNF and Guinea pigs, and mice. Analogues V-34 and F-35 give the strongest inhibitory effect in Guinea pigs (ED50=0,04 nm and of 0.66 nm, respectively), analogues V-32 and F-35 highly efficient inhibition for mice (ED50= 1.3 nm and 2.26 nm, respectively). The magnitude of the ED50obtained in experiments with macrophages of Guinea pigs, are in the range of 0.04 to 18.5 nm. ED50measured in experiments with macrophages of mice, are in the range of 1.0-1.0 nm.

Example 4. As a system for in vivo testing inhibitory effect of analogues of lipid A: 1) LPS induced production of TNF and 2) caused by LPS mortality, we used mouse initiated by BCG (as described above).

Male C57BL/6 mice (see above) 5 weeks of age initiate intravenous BBG (2 mg) into the tail vein. 10 days after intravenous injection through the tail vein initiated by BC mice were administered LPS of E. coli (see above) containing no pyrogen 5% glucose solution (Otsuka Pharmaceuticals Inc. Tokyo, Japan). L is erementar involving analogue of lipid A was introduced as a component of injectate LPS at a concentration of 10-300 μg/mouse. After 1 h after administration of LPS took plasma and analyzed its content TNF above IFU. Caused by septic shock mortality was recorded after 36 h after administration of LPS.

Analogues of lipid A effectively inhibit the processing of TNF caused by doing LPS. Analogues V-32 and F-35 effectively inhibit the production of TNF in mice in vivo (ED50=5,4 mg/mouse and 16.2 μg/mouse, respectively). Analogues V-32, V-33, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, V-32, b425 through-32 and b425 through-32 also inhibit the production of TNF.

In a series of parallel experiments on Guinea pigs, these analogues have also been shown to be effective inhibitors caused by LPS produce TNF in vivo (optimum ED50=7,5 mg/Guinea pig, for similar V-32 ED50=5 mg/Guinea pig).

Example 5. Inhibition by analogues of lipid A LPS-stimulated production of viruses.

LPS is a potent stimulator of the virus that resides in latent form in monocytes or macrophages (see, for example, Pomerantz etc., J. Exp. Med. 172: 253, 1990, mazini, etc., J. of Acquired Imm. Deficiency = MKD Syndromes 3: 200, 1990). In the case of HIV-1 increased production of the virus, apparently, is a consequence of the activation cleto is motiram linking transmastoid factors to the site of NF-KB HIV-1, this in turn leads to increased transcription and replication of the virus (e.g., Dax and others, Proc. Natl. Acad. Sei. USA 86:5974, 1989).

Described in the invention analogues of lipid A inhibit LPS mediated amplification of HIV-1 replication. This was shown using a model system in vivo, which allows you to monitor the transcription of the long terminal repeat (DCT). Because activation of the enhancer (amp) transcription DCT HIV-1 correlates with viral replication (Coleman and others, AIDS 2:185, 1988, Nabeul and Baltimore, Nature 326/711, 1987), this test allows to reliably measure the level of replication, and, consequently, the production of viruses.

Plasmid HIV-1 DCT-HAT (Pomerantz and others, 1990, see above), which is a structure containing DCT HIV-1, attached to the frame with the gene chloramphenicolchloramphenicol (HUT), multiply in the cells of NV-101 (Flexible-Bearer, Grand island, new York). The plasmids isolated from cellular extracts using affinity column "Quiagen" according to the manufacturer's instructions (Quiagen Jn., Chatsworth, California) and temporarily infect her cell U 937 (N CRL 1593 in American culture Collections, Rockville, MD) according to the method Pomerania and others (1990, see above) with the only difference that the entire process of infection Prov μg of HIV-1 DCT-HAT, or 10 µg of PATH (i.e., a control plasmid carrying only the gene THAT, Promega Biotec, Madison, Wisconsin). At 24 h after infection cells incubated with similar lipid A or without it (usually at a concentration of 0.0 to 1.0 μm). After 30 min incubation, cells are added formalparameterlist (PMA, Sigma chemical Co., St. Louis, mo) at a concentration of 50 ng/ml and LPS 5 Ecoli 0III:B4 (see above) at a concentration of 100 ng/ml and incubated for another 24 h the cells are Then collected and are lysed as described by Ausubel and other (Current notes on molecular biology". John Wiley and sons, new York, 1987), and determine the protein concentration in the extract using the system for the analysis of protein Micro-Bees", pierce chemical Co. (Rockford, Illinois), and measure the activity of HAT as the rate of acylation of chloramphenicol (PM/min), as described in Biotech Npd ate 5(2):28 ("New pluarity diffusion analysis HAT facilitates the handling and analysis of samples". Publication DuPont Co., Biotechnology Systems, Wilmington, Delaware). Similar V-32 lipid A inhibits LPS mediated induction of transcription DCT HAT with a mean IC50equal to 85 nm.

Similar results were obtained using the cell line U 937, persistently infected hybrid genome of HIV-1 precise line U 938 Latama and other (Cell Immunol., 129:513, 1990). Cells were cultured as described by Latama and others (1990, see above), and was treated with 106cells similar to lipid A (at a concentration of 0.0 to 1.0 μm). After 30 min after addition of similar cells were treated with phorbolmiristatacetate (at a concentration of 0.33 ng/ml, above), and E. coli LPS 0III:B4 (at a concentration of 33 ng/ml, as described above). Cells were kept in culture medium for another 24 h, collected and determined the activity HAT as described above. The results show that V inhibit LPS-stimulated activation of prep for HIV with IC50equal to 15 nm. Analogues V-32, B400-32, B427-32, B464-32 and B466-32 also inhibit LPS-stimulated ACTIVATION of prep for HIV with IC50in the interval from 15 to 260 nm. B464-32 also inhibit the activation of DCT HIV mediated LPS of other gram-negative bacteria (e.g., Salmonella typhimurium).

Adjustable NF-KB control transcription is not unique to HIV-1. Other viral genomes, such as the genome of simian vacuolating virus (S-40), contain the binding site of NF-KB in enhancemen element early promoter (Nakamura and others, J. Biol. Chem, 264:20190, 1989). Plasmid construct containing the hybrid gene enhancer promoter S-40 HAT, marked Pat (Promega Biotec), temporarily infect cells U 937 as described is adding the equivalent cells treated with forbesmarshall.com (at a concentration of 50 ng/ml) and LPS E. coli 0III:B4 (at a concentration of 100 ng/ml). Cells incubated in culture medium for another 24 h, harvested and examined for the activity of the HUT, as described above. Similar lipid W-32 inhibited or completely blocked LPS-stimulated expression of the HUT. In another experiment (Experiment # 4") LPS-stimulated expression of HAT inhibited or completely blocked by the analogue of lipid W-32. These results show that the described analogs of lipid A effectively inhibit LPS mediated amplification replication S-40.

Described in the invention analogues of lipid A can similarly suppress the activation of any virus, the replication of which is directly or indirectly controlled by a regulatory region of NF-KB. Examples of such viruses include, without limitation, cytomegalovirus or herpes viruses (e.g. Herpes simplex). In addition, since the activation of the influenza virus (monocytes and macrophages) enhanced LPS (Nein, etc., J. Immunol, 145:1921, 1990) and the excessive secretion of TNF-alpha is involved in the observed complications when combined influenza A bacterial infection, these analogues of lipid A, in all probability, also inhibit activation of the influenza virus.

therapy. Described in the invention analogues of lipid A permit violations include, without limitation, the following examples) in the blood endotoxin (or sepsis syndrome) gram-negative bacteria (with accompanying symptoms of fever, General inflammation, disseminated intravascular coagulation, hypothesia, acute renal failure, acute respiratory distress syndrome, hepatocellular destruction, and/or heart failure), LPS mediated exacerbation of latent or active viral infections (such as HIV-1, cytomegalovirus, herpes viruses, and influenza virus).

Typically, the analog of lipid A is injected in the form of pharmaceutically acceptable compositions, for example in the form of a solution in physiological saline or physiological saline solution, which may contain 5 % glucose (to increase the solubility analogue). The introduction can be accomplished in any convenient way, but usually it is carried out by intravenous intravenous injection or intravenous infusion. When using analogue of lipid A for the treatment of viral infection it can be administered in combination with antiviral agents. Analogues of lipid A can be stored in the form of liofilizovannyh composition.

Analogues of lipid A is injected in doses that provide the desired level of inhibition of the activation of target cells LPS, as a rule, these doses are preferably 0.001 to 500 mg per patient, more preferably 0,>/BR>< / BR>
where at least one of R1- R4represents a

< / BR>
where L is oxygen or CH2;

m = 0 to 14 integer;

n = 0 to 14 integer;

p = 0 to 10, an integer;

q = 0 to 10, an integer;

each of the remaining groups R1- R4independently represents a

< / BR>
< / BR>
where G is the group /S = 0;

x = 0 - 14;

z = 0 to 10;

each group AND1and2regardless - HE, och3,

< / BR>
< / BR>
where d = 0 to 5;

X - (CH2)tO(CH2)vCH3, -(CH2)tOPO(OH)2where t and v = 9 to 14; Y IS-OH, -O(CH2)wCH3, halogen, - OC(O)-(CH2)wCH3where w = 0 - 14,

or pharmaceutically acceptable salt of this compound.

2. The compound of General formula I under item 1, in which at least one of the groups R1- R4represents a

< / BR>
in which m = 0 to 10;

n = 0 to 10;

for any p and q, the condition 0 p + q 12;

each of the remaining groups R1- R4independently represent

< / BR>
where each x = 0 to 10;

z = 0 - 3;

G -

each group AND1and2independently -

< / BR>
or

< / BR>
where d = 0 - 2;

X IS -(CH2)tO(CH2)vCH group, R1- R4represents a

< / BR>
where n = 6 to 10;

6 p + q 10;

each of the remaining groups R1- R4independently -

< / BR>
or

< / BR>
where x = 6 - 11;

G -

each group AND1and2independently -

< / BR>
X - CH2OCH3or-CH2O(CH2)vCH3where v = 1 - 3;

Y - IT.

4. The compound of General formula I

< / BR>
where at least one of the groups R1- R4represents a

< / BR>
< / BR>
where L is oxygen or CH2;

m = 0 - 14;

n = 0 to 14;

p = 0 to 10;

q = 0 to 10;

x = 0 - 14;

z = 0 to 10;

each of the remaining groups R1- R4represents a

< / BR>
< / BR>
where G is the

each AND1and2regardless - HE,

< / BR>
< / BR>
where d = 0 to 5;

X IS -(CH2)t-0(CH2)vCH3where t and v = 0 - 14;

Y - OH, -O(CH2)wCH3, halogen,

< / BR>
where w = 0 - 14,

or pharmaceutically acceptable salt of this compound.

5. Connection on p. 4, in which at least one of the groups R1- R4-

< / BR>
where m = 0 to 10;

n = 0 to 10;

for p and q, the condition 0 p + q 12;

each of the remaining R1- R4-

< / BR>
where x = 0 to 10;

each is UB>)vCH3where t = 0 - 6, v = 0 - 6;

Y - IT.

6. The compound according to any one of paragraphs.2, 3, or 5, in which n = 6 or q = 5 or x = 6 or 10 or both n = 6, q = 5 and x = 6 or 10.

7. The compound according to any one of paragraphs.1 - 6, which represents a lysine salt, Tris-salt.

8. Connection PP.1 - 6 formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
9. Pharmaceutical composition having antiviral activity, including an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient contains a compound of the formula I in amounts of 0.001 - 500,0 mg per dosage unit.

10. The connection formulas

< / BR>
where R1HE, HE protected or protected group AND1where AND1-

< / BR>
in which d = 0 to 5;

R2HE protected IT, (CH2)wCH3where w = 0 to 3, halogen;

< / BR>
< / BR>
< / BR>
where J is - OH or protected IT;

L is oxygen;

m and n = 0 to 14;

p and q = 0 to 10;

x = 0 - 14;

z = 0 - 10,

or pharmaceutically acceptable salt of this compound.

11. Connection on p. 10, where R2represents a

< / BR>
< / BR>
where J is - OH or protected IT;

m and n/SUB>)wCH3where w = 0 - 3.

12. The connection formulas

< / BR>
where R4-

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where J IS HE or protected IT;

L is oxygen or CH2;

G/S = O

each m and n = 0 to 14;

each of p and q = 0 to 10;

x = 0 - 14;

z = 0 to 10;

R3HE protected IT, och3group a21or a protected group AND21where the group AND21-

< / BR>
< / BR>
where d = 0 to 5;

X1- X or protected X, where X is -(CH2)tHE, (CH2)tO(CH2)vCH3, (CH2)tORO(OH)2where t and v = 0 - 14;

Z - HE or protected IT,

< / BR>
or pharmaceutically acceptable salt of this compound.

13. Connection on p. 12, in which R4-

< / BR>
< / BR>
where J is independently - IT or secure IT;

m and n = 0 to 10;

x = 0 to 10;

z = 0 - 3;

G/S = O,

for p and q, the condition 0 p + q 12;

R3HE protected IT or the group AND21or a protected group AND21where the group AND21-

< / BR>
< / BR>
where d = 0 - 2;

X1- (CH2)tHE, (CH2)tO(CH2)v-CH3where t = 0 - 6;

v = 0 - 6.

14. BR>R3group IT, protected IT, the group AND21or a protected group AND21where the group AND21-

< / BR>
X - CH2HE, CH2OCH3or CH2O(CH2)vCH3where v = 1 - 3 .

15. The connection formulas

< / BR>
where each R2and R4independently -

< / BR>
< / BR>
< / BR>
J - OH, protected IT;

m and n = 0 to 14;

p and q = 0 to 10;

x = 0 - 14;

z = 0 to 10;

L is oxygen, CH2;

Q - N3or NH2;

R1HE, HE protected protected group AND1;

R3HE protected IT, the group AND21protected group AND21where AND1and21are

< / BR>
< / BR>
d = 0 to 5;

R2HE protected IT, halogen, (CH2)wCH3where w = 0 - 14;

X1- X or protected X, where X is - (CH2)t-O-(CH2)vCH3where t and v = 0 - 14.

16. Connection on p. 15, in which each R2and R4is

< / BR>
< / BR>
where J is independently OH, protected IT;

m and n = 0 to 10;

x = 0 to 10;

z = 0 - 3;

for any p and q, the condition 0 p + q 12;

P1- HE protected, protected AND1;

R3HE protected
where d = 0 - 2;

P2HE protected IT or O(CH2)wCH3where w = 0 - 2;

X1- (CH2)tO(CH2)vCH3where t and v = 0 - 6.

17. Connection on p. 16, in which R2and R4are

< / BR>
< / BR>
where J is - OH or protected IT;

x = 6 - 11;

n = 6 to 10;

6 (p + q) 10;

R1HE protected IT, or AND1;

R3HE protected IT, the group AND21or a protected group AND21where AND1and21< / BR>
< / BR>
R2- HE;

X - CH2OCH3or CH2- (CH2)vCH3where v = 1 - 3.

18. The connection formulas

< / BR>
in which each R1- R4independently -

< / BR>
< / BR>
< / BR>
< / BR>
where J is - OH or protected IT;

L is oxygen or CH2,

m and n = 0 to 10;

p and q = 0 to 10;

x = 0 - 14;

z = 0 to 10;

G - SO;

R1HE, HE protected or protected group AND1;

R3- group a21or a protected group AND21where AND1and21-

< / BR>
< / BR>
d = 0 to 5;

R2- halogen, HE protected IT, O(CH2)wCH3, OS(O)(CH2)wCH3where w = 0 - 14;

X1R4are

< / BR>
< / BR>
< / BR>
< / BR>
where J is - OH or protected IT;

m and n = 0 to 10;

x = 0 to 10;

z = 0 - 3;

for any p and q, the condition 0 p + q 12;

R1HE, HE protected protected group AND1;

R3- group a21or a protected group AND21where AND1and21< / BR>
< / BR>
< / BR>
where d = 0 - 2;

P2HE protected IT, (CH2)wCH3where w = 0 - 3;

X1- (CH2)tO(CH2)vCH3where t and v = 0 - 6.

20. Connection on p. 19, where R1- R4are

< / BR>
< / BR>
where x = 6 - 11;

n = 6 to 10;

6 p + q 10;

R1HE, HE protected protected group AND1;

R3- AND21or a protected group AND21where AND1and21< / BR>
< / BR>
R2- HE;

X - CH2O(CH2)vCH3where v = 1 - 3.

Priority signs:

11.10.91 connection formula I on p. 1, except X - (CH2)tORO(OH)2connection on p. 10, a connection on p. 12, in addition to R3- OCH3X IS -(CH2)tORO(OH)2, connecting via PM.15 and 18, the pharmaceutical composition.

25.08.92 p is

 

Same patents:

The invention relates to a method of producing aminosaccharides used as chemical reagents and drugs

The invention relates to new compounds of the number of semicarbazides, namely 4-(glucopyranosyl) semicarbazides General formula

R-NH-CO-NH-NH2(I) where R = D-glucosyl-D-galactosyl-L-arabinosyl-that can be used for the synthesis of compounds possessing anti-inflammatory, antimicrobial activity

The invention relates to medicine and chemistry, in particular to pharmacology, particularly to a method of obtaining medical treatment for patients affected with radiation sickness, as well as for treatment and prevention of poisoning by salts of heavy metals

The invention relates to methods of producing compositions on the basis of new associates (complexes) deprotonated hyaluronic acid with 3d ions of metals of the fourth period of the periodic table and compounds, namely, Co and Zn

FIELD: chemistry.

SUBSTANCE: in method of obtaining compound aminoalkyl glucosaminide 4-phosphate of formula , X represents , Y represents -O- or NH-; R1, R2 and R3, each is independently selected from hydrogen and saturated and unsaturated (C2-C24) aliphatic acyl groups; R8 represents -H or -PO3R11R11a, where R11a and R11a, each is independently -H or (C1-C4) aliphatic groups; R9 represents -H, -CH3 or -PO3R13aR14, where R13a and R14, each is independently selected from -H and (C1-C4) aliphatic groups, and where indices n, m, p, q each independently is a integer from 0 to 6 and r is independently integer from 2 to 10; R4 and R5 are independently selected from H and methyl; R6 and R7 are independently selected from H, OH, (C1-C4) oxyaliphatic groups -PO3H2, -OPO3H2, -SO3H, -OSO3H, -NR15R16, -SR15, -CN, -NO2, -CHO, -CO2R15, -CONR15R16, -PO3R15R16, -OPO3R15R16, -SO3R15 and -OSO3R15, where R15 and R16, each is independently selected from H and (C1-C4) aliphatic groups, where aliphatic groups are optionally substituted with aryl; and Z represents -O- or -S-; on condition that one of R8 and R9 represents phosphorus-containing group, but R8 and R9 cannot be simultaneously phosphorus-containing group, including: (a) selective 6-O- silylation of derivative of 2-amino-2-desoxy-β-D-glucopyranose of formula , where X represents O or S; and PG independently represent protecting group, which forms ester, ether or carbonate with oxygen atom of hydroxy group or which forms amide or carbamate with amino group nitrogen atom, respectively; by means of tri-substituted chlorosilane RaRbRcSi-Cl, where Ra, Rb and Rc are independently selected from group, consisting of C1-C6alkyl C3-C6cycloalkyl and optionally substituted phenyl, in presence of tertiary amin, which gives 6-silylated derivative; (b) selective acylation of 4-OH position of obtained 6-O-silylated derivative with 6-3-alkanoyloxyalcanoic acid or hydroxyl-protected (R)-3-hydroxyalkanoic acid presence of a carbodiimide reagent and catalytic 4-dimethylaminopyridine or 4-pyrrolidinopyridine to give a 4-O-acylated derivative; (c) selectively deprotecting the nitrogen protecting groups, sequentially or simultaneously and N,N-diacylating the resulting diamine with (R)-3-alkanoyloxyalkanoic acid or a hydroxy-protected (R)-3-hydroxyalkanoic acid in presence of peptide condensation reagent; (d) introducing a protecting phosphate group at 3-position with a chlorophosphate or phosphoramidite reagent to give a phosphotriester; and (e) simultaneous or sequential deprotecting phosphate, silyl, and remaining protecting groups.

EFFECT: method improvement.

11 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention claims derivatives of 1-α-halogen-2,2-difluoro-2-deoxy-D-ribofuranose of the general formula (I) in solid state, where R1 is benzoyl or ; R2 is hydrogen; and X is CI, Br or I; which can be applied as intermediates in stereoselective method of gemcitabine obtainment. In addition, invention claims stereoselective method of obtaining compounds of the general formula (I), including stages of: (i) recovery of 1-oxoribose of formula to obtain lactol of formula ; (ii) interaction of compound of formula (III) with halogen phosphate compound of formula in the presence of a base to obtain 1-phosphatefuranose derivative of formula ; and (iii) interaction of compound of formula (V) (also included in the claim) with halogen source, with further recrystallisation of obtained product; where R1, R2 and X are the same as indicated above while R3 is phenyl.

EFFECT: efficient method of obtaining derivatives of the abovementioned agent.

11 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to oligosaccharide, suitable for vaccine against meningitis A, which includes first mannose unit, which has spacer in alfa-configuration in C-1, where said spacer is able to conjugate with protein, and bound to second mannose unit by 1,6-bond, which binds C-6 of first unit with C-1 of second unit, 1,6-bond including phosphonate. Invention also relates to methods of obtaining oligosaccharide and improved methods of obtaining mannose derivative, suitable for obtaining immunogenic oligosaccharide. Invention also relates to pharmaceutical composition for induction of immune response, immunogenic composition, capable of inducing formation of protective antibodies against meningitis A and vaccine against meningitis A, which include oligosaccharide.

EFFECT: obtained glycoconjugates have C-phosphonate bond, which is much more stable than natural phosphodiester bonds, as well as higher immunologic activity.

51 cl, 4 dwg, 3 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to immunoeffectors of formula:

,

where n equals 1 (C6alkyl) or 5 (C10 alkyl), and R1 represents CO2H.

EFFECT: claimed novel compounds and pharmaceutical compositions based on them enhance immune response, increase production of antibodies in immunised animals, stimulate production of cytokines and activate macrophages.

7 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to immune-stimulating compounds of formula:

(I),

where L1, L2, L3, L4, L5 and L6 independently represent -O- or -NH-; L7, L8, L9 and L10 is independently absent or represent -C(=O)-; Y1 represents -OP(O)(OH)2; Y2, Y3 and Y4 each represents -OH; R1, R3, R5 and R6 independently represent C8-13alkyl; and R2 and R4 independently represent C6-11alkyl.

EFFECT: novel compounds, based on them pharmaceutical and vaccine compositions, suitable for immune system stimulation, are claimed.

21 cl, 45 ex, 12 dwg

FIELD: biotechnologies.

SUBSTANCE: invention refers to biotechnology, and namely to analysis method of heparins or low-molecular heparins, and can be used when controlling samples, and for standardising Lovenox method and obtaining homogeneous products. Method of quantitative determination of heparins or low-molecular heparins is implemented by means of the following stages: sample is depolymerised with heparinases, then the obtained depolymerisate is reduced, and after that the analysis is performed by means of high-efficiency liquid chromatography.

EFFECT: this invention allows to clearly differentiate Lovenox from other low-molecular heparins not containing "1,6-anhydro" derivatives.

7 cl, 2 dwg, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to oligosaccharides for synthesis of sugars, as well as a method for production thereof, where the oligosaccharides contain a fragment:

.

Wherein tetrasaccharide includes X1, hexasaccharide includes X1, X2, octasaccharide includes X1, X2, X3, decasaccharide includes X1, X2, X3, X4, dodecasaccharide includes X1, X2, X3, X4; X1-X4 represent:

or ,

where R8 is hydrogen or alkyl; R1 - R2, R5 - R7 are protective groups. The disclosed method comprises joining the structures:

or to the structure or ,

where R1 - R10 are protective groups. Novel oligosaccharides and methods for production thereof for industrial use are disclosed.

EFFECT: improved properties of compounds.

82 cl, 18 dwg, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to biotechnology. Disclosed is a method of producing an ethylenically unsaturated glycoside of formula

The method includes reacting an ethylenically unsaturated compound of formula with a polysaccharide containing 10 to about 200000 monosaccharide links, such as starch, amylose, amylopectin, cellulose, in the presence of a glycosidase, such as amylase, cellulase, glucosidase and galactosidase, or a glycosyltransferase, such as cyclomaltodextrin glucanotransferase.

EFFECT: high purity of the product.

7 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of biotechnology. Claimed is method for obtaining ethylene-unsaturated glycoside of formula I , where n, A, X, R3 and R4 have values, given in the formula. Formula I glycoside is obtained by reaction of ethylene-unsaturated alcohol of formula II with saccharide of formula III in presence of β-glucosidase. Molar ratio of ethylene-unsaturated alcohol of formula II to saccharide of formula III constitutes from 2:1 to 30:1. Reaction is carried out in presence of mixture of solvents, consisting of water and 1,4-dioxane. Weight ratio of water and 1,4-dioxane constitutes from 0.1:1 to 9:1. Weight ratio of mixture of solvents to saccharide constitutes from 3:1 to 30:1.

EFFECT: invention makes it possible to increase output of ethylene-unsaturated glycoside after certain time of reaction process and/or when equilibrium is achieved.

3 cl, 3 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing 1-isonicotinyl-2-D-glucosyl hydrazone. In the glucosylation reaction of isonicotinic acid hydrazide the method involves using anionite AN 31 GS as a catalyst of the enhanced effectiveness, and using 95-96.5% ethanol or 85-90% isopropanol as the reaction medium. At the final stage the method involves sorption of contaminating impurities with activated carbon followed by drying the end product in nitrogen atmosphere.

EFFECT: improved preparing method.

2 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to geranyl compounds represented by the following formulas (I-1) , (I-2) or (I-3) wherein R1 means compounds of the following formulas: or R2 means a group remaining after removing all carboxyl groups presenting in carboxylic acid chosen from group consisting of malic acid, citric acid, succinic acid, fumaric acid and others; m = 1, 2 or 3; n = 0, 1 or 2, and m + n represent a number of carboxylic groups presenting in indicated carboxylic acid; R3 means p-hydroxyphenyl or mercapto-group. Also, invention relates to derivatives of mevalonic acid represented by the following formula (I-4): wherein R means -CH2OH or CH3. Also, invention to an antitumor agent comprising as an active component geranyl compound of formulas (I-1), (I-2) or (I-3) or derivative of mevalonic acid of the formula (I-4), and optionally a pharmaceutically acceptable carrier or solvent. Also, invention relates to a method for treatment of liver cancer based on using geranyl compound of formulas (I-1), (I-2) or (I-3), or derivative of mevalonic acid of the formula (I-4) and using proposed compounds in manufacturing an antitumor agent. Invention provides using geranyl compounds or derivatives of mevalonic acid as antitumor agents.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 3 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: method involves preliminary acetylation of chitin with acetic anhydride, washing and drying the acetylated chitin in order to reduce degree of deacetylation thereof and, as a result, increase output of the desired product - D(+)-glucosamine hydrochloride when obtaining said product through hydrolysis of acetylated chitin with concentrated hydrochloric acid while heating, followed by evaporation, crystallisation, separation, washing and drying the desired product.

EFFECT: high output of the desired product while maintaining its high quality; method is more environmentally friendly since pre-treatment of chitin reduces the amount of processing wastes.

1 cl, 2 ex

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