Synthetic polysaccharides, the method of receiving and containing pharmaceutical composition

 

(57) Abstract:

Describes a new synthetic polysaccharides of the General formula I, where the wavy line represents a relationship that is located either above or below the plane of the pyranose cycle; formula II means polysaccharide Ro containing n identical or different monosaccharide units linked to its anomeric carbon with PE; formula III is a schematic illustration of the monosaccharide residue with pyranose structure selected among the hexoses, and this residue is linked to its anomeric carbon to another monosaccharide residue and the hydroxyl group of this residue is substituted by an identical or different groups X selected among (C1-C6)-alkyl groups, and sulfo; h = 2, n means an integer from 10 to 25; D means pentasaccharide structure IV, where R1means (C1-C6)-alkyl group, or alphagroup; R1a is specified for R1the value of, or with the oxygen atom to which it is attached and with the carbon atom containing carboxyl function in the same cycle, form the group-CH2-Oh; R means (C1-C6)-alkyl group; W denotes an oxygen atom or methylene group, or one of its salts, in micromotions pharmacological activities of heparin. Describes how they are receiving and containing the pharmaceutical composition. 4 C. and 11 C. p. F.-ly, 4 PL.

The invention relates to new synthetic polysaccharides with angiladooney and antithrombotic pharmacological activities of heparin. Heparin belongs to the family of glycosaminoglycans (GAGs), which are natural heterogeneous sulfated polysaccharides.

Heparin preparations are a mixture of chains, including the number of monosaccharide residues from 10 to 100 and more. This heterogeneity of size is added to the heterogeneous structure at the level of the constitutive nature of monosaccharides, as well as at the level of existing substituents (L. Roden "Biochemistry of glycoproteins and glycosaminoglycans", ed. Lennarz, W. J., Plenum Press, new York and London, 267-371, 1980).

Each family natural GAGs usually has a range of pharmacological activities. All of them are drugs that can be obtained from natural products. So, for example, sulfated heparins and heparan possess antithrombotic activity, which is associated with the simultaneous effect of several coagulation factors.

Heparin catalyzes, otzia blood, namely, factor XA and factor IIa (or thrombin). Heparin preparations with a low molecular weight (NWRM) contain chain from 4-30 monosaccharides and have the ability to more selectively influencing factor XA than thrombin.

Some synthetic oligosaccharides, in particular those described in European patent 84999 have the ability to selectively inhibit, via antithrombin III, factor XA without any effect on thrombin.

It is known that the inhibition of factor XA requires fixation of heparin to at III through domain binding to antithrombin (DLA) and that the inhibition of factor IIa (thrombin) necessitates commit to AT (III) through DLA, and thrombin through less specific domain binding (DLT).

Synthetic oligosaccharides corresponding to the domain DLA heparin, known and exhibit antithrombotic activity in venous thrombosis. These compounds are described in European patents 529715 and 621282 and patent Canada 2040905.

The effectiveness of these oligosaccharides in the prevention of arterial thrombosis, however, is limited by their inability to inhibit thrombin.

The synthesis of glycosaminoglycans heparin type, capable the of westlin.

In order to identify the active ingredients, which are inhibitors of thrombin and factor XA, it was proposed to link the two oligosaccharide small size (DLA and DLT) with the remainder ("spacer"), not involved in the biological activity.

Currently, it is found that the new polysaccharide derivatives can be synthesized relatively simple manner and at the same time they are biologically active. In particular, they have anticoagulant and antithrombotic properties. Moreover, in connection with obtaining a synthetic way of these polysaccharides, can be selectively modify their structure and, in particular, to remove unwanted sulfate deputies involved in the interaction with certain proteins. Thus, it is possible to obtain polysaccharides that are effective antithrombotic and anticoagulant agents and, in addition, in vivo can not be exposed to proteins such as platelet factor 4 (FP4), which neutralize the effects of heparin, in particular, on thrombin.

Thus, unexpectedly found that sulfated and alkylated polysaccharides can be an effective antithrombotic agentiilede.

Thus, it is found that the use of polysaccharide synthesis sequences can accurately modulate activity type GAGs and get very active products having the properties of heparin.

Thus, according to one of its aspects, the present invention relates to a new synthetic polysaccharide, including domain binding to antithrombin III, formed by a sequence of five monosaccharides containing generally two carboxyl functions and at least four sulfate groups, and the domain of its non-end is directly connected with the domain binding to thrombin, comprising a sequence of from 10 to 25 monosaccharide residues selected among the hexoses, pentoses and deoxysaccharides, all hydroxyl groups are, independently from each other, turned into a simple ester groups with (C1-C6)-alkyl group or tarifitsirovana to ester groups in the sulfate form; and its salts, in particular pharmaceutically acceptable salts.

Preferably the invention relates to polysaccharide above, characterized in that all of its hydroxyl groups are methylated or ptx2">

The products of the present invention are, in particular, polysaccharides, represented by the following formula (I):

< / BR>
in which

- the wavy line denotes a bond, located either above or below the plane of the pyranose cycle

< / BR>
means polysaccharide Po containing n identical or different monosaccharide residues linked to its anomeric carbon to Pe;

< / BR>
is a schematic illustration of the monosaccharide residue with pyranose structure selected among the hexoses, and this residue is linked to its anomeric carbon to another monosaccharide residue and the hydroxyl group of this residue is substituted by an identical or different groups X selected among (C1-C6)-alkyl groups, and sulfo; h is 2,

- n means an integer from 10 to 25;

- Re means pentasaccharide patterns:

< / BR>
where R1means (C1-C6)-alkyl group, or alphagroup;

R1a is specified for R1value or with the oxygen atom to which it is attached, and the carbon atom containing carboxyl function in the same cycle, forms a group C-CH2-O;

- R means (C1-C6) -alkyl group;

- W oznacza CLASS="ptx2">

It should be noted that in the present description the wavy line signifies usually link located either below or above the plane of the pyranose cycle.

Contained in Po monosaccharides may be the same or different one relative to the other, migliozzi communication can be of type or .

These monosaccharides are preferably chosen among the D - or L-hexoses, as allose, altrose, glucose, mannose, galasa, idose, galactose, talose (in this case h = 2), or the D - or L-pentoses, as ribose, arabinose, xylose, lyxose (in this case h = 2). Can also be used other monosaccharides, such as, for example, detoxifer (h = 1 and/or CH2OX = CH3).

When pentasaccharide Pe the remainder of the W stands for an oxygen atom and R1a is specified for R1the value of these pentasaccharide are known compounds, described in particular in European patent 300099, 529715, 621282 and 649854, as well as in the literature. Get them from synthons, also described in the literature (according to C. Van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engl., 32 1671- 1690 (1993)).

When pentasaccharide Pe R1a is different from R1value and/or W means the carbon atom, these pentasaccharide get with the help of new synthons, Katy acid is replaced by a residue the conformation of which is blocked by the bridge, these pentasaccharide get with the help of new synthons, which constitute a further aspect of the invention.

Thus, according to another of its aspects, the present invention relates to new intermediate products suitable for producing compounds of formula (I).

The polysaccharide part of the Po can be formed 10-25 and alkylated di - or resultativity monosaccharide residues.

The polysaccharide part of the Po can be formed 10-25 and alkylated mono - or desulfation monosaccharide residues.

The polysaccharide part of the Po can be formed 10-25 alkylated, unsubstituted or partially substituted and/or fully substituted monosaccharide residues.

Substituted or unsubstituted residues may be located along the entire circuit or, alternatively, they can be grouped in a substituted or unsubstituted sharidny domains.

Communication can be of type 1,2; 1,3; 1,4; 1,5; 1,6; and type or .

In the present description are given the designation of conformations: 1WITH4for L-iduronovoy acid,4WITH1for D-glucuronic acid, however, it should be noted that usually the conference is met conformation1WITH42S0or4C1.

Preferred according to the invention the compounds are compounds of formula I. A):

< / BR>
where

< / BR>
means a special family of polysaccharides Po related to its anomeric carbon to Pe specified in the formula (I);

< / BR>
is specified for formula (I) is,

- OX are specified for formula (I) is in the case of the same monosaccharide may be the same or different;

- monosaccharides contained in [ ]mform a repeating m times the disaccharide;

the monosaccharides contained in [ ]tform repeated t times the disaccharide;

- m varies from 1 to 8; t varies from 0 to 5 and p varies from 0 to 1, provided that 5 m + t 12; and their salts, in particular pharmaceutically acceptable salts.

The preferred compounds are salts, the anion of which corresponds to the formula (I. 1):

< / BR>
where t means 5, 6 or 7, and the cation is a pharmaceutically acceptable monovalent cation and the corresponding acid.

Also preferred are salts, the anion of which corresponds to the formula (I. 2):

< / BR>
where t means 5, 6 or 7, and the cation is pharmaceutically acceptable od the Nyon which corresponds to the formula (I. 3):

< / BR>
in which m denotes 1, 2 or 3 and t is 2, 3, 4 or 5, and the cation is a pharmaceutically acceptable monovalent cation; and the corresponding acid.

Other preferred according to the invention the compounds are compounds of formula II. A):

< / BR>
in which

< / BR>
means a special family of polysaccharides Po related to its anomeric carbon to Pe specified in the formula (I);

< / BR>
is specified in the formula (I) value;

- OX are specified in the formula (I) is in the case of the same monosaccharide may be the same or different;

the monosaccharide contained in [ ]mrepeated m times; monosacharides contained in [ ]trepeated t' time; the monosaccharide contained in [ ]prepeated p';

- m' varies from 1 to 5; t' varies from 0 to 24 and p' varies from 0 to 24, provided that 10 m' + t' + p' 25;

and their salts, in particular pharmaceutically acceptable salts.

Preferred according to the invention salts are those salts, the cation of which is chosen among cations of alkali metals, and even more preferred such cation which is Na+or+.

Especially preferred aflault- -D-glyukopiranozil)- (1--->4)-[O-(3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)- (1--->4)]4-O-(2,3-di-O-methyl - 6-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)- (1--->4)-O-(2,3,6-tri-O-sulfo- -D-glyukopiranozil)- (1--->4)-O-(2,3-di-O-methyl-L-ecoperestorika acid) -(1--->4)-2,3,6-tri-O-sulfo- -D-glucopyranoside in the form of sodium salts;

- methyl-O-(3-O-methyl-2,4,6 - tri-O-sulfo--D - glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di - O-sulfo--D-glyukopiranozil) -(1--->4)-[O-(3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6 - di-O-sulfo--D-glyukopiranozil) -(1--->4)]5-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(2,3-di-O-methyl - D-glucopyranosyloxy acid) -(1--->4)-O-(2,3,6-tri-O-sulfo- -D-glyukopiranozil)- (1--->4)-O-(2,3-di-O-methyl-L-ecoperestorika acid) -(1--->4)-2,3,6-tri-O-sulfo- -D-glucopyranoside in the form of sodium salts;

- methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-[O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)]6-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(2,3-di-O - methyl-D-glucopyranosyloxy acid)-(1--->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(2,3-di-O-methyl--L - ecoperestorika acid) -(1--->4)-2,3,6-tri-O-sulfo- -D-glucopyranosid is life--D - glyukopiranozil)- (1--->4)]11-O-(2,3-di-O-methyl-D - glucopyranosyloxy acid)- (1--->4)-O-(2,3,6-tri-O-sulfo- -D-glyukopiranozil) -(1--->4)-O-(2,3-di-O-methyl-L-ecoperestorika acid) -(1--->4)-2,3,6-tri-O-sulfo- -D-glucopyranoside in the form of sodium salts;

- methyl-O-(2,3-di-O-methyl-4,6 - di-O-sulfo--D - glyukopiranozil)-(1--->4)-[O- (2,3-di-O-methyl-6-O-sulfo- -D-glyukopiranozil)- (1--->4)]13-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1--->4)-O-(2,3,6-tri-O-sulfo- -D-glyukopiranozil)- (1--->4)-O-(2,3-di-O-methyl-L-ecoperestorika acid)- (1--->4)-2,3,6-tri-O-sulfo- -D-glucopyranoside in the form of sodium salts;

- methyl-O-(2,3-di-O-methyl-4,6-di - O-sulfo--D-glyukopiranozil) -(1--->4)-[O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil) -(1--->4)]15-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1--->4)-O-(2,3,6-tri-O-sulfo--D - glyukopiranozil)-(1--->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid) -(1--->4)-2,3,6-tri-O-sulfo--B-glucopyranoside in the form of sodium

salt;

- methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D - glyukopiranozil) -(1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-[O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)]2-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil) -(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil) -(1--->4)]
- methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-[O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)]2-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil) -(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil) -(1--->4)]3-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1--->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil) -(1--->4)-(2,3-di-O-methyl-L-ecoperestorika acid)-(1--->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

- methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil) -(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil) -(1--->4)]4-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1--->4)-O-(2,3,6-tri-O - sulfo--D-glyukopiranozil) -(1--->4)-(2,3-di-O-methyl--L - ecoperestorika acid)-(1---> what nosil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) - (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)- (1--->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil) - (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil) - (1--->4)]3-O-(2,3-di-O-methyl-6-O-sulfo- -D-glyukopiranozil) - (1--->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid) - (1--->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil) - (1--->4)-(2,3-di-O-methyl--L - ecoperestorika acid)-(1--->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

- methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil) -(1--->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil) -(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil) - (1--->4)]4-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil) - (1--->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)- (1--->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil) -(1--->4)-(2,3-di-O-methyl--L-ecoperestorika acid) -(1--->4)-2,3,6-tri-O-sulfo- -D-glucopyranoside in the form of sodium salts;

- methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo- -D-glyukopiranozil) -(1--->4)-O-(D-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)-(1--->4)-[O-(2,3,6-tri-O-methyl-O-glyukopiranozil) -(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)] 5-O-(2,3-di-O-methyl-6-O-sulfo- -D-glyukopiranozil) -(1--->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid) -(1--->4)-O-(2,3,6-glucopyranosid in the form of sodium salt.

The present invention also relates to a method for producing compounds of formula (I), namely, that at the first stage synthesize fully protected precursor of the target polysaccharide of formula (I) containing a protected precursor of Pe domain (this domain is presented in figure 1 (see end of description)), extended at its non-protected precursor of sulfated polysaccharide Po, then, in the second stage, introduce and/or remove negatively charged group.

On the one hand, you can use the fully protected precursor tetrasaccharides part of EFGH pentasaccharide. Then add the polysaccharide Po, which contains at its pampering the end of the missing balance D pentasaccharide Pe, with the aim of obtaining, after combination, the entire field of DLA, which is thus restored.

On the other hand, you can use the fully protected precursor of the disaccharide glycosides part of GH pentasaccharide. Then add the polysaccharide Po, the predecessor of the DLT, which contains at its pampering the end of the missing residue DEF pentasaccharide Pe, with the aim of obtaining, after combination, the entire field of DLA, which thus Vosstania the data in the literature or are part of the present invention. The synthesis of the polysaccharide part of the predecessor Po is carried out according to well-known specialist reactions using the methods of synthesis of oligosaccharides (G. J. Boons, Tetrahedron, 52, 1095-1121 (1996)) or oligosaccharide, when the oligosaccharide, which is the donor of glycosidic bonds, combined with the oligosaccharide, which is the acceptor of the glycosidic bonds, with the aim of obtaining another oligosaccharide, the size of which is equal to the sum of the values of the two reactive species of oligosaccharides.

This sequence is repeated up to obtain the target compounds of formula (I). The nature and profile of the replacement target compounds are determined by the nature of the residues of chemical compounds used in the various stages of the synthesis, according to well-known expert rules.

The preferred method of obtaining predecessors Po according to the present invention is presented in scheme 2 (see the end of the description).

Under temporary understand Deputy, continuing for a limited number of stages; understand semi-permanent Deputy, continued for a much larger number of stages; and under constant realize Deputy, continuing until the end of the synthesis; permanent replace the CLASS="ptx2">

In scheme 2 (a) means a monosaccharide, which is the donor of glycosidic bonds, where Z means a temporary protective group of the hydroxyl function and Y means the activator anomeric carbon, Tn, identical or different, denote temporary, semi-permanent or permanent substitutes all other hydroxyl functions.

The compound (b) containing the unsubstituted hydroxyl group, is a monosaccharide, which is the acceptor glycoside bond, where Tn, identical or different, represent a temporary, semi-permanent or permanent substituents of hydroxyl groups. T1means a temporary, semi-permanent or permanent protective group at the anomeric position, which is removed when you want to activate the anomeric carbon.

With the aim of producing compounds according to the invention donor glycoside bond (a) enter into interaction with the acceptor glycoside bond (b) to obtain the disaccharide (s).

Videolocity disaccharide (C) specific make disaccharide (d), which is the donor of glycosidic bonds by deleting T1and the introduction of Y and/or acceptor glycoside bond (e) by removing Z. Then the donor glycoside bond (d) enter into interaction is outermost reactions leads to the oligo - or polysaccharide (f), in which t is greater than 1.

Using presented in scheme 2 way, you can also get a large variety of fully protected oligo - or polysaccharides, as (g), in which oligosaccharides [ ]m[ ]tare fully protected predecessors variously substituted domains compounds according to the invention.

In the next stage of the method of the compound (f) and (g) make donors glycosidic bonds and combine with non end balance fully protected predecessors Pe.

As mentioned above, the oligosaccharide end non residue of the polysaccharide (g), which is the donor glycoside bond, it may form part of Pe, in the case when (g) is connected with terminal non-residue fully protected oligosaccharide, which is a precursor to the rest of the structure Pe.

Compounds according to the invention is obtained from their fully protected polysaccharide precursors, using the following sequence of reactions:

- alcohol functions transform in O-alphagroup and carboxylic acids otscheplaut protective group by removing groups Tn, used for protection in uraniu, of course, can be obtained by using various known specialist pathways for the synthesis of oligosaccharides.

The above method is a preferred method according to the invention. However, the compounds of formula (I) may be obtained by other, well-known in the chemistry of sugars by methods described, for example, in the book P. M. Collins and R. J. Ferrier "Monosaccharides, their chemistry and their roles in natural products, ed. J. Wiley and Sons, 1995, and G. J. Boons, Tetrahedron, 52, 1095-1121 (1996).

Predecessor part of pentasaccharide Pe, when W denotes an oxygen atom and R1a means R1receive according to the methods of synthesis of oligosaccharides and especially according to the methods described in the European patents 84999, 301618, 454220 and 529715 and applications for European patents 9304769 and 94202470. When carrying out the full protection, it is possible, using appropriate protective group, to obtain a free hydroxyl group in position 4 non terminal residue (D). Fully protected precursor of Pe then combine in this position, using known methods for the synthesis of oligosaccharides.

Pentasaccharide Pe, where W denotes the carbon atom, and R1a means R1formula (II):

< / BR>
in which R and/SUB> and Tn are the same or different, signify a temporary, semi-permanent or permanent Deputy; Z means a protective group of the hydroxyl function, and the synthon is obtained by synthesis, carried out by a radical reaction between a monosaccharide, which is a generator of free radicals, and a monosaccharide containing a double bond, then turning the thus obtained C-disaccharide in the synthon of formula (II).1) classic ways described above, according to C. Van Boeckel, M. Petitou.

Synthon of formula (II).1), especially suitable for the synthesis of compounds of formula (II) corresponds to the formula (II).1):

< / BR>
This synthon receive according to the reaction scheme 22, provided at the end of the description.

Pentasaccharide Pe, which appears substituent R1a, which includes the remainder of the L-iduronovoy acid blocked configuration of formula (III)

< / BR>
in which R and R1have the above for formula (I) values, and W denotes an oxygen atom derived from Cinchona formula (III).1)

< / BR>
in which T1and Tn, identical or different, denote a temporary, semi-permanent or permanent Deputy; Z means a protective group of the hydroxyl function, and the synthon is obtained by synthesis, SS="ptx2">

Synthon of formula (III).1), especially suitable for the synthesis of compounds of formula (III) corresponds to the formula (III).1)

< / BR>
This synthon receive according to the reaction scheme 34 provided in the end of the description.

Intermediate compounds of formulas (II. 1), and (III.1) represent a new intermediate products, especially suitable for producing compounds of formula (I) according to the invention.

Pentasaccharide Pe, therefore, can be obtained from these disaccharide glycosides synthons of formula (II).1), or (III.1) according to the method described in the publication of C. A. A. Van Boeckel and M. Petitou, Angew. Chem.Int.Ed.Engl, cited above.

Under the above-used semi-permanent groups understand the groups that are removed in the first place after glycosylation reactions when glatigny skeleton contains the desired number of parts, without removing or changing other audience groups, which allows then to introduce a desired functional group at the position that was occupied by these semi-permanent groups.

Regular groups are groups that are able to maintain protection of hydroxy functions during the introduction of functional groups instead of semi-permanent groups.

These groups choose among such groups that are compatible with artnik in relation to the reactions carried out for the introduction of these functional groups, and which are easily removed without changing these functional groups.

According to the invention, the permanent groups are preferably alkyl groups with 1-6 carbon atoms.

As an example, semi-permanent and/or temporary group can be called benzyl and acetyl, levulinic, p-methoxybenzyloxy etc. of the group.

Substituents in position 3 of the uronic units of the target compounds, and the substituent R1may already be present in the source synthons.

The protective group used in the method of obtaining compounds of formula (I) are groups commonly used in the chemistry of sugars, such as is described in the book by T. W. Greene "Protective groups in organic synthesis", ed. John Wiley and Sons, new York, 1981

The protective groups are preferably chosen among, for example, acetyl, halogenmethyl, benzoline, levulinic, benzyl, substituted benzyl, possibly substituted trailing, tetrahydropyranyl, allyl, pantanelli, tert-butyldimethylsilyl (tBDMS) or trimethylsilylethynyl groups (...).

Activating groups are groups, usually ispolzuet, among imidates, thioglycosides, interglacial, xanatos, phosphites or halides.

The above method allows to obtain compounds according to the invention in the form of salts. To obtain the corresponding acid compounds according to the invention in the form of salts enter into contact with the cation exchange resin in acid form.

Compounds according to the invention in the form of acids can then be neutralized with base to obtain the desired salt.

To obtain the salts of the compounds of formula (I) you can use any inorganic or organic base, forming with the compounds of formula (I) pharmaceutically acceptable salts.

As the base is preferably used sodium hydroxide, potassium, calcium or magnesium. Sodium and calcium salts of compounds of formula (I) are the preferred salts.

At the stage of (a) the method used protective groups are the groups that are frequently used by a specialist in the chemistry of sugars, for example, according to European patent 84999 or even according to T. W. Greene "Protective groups in organic synthesis", ed. J. Wiley and Sons, 1995

The thus obtained compounds of formula (I) in case of necessity, the connection, in which one or more hydrogen atoms or carbon substituted their radioactive isotope, for example tritium or carbon-14. Such labeled compounds are suitable as ligands in research works, studies on the metabolism or pharmacokinetics, biochemical experiments. Compounds according to the invention were used as the object of biochemical and pharmacological research, which showed that they have very interesting properties.

Compounds of the present invention, which selectively contact AT III with affinity equal to or higher than that of heparin, have anticoagulant and antithrombotic properties of heparin.

Overall antithrombotic activity of the products of formula (I) are estimated by intravenous injection or subcutaneous rat model of venous stasis and by induction the device according to the method described in J. Reyers and others in Thrombosis Research, 18, 669-674 (1980), as well as on the model of arterial thrombosis caused by an implanted shunt between the carotid artery and jugular vein of rats, such as described Umetsu and others, Thromb. Haemost., 39, 74-83 (1978). In the case of these two experimental models the value of the ED50(DE50connection with which the shaft of synthetic gearoid (ED50is from 5 to 500 µg/kg). Therefore, the compounds according to the invention have a particularly interesting specific effect and anticoagulant and antithrombotic activity.

Due to its biochemical and pharmaceutical activity of the compounds of the present invention are of great interest as medicines. Their toxicity is quite compatible with this use. They are also very stable and therefore applicable as applicable beginning in pharmaceutical compositions.

Moreover, the compounds according to the invention is not neutralized high amounts of platelet-derived cationic proteins such as platelet factor 4 (FP4), which increase during their activation during the process of thrombosis. Therefore, the compounds according to the invention in the highest degree of interest for the treatment and prevention of thrombosis of arterial or venous origin.

They can be used in the case of different pathologies resulting from modification of hemostasis coagulation system, resulting, in particular, during the disorders of the cardiovascular and cerebral-vascular system, kanakaria, stroke, restenosis after angioplasty, endarterectomy, installation intravascular prostheses, or thromboembolic disorders associated with rethrombosis after thrombolyse, heart attack, dementia ischemic origin, peripheral arterial disease, hemodialysis, the auricular fibrillyatsy, or during use of the prosthetic vessels during coronary artery bypass surgery. In addition, these products can be used for treating or preventing thromboembolic pathologies of venous origin, such as embolism pulmonary arteries. They can be used or for the prevention or treatment of thrombotic complications occurring during surgery or in conjunction with other diseases as cancer, bacterial or viral infection. In the case of their use during installation of the prosthesis compounds according to the present invention can cover the prosthesis and thus make them hemocompatible. In particular, they can be locked on intravascular prostheses (stents). In this case, they can be chemically modified by introduction of non or Vosstania the deposits according to the present invention can also be used as an aid during endarterectomy, carried out with the use of porous beads.

Compounds according to the invention are very stable and therefore also particularly applicable as the beginning of the current medicines.

According to another of its aspects, a subject of the present invention, therefore, is a pharmaceutical composition containing as an active early synthetic polysaccharide, such specified above.

The invention preferably relates to pharmaceutical compositions containing as an active beginning of the connection formula (I), (I. 1), (I. 2), (I. 3) or one of its pharmaceutically acceptable salts, if necessary in combination with one or more appropriate inert excipients.

In each case the dose of active principle is in quantities adapted to the envisaged daily doses. Typically, each single dose of properly executed depending on the dosage and the envisaged type of administration, such as tablets, gelatin capsules with the medicine and similar forms, sachets, ampoules, syrups and the like forms, drops, percutaneous or for insertion through the mucous membrane of the patches of the invention can also be used in combination with another active principle, suitable for the desired therapy, such as, for example, antithrombotic agents, anticoagulants, platelet antiaggregants, such as, for example, dipyridamole, aspirin, ticlopidine, clopidogrel, or antagonists of glycoprotein complex IIb/IIIa.

The pharmaceutical compositions are for the introduction of mammals, including humans, for treatment of the above diseases.

Thus, the pharmaceutical compositions are preferably in different forms, such as solutions for injection or drinking, pills, tablets or gelatine capsules with the medicine. Solutions for injection are preferred pharmaceutical forms. The pharmaceutical compositions according to the present invention is particularly suitable for prophylactic treatment or treatment of disorders of the vessel wall, such as atherosclerosis, hypercoagulable States, see for example due to surgery, tumor growth or coagulation disorders caused by bacterial, viral or enzymatic activators. The dosage can be modified within wide limits depending on age, weight and health of the patient, nature and severity of Zabol 100 mg per day, preferably about 0.5-50 mg per day, when introduced subcutaneously or intramuscularly, continuously or regularly.

Therefore, the object of the present invention are also pharmaceutical compositions containing as an active start one of the above compounds, if necessary in combination with another active principle. These compositions comprise so that you can enter through the digestive tract or parenteral.

In the pharmaceutical compositions according to the present invention for the introduction of oral, sublingual, subcutaneous, intramuscular, intravenous, percutaneous, through the mucous membrane, locally or rectally, the active ingredient can be introduced in unit forms of administration, mixed with conventional pharmaceutical carriers, to animals and people. The appropriate unit forms of introduction include oral forms such as tablets, gelatin capsules with the medicine, powders, granules and oral solutions or suspensions; sublingual and transbukkalno forms of administration; subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

When preparing Terim excipients, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic or similar components. Tablets may be coated with sucrose or other appropriate substances or they can be treated so that they have a prolonged or delayed activity and released continuously for a specified number of the current beginning.

Dosage form in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and introducing the resulting mixture into soft or hard gelatin capsules.

Dispergirujutsja in water powders or granules can contain the active ingredient mixed with dispersing agents or wetting or suspendresume agents, as polyvinylpyrrolidone, just as with sweetening means or improving the taste substances.

For rectal use of suppositories which are prepared with binders, melting at rectal temperature, as for example cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular administration, using aqueous suspensions, isotonic saline solutions or sterile solutions for injection, which lepicol.

For administration through mucosa, preparative form the beginning of the current can be obtained in the presence of a promoter, such as a salt of bile acid, a hydrophilic polymer, such as, for example, hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, ethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, pectins, starches, gelatin, casein, acrylic acid, esters of acrylic acids and their copolymers, vinyl polymers or copolymers, vinyl alcohols, alkoxyalkane, polymers of polyethylene oxide, polyether or a mixture thereof.

Preparative form the beginning of the current can also be obtained in the form of microcapsules, if necessary with one or more carriers or additives.

The active principle may also be in the form of a complex with a cyclodextrin, for example -, or-cyclodextrin, 2-hydroxypropyl--cyclodextrin or methyl--cyclodextrin.

The active principle can also be released from its containing ball or due to intravascular dilator is introduced into the blood vessels. Pharmacological efficacy of the current beginning thus not deteriorating.

Dowex, Sephadex, Chelex, Toyopearlare registered trademarks.

In the methods of preparative examples and examples described below, the General methodologies related to the catalytic combination of imidates, splitting complex levulinate esters, catalytic combination of thioglycosides, saponification, methylation and selective removal of the protective p-methoxybenzyloxy group, removal of the protective group and sulfation oligo - and polysaccharides by hydrogenolysis complex or simple benzyl esters, saponification of esters or of sulfation can be implemented using appropriate following the General methods of obtaining intermediates.

GENERAL METHODS

Method 1. The combination of imidates catalyzed tert-butyl-dimethylsilane-triflate

A solution of tert-butyldimethylsilyl in dichloromethane (1 M, 0.2 mol/mol of imidate), in an argon atmosphere and at a temperature of -20oC add to rest minutes (TLC) is added solid sodium bicarbonate. The solution is filtered, washed with water, dried and evaporated to dryness.

Method 2. Cleavage of levulinate group

Connection, a protective group which you want to remove, dissolve in a mixture of ethanol with toluene in the ratio of 2:1 (42 ml/mmol) and add hydrazinoacetate (5 mol/mol). Stirred for 15-30 minutes (TLC), and concentrate.

Method 3. The combination of thioglycosides catalyzed N-yogakriya and triptolemos silver

In nonactinic glass flask thioglycosides and Picatinny acceptor dissolved in anhydrous toluene (18 ml/mmol of thioglycoside) in the presence of molecular sieves is Stirred for 1 hour at room temperature. Cooled to a temperature of 0oC and add N-jodatime (3 mol/mol of thioglycoside), then triplet silver (0.28 mol/mol thioglycoside).

After 10-15 minutes (TLC) is added solid sodium bicarbonate. After filtration, the solution was washed with 1 M aqueous sodium thiosulfate solution, water, dried and evaporated.

Method 4. Saponification, methylation and selective removal of the protective p-methoxybenzyloxy group

Saponification of esters. Omilteme compound dissolved in a mixture of dichloromethane with methanol in Yu resin Dowex50 H+. Concentrate and this compound was used in the next stage without purification.

Methylation. At a temperature of 0oC in small portions add sodium hydride to the mixture videolooking untreated connection and methyliodide in N, N-dimethylformamide (7 ml/mmol). After the reaction mixture was poured into water and extracted with ethyl acetate. The organic phase is washed with water, dried and evaporated to dryness.

Cleavage of the p-methoxybenzyloxy group. Visaelectron the crude compound is dissolved in a mixture of acetonitrile with water in the ratio of 9:1 (20 ml/mmol). At a temperature of 0oC add cerium nitrate and ammonium (0.5 mol/mol). The reaction mixture is stirred for two hours (control by TLC), add a saturated solution of sodium bicarbonate, extracted with ethyl acetate, dried and evaporated.

Method 5. Removal of protective groups and sulfation oligo - and polysaccharides

Hydrogenolysis of simple and complex benzyl esters. In 6-12 hours (TLC) is stirred solution of the compound in glacial acetic acid in an atmosphere of hydrogen (40 bar) in the presence of a catalyst of 5% palladium-on-coal (twice the mass of compound). After otfiltrovana sodium (in such number, so after adding the concentration of sodium hydroxide was 0.5 mol) are added to a solution of ester in methanol (150 ml/mmol). After 2-5 hours enter the water and passed through a column of Sephadex gelG-25 (1.6 x 115 cm), elwira water. Concentrate was passed through a column c Dowex50 H+(2 ml) and lyophilizers. At this stage control using the1H-NMR that all protective groups have been removed. If necessary, the product is again subjected to hydrogenation and/or saponification.

The sulfation. To a solution of sulfatrim compounds in dimethylformamide (5 mg/ml) add complex with triethylamine-sulfur trioxide (5 mol/mol of hydroxyl functions). After keeping during the day at a temperature of 55oC solution contribute in the upper part of the column Sephadex cG-25 (1.6 x 115 cm), elwira of 0.2 M solution of sodium chloride. Containing the product fractions are concentrated and absoluut using the same column during the elution with water. The target compound is obtained after lyophilization.

Preparatively example 1

Ethyl-2,4,6-tri-O-acetyl-3-O-methyl-1-thio--D-glucopyranoside (2)

69 g 1,2,4,6-Tetra-O-acetyl-3-O-methyl-a-D-glucopyranose (1) (0,19 mmol) [Century Helferich, etc., J. the thief of titlefirst of boron TRIFLUORIDE in toluene. Stirred for one and a half hours, dried and concentrated. The chromatography was carried out on a column of silica (cyclohexane/ethyl acetate in the ratio 3:1) to give 37 g (54%) of compound (2) (see scheme 3, shown at the end of the description).

[]D= -26(C=1; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

of 5.05-4,96 (m, 2H, H-2, H-4), 4,39 (d, 1H, J=9.5 Hz, H-1), 4,18-4,12 (m, 2H, H-6, H-6'), of 3.60 (m, 1H, H-5), 3,50 (DD, 1H, J=9,3 Hz, H-3), to 3.41 (s, 3H, OCH3), 2,65 of $ 2.53 (m, 2H, SCH2CH3), 2,12, 2,11, 2,09 (3c, 9H, 3 acetyl), 1,25 (t, 1H, SCH2CH3).

Preparative example 2

Ethyl-4,6-O-benzylidene-3-O-methyl-1-thio- -D-glucopyranoside (3)

37 g (0.1 mmol) of the compound (2) dissolved in 1.5 liters of a mixture of methanol with dichloromethane in the ratio of 1:2. Add 150 ml of 2 M solution of methanolate sodium. After standing for half an hour at room temperature, neutralized with resin Dowex50 (H+), filtered and concentrated.

Visaelectron the crude compound was dissolved in 1 l of anhydrous acetonitrile, and add 30 ml (0.2 mol), dimethoxytoluene and 2.3 g (10 mmol) camphorsulfonate. Stirred for one and a half hours (TLC), added to 1.4 ml of triethylamine and concentrated. The obtained residue precipitated the D= -60(C = 1,63; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,51-7,34 (m, 5H, phenyl), of 5.55 (s, 1H, C6H5CH), 4,56 (d, 1H, J=9,2 Hz, H-1) of 2.75 (m, 2H, SCH2CH3) to 1.32 (t, 3H, SCH2CH3).

Analysis for C16H22O5S (326,41):

calculated, %: C 58,58 H 6,79 S 9,82

found, %: C 58,99 H 6,74 S 9,75

Preparative example 3

Ethyl-2-O-benzyl-4,6-O-benzylidene-3-O-methyl-1-thio--D - glucopyranoside (4)

At a temperature of 0oC, 2.00 g (83,3 mmol) of sodium hydride are added to a solution of 23 g (71,0 mmol) of the compound (3) and 11 ml (93,0 mmol) benzylbromide in 200 ml of N,N-dimethylformamide. Stirred for two hours (TLC), add methanol and the reaction mixture is poured into water. Extracted with ethyl acetate, washed with water, dried and concentrated. Precipitated in diethyl ether, receiving 18,8 g (63%) of compound (4) (see scheme 3, shown at the end of the description).

So pl. = 123oC.

[]D= -35(c=0,63; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,50-7,25 (M, 10H, 2 phenyl), of 5.55 (s, 1H, C6H5CH), of 4.54 (d, 1H, J=9.7 Hz, H-l), 4,34 (m, 1H, H-6 in), 3.75 (t, 1H, J=10,2 Hz, H-6'), the 3.65 (s, 3H, OCH3), 3,60-to 3.33 (m, 4H, H-5, H-4, H-3, H-2), a 2.75 (m, 2H, SCH2CH3), to 1.32 (t, 3H, SCH2CH3).

Analysis of the tive example 4

Ethyl-2,6-di-O-benzyl-3-O-methyl-1-thio- -D-glucopyranoside (5)

In argon atmosphere, a solution of 0.65 ml (4,50 mmol) triperoxonane anhydride in 16 ml (0.21 mol) triperoxonane acid are added to a solution of 28.8 g (69,0 mmol) of the compound (4) and 33 ml (0.21 mol) triethylamine in 120 ml of dichloromethane. Stirred for two hours, diluted with ethyl acetate and add aqueous 1 M sodium hydroxide solution until pH = 9. Extracted with ethyl acetate, washed with water, dried and evaporated to dryness. The residue is purified on a column of silica (cyclohexane/ethyl acetate in a ratio of 3:1, then 2:1), receiving of 17.4 g (60%) of compound (5) (see scheme 3, shown at the end of the description).

[]D= -47(C=1; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,45-7,25 (m, 10H, 2 phenyl), 4,47 (d, 1H, J=9,3 Hz, H-1), 3,66 (s, 3H, OCH3), 3,61 is 3.40 (m, 2H, H-4 and H-5), 3,36-3,19 (m, 2H, H-2 and H-3), by 2.73 (m, 2H, SCH2CH3), is 1.31 (t, 3H, SCH2CH3).

Analysis for C23H30O5S (418,55):

calculated, %: C of 66.00 H 7,22 S 7,66

found, %: C 65,62 H 7,28 S 7,21

Preparative example 5

Ethyl-2,6-di-O-benzyl-4-O-levulinic-3-O-methyl-1-thio--D-glucopyranoside (6)

17.3 g (41,4 mmol) of the compound (5) is dissolved in 400 ml of anhydrous dioxane. Add the 3 mmol) of 4-dimethylaminopyridine. Stirred for four hours, extracted with ethyl acetate, washed sequentially aqueous 5% solution of potassium hydrosulfate, water, aqueous saturated sodium hydrogen carbonate solution, water, dried and concentrated. Purified on a column of silica (toluene/ethyl acetate in the ratio 6:1) to give 19.9 g (93%) of pure compound (6) (see scheme 3, shown at the end of the description).

[]D= -5(C= 1,46; dichloromethane).

LSIMS (positive ions): m/e: (thioglycerol + NaCl) 539 (M+Na)+; (thioglycerol + KF) 555 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,40-7,20 (m, 10H, 2 phenyl), to 4.92 (m, 1H, H-4), 2,8-2,4 (m, N, SCH2CH3and O(C: O)CH2CH2(: O)CH3), of 2.16 (s, 3H, O(C:O)CH2CH2(: O)CH3), 1,32 (t, 1H, J=7,3 Hz, SCH2CH3).

Analysis for C28H36O7S (516,65):

calculated, %: C 65,09 H 7,02 S 6,21

found, %: C 65,30 H 7,03 S 5,75

Preparative example 6

Allyl-4,6-O-benzylidene-3-O-methyl-,-D-glucopyranoside (7)

1,10 ml (0.012 mol) of triftoratsetata added to the suspension 135 g (0.7 mol) selling 3-O-methylglucose in 1 l of allyl alcohol. Heated for two hours at a temperature of 120oC, neutralized by adding 2 ml tried add 136 ml (0.9 mol), dimethoxytoluene and 25 g (0.13 mmol) of camphorsulfonate. Heated for 1 hour at a temperature of 80oC in vacuum. Neutralize by adding 21 ml of triethylamine and extracted with ethyl acetate, washed with water, dried and concentrated, gaining 144 g (57%) of a solid substance in mixture / ratio 3/2. Will recrystallized from ethanol to obtain 60 g (26%) of pure compound (7-a). By chromatography was carried out part of the mother solutions on a column of silica (cyclohexane/ethyl acetate in the ratio 3:1) obtain 7.6 g of pure compound (7-), 6.8 g of the compound (7-/) and 1.4 g of pure compound (7-a) (see scheme 3, shown at the end of the description).

The compound 7-: []D= -43(C = 1; dichloromethane); so pl.= 131oC.

1H-NMR (deuterochloroform); (M. D.):

7,50-7,26 (m, 5H, phenyl), 6,01-5,90 (m, 1H, OCH2(CH:CH2)), of 5.55 (s, 1H, C6H5CH), 5,38-5,32 (m, 2H, OCH2(CH: CH2)), 4,47 (d, 1H, J=7.5 Hz, H-1), 4,42-4,32 (m, 2H, H-6' and OCH2(CH:CH2)), 4,21 - to 4.15 (m, 1H, OCH2(CH:CH2)), 3,80 (DD, 1H, J=10,2 Hz, H-6), to 3.67 (s, 3H, OCH3)

Analysis for C17H22O6(322,36):

calculated, %: C 63,34 H 6,88

found, %: C 63,23 H 7,12

Preparative example 7

Allyl-2-O-acetyl-4,6-O-benzylidene-3-O-methyl-a-D - glucopyranoside (8)

11.5g (35,7 mmol) of the compound (7) is dissolved in 100 ml of dichloropyridine. Stirred for two hours (TLC), washed sequentially aqueous 5% solution of potassium hydrosulfate, water, aqueous saturated sodium hydrogen carbonate solution, water, dried and evaporated, receiving 12.3 g (95%) solids (8) (see scheme 3, shown at the end of the description).

So PL, = 115oC; []D= -68(C = 1; dichloromethane).

LSIMS (positive ions): m/e: (thioglycerol + NaCl)+387 (M+Na)+; (thioglycerol + KF) 403 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,51-7,34 (m, 5H, phenyl), 5,98-5,78 (m, 1H, OCH2(CH:CH2)), to 5.56 (s, 1H, C6H5CH), 5,32-5,17 (m, 2H, OCH2(CH:CH2)), of 4.49 (DD, J=8 Hz, 1H, H-2), 4,55 (d, J=7.9 Hz, 1H, H-1), 4,39-the 4.29 (m, 2H, H-6 and OCH2(CH:CH2)), 4,14-Android 4.04 (m, 1H, OCH2(CH: CH2)), 3,82 (t, J=10,2 Hz, 1H, H-6'), of 3.60 (s, 3H, OCH3), a 2.12 (s, 3H, acetyl).

Analysis for C19H24O7(366,39):

calculated, %: C 62,63 H 6,64

found, %: C 62,63 H 6,64

Preparative example 8

Allyl-2-O-acetyl-6-O-benzyl-3-O-methyl-a-D - glucopyranoside (9)

At a temperature of 0oC to a solution of 12.0 g (33.3 mmol) of the compound (8) and 21.3 ml (133 mmol) of triethylsilane in 50 ml of anhydrous dichloromethane add a solution of 306 ml (2.10 mmol) triperoxonane anhydride in 10 ml triperoxonane kishtwar sodium hydroxide until pH 9. Extracted with ethyl acetate, washed with water, dried and concentrated. Purified on a column of silica (cyclohexane/acetone in a ratio of 8:5) to give 10 g (82%) of pure compound (9) (see scheme 3, shown at the end of the description).

[]D= -40(C = 1,06; dichloromethane);

1H-NMR (deuterochloroform); (M. D.):

7,35-7,28 (m, 5H, phenyl), by 5.87-5,79 (m, 2H, OCH2(CH:CH2)), 5,28-5,14 (m, 2H, OCH2(CH: CH2)), 4,43 (d, 1H, J=7.9 Hz, H-1), to 4.41-to 4.28 (m, 1H, OCH2(CH: CH2)), 4,10-was 4.02 (m, 1H, OCH2(CH:CH2)), of 3.77 of 3.75 (m, 2H, H-6 and H-6'), 3,51 (s, 3H, OCH3), 3,30 (DD, 1H, J=8,9 Hz, H-3), and 2.8 (d, 1H, OH).

Analysis for C19H26O7(366,39):

calculated, %: C 62,28 H 7,15

found, %: C 61,73 H 7,19

Preparative example 9

Allyl-2-O-acetyl-6-O-benzyl-3-O-methyl-4-O- (2,6-di-O-benzyl-4-O-levulinic-3-O-methyl - D-glyukopiranozil)--D - glucopyranoside (10)

of 17.4 g (33,7 mmol) thioglycoside (6) and 10.3 g (28.1 mmol) glycosylase acceptor (9) is dissolved in 150 ml of dichloroethane. Type molecular sieve and stirred for 1 hour. At -20oC in an argon atmosphere, add a solution 8,30 g (33,7 mmol) N-jodatime and 0.30 ml (3,30 mmol) triftoratsetata in 415 ml of a mixture of dichloromethane with diethyl ether in a ratio of 1:1. Displacement is M aqueous solution of sodium thiosulfate, with water, aqueous saturated sodium hydrogen carbonate solution, water, dried and concentrated. Purified on a column of silica (dichloromethane/ethyl acetate in the ratio of 11:1) to give 11.7 g (52%) of pure disaccharide (10-) (see scheme 4, is provided at the end of the description).

[]D= +38(c = 1,01; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,35-of 7.23 (m, 15H, 3 phenyl), 5,90-5,80 (m, 1H, OCH2(CH:CH2)), vs. 5.47 (d, 1H, J=3.6 Hz, H-1'), 5,27-5,14 (m, 2H, OCH2(CH:CH2)), of 5.05-of 4.90 (m, 2H, H-4' and H-2), 4,42 (d, 1H, J and 7.6 Hz, H-1), to 4.38-4,32 (m, 1H, OCH2(CH:CH2)), 4,15 to 4.0 (m, 1H, OCH2(CH: CH2)), 3,90 (DD, 1H, J=8,8 Hz, H-4), 3,54, 3,34 (2c, 6H, 2 OCH3), of 2,75 2,40 (m, 4H, O(C:O)CH2CH2(: O)CH3), 2,16, 2,10 (2c, 6H, acetyl and O(C:O)CH2CH2(C:O)CH3).

Analysis for C45H56O14(820,94):

calculated, %: C 65,84 H 6,88

found, %: C 65,74 H 6,90

Preparative example 10

Prop-1'-enyl-2-O-acetyl-6-O-benzyl-3-O-methyl-4-O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl - D-glyukopiranozil)--D-glucopyranoside (11)

5,80 mg (0.70 mmol) of 1, 5cyclooctadiene-bis[methyldiphenylphosphine] redirecttoroute added to a solution of 1.36 g (of 1.66 mmol) of the compound (10) in 4,30 ml of tetrahydrofuran without peroxides. The solution Tegaserod, create an atmosphere of argon and injected € dichloromethane phase aqueous saturated solution of sodium bicarbonate, water, dried and concentrated. Purified on a column of silica (toluene/ethyl acetate in the ratio 3: 1) to give 1.04 g (76%) of pure compound (11) (see scheme 4, is provided at the end of the description).

[]D= +47(C = 1,1; dichloromethane).

LSIMS (positive ions): m/e; (thioglycerol + NaCl) 951 (M+Na)+; (thioglycerol + KF) 967 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,34-of 7.23 (m, 15H, 3 phenyl), 6,21-6,16 (m, 1H, O(CH:CH)CH3), the 5.45 (d, 1H, J=3.5 Hz, H-1'), 5,13-equal to 4.97 (m, 3H, H-4', H-2 and O(CH:CH)CH3), and 4.6 (d, 1H, J= at 7.55 Hz, H-1), of 3.96 (DD, 1H, J=8,9 Hz, H-4'), 3,54, 3,34 (2c, 6H, 2OCH3), 2,74-of 2.36 (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,15, 2,08 (2c, 6H, acetyl and O(C: O)CH2CH2(: O)CH3), 1.56 to 1,51 (DD, 3H, O(CH:CH)CH3).

Analysis for C45H56O14(820,94):

calculated, %: C 65,84 H 6,88

found, %: C 66,21 H 6,92

Preparative example 11

2-O-Acetyl-6-O-benzyl-3-O-methyl-4-O-(2,6-di - O-benzyl-4-O-levulinic-3-O-methyl-D-glyukopiranozil)-,-D - glucopyranose (12)

A solution of 3.9 g (of 14.3 mmol) of mercury chloride in 26 ml of a mixture of acetone with water in the ratio 5:1 was added dropwise to a solution of 7.8 g (at 9.53 mmol) of the compound (11) and mercury oxide in 80 ml of the same solvent. Stirred for 1 hour, filtered and concentrated. Extracted dichlormethane with silica (dichloromethane/acetone in a ratio of 10:1, then 4:1), receiving 6,70 g (90%) of compound (12) (see scheme 4, is provided at the end of the description).

[]D= +92(c = 1,37; dichloromethane).

TLC: RF= 0,31 (dichloromethane/acetone in a ratio of 14:1).

1H-NMR (deuterochloroform); (M. D.):

7,37-7,24 (m, 15H, 3 phenyl), 5,46 (d, 1H, J=3.5 Hz, H-1'), lower than the 5.37 (d, J= 3.6 Hz, H-1), 4,58 (d, J=8 Hz, H-1), 3,54, 3,39, 3,36 (3c, 6H, 2OCH3), a 2.75-2,4 (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,16, 2,15 (2c, 6H, acetyl and 0(C: O)CH2CH2(C:O)CH3).

Analysis for C42H52O14(780,83):

calculated, %: C 64,60 H of 6.71

found, %: C 65,09 H 6,82

Preparative example 12

2-O-Acetyl-6-O-benzyl-3-O-methyl-4-O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl-D-glyukopiranozil)-,-D - glucopyranosilchloride (13)

to 5.00 g (6.4 mmol) of the compound (12) is dissolved in 50 ml of dichloromethane and in the atmosphere of argon added to 3.9 ml (38,8 mmol) trichloroacetonitrile and 1.6 g (11.6 mmol) of potassium carbonate. Stirred for 16 hours (TLC) and filtered. Purified on a column of silica (dichloromethane/acetone in a ratio of 8: 1, then 4:1), receiving with 5.22 g (87%) blend / = 60/40) imidates (13) (see scheme 4, is provided at the end of the description).

TLC : RF= to 0.66 and 0.51 (dichloromethane/acetone in a ratio of 20:1).;

1H-NMR (dei-1'), 3,55, 3,41, 3,37 (3c, 9H, 3OCH3), of 2,75 2,40 (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,16, 2,07, 2,04 (3c, 6H, acetyl and O(C:O)CH2CH2(C:O)CH3).

Analysis for C44H52Cl3NO14(925,26):

calculated, %: C 57,12 H 5,66 N 1,51

found, %: C 57,31 by 5.87 H N 1,55

Preparative example 13

Allyl-2-O-acetyl-6-O-benzyl-3-O-methyl-4-O-(2,6-di-O-benzyl-3-O - methyl-D-glyukopiranozil)- -D-glucopyranoside (14)

3.11 g (of 3.80 mmol) of the compound (10) is treated according to Method 2 to obtain 2.70 g (97%) of compound (14) (see scheme 4, is provided at the end of the description).

[]D= +25(C = 1,7; dichloromethane).

LSIMS (positive ions): m/e; (thioglycerol + NaCl) 745 (M + Na)+; (thioglycerol + KF) 761 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,33-7,20 (m, 15H, 3 phenyl), by 5.87-5,78 (m, 1H, OCH2(CH:CH2)), of 5.50 (d, 1H, J= 3.5 Hz, H-1'), and 5.30-5,17 (m, 2H, OCH2(CH:CH2)), 5,02 (DD, 1H, H-2), 4,43 (d, 1H, J=7,6 Hz, 1-H), 4,34-to 4.28 (m, 1H, OCH2(CH:CH2)), 4,12-was 4.02 (m, 1H, OCH2(CH:CH2)), 3,63, 3,36 (2c, 6H, 2 OCH3), 2,10 (c, 3H, acetyl).

Analysis for C40H50O12(722,84):

calculated, %: C 66,47 H 6,97

found, %: C 66,31 H 7,24

Preparative example 14

Allyl-O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl - D-glyukopiranozil)-(1--->4) -O(2-O-ACET SIL - 3-O-methyl-a-D-glucopyranoside (15)

The mixture 4,22 g (4,56 mmol) of imidate (13) and 2,63 g (of 3.64 mmol) glycosylase acceptor (14) is treated according to Method 1. Purified on a column of silica (toluene/diethyl ether in the ratio 3:2, then 1:1), obtaining or 4.31 g (80%) of tetrasaccharide (15) (see scheme 5, provided at the end of the description).

[]D= +52(c = 0,66; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,35-of 7.23 (m, 30H, 6 phenyl), of 5.83-5,79 (m, 1H, OCH2(CH:CH2)), vs. 5.47 (d, 2H, J=3.5 Hz, H-1"' and H-1'), a 5.25-5,14 (m, 2H, OCH2(CH:CH2)), to 4.38 (d, 1H, J= 7.7 Hz, H-1"'), 4,30 (d, 1H, J=8 Hz, H-1), 4,32-of 4.25 (m, 1H, OCH2(CH: CH2)), 4,08-was 4.02 (m, 1H, OCH2(CH:CH2)), 3,56, 3,53, 3,34, 3,27 (4c, 12H, 4 OCH3), 2,78-to 2.40 (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,15, 2,09, 1,85 (3c, 9H, 2 acetyl and O(C:O)CH2CH2(C:O)CH3).

Analysis for C82H100O25(1485,7):

calculated, %: C 66,29 H 6,78

found, %: C 66,10 H 6,79

Preparative example 15

O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl-D -

glyukopiranozil)-(1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O - methyl-D-glyukopiranozil) -(1--->4)-O-(2,6-di-O-benzyl-3-O - methyl-D-glyukopiranozil) -(1--->4)-2-O-acetyl-6-O-benzyl-3-O - methyl-,-D-glucopyranose (16)

2.30 g (1.54 mmol) of the compound (15) is treated as described in preparative example 10. After 10 Stirred for 5 minutes (TLC), diluted with dichloromethane, washed with aqueous saturated solution of sodium hydrosulphate, water, dried and concentrated. The residue is purified on a column of silica (toluene/ethyl acetate in the ratio 3: 2), receiving of 1.57 g (71% over two stages) of pure compound (16) (see scheme 5, provided at the end of the description).

[]D= +69(s = 0,87; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,38-7,20 (m, 30H, 6 phenyl), vs. 5.47 (d, 1H, J=3.5 Hz, H-1"' and H-1'), are 5.36 (d, 1H, J= 3.5 Hz, H-1), 4,55 (d, 1H, J=8 Hz, H-1), 4,36 (d, 1H, J=8 Hz, H-1"), 3,56, 3,54, 3,39, 3,36, 3,28 (5c, 9H, 3 OCH3), 2,75 to 2.35 (m, 4H, O(C: O)CH2CH2(C: O)CH3), 2,16, 2,13, 2,12, 1,86 (4c, 9H, 2 acetyl and O(C: O)CH2CH2(C:O)CH3).

Preparative example 16

O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl - D-glyukopiranozil)-(1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil-(1--->4)-O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil) -(1--->4)-2-O-acetyl-6-O-benzyl-3-O-methyl-,-D-glucopyranose-trichloroacetimidate (17)

For 16 hours at room temperature stirred mixture of 1.5 g (1.04 mmol) of the compound (16), 0.63 ml (from 6.22 mmol) trichloroacetonitrile and 0.26 g (of 1.87 mmol) of potassium carbonate in 15 ml of dichloromethane. The solution is filtered and concentrated. The residue is purified on a column dioxide kr is

TLC: RF= 0.5 (toluene/acetone in a ratio of 7:2).

Preparative example 17

Allyl-O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil- (1--->4)-O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)- (1--->4)-2-O-acetyl-6-O-benzyl-3-O-methyl-a-D-glucopyranoside (18)

To remove levulinate group 1.3 g (0.87 mmol) of the compound (15) is treated according to Method 2, receiving of 1.05 g (86%) of compound (18) (see scheme 5, provided at the end of the description).

[]D= +40(or=0.6; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

of 7.36-7.23 percent (m, 30H, phenyl), of 5.83-5,78 (m, 1H, OCH2(CH:CH2)), of 5.50 (d, 1H, J= 3.5 Hz, H-1"'), vs. 5.47 (d, 1H, J=3.5 Hz, H-1'), 5.25-in to 5.21 (DD, 1H, J=1.6 Hz, J= 17 Hz, OCH2(CH:CH2)), 5,16-5,13 (DD, 1H, J=1.4 Hz, J=10 Hz, OCH2(CH: CH2)), to 4.38 (d, 1H, J=6,5 Hz, H-1"), or 4.31 (d, 1H, J=6,5 Hz, H-1), 4,08-was 4.02 (m, 1H, OCH2(CH: CH2)) and 3.59 (m, 1H, H-4"'), 3,67, 3,53, 3,39, 3,29 (4c, 12H, 4 OCH3), 2,09, 1,86 (2c, 6H, 2 acetyl).

Preparative example 18

Allyl-O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl-D-glyukopiranozil)-(1--->4) -[O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil- (1--->4)-O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)- (1--->4)]3-2-O-acetyl-6-O-benzyl - 3-O-methyl-a-D-glucopyranoside (19)

The mixture 842 mg (0,53 mmol) compounds>HW-50 (110 x 3.2 cm; dichloromethane/ethanol in a ratio of 1:1) to give 1.44 g (85 %) of compound (19) (see scheme 5, provided at the end of the description).

[]D= +57(C = 1,01 dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,35-7,20 (m, 60H, 12 phenyl), of 5.83-5,78 (m, 1H, OCH2(CH:CH2)), 5,24-to 5.21 (DD, 1H, OCH2(CH:CH2)), 5,16-5,13 (DD, 1H, OCH2(CH:CH2)), 3,59, 3,56, 3,51, 3,47, 3,33, 3,26 (6c, 24H, 8 OCH3), 2,75 to 2.35 (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,15, 2,09, 1,85, 1,84 (4c, 15H, 4 acetyl and O(C:O)CH2CH2(C:O)CH3).

(M. D.) Major anomeric protons: 5,48; 4,37; 4,29; 4,23.

Analysis for C156H188O47(2815,51):

calculated, %: C 66,56 H 6.73 x

found, %: C 66,22 H 6,75

Preparative example 19

O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl - D-glyukopiranozil)-(1--->4) -[O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil- (1--->4)-O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)- (1--->4)]3-2-O-acetyl-6 - O-benzyl-3-O-methyl-,-D-glucopyranose (20)

720 mg (0.25 mmol) of the compound (19) is treated as described in preparative example 15. Purified on a column of silica (toluene/ethyl acetate in the ratio 3:2, then 4:3) to give 555 mg (78%) of compound (20) (see scheme 6, provided at the end of the description).

[]D= +70
O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl-a-D glyukopiranozil)-(1--->4)-[O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil- (1--->4)-O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)- (1--->4)]3-2-O-acetyl-6-O-benzyl - 3-O-methyl-,-D-glucopyranose-trichloroacetimidate (21)

540 mg (of € 0.195 mmol) of the compound (20) was worked up as described in preparative example 16. Purified on a column of silica (toluene/ethyl acetate [3:2] +1/ triethylamine) to give 455 mg (80%) mixture ( , = 27/73) imidates (21) (see scheme 6, provided at the end of the description).

TLC: RF= 0,48 (toluene/ethyl acetate in the ratio 3 : 2).

1H-NMR (deuterochloroform); (M. D.):

at 8.60, 8,59 (2c, 1H, N H ), 7,35-7,21 (m, 60H, 12 phenyl), of 2,75 2,40 (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,16, 2,06, 2,04, 1,85, 1,84 (5c, 15H, 4 acetyl and O(C:O) CH2CH2(C:O)CH3).

H-NMR (deuterochloroform); (M. D.) major anomeric protons: 6,50; 5,79; 5,51; 5,48; 4,29; 4,25.

Preparative example 21

Phenyl-2,4,6-tri-O-acetyl-3-O-methyl-1-thio--D - glucopyranoside (22)

5,23 g (14.4 mmol) 1,2,4,6-Tetra-O-acetyl-3-O-methyl-a-D-glucopyranose (1) is dissolved in 45 ml of toluene. Add 3.0 ml (28.8 mmol) of thiophenol and added dropwise to 1.77 ml (14.4 mmol) of titlefirst of boron TRIFLUORIDE, then heated at tempermant sodium, water, dried, concentrated. Purified on a column of silica (cyclohexane/ethyl acetate in the ratio 5:2), receiving of 1.00 g (17%) of compound (22) and a 2.71 g (46%) of compound (22-).

The connection 22 is:

RF= 0,44 (cyclohexane/ethyl acetate in the ratio 3:2);

[]D= +230(C = 1; dichloromethane);

ESIMS (positive ions): m/e (+ NaCl) 435 (M + Na)+; (+ KF) 451 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,46-7,27 (m, 5H, phenyl), of 5.89 (d, 1H, J=5.6 Hz, H-1), of 5.05-equal to 4.97 (m, 2H, H-2 and H-4), 4,49 was 4.42 (m, 1H, H-5), 4,25-4,18 (m, 1H, H-6), 4,05-4,00 (m, 1H, H-6'), 3,66 (DD, 1H, J=9.5 Hz, H-3), 3,51 (s, 3H, OCH3), 2,16, 2,12, 2,00 (3c, 9H, 3 acetyl).

Analysis for C19H24O8S (412,46):

calculated, %: C 55,33 by 5.87 H S TO 7.77

found, %: C 55,25 H 5,90 S 7,75

Preparative example 22

Phenyl-4,6-O-benzylidene-2,3-di-O-methyl-1-thio--D - glucopyranoside (23)

970 mg (2,35 mmol) of the compound (22) was dissolved in 18 ml of a mixture of methanol with dichloromethane in the ratio of 2:1. Add 150 ml of 2 M solution of methanolate sodium. After standing for half an hour at room temperature, neutralized with Dowex50 (H+), filtered and concentrated.

To visaelectron crude residue in 22 ml of acetonitrile, add 0.7 ml (4.0 mmol) of (,, dimethoxytoluene is ethylamine and concentrate.

At a temperature of 0oC to a solution of videolooking raw connection and 163 μl (4.0 mmol) of methyliodide in 9 ml of N,N-dimethylformamide add 73,0 mg (2,80 mmol) of sodium hydride. Stirred for 1 hour and add methanol. Extracted with ethyl acetate, washed with water, dried and concentrated, obtaining 840 mg (94%) of compound (23) in solid form (see figure 7, is provided at the end of the description). So pl. = 178oC.

[]D= +330(C = 1; dichloromethane).

ESIMS (positive ions): m/e (+ NaCl) 411 (M + Na)+; (+ KF) 427,4 (M + K)+.

1H-NMR (deuterochloroform); (M. D.):

7,50-of 7.24 (m, 10H, 2 phenyl), 5,71 (d, 1H, J=3,4 Hz, H-1), 5,52 (s, 1H, C6H5CH), 3,62 (s, 3H, OCH3), 3,55 (s, 3H, OCH3).

Analysis for C21H24O5S (388,48):

calculated, %: C 64,92 H 6,23 S 8,25

found, %: C 64,87 H 6,17'S A 7.85

Preparative example 23

Phenyl-6-O-benzyl-2,3-di-O-methyl-1-thio--D - glucopyranoside (24)

792 mg (0.47 mmol) of the compound (23) is treated as described in preparative example 4. Purified on a column of silica (cyclohexane/ethyl acetate in the ratio 7:2 then 2:1) to give 318 mg (80%) of the compound (24) (see scheme 7, provided at the end of the description).

[]D= +243(C = 1; dichlormid uteroglobin); (M. D.):

7,52-7,22 (m, 10H, 2 phenyl), 5,71 (d, 1H, J=5.3 Hz, H-1), and 3.49 points to 3.64 (2s, 6H, 2 OCH3), to 3.36 (DD, 1H, H-3).

Analysis for C21H26O5S (390,50):

calculated, %: C 64,59 of 6.71 H S 8,21

found, %: C 64,05 H 6,88 S 7,74

Preparative example 24

Phenyl-O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl - D-glyukopiranozil)-(1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil) -(1--->4)-6-O-benzyl-2,3-di-O - methyl-1-thio--D-glucopyranoside (25)

A mixture of 436 mg (0.47 mmol) of the compound (13) and 153 mg (0,39 mmol) of the compound (24) is treated according to Method 1. Purified on a column of Sephadex cLH 20 (ethanol/dichloromethane in the ratio 1:1) to give 309 mg (68%) of pure compound (25).

[]D= +144(c = 1; dichloromethane).

ESIMS (positive ions): m/e (+ NaCl) 1175 (M + Na)+; (+ KF) 1191 (M + K)+.

1H-NMR (deuterochloroform); (M. D.):

7,51-7,21 (m, 25H, 5 phenyl), 5,73 (d, 1H, J=5,2 Hz, H-1), of 5.48 (d, J=3.5 Hz, H-1", to 4.46 (d, 1H, J=8 Hz, H-1'), 3,7, 3,54, 3,5, 3,31 (4c, 12H, 4 OCH3), 2,70-to 2.41 (m, 4H, O(C:O)CH2CH2(: O)CH3), 2,16, 2,01 (2c, 6H, 1 acetyl and O(C:O)CH2CH2(: O)CH3).

Analysis for C63H76O18S:

calculated, %: C 65,61 H 6,64 S 2,78

found, %: C 65,02 H 6,60 S 2,72

Preparative example 25

Methyl-O-(2,6-di-O-benzyl-4-O-leveli the O-methyl-D-glyukopiranozil)- (1--->4)-O-(benzyl-2,3-di-O-methyl-a-D-glucopyranosyloxy)- (1--->4)-O-(3,6-di-O-acetyl-2-O - benzyl-a-D-glyukopiranozil)- (1--->4)-O-(benzyl-2,3-di-O - methyl--L-iodopyrazine)- (1--->4)-2,3,6-tri-O - benzyl-a-D-glucopyranoside (27)

At a temperature of -25oC in an argon atmosphere a solution of 92 mg (0.38 mmol) N-jodatime and 37.5 μl (0.38 mmol) of triftoratsetata in 22 ml of a mixture of 1,2-dichloroethane with di - ethyl ether in the ratio 1:1 is added to a mixture of 451 mg (0,39 mmol) of the compound (25) and 434 mg (0.31 mmol) of the compound (26) [Westerduin, P. and others, BioOrg, Med. Chem, 2, 1267 (1994)] 7.5 ml of 1,2-dichloroethane in the presence of 400 mg of molecular sieves After 30 minutes add solid sodium bicarbonate. The solution is filtered, washed with sodium thiosulfate solution, water, dried and evaporated. Purified on a column with SephadexLH-20 (dichloromethane/ethanol in a ratio of 1:1), then on a column of silica (cyclohexane/ethyl acetate in a ratio of 1:1, then 2:3) to give 487 mg (64%) of pure compound (27) (see scheme 7, provided at the end of the description).

[]D= +63(C = 0,54; dichloromethane).

TLC: RF= 0,28 (cyclohexane/ethyl acetate 2:1 ratio).

ESIMS (positive ions): m/e (+ NaCl) 2454 (M+Na)+; (+ KF) 2469 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,38 to 7.2 (m, 50H, 10 phenyl), 3,56, 3,52, 3,48, 3,46, 3,44, 3,42, 3,39, 3,30, 3,17, (9c, 27H, 9 OCH3), a 2.75-2,4 (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,15, 1,98, 1,97, 1,87 (4c, 12H, 3 acetyl and O(C:O)CH2CH2(: O)CH3 Methyl-O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil) - (1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl - D-glyukopiranozil)-(1--->4)-O-(6-O-benzyl-2,3-di-O-methyl - D-glyukopiranozil)-(1--->4) -O-(benzyl-2,3-di-O-methyl-a-D - glucopyranosyloxy)-(1--->4) -O-(3,6-di-O-acetyl-2-O-benzyl-a-D-glyukopiranozil)-(1--->4) -O-(benzyl-2,3-di-O-methyl--L-iodopyrazine)-(1--->4) -2,3,6-tri-O-benzyl-a-D - glucopyranoside (28)

To remove levulinate group 498 mg (0.2 mmol) of the compound (27) is treated according to Method 2, receiving 402 mg (84%) of compound (28) (see scheme 7, provided at the end of the description).

[]D= +64(C = 1; dichloromethane).

ESIMS (positive ions): m/e 2352,9 (M+NH4)+.

1H-NMR (deuterochloroform); (M. D.):

7,38-7,20 (m, 50H, 10 phenyl), 3,67, 3,52, 3,49, 3,46, 3,44, 3,41, 3,40, 3,28, 3,17 (9c, 27H, 9 acetyl), 2,65 (d, 1H, J=2,14 Hz, OH), 1,98, 1,96, 1,87 (3c, 9H, 3 acetyl).

The main anomeric protons: 5,55; 5,49; 5,30; 5,18; 4,56; 4,31; 4,08.

Analysis for C127H152O41(2334,48):

calculated, %: C 65,34 H 6,56

found, %: C 65,40 H 6,62

Preparative example 27

Methyl-O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl - a-D - (glyukopiranozil)-(1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil)-(1--->4)-[O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil-(1--->4)]4
A mixture of 340 mg (1,16 mmol) of the compound (21) and 256 mg (1,09 mmol) of the compound (28) is treated according to Method 1. The residue is purified on a column of c ToyopearlHW-40 (3.2 x 70 cm; dichloromethane/ethanol in a ratio of 1:1) to give 421 mg (76%) of pure 15-measure (29) (see scheme 8, provided at the end of the description).

[]D= +65(c = 1; dichloromethane).

ESIMS (positive ions): m/e (+KF) 2584,3 (M+2K)2+; 1736,5 (M+3K)3+.

1H-NMR (deuterochloroform); (M. D.):

7,35-to 7.18 (m, 105H, 21 phenyl), 2,75-2,4 (m, 4H, O(C:O)CH2CH2(C+O)CH3), 2,15, 1,97, 1,95, 1,87, 1,84, 1,83 (6c, 24H, 7 acetyl and O(C:O)CH2CH2(C: O)CH3).

The main anomeric protons: 5,55; 5,48, 5,30, 5,18, 4,56, 4,29; 4,22, 4,08.

Preparative example 28

Methyl-O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl - D-glyukopiranozil)-(1--->4)-[O-(2,6-di-O-benzyl-3-O-methyl - D-glyukopiranozil)-(1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil-(1--->4)]4-O-(6-O-benzyl-2,3-di-O-methyl-D-glyukopiranozil) -(1--->4)-O-(benzyl-2,3-di-O-methyl-a-D - glucopyranosyloxy)-(1--->4)-O-(3,6-di-O-acetyl-2-O-benzyl-a-D-glyukopiranozil) -(1--->4)-O-(benzyl-2,3-di-O-methyl--L-iodopyrazine) -(1--->4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (30)

342 mg (0,067 mmol) zapisanie).

[]D= +59(C = 0,92; dichloromethane).

ESIMS (positive ions): m/e (+KF) 2535,6 (M+2K)2+.

1H-NMR (deuterochloroform); (M. D.) major anomeric protons: 5,55; 5,50; 5,48; 5,30; 4,56; 4,30; 4,22; 4,08.

Analysis for C275H328O85(4993,37):

calculated, %: C 65,57 N 6,60

found, %: C 65,09 H 6,57

Preparative example 29

Methyl-O-(2,6-di-O-benzyl-4-O-levulinic-3-O-methyl-D-glyukopiranozil) -(1--->4)-O-(2-O-acetyl-6-O-benzyl-3-O-methyl - D-glyukopiranozil)-(1--->4) -[O-(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2-O-acetyl-6-O-benzyl-3-O-methyl-D-glyukopiranozil- (1--->4)]6-O-(6-O - benzyl-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O- (benzyl-2,3-di-O-methyl-a-D-glucopyranosyloxy)- (1--->4)-O-(3,6-di-O-acetyl-2-O-benzyl-a-D-glyukopiranozil)- (1--->4)-O-(benzyl-2,3-di-O-methyl--L-iodopyrazine) -(1--->4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (31)

A mixture of 32.7 mg (to 20.6 mmol) of the compound (17) and 80.7 mg (16.3 mmol) of the compound (30) is treated according to Method 1. Purify by column c ToyopearlHW-40 (dichloromethane/ethanol in a ratio of 1:1) to give 60 mg (59%) 19-measure (31) (see scheme 8, provided at the end of the description).

[]D= +61(s = 0,82; dichloromethane).

ESIMS (positive ions): m/e (+NaCl) 2162 is in: 5,55; 5,48; 5,30; 5,17; 4,56; 4,28; 4,22; 4,08.

Preparative example 30

Ethyl-O-(4,6-O-benzylidene--D-glyukopiranozil)-(1--->4) -6-O-trityl-1-thio--D - glucopyranoside (33)

To a suspension of 50.0 g (0,105 mol) of the compound (32) [J. Westman and M. Nilsson, J. Carbohydr. Chem., 14(7), 949-960 (1995)] in 620 ml of dichloromethane in an argon atmosphere add 35 ml (0,252 mol) of triethylamine, to 29.3 g (105 mol) of Fritillaria and 1.28 g (10 mmol) of 4-dimethylaminopyridine. The reaction mixture is refluxed for two hours (TLC), leave it to cool to room temperature, diluted with 500 ml of dichloromethane, then washed it successively with cold aqueous 10% solution of potassium hydrosulfate, water and a saturated solution of sodium chloride. Dried, concentrated and filtered through a column with silica (toluene/acetone in a ratio of 65:35, then 50:50) to give the crude product (33) of sufficient purity for use in the next stage (see figure 9, is provided at the end of the description). The sample for analysis chromatographic.

[]D= +53(s = 0,74; dichloromethane).

ESIMS (negative ions): m/e 715 (M-H)-.

1H-NMR (CD2Cl2); (M. D.):

7,52-7,25 (m, 20H, 4 phenyl), 5,42 (C, C6H5CH), equal to 4.97 (d, J=3.5 Hz, H-1'), and 4.40 (d, J=9,6,5 Hz, H-6'a), to 3.33 (DD, H-6'b), 3,30-of 3.27 (m, 2H, H-4', H-6b), 2,90-2,77 (m, 2H, SCH2CH3), 1,40 to 1.37 (t, 3H, CH2CH3).

Analysis for C40H44O10S:

calculated, %: C 67,02 to 6.19 H S 4,47

found, %: C 66,83 to 6.19 H S 4,19

Preparative example 31

Ethyl-O-(4,6-O-benzylidene-2,3-di-O-methyl - D-glyukopiranozil) (1--->4)-2,3-di-O-methyl-6-O-trityl-1-thio--D-glucopyranosid) (34)

In an argon atmosphere 34 ml (0,536 mol) of methyliodide was added dropwise to a solution of the 64.1 g of compound (33) in 600 ml of N,N-dimethylformamide. Cooled to a temperature of 0oC and slowly added 13.5 g (0,536 mol) of sodium hydride. The suspension is stirred for two hours at room temperature, then cooled to a temperature of 0oC, was added dropwise 35 ml of methanol and after stirring for two hours the mixture was poured into 500 ml of ethyl acetate and 600 ml of water. The aqueous phase is extracted with ethyl acetate, the organic phase is washed with water, dried and concentrated. The remainder (34) has a sufficient degree of purity for use in the next stage (see figure 9, is provided at the end of the description). The sample for the analysis of purified on a column of silica (cyclohexane/acetone in a ratio of 70:30).

[]D= +45(c = 0,83; dichloromethane).

ESIMS (positive ions): m/e is, J=3.3 Hz, H-1'), 5,43 (C, C6H5CH), of 4.45 (d, J=9.8 Hz, H-1), 3,60, 3,59, 3,51, 3,49 (4c, 12H, 40CH3), 2,86 (K, 2H, J=7.5 Hz, SCH2CH3), of 1.40 (t, 3H, SCH2CH3).

Analysis for C44H52O10S:

calculated, %: C 68,37 H 6,78 S 4,15

found, %: C 68,28 H 6,98 S 4.09 TO

Preparative example 32

Ethyl-O-(2,3-di-O-methyl - D-glyukopiranozil)-(1--->4) -2,3-di - O-methyl-1-thio--D-glucopyranoside (35)

Suspension of 67.4 g of crude product (34) in 470 ml of aqueous 60% solution of acetic acid is heated at a temperature of 80oC for two hours. Cooled, filtered and the reaction mixture was concentrated. The residue is treated with 940 mg methanolate of sodium in 200 ml of methanol for 1 hour. Then the solution is neutralized with resin Dowex50 WX 4 (H+), filtered, concentrated and the residue purified on a column of silica (toluene/acetone in a ratio of 60:40) to give 27.9 g (60% (based on three stages) of the compound (35) (see scheme 9, is provided at the end of the description).

[]D= +26(C = 1,07; dichloromethane).

ESIMS (positive ions): m/e (+NaCl) 465 (M+Na)+; (+KF) 481 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

5,62 (d, J=3,9 Hz, H-1), 4,35 (d, J=9.8 Hz, H-1), 3,64, 3,64, 3,59, 3,58 (4c, 12H, 4OCH3), 7,87 S OF 6.96

found, %: C 47,19 H 7,72 S 6,70

Preparative example 33

Ethyl-O-(6-O-acetyl-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-6-O-acetyl-2,3-di-O-methyl-1-thio--D-glucopyranoside (36)

The solution 5,86 g (13,2 mmol) Tirol (35) and 3.21 g (of 29.1 mmol) of N-acetylimidazole in 120 ml of 1,2-dichloroethane is refluxed for 16 hours. Add another portion of 440 mg (3,96 mmol) of N-acetylimidazole and stirred for four hours. Leave to stand for bringing to room temperature, then add 2 ml of methanol. Again stirred for 1 hour, after which the mixture is diluted with 1 l of dichloromethane and washed successively with cold aqueous 1 M solution of hydrochloric acid, cold water, aqueous saturated sodium hydrogen carbonate solution, water, dried and concentrated. The remainder chromatographic (toluene/acetone in a ratio of 3.5:1), receiving of 3.97 g (57%) diacetate (36) (see scheme 9, is provided at the end of the description).

[]D= +33(C = 1,90; dichloromethane).

ESIMS (positive ions): m/e (+NaCl) 549 (M+Na)+; (+KF) 565 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

the 5.51 (d, J= 3,9 Hz, H-1'), 4,34 (d, J=9.8 Hz, H-1), 3,64, 3,63, 3,59, 3,56 (4c, 12H, 40CH3), 2,11, to 2.06 (2c, 6H, 2 acetyl), is 1.31 (t, 3H, J=7,4 Hz, SCH2CH3).

the operational example 34

Ethyl-O-(6-O-acetyl-4-O-levulinic-2,3-di-O-methyl - D-glyukopiranozil)-(1--->4)-6-O-acetyl-2,3-di-O-methyl-1-thio--D - glucopyranoside (37)

In argon atmosphere, to a solution of 19.4 g (to 36.8 mmol) diacetate (36) in 400 ml of dioxane add 7,53 ml (73,5 mmol) levulinate acid, 14.1 g (of 73.5 mmol) of 1-(3-dimethylaminopropyl) -3-ethylcarbodiimide and 900 mg (7,35 mmol) of 4-dimethylaminopyridine. The mixture is stirred for 3.5 hours, diluted with 1.5 liters of dichloromethane, then washed successively with water, aqueous 10% solution of potassium hydrosulfate, water, aqueous 2% sodium hydrogen carbonate solution, water, then dried and concentrated. The remainder chromatographic (dichloromethane/acetone in a ratio of 97:3, then 79:21), receiving 21.8 g (95%) derivative (37).

[]D= +40(C = 0,72; dichloromethane).

ESIMS (positive ions): m/e (+NaCl) 647 (M+Na)+; (+KF) 663 (M+K)+.

1H-NMR(deuterochloroform); (M. D.):

to 5.56 (d, J=3,9 Hz, H-1), 4,35 (d, J=9.8 Hz, H-1), 3,64, 3,60, 3,58, 3,55 (4c, 12H, 4OCH3), was 2.76-2.71 to (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,19, 2,08, 2,07 (3c, 9H, 2 acetyl and O(C:O)CH2CH2(: O)CH3), is 1.31 (t, 3H, J=7,4 Hz, SCH2CH3).

Analysis for C27H44O14S:

calculated, %: C 51,91 H 7,10 S 5,13

found, %: C 51,88 cetyl-2,3-di-O-methyl-,- D-glucopyranose-trichloroacetimidate (38)

To the solution at 9.53 g (15,3 mmol) thioglycoside (37) in 180 ml of a mixture of dichloromethane with diethyl ether in the ratio 1:1 add to 1.4 ml (76,3 mmol) of water, at 6.84 g (30,5 mmol) N-jodatime and 0.51 g (to 1.98 mmol) of silver triflate. After 15 minutes (TLC) add 5 ml of aqueous saturated solution of sodium bicarbonate and the reaction mixture is diluted with 1.5 l of dichloromethane, washed with water, aqueous 1 m solution of sodium thiosulfate, aqueous 2% sodium hydrogen carbonate solution. Dried, concentrated and the residue purified on a column of silica (ethyl acetate/cyclohexane in the ratio of 80: 40, then 100:0) to give a solid which is used without okharakterizovanie in the next stage.

The solution 7,88 g (to 13.6 mmol) videolounge connection in 120 ml of dichloromethane in an atmosphere of argon is treated with 7,08 g (21,7 mmol) of cesium carbonate and for 6.81 ml (67,9 mmol) trichloroacetonitrile. After 40 minutes (TLC), the mixture is filtered, concentrated it, and clean (toluene/acetone in a ratio of 85:15), receiving 9,16 g (83% over two stages) of imidate (38) (see scheme 10, provided at the end of the description).

[]D= +118(c = 1,00; dichloromethane).

ESIMS (positive ions): m/e (+NaCl) 746 (M+Na)+; 741 (M+NH4)+.<,7 Hz, H-1), 2,78 - to 2.57 (m, 4H, O(C:O)CH2CH2(C: O)CH3), 2,18, 2,07, to 2.06 (3c, 9H, 2 acetyl and O(C:O)CH2CH2(C:O)CH3).

Analysis for C27H40Cl3NO150.5 H2O:

calculated, %: C 44,18 H 5,63 N 1,98

found, %: C 44,14 H 5,61 N 1,97

Preparative example 36

2-(Trimethylsilyl)ethyl-O-(6-O-acetyl-4-O-levulinic-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-6-O-acetyl-2,3-di-O-methyl-,-D-glucopyranosid (39)

10.6 g (16,94 mmol) thioglycoside (37) is treated according to Method 3 with 4.8 ml (33,90 mmol) of 2- (trimethylsilyl)ethanol in 105 ml of a mixture of dichloromethane with diethyl ether in the ratio 1:2. The resulting residue is purified by chromatography was carried out (acetone/dichloromethane in the ratio 1:1) to give 9.80 g (85%) of compound (39) as a mixture of anomers (/= 65:35) (see scheme 10, provided at the end of the description).

ESIMS (positive ions): m/e (+NaCl) 703 (M+Na)+.

1H-NMR(deuterochloroform); (M. D.):

to 5.58 (d, J=3,9 Hz, H-1'), 4,94 (d, J=3.5 Hz, H-1), 4.26 deaths (d, J=7.7 Hz, H-), was 2.76-of 2.56 (m, 4H, O(C:O)CH2CH2(: O)CH3), 2,17, 2,08, 2,05 (3c, 9H, 2 acetyl and O(C:O)CH2CH2(: O)CH3), 1,18-0,88 (m, 2H, OCH2CH2Si(CH3)3), of 0.02 (s, 9H, CH2CH2Si(CH3)3).

Analysis for C30H52O15Si:

rasschitani-O-methyl - D-glyukopiranozil)-(1--->4)-6-O-acetyl-2,3-di-O-methyl-,-D - glucopyranoside (40)

9,41 g (13,82 mmol) of the compound (39) is treated according to Method 2 using hydrazinoacetate (10 mol/mol) in a mixture of toluene with ethanol in the ratio 1:2 (21 ml/mmol). The remainder chromatographic (acetone/toluene in a ratio of 60: 40), getting to 4.81 g (60%) of compound (40) as well as of 3.06 g (37%) mixture (40/) (see scheme 10, provided at the end of the description).

The compound (40):

[]D= +132(C = 0,61; dichloromethane);

ESIMS (positive ions): m/e (+NaCl) 605 (M+Na)+; (+KF) 621 (M+K)+;

1H-NMR (deuterochloroform); (M. D.):

of 5.55 (d, J=3.8 Hz, H-1'), of 4.95 (d, J=3.6 Hz, H-1), 2,10, 2,08 (2s, 6H, 2 acetyl), 1,16-0,89 (m, 2H, OCH2CH2Si(CH3)3), 0,02 (c, 9H, OCH2CH2Si(CH3)3).

Analysis for C25H46O13Si:

calculated, %: C 51,53 H of 7.96

found, %: C 51,37 H 8,06

Preparative example 38

2-(Trimethylsilyl)ethyl-O-(6-O-acetyl-4-O-levulinic-2,3 - di-O-methyl-D-glyukopiranozil)- (1--->4)[O-(6-O - acetyl-2,3-di-O-methyl-D-glyukopiranozil- (1--->4)]2-6-O-acetyl-2,3-di-O - methyl-a-D-glucopyranoside (41)

4,21 g (6,74 mmol) thioglycoside (37) and 3.57 g (6,13 mmol) glycosylase acceptor (40) in 105 ml of a mixture of dichloromethane with diethyl ether in the ratio 1: 2 is treated according to Method 3. The residue is purified by chromatogra is. circuit 11 provided in the end of the description).

[]D= +143(C = 0,56; dichloromethane).

ESIMS (positive ions): m/e (+NaCl) 1167 (M+Na)+; (+KF) 1183 (M+K)+.

1H-NMR(deuterochloroform); (M. D.):

to 5.57 (d, J=3,9 Hz, H-1"'), 5,54, 5,41 (2D, J=3.8 Hz, H-1, H-1'), 4,96 (d, J= 3.6 Hz, H-1), 2,78-of 2.58 (m, 4H, O(C:O)CH2CH2(: O)CH3), 2,18 2,12, 2,12, 2,09, 2,06 (5c, 15H, 4 acetyl and O(C:O)CH2CH2(: O)CH3), 1,21 to 0.97 (m, 2H, OCH2CH2Si(CH3)3).

Analysis for C50H84O27Si:

calculated, %: C 52,44 H 7,39

found, %: C 52,29 H 7,46

Preparative example 39

Ethyl-O-(6-O-acetyl-4-O-levulinic-2,3-di-O-methyl - D-glyukopiranozil)-(1--->4)[O-(6-O-acetyl-2,3-di-O-methyl - D-glyukopiranozil-(1--->4)]2-6-O-acetyl-2,3-di-O - methyl-1-thio--D-glucopyranoside (42)

A solution of 1.10 g (of 1.52 mmol) of imidate (38) and 806 mg (1.38 mmol) glycosylase acceptor in 22 ml of a mixture of dichloromethane with diethyl ether in the ratio 1: 2 is treated according to Method 1. Purify by chromatography was carried out on silica (ethyl acetate/cyclohexane in the ratio of 2.5:1, then 3:1) to give 1.12 g (71%) of compound (42) (see scheme 12, provided at the end of the description).

[]D= +95(C = 1,00; dichloromethane).

ESIMS (positive Hz, N-1"'), 5,39, 5,37 (2D, J=3,8 and 3.9 Hz, H-1', H-1'), 4,34 (d, J= 9.7 Hz, H-1), 2,84 is 2.51 (m, 6H, SCH2CH3, O(C:O)CH2CH2(: O)CH3), 2,17, 2,10, 2,09, 2,08, 2,04 (5c, 15H, 4 acetyl and O(C:O)CH2CH2(: O)CH3), of 1.30 (t, 3H, J=7,4 Hz, SCH2CH3).

Analysis for C47H76O26S:

calculated, %: C 51,83 H 7,03 S 2,94

found, %: C 51,66 H 7,02 S 2,94

Preparative example 40

2 - Trimethylsilyl)ethyl-[O-(6-O-acetyl-2,3-di-O-methyl-D-glyukopiranozil) -(1--->4)]3-6-O-acetyl-2,3-di-O - methyl-a-D-glucopyranosid (43)

4.71 g (4,11 mmol) of the compound (41) is injected into the interaction, as described in preparative example 37, after receiving column chromatography (cyclohexane/acetone in a ratio of 3:2), 4.11 g (95%) derivative (43) (see scheme 13 provided at the end of the description).

[]D= +154(s = 0,63; dichloromethane).

ESIMS (positive ions): m/e (+NaCl) 1069 (M+Na)+; (+KF) 1085 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

5,46, 5,46, 5,41 (2D, 3H, J=3,9 Hz, H-1', H-1', H-1"'), of 4.95 (d, J=3.5 Hz, H-1), of 2.81 (d, J= 4.4 Hz, OH), 2,11, 2,09, 2,08 (3c, 12H, 4 acetyl), 1,19 is-0.97 (m, 2H, OCH2CH2Si(CH3)3), of 0.03 (s, 9H, OCH2CH2Si(CH3)3).

Analysis for C45H78O25Si:

calculated, %: C 51,61 H 7,51

found, %: C 51,39 7 H, the ZIL)-(1--->4) -[O-(6-O-acetyl-2,3-di - O-methyl-D-glyukopiranozil-(1--->4)]6-6-O-acetyl-2,3-di - O-methyl-a-D-glucopyranoside (44)

3,86 g (3.54 mmol) of thioglycoside (42) and of 3.60 g (3,44 mmol) glycosylase acceptor (43) the process according to preparative example 38. Are chromatographicaliy (dichloromethane/acetone in a ratio of 7:2 then 2:1), receiving 5,71 g (80%) of the compound (44) (see scheme 13 provided at the end of the description).

[]D= +161(C = 0,65; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 2072,8; chemical mass = 2074,2; experimental mass = 2074 1 Rel.mass. units (relative mass units).

1H-NMR (deuterochloroform); (M. D.):

5,54 (d, J=3.8 Hz, H-1 residue NR), 5,47-of 5.40 (m, 6H, H-1), of 4.95 (d, J= 3,7 Hz, H-1, the remainder R), 2,84 is 2.51 (m, 4H, O(C:O)CH2CH2(C:O)CH3), 2,17, 2,13, 2,12, 2,11, 2,11, 2,08, 2,05 (7c, 27H, 8 acetyl and O(C:O)CH2CH2(: O)CH3), 1,18-0,97 (m, 2H, OCH2CH2Si(CH3)), of 0.03 (s, 9H, OCH2CH2Si(CH3)3).

Analysis for C90H148O51Si:

calculated, %: C 52,12 H 7,19

found, %: C 51,98 H 7,25

Preparative example 42

2-(Trimethylsilyl)ethyl-[O-(6-O-acetyl - 2,3-di-O-methyl-D-glyukopiranozil)-(1--->4)]7-6-O-acetyl-2,3-di-O-methyl-a-D - glucopyranoside (45)

At a temperature of 0oC 7.3 ml 1 M solution hydrazinehydrate is (44) in 5 ml of pyridine. After stirring for 20 minutes the reaction mixture is evaporated, diluted with 400 ml of dichloromethane, washed with aqueous 10% solution of potassium hydrosulfate, water, aqueous 2% sodium hydrogen carbonate solution and water. Dried, concentrated and the residue chromatographic getting 2,43 g (85%) of compound (45) (see scheme 13 provided at the end of the description).

[]D= +167(C = 0,57; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 1974,8; chemical mass = 1976,1; experimental mass = 1975 2 Rel.mass.ed.

1H-NMR (deuterochloroform); (M. D.):

5,47-of 5.40 (m, 7H, H-1), of 4.95 (d, J=3,7 Hz, H-1 remainder R) 2,80 (d, J= 4.4 Hz, OH), 2,13, 2,11, 2,10, 2,08, 2,07 (5c, 24H, 8 acetyl), 1,18-0,97 (m, 2H, OCH2CH2Si(CH3)3), 0,03 (c, 9H OCH2CH2Si(CH3)3).

Analysis for C85H142O49Si:

calculated, %: C 51,66 H 7,24

found, %: C 51,32 H 7,26

Preparative example 43

2-(Trimethylsilyl)ethyl-O-(6-O-acetyl-4-O-levulinic-2,3-di - O-methyl-D-glyukopiranozil)-(1--->4)-[O-(6-O-acetyl-2,3-di-O-methyl-D-glyukopiranozil-(1--->4)]10-6-O-acetyl-2,3 - di-O-methyl-a-D-glucopyranosid (46)

1.35 g (1,24 mmol) of the compound (42) and 2.38 g (1.20 mmol) of the compound (45) is treated according to preparative example (46) (see circuit 13 provided in the end of the description).

[]D= +166(c = 0,88; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 3001,3; chemical mass = 3003,2; experimental mass = 3004 + 1 Rel.mass.ed.

1H-NMR (deuterochloroform); (M. D.):

5,54 (d, J=3.8 Hz, H-1 residue NR), 5,47-of 5.40 (m, 10H, H-1), of 4.95 (d, J= 3,7 Hz, H-1 remainder R), 2,81 is 2.51 (m, 4H, O(C:O)CH2CH2(: O)CH3), 2,17, 2,13, 2,12, 2,11, 2,11, 2,08, 2,05 (7c, 39H, 12 acetyl and O(C:O)CH2CH2(: O)CH3), 1,17-to 0.96 (m, 2H, OCH2CH2Si(CH3)3), of 0.03 (s, 9H, OCH2CH2Si(CH3)3).

Analysis for C130H212O75Si:

calculated, %: C 51,99 H 7,12

found, %: C 51,63 H 7,12

Preparative example 44

(6-O-Acetyl-4-O-levulinic-2,3-di-O-methyl - D-glyukopiranozil) -(1--->4)-[O-(6-O-acetyl-2,3-di-O-methyl-D-glyukopiranozil- (1--->4)]10-6-O-acetyl-2,3-di-O-methyl-,-D - glucopyranosilchloride (47)

(a) for 1.5 hours (TLC) is stirred solution of 400 mg (0.133 mmol) of glycoside (46) in 2 ml of a mixture of triperoxonane acid and dichloromethane in the ratio of 2:1. Diluted with 12 ml of a mixture of toluene with n-propyl in the ratio 2: 1, concentrated and evaporated together with toluene (5 times 10 ml). The residue is cleaned (acetone/cyclogram in 2.5 ml of dichloromethane, added 65 mg (0,200 mmol) of cesium carbonate and 63 ml (0,620 mmol) trichloroacetonitrile. The mixture is stirred for 2.5 hours, then filtered (celite), concentrated and the residue purified on a column of silica (cyclohexane/acetone/triethylamine in the ratio of 50:50:0,1), getting 348 mg (86%) of imidate (47) (see scheme 13 provided at the end of the description).

[]D= +185(C = 0,91; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 3044,1; chemical mass = 3047,3; experimental mass = 3046,9 0.2 Rel.mass.ed.

1H-NMR (deuterochloroform); (M. D.):

8,61, 8,58 (2c, 1H, N:N), 6.35mm (d, J=3,7 Hz, H-1 remainder R) 5,59 (d, J= 7.5 Hz, H-1 remainder R) 5,38 (d, J=3.8 Hz, H-1 prosperity NR), 5,32-a 5.25 (m, 10H, H-1), 2,64-to 2.40 (m, 4H, O(C:O)CH2CH2(: O)CH3), 2,02, 1,96, 1,95, 1,94, 1,93, 1,89 (6c, 39H, 12 acetyl and O(C:O)CH2CH2(: O)CH3).

Analysis for C127H200Cl3NO25:

calculated, %: C 50,06 H 6,61 N 0,46

found, %: C 49,93 H 6,52 N 0,42

Preparative example 45

(6-O-Acetyl-4-O-levulinic-2,3-di-O-methyl - D-glyukopiranozil)-(1--->4)-[O-(6-O-acetyl-2,3-di-O-methyl - D-glyukopiranozil-(1--->4)]2-6-O-acetyl-2,3-di-O-methyl-,-D - glucopyranosilchloride (48)

200 mg (0,174 mmol) of the compound (41) is treated according to ven is 2), getting 230 mg (77%) of imidate (48) (see scheme 14 provided in the end of the description).

ESIMS (positive ions): m/e (+NaCl) 1210 (M+Na)+; (+KF) 1226 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

8,66-8,64 (2c, 1H, N-H), 6,51 (d, J=3.6 Hz, H-1), 5,71 (d, J=7.5 Hz, H-1), 2,90-2,52 (m, 4H, O(C:O)CH2CH2(: O)CH3), 2,17, 2,11, 2,11, 2,09, 2,05 (5c, 4 acetyl and O(C:O)CH2CH2(: O)CH3).

Preparative example 46

Methyl-O-(6-O-acetyl-4-O-levulinic-2,3-di-O-methyl-D-glyukopiranozil) -(1--->4)-[O-(6-O-acetyl-2,3 - di-O-methyl-D-glyukopiranozil) -(1--->4)]3-O-(benzyl-2,3-di-O-methyl-a-D-glucopyranosyloxy) -(1--->4)-O-(3,6-di-O-acetyl-2-O-benzyl-a-D-glyukopiranozil) -(1--->4)-O-(benzyl-2,3-di-O-methyl--L-iodopyrazine)-(1--->4) -2,3,6-tri-O-benzyl-a-D-glucopyranosid (49)

73 mg (0.061 mmol) of imidate (48) and 82 mg (0,059 mmol) glycosylase acceptor (26) the process according to preparative example 39. Connection purified using a chromatographic column with SephadexLH-20 (dichloromethane/ethanol in a ratio of 1:1), then on a column of silica (toluene/acetone in a ratio of 3: 1) to give 98 mg (69%) derivative (49) (see scheme 14 provided in the end of the description).

[]D= +95(C = 1,01; dichloromethane).

ESIMS (positive P (deuterochloroform); (M. D.):

7,43-7,20 (m, 30H, 6 phenyl), of 5.55 (d, J=3,9 Hz, H-1 residue NR), of 5.50 (d, J=3,9 Hz, H-1 residue NR-3), 5,44, 5,38 (2D, J=3.7 and 3.9 Hz, H-1 the remainder of the NR-1, the remainder of the NR-2), from 5.29 (d, J=6,8 Hz, H-1 residue R-1), of 5.17 (d, J=3.5 Hz, H-1 the remainder is R-2), 4,56 (d, J=3,7 Hz, H-1 remainder R), 4,10 (d, J=7.9 Hz, H-1 residue R-3), 2,81-of 2.50 (m, 4H, O(C:O) CH2CH2(: O)CH3), 2,17, 2,15, 2,11, 2,09, 2,05, 2,00 (7c, 21H, 6 acetyl and O(C:O)CH2CH2(: O)CH3).

Analysis for C120H158O51:

calculated, %: C 59,63 H 6,59

found, %: C 59,23 H 6,58

Preparative example 47

Methyl-[O-(6-O-acetyl-2,3-di-O-methyl-D-glyukopiranozil) -(1--->4)]4-O-(benzyl-2,3-di-O-methyl-a-D-glucopyranosyloxy) -(1--->4)-O-(3,6-di-O-acetyl-2-O-benzyl-a-D-glyukopiranozil) -(1--->4)-O-(benzyl-2,3-di-O - methyl--L-iodopyrazine)- (1--->4)-2,3,6-tri-O-benzyl-a-D-glucopyranoside (50)

120 mg (0,050 mmol) octasaccharide (49) is injected into the interaction, as described in preparative example 37. The residue is purified on a column of silica (toluene/acetone in a ratio of 3:1) to give 95 mg (83%) of compound (50) (see scheme 14 provided in the end of the description).

[]D= +80(C = 0,62; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 2316,9; chemical mass = 2318,4; experimental mass = 2318,2 0.4 Rel.mass.ed.

1

Analysis for C115H152O49:

calculated, %: C 59,57 H 6,60

found, %: C 59,49 H 6,61

Preparative example 48

Methyl-O-(6-O-acetyl-4-O-levulinic-2,3-di-O-methyl - D-glyukopiranozil)-(1--->4)- [O-(6-O-acetyl-2,3-di-O-methyl - D-glyukopiranozil)-(1--->4)]15-O-(benzyl-2,3-di-O-methyl-a-D - glucopyranosyloxy)-(1--->4) -O-(3,6-di-O-acetyl-2-O - benzyl-a-D-glyukopiranozil)-(1--->4) -O-(benzyl-2,3-di-O-methyl--L-iodopyrazine)-(1--->4)-2,3,6-tri-O-benzyl-a-D-glucopyranosid (51)

84 mg (0,027 mmol) of Imidate (47) is treated with 62 mg (0,027 mmol) glycosylase acceptor (50) according to preparative example 39. The residue is purified first on a column of ToyopearlHW-40, then on a column of silica (cyclohexane/acetone in a ratio of 1:1) to give 71 mg (51%, not optimized) derivative (51) (see scheme 15 provided at the end of the description).

[]D= +136(C = 0,95; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 5200,11; chemical mass = 5203,39; experimental mass = 5203,5.

1H-NMR(deuterochloroform); (M. D.):

7,42-to 7.18 (m, 30H, 6 phenyl), 5,54 (d, J=3.8 Hz, H-1 residue NR), 5,51-of 5.40 (m, 15 H-1), and 5.30 (d, J=6,8 Hz, H-1 residue R-1), of 5.17 (d, J=3UB>), 2,17, 2,16, 2,13, 2,11, 2,08, 2,05, 2,00, 1,88 (8c, 57H, 18 acetyl and O(C:O)CH2CH2(C:O)CH3).

Analysis for C240H350O1234H2O:

calculated % C 54,64 H 6,84

found, %: C 54,51 H 6,79

Preparative example 49

Ethyl-O-(4,6-O-p-methoxy - benzilidene - - D-glyukopiranozil- (1--->4)-1-thio- -D-glucopyranosid (53)

At a temperature of +5oC and in an atmosphere of argon, a 35.8 ml (0.21 mol) of dimethylacetal anisic aldehyde and 4.44 g (19,1 mmol) camphorsulfonate added to a solution 73,89 g (to 0.19 mol) of the compound (52) [W. E. Dick Jr and J. E. Hodge "Methods in carbohydrate chemistry", 7, 15-18 (1976)] in 990 ml of a mixture of acetonitrile with N,N-dimethylformamide in a ratio of 3.5:1. After stirring for six hours at room temperature, neutralized by adding 2,96 ml (21,0 EQ.) of triethylamine, concentrated and the resulting syrup is purified on a column of silica (dichloromethane/methanol in the ratio of 100: 0, then 50: 50), receiving of 58.6 g (61%, not optimized) of the compound (53) (see scheme 16 provided in the end of the description).

[]D= +47(C = 1,03; methanol).

ESIMS (negative ions): m/e 503 (M-H)-.

1H-NMR (CD3OD); (M. D.):

7,41, 6,89 (2D, 4H, CH3OC6H4), the 5.51 (s, CHC6H4), 5,20 (d, J=3.6 Hz, H-1'), 4,39 CLASS="ptx2">

Analysis for C22H32O11S:

calculated, %: C 52,37 H 6,39 S 6,35

found, %: C 52,15 H 6,61 of 5.84 S

Preparative example 50

Ethyl-O-(2,3-di-O-acetyl-4,6-p-methoxybenzylidene--D - glyukopiranozil)-(1--->4)-2,3,6-tri-O-acetyl-1-thio--D - glucopyranoside (54)

At a temperature of 0oC, 65 ml (0.47 mol) of triethylamine and 89 ml of 0.94 mol) of acetic anhydride was added dropwise to a suspension 47,22 g (93,6 mmol) of the compound (53) in 450 ml of dichloromethane. Then add 5,71 g (46.8 mmol) of 4-dimethylaminopyridine and stirred for half hour at room temperature. The reaction is stopped by adding 45 ml (1.12 mol) of methanol, and then the reaction mixture is washed successively with cold aqueous 10% solution of potassium hydrosulfate, water, saturated sodium hydrogen carbonate solution and water. Dried, concentrated and crystallized (from a mixture of cyclohexane to ethyl acetate), obtaining 64,9 g (97%) of compound (54) (see figure 16, is provided at the end of the description).

[]D= +21(C = 1,00 dichloromethane); so pl.= 213-215oC.

ESIMS (positive ions): m/e (+NaCl) 737 (M+Na)+; (+KF) 753 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,34, 6,86 (2D, 4H, CH3OC6H4), 5,43 (s, CHC6H4), of 5.34 (d, J=4,1 Hz, H-1'), and 4.5(t, 3H, SCH2CH3).

Analysis for C32H42O16S:

calculated, %: C 53,78 of 5.92 H S 4,49

found, %: C 53,74 between 6.08 H S 4,40

Preparative example 51

Ethyl-O-(2,3-di-O-acetyl-4 - p-methoxybenzyl--D-glyukopiranozil)- (1--->4)-2,3,6-tri-O-acetyl - 1-thio--D-glucopyranoside (55) and ethyl-O-(2,3-di-O-acetyl-4-p-methoxybenzyl--D-glyukopiranozil) -(1--->4)-2,3-di-O-acetyl - 1-thio--D-glucopyranoside (56)

A suspension of 25.0 g (35,0 mmol) of the compound (54), with 20.4 g (0.28 mol) complex with borane-trimethylamine and 33 g of molecular sieves in 810 ml of toluene is stirred for 1 hour in argon atmosphere. Cooled to a temperature of 0oC and slowly added 14.0 g (0.11 mol) of aluminum chloride. Stirred for 25 minutes (TLC), the reaction medium was poured into cold aqueous 20% solution of potassium hydrosulfate and stirred for 1 hour at a temperature of 0oC, then filtered (celite). The organic phase is washed with water, 2% aqueous solution of sodium bicarbonate, water, dried and concentrated. The residue is purified on a column of silica, getting 7,37 g (29%, not optimized) of the compound (55) and 1.36 g (6%) of compound (56) (see scheme 16 provided in the end of the description). The sample for analysis of compound (55) is crystallized from a mixture of cyclohexane with those who sustained fashion ions): m/e (+NaCl) 739 (M+Na)+; (+KF) 755 (M+K)+.

1H-NMR(deuterochloroform); (M. D.):

7,19, 6,87 (2D, 4H, CH3OC6H4), are 5.36 (d, J = 3.5 Hz, H-1'), of 4.54 (s, 2H, C6H4CH2), a 4.53 (d, J=9.0 Hz, H-1), 2,70-to 2.65 (m, 2H, SCH2CH3).

Analysis for C32H42O16S:

calculated, %: C 53,62 to 6.19 H S 4,47

found, %: C 53,57 H 6,21 S 4,43

Connection (56):

[]D= +19(=1,11; dichloromethane);

ESIMS (positive ions): m/e (+NaCl) 697 (M+Na)+; (+KF) 713 (M+K)+;

1H-NMR (deuterochloroform); (M. D.):

7,17, 6,84 (2s, 4H, CH3OC6H4), are 5.36 (d, J=4.5 Hz, H-1'), of 4.54 (d, J=10.1 Hz, H-1), of 4.49 (s, 2H, C6H4CH2), 2,69-of 2.64 (m, 2H, SCH2CH3), 2,02, 2,01, 2,00, 1,96 (4c, 12H, 4 acetyl), a 1.25 (t, 3H, SCH2CH3).

Analysis for C30H42O15S:

calculated, %: C 53,40 H 6,27 S 4,75

found, %: C 53,29 H 6,39 S 4,53

Preparative example 52

Ethyl-O- (2,3,6-tri-O-acetyl-4-p-methoxybenzyl--D - glyukopiranozil)-(1--->4)-2,3,6-tri-O-acetyl-1-thio--D - glucopyranoside (57)

At a temperature of 0oC 1,47 ml (15,5 mmol) of acetic anhydride is added to a mixture of 5.6 g (to 7.77 mmol) of the compound (55), 1,19 ml (8,54 mmol) of triethylamine and 190 mg (1.55 mmol) of 4-dimethylaminopyridine in 40 ml of dichloromethane. After stirring for 40 minute solution of potassium hydrosulfate, water, a saturated solution of sodium bicarbonate and water. Dried, concentrated and purified on a column of silica (ethyl acetate/cyclohexane in the ratio 35:65), getting to 5.66 g (96%) of compound (57) (see scheme 16 provided in the end of the description).

[]D= +44(C = 1,03; dichloromethane).

ESIMS (positive ions): m/e (+NaCl) 781 (M+Na)+; (+KF) 797 (M+K)+.

1H-NMR(deuterochloroform); (M. D.):

7,15, 6,85 (2D, 4H, CH3OC6H4), and 5.30 (d, J=4,2 Hz, H-1'), a 4.53 (d, J=10.0 Hz, H-1), 2,69-of 2.64 (m, 2H, SCH2CH3), 2,09, 2,07, 2,04, 2,01, 2,00, 1,98 (6c, 18H, 6 acetyl), 1,25. (t, 3H, SCH2CH3).

Analysis for C34H46O17S:

calculated, %: C 53,82 H 6,11 S 34,22

found, %: C 53,77 H 6,24 S 4.09 TO

Preparative example 53

Ethyl-4,6-O-benzylidene-2,3-di - O-methyl-1-thio--glucopyranoside (59)

At a temperature of 0oC 500 mg (to 19.9 mmol) of sodium hydride is added to a mixture of 2,59 g (8,29 mmol) of the compound (58) [A. F. Gods and others, Izv. Acad. Of Sciences of the USSR, a series of chemical, 1, 179 (1968)] and 1.70 ml (to 19.9 mmol) methyliodide in 25 ml of N,N-dimethylformamide and leave the temperature to rise to 20oC. Stirred for 30 minutes (TLC), then add methanol. The mixture was poured into water and extracted with ethyl acetate. The extract is washed with jetelova ether, getting 0,42 g (15%) of the compound (59) (see scheme 17 provided in the end of the description); treatment of uterine solutions on a column of silica (toluene/acetone in a ratio of 12:1) followed by crystallization allows you to receive an additional amount of compound (59) of 1.6 g (total yield is 71%).

[]D= -78(c = 1,00; dichloromethane); so pl. = 108oC.

LSIMS (positive ions): m/e (thioglycerol + NaCl) 363 (M+Na)+; (thioglycerol +KF) 379 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,51-7,33 (m, 5H, phenyl), 5,52 (s, 1H, C6H5CH), of 4.45 (d, 1H, J=9.8 Hz, H-1), to 3.64 (s, 3H, OCH3), 3,62 (s, 3H, OCH3), 2,78 of 2.68 (m, 2H, SCH2CH3), is 1.31 (t, 3H, J=2.7 Hz, SCH2CH3).

Analysis for C17H24O5S:

calculated, %: C 59,98 H 7,11 S 9,42

found, %: C 59,91 H 7,15 S 8,96

Preparative example 54

2-(Trimethylsilyl)ethyl-4,6-O-benzylidene-2,3-di-O-methyl-a-D-glucopyranoside (60)

23,0 g (of 67.5 mmol) of the compound (59) and to 19.4 ml (135 mmol) of 2-(trimethylsilyl) ethanol dissolved in 345 ml of a mixture of diethyl ether and dichloromethane in the ratio of 2:1 and added 11 g of molecular sieves is Stirred for 1 hour at a temperature of 25oC add 49,7 g (220 mmol) of N-jodatime, then, when those who make solid sodium bicarbonate. Diluted with dichloromethane, filtered through celite, washed successively 1 M aqueous sodium thiosulfate solution, water, dried and evaporated to dryness. The residue is purified on a column of silica (cyclohexane/ethyl acetate in a ratio of 15:1, then 5:1), receiving 4,20 g (15%) of the compound (60 and of 8.40 g (31%) of compound (60) (see scheme 17 provided in the end of the description).

Connection (60):

[]D= +96(C = 0,4; dichloromethane);

ESIMS (positive ions): m/e 419 (M+Na)+; 435 (M+K)+;

1H-NMR (deuterochloroform); (M. D.):

7,52-to 7.35 (m, 5H, phenyl), 5,54 (s, 1H, C6H5CH), to 4.98 (d, 1H, J=3,7 Hz, H-1), to 3.64 (s, 3H, OCH3), 3,62 (s, 3H, OCH3), 1,24-to 0.96 (m, 2H, OCH2CH2Si(CH3)h), 0,00 (s, 9H, OCH2CH2Si(CH3)3).

Analysis for C20H32O6S (396,56):

calculated, %: C 60,58 H 8,13

found, %: C 60,26 H 8,39

Preparative example 55

2-(Trimethylsilyl)ethyl-6-O-benzyl-2,3-di-O-methyl-a-D - glucopyranosid (61)

21.1 g (53,3 mmol) of the compound (60) was dissolved in 154 ml of dichloromethane. At room temperature add 34 ml (213 mmol) of triethylsilane, then was added dropwise a mixture of 16.3 ml (213 mmol) triperoxonane acid and 0.49 ml (3,47 mmol) triperoxonane anhydride. Stirred for TLD is ncacii the aqueous phase is extracted with ethyl acetate, then the combined organic phases, dried and concentrated. The residue is purified on a column of silica (dichloromethane/acetone in a ratio of 14:1 and 12:1) to give 12.5 g (59%) of compound (61) (see scheme 17 provided in the end of the description).

[]D= +100(c = 1,45; dichloromethane).

1H-NMR; (M. D.):

7,40-7,20 (m, 5H, phenyl), to 4.98 (d, 1H, J=3.5 Hz, H-1), 3,62 (s, 3H, OCH3), to 3.49 (s, 3H, OCH3), 1,14-of 0.91 (m, 2H, CH2CH2Si(CH3)3), is 0.00 (s, 9H, CH2CH2Si(CH3)3).

Analysis for C20H30O6Si (398,58):

calculated, %: C 60,27 H 8,60

found, %: C 60,18 H 8,81

Preparative example 56

2-(Trimethylsilyl)ethyl-O-(2,3,6-tri-O-acetyl-4-O-p-methoxybenzyl-- D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-acetyl- -D-glyukopiranozil)-(1--->4)-6-O-benzyl-2,3-di-O-methyl-D-glucopyranosid (62)

A mixture of 19.1 g (25,1 mmol) thioglycoside (57) and 7.5 g (to 18.7 mmol) glycosylase acceptor (61) is treated according to Method 3 to give, after purification on a column of silica (dichloromethane/acetone in a ratio of 20: 1, then 10: 1), 19.7 g (95%) of compound (62) (see scheme 17 provided in the end of the description).

[]D= +90(C = 1,15; dichloromethane).

Analysis for C52H74O23Si (1095 the sludge-O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4)-6-O-benzyl-2,3-di-O-methyl-a-D - glucopyranosid (63)

19.7 g (18.0 mmol) of the compound (62) is treated according to Method 4 to give, after purification on a column of silica (toluene/acetone in a ratio of 3:1, then 2:1), and 11.2 g (79% in the calculation of the three stages) of the compound (63) (see scheme 18 provided at the end of the description).

[]D= +95(C = 1,15; dichloromethane).

ESIMS (positive ions): m/e (+ NaCl) 829 (M+Na)+; (+ KF) 845 (M+K)+.

1H-NMR (deuterochloroform); (M. D.):

7,34-7,25 (m, 5H, phenyl), the ceiling of 5.60 (d, 1H, J=3.8 Hz, H-1"), 4,96 (d, 1H, J= 3.8 Hz, H-1), the 4.29 (d, 1H, J=8.0 Hz, H-1'), 1,08-of 0.91 (m, 2H, CH2CH2Si(CH3)3). 0,00 (s, 9H, CH2CH2Si(CH3)3).

Preparative example 58

2-(Trimethylsilyl) ethyl-O-(2,3,6-tri-O-acetyl-4-O-p-methoxybenzyl--D-glyukopiranozil) -(1--->4)-O-(2,3,6-tri-O-acetyl--D-glyukopiranozil) -(1--->4)-O-(2,3,6-tri-O - methyl-D-glyukopiranozil) -(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-6-O-benzyl-2,3-di-O-methyl-a-D-glucopyranosid (64)

The mixture 6,87 g (9,10 mmol) thioglycoside (57) and 6.67 g (8,30 mmol) glycosylase acceptor (63) is treated according to Method 3 and the residue purified on a column of silica (toluene/acetone in the ratio 2:5) to give 10.7 g (86%) of compound (64) (see scheme 18 provided at the end of the description).

[]D= +90CLASS="ptx2">

1H-NMR (deuterochloroform); (M. D.):

7,33-7,25 (m, 5H, phenyl), 7,15-6,84 (m, 4H, C6H4OCH3), to 5.56 (d, 1H, J= 3,9 Hz, H-1"), from 5.29 (d, 1H, J=4.0 Hz, H-1""), equal to 4.97 (d, 1H, J=3,7 Hz, H-1), 4,71 (d, 1H, J=8,l Hz, H-1"'), 4,27 (d, 1H, J=7.9 Hz, H-1'), 1,08 - of 0.91 (m, 2H, CH2CH2Si(CH3)3), is 0.00 (s, 9H, CH2CH2Si(CH3)3).

Analysis for C70H106O33Si (1503,69):

calculated, %: C 55,91 H 7,11

found, %: C 56,05 H 7,24

Preparative example 59

2-(Trimethylsilyl)ethyl-[O-(2,3,6 - tri-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)- (1--->4)]2-6-O-benzyl-2,3-di-O-methyl-a-D-glucopyranosid (65)

10.7 g (7.2 mmol) of the compound (64) is treated according to Method 4, and the residue is purified on a column of silica (toluene/acetone in a ratio of 2: 1, then 6: 5) to give 6.50 g (74% over three stages) of the compound (65) (see scheme 18 provided at the end of the description).

[]D= +102(C = 0,68; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,33-7,25 (m, 5H, phenyl), 5,65 (l, 1H, J=3.8 Hz, H-1""), 5,62 (d, 1H, J= 3.8 Hz, H-1"), to 4.98 (d, 1H, J=3,7 Hz, H-1), or 4.31 (d, 1H, J=8,1 Hz, H-1"'), the 4.29 (d, 1H, J=7.9 Hz, H-1'), 1,08-of 0.91 (m, 2H, CH2CH2Si(CH3)3), is 0.00 (s, 9H, CH2CH2Si(CH3)3).

Analysis for C56H982-6-O-benzyl-2,3-di-O-methyl-a-D - glucopyranosid (66)

The mixture is 4.03 g (5,31 mmol) thioglycoside (57) and 5,78 g (4,75 mol) glycosylase acceptor (65) is treated according to Method 3, and the residue is purified on a column of silica (toluene/acetone in the ratio 2:5), receiving 8,63 g (95%) of compound (66) (see scheme 18 provided at the end of the description).

[]D= +94(s = 0,74; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 1910,83; chemical mass = 1912,14; experimental mass = 1911,61 0.12 Rel. mass. unit

1H-NMR (deuterochloroform); (M. D.):

7,33-7,25 (m, 5H, phenyl), 7,15-6,83 (m, 4H, C6H4OCH3), 5,62 (d, 1H, J= 3.8 Hz, H-1 residue R-2), the ceiling of 5.60 (d, 1H, J=3.8 Hz, H-1 residue NR-2), and 5.30 (d, 1H, J= 4.0 Hz, H-1 residue NR), to 4.98 (d, 1H, J=3,7 Hz, H-1 remainder R), 4,71 (d, 1H, J=7.9 Hz, H-1 residue NR-1), 4,30 (d, 1H, J=8,1 Hz, H-1 balance C), the 4.29 (d, 1H, J=8,4 Hz, H-1 residue R-1), of 2.08 (s, 3H, acetyl), 2,07 (s, 3H, acetyl), 2,03 (s, 3H, acetyl), of 1.99 (s, 3H, acetyl), to 1.98 (s, 3H, acetyl), a 1.96 (s, 3H, acetyl), 1,08-of 0.91 (m, 2H, CH2CH2Si(CH3)3), is 0.00 (s, 9H, CH2CH2Si(CH3)3).

Analysis for C88H138O43Si (1912,14):

calculated, %: C 55,28 H 7,27

found, %: C 55,61 H 7,35

Preparative example 61

2-(Trimethylsilyl)ethyl-[O-(2,3,6-tri-O-methyl - D-BR> 8,63 g (4,50 mmol) of the compound (66) is treated according to Method 4, and the residue is purified on a column of silica (toluene/acetone in a ratio of 3: 2, then 4: 3), receiving 5,67 g (77% in the calculation of the three stages) of the compound (67) (see scheme 19 provided in the end of the description).

[]D= +102(c = 0,70; dichloromethane).

LSIMS (positive ions): m/e (thioglycerol + NaCl) 1645 (M+Na)+.

1H-NMR (deuterochloroform); (M. D.):

7,33-to 7.32 (m, 5H, phenyl), the 5.65 (d, 2H, J=3.8 Hz, H-1 residue NR and H-1 the remainder of the NR-2), 5,62 (d, 1H, J=3.8 Hz, H-1 residue R-2), to 4.98 (d, 1H, J=3,7 Hz, H-1 remainder R), or 4.31 (d, 1H, J=8,1 Hz, H-1 residue NR-1), 4,30 (d, 1H, J=7.9 Hz, H-1 balance C), the 4.29 (d, 1H, J=7.9 Hz, H-1 residue R-1), 1,08-of 0.91 (m, 2H, CH2CH2Si(CH3)3), is 0.00 (s, 9H, CH2CH2Si(CH3)3).

Analysis for C74H130O36Si (1912,14):

calculated, %: C 54,73 H 8,07

found, %: C 54,61 H 8,07

Preparative example 62

2-(Trimethylsilyl)ethyl-O-(2,3,6-tri-O-acetyl-4-O-p - methoxybenzyl- -D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O - acetyl- -D-glyukopiranozil)-(1--->4)-[O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-[O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]3-6-O-benzyl-2,3-di-O-methyl-D-glucopyranosid (68)

A mixture of 1.47 g (1,95 mmol) thioglycoside (57) and 2,89 g (1.77 mmol) of glycosyl lovekin/acetone in a ratio of 3:2), getting 3,71 g (92%) of compound (68) (see scheme 19 provided in the end of the description). The sample for the analysis of purified on a column of silica (toluene/acetone in a ratio of 3:2).

[]D= +99(C = 0,58; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 2319,03; chemical mass = 2320,59; experimental mass = 2319,03 0.12 Rel. mass. unit

1H-NMR (deuterochloroform); (M. D.):

7,33-to 7.32 (m, 5H, phenyl), 7,15-6,83 (m, 4H, C6H4OCH3), 5,62 (d, 1H, J= 3.8 Hz, H-1 residue R-2), the ceiling of 5.60 (d, 2H, J=3.8 Hz, H-1 residue NR-2 and the remainder C) of 5.29 (d, 1H, J=4.0 Hz, H-1 residue NR), equal to 4.97 (d, 1H, J=3,7 Hz, H-1 remainder R), 4,70 (d, 1H, J=7.9 Hz, H-1 residue NR-1), 4,30 (d, 2H, J=8,1 Hz, H-1 residue NR-3 and the remainder is R-3), the 4.29 (d, 1H, J=7.9 Hz, H-1 residue R-1), of 2.08 (s, 3H, acetyl), to 2.06 (s, 3H, acetyl), 2,02 (s, 3H, acetyl), of 1.99 (s, 3H, acetyl), to 1.98 (s, 3H, acetyl), a 1.96 (s, 3H, acetyl), 1,08-of 0.91 (m, 2H, CH2CH2Si(CH3)3), is 0.00 (s, 9H, CH2CH2Si(CH3)3).

Analysis for C106H170O53Si (2320,59):

calculated, %: C 54,86 H 7,38

found, %: C 54,76 H 7,45

Preparative example 63

2-(Trimethylsilyl)ethyl-[O-(2,3,6 - tri-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)- (1--->4)]4-6-O-benzyl-2,3-di-O-methyl-a-D - glucopyranosid (69)

3,61 g (1.55 mmol) of the compounds in the ratio 4: 5), getting 2,22 g (70% based on three stages) of the compound (69) (see scheme 19 provided in the end of the description).

[]D= +103(C = 0,80; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 2031,01; chemical mass = 2032,38; experimental mass = 2032,38 Rel. mass. unit

1H-NMR (deuterochloroform); (M. D.):

7,33-to 7.32 (m, 5H, phenyl), the 5.65 (d, 1H, J=3.8 Hz, H-1 residue NR), 5,64 (d, 1H, J=3.8 Hz, H-1 residue NR-2), 5,62 (d, 2H, J=3.8 Hz, H-1 residue C and the remainder R-2), equal to 4.97 (d, 1H, J=3,7 Hz, H-1 remainder R) 4,30 (d, 1H, J=7.9 Hz, H-1 residue NR-1), the 4.29 (d, 3H, J=7.9 Hz, H-1 the remainder is R-1, the remainder is R-3 and the remainder of the NR-3), 1,08-of 0.91 (m, 2H, CH2CH2Si(CH3)3), 0,00 (s, N, CH2CH2Si(CH3)3).

Analysis for C92H162O46Si (2032,38):

calculated, %: C 54,37 H 8,03

found, %: C 54,51 H 8,04

Preparative example 64

2-(Trimethylsilyl)ethyl-O-(4-O-levulinic-2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4)-[O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-((1--->4)-O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4)]3-6-O-benzyl-2,3-di-O-methyl-a-D - glucopyranosid (70)

855 mg (0.42 mmol) of the compound (69) was dissolved in 8 ml dichloromethane and at a temperature of 25oC add 83 ml (0.59 mmol) of triethylamine, 5,14 mg (0.04 mmol) 4-d is dobavlaut dichloromethane, washed with aqueous 10% solution of potassium hydrosulfate, then water, dried and evaporated to dryness. This connection can be used without purification in the next stage. The sample for the analysis of purified on a column of silica (cyclohexane/acetone in the ratio 5:4) to give the pure compound (70) (see scheme 19 provided in the end of the description).

[]D= +101(C = 0,89; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 2129,05; chemical mass = 2130,48; experimental mass = 2130,00 Rel. mass. unit

1H-NMR (deuterochloroform); (M. D.):

7,33-to 7.32 (m, 5H, phenyl), the 5.65 (d, 3H, J=3.8 Hz, H-1 residue NR, the remainder of the NR-2 and the remainder C), 5,63 (d, 2H, J=3.8 Hz, H-1 residue R-2), 5,02 (t, 1H, J= 10.1 Hz, H-4 balance NR), to 4.98 (d, 1H, J=3,7 Hz, H-1 remainder R), 4,32 (d, 1H, J= 7.9 Hz, H-1 residue NR-1), 4,30 (d, 2H, J=7.9 Hz, H-1 residue NR-3 and the remainder is R-3), the 4.29 (d, 1H, J=7.9 Hz, H-1 residue R-1), 2,80-of 2.50 (m, 4H, O(C:O)CH2CH2(C:O)CH3), to 2.18 (s, 3H, O(C:O)CH2CH2(C:O)CH3), 1,08-of 0.91 (m, 2H, CH2CH2Si(CH3)3), 0.00 (s, 9H, CH2CH2Si(CH3)3).

Analysis for C97H168O48Si (2032,38):

calculated, %: C 54,69 H of 7.95

found, %: C 54,55 H 8,07

Preparative example 65

O-(4-O-Levulinic-2,3,6-tri-O-methyl-D-glucopyranosyl- -D-glyukopiranozil)-(1--->4)]3-6-O-benzyl-2,3-di-O - methyl-,-D-glucopyranose (71)

876 mg (0.41 mmol) of the compound (70) was worked up as described in preparative example 44 (a). The residue is purified on a column of silica, receiving 600 mg (50% over two stages) of the compound (71) in the form of a mixture of isomers (/ = 60/40) (see scheme 19 provided in the end of the description).

[]D= +89(s = 0,74; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 2028,97; chemical mass = 2030,24; experimental mass = 2030,19 0,09 Rel. mass. unit

1H-NMR (deuterochloroform); (M. D.):

7,33-to 7.32 (m, 5H, phenyl), the 5.65 (d, 3H, J=3.8 Hz, H-1 residue NR, the remainder of the NR-2 and the remainder C), 5,63 (d, 1H, J=3.8 Hz, H-1 residue R-2), 5,33 (d, 1H, J= 3.2 Hz, H-1 remainder R) 5,02 (t, 1H, J=10.1 Hz, H-4 balance NR), 4,59 (d, 1H, J= 5.3 Hz, H-1 remainder R), 4,32 (d, 1H, J=7.9 Hz, H-1 residue NR-1), 4,30 (d, 2H, J=7.9 Hz, H-1 residue NR-3 and the remainder is R-3), the 4.29 (d, 1H, J=7.9 Hz, H-1 residue R-1), 2,80-of 2.50 (m, 4H, O(C:O)CH2CH2(C:O)CH3), to 2.18 (s, 3H, O(C:O)CH2CH2(C:O)CH3).

Preparative example 66

O-(4-O-Levulinic-2,3,6-tri-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)- [O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]3-6-O-benzyl-2,3-di-O-methyl-,-D-glucopyranose-trichloracetate is Leah and 176 μl (1,75 mmol) trichloroacetonitrile. Stirred for 16 hours, filtered and evaporated. Filtered through silica gel (cyclohexane/acetone [in the ratio 5:4] 1/ triethylamine) to give 414 mg (46%) of imidate (72) in the form of a mixture of anomers (/ = 47/53) (see scheme 19 provided in the end of the description).

[]D= +86(s = 0,84; dichloromethane).

1H-NMR (deuterochloroform); (M. D.):

7,33-to 7.32 (m, 5H, phenyl), of 6.50 (d, 1H, J=3.5 Hz, H-1 remainder R), the 5.65 (d, 1H, J=8,2 Hz, H-1 remainder R), the 5.65 (d, 1H, J=3.8 Hz, H-1 residue NR), 5,64 (d, 2H, J=3.8 Hz, H-1 residue NR-2 and the remainder C), 5,61 (d, 1H, J=3.8 Hz, H-1 the remainder is R-2), 5,02 (t, 1H, J=10.1 Hz, H-4 balance NR), 4,37 (d, 1H, J= 7.9 Hz, H-1 residue R-1), 4,30 (d, 3H, J=7.9 Hz, H-1 the remainder of the NR-1, the remainder of the NR-3 and the remainder is R-3), 2,80-of 2.50 (m, 4H, O(C:O)CH2CH2(C:O)CH3), to 2.18 (s, 3H, O(C:O)CH2CH2(C:O)CH3).

Preparative example 67

Methyl-O-(4-O-Levulinic - 2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)- [O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]3-O-(6-O-benzyl-2,3-di-O - methyl-D-glyukopiranozil) -(1--->4)-O-(benzyl-2,3-di-O-methyl-a-D - glucopyranosyloxy)-(1--->4)-O-(3,6-di-O-acetyl-2-O-benzyl-a-D-glyukopiranozil)- (1--->4)-O-(benzyl-2,3-di-O - methyl--L-iodopyrazine- (1--->4)-O-2,3,6-tri-O-benzyl-a-D-glucopyranosid (the Tana with diethyl ether in the ratio 1:2. Add 750 mg/mmol molecular sieves and stirred for 1 hour at a temperature of 25oC. the Mixture is cooled to a temperature of -25oC and added 1 M solution of tributyltinchloride in dichloromethane (0.20 mol/mol of imidate). Stirred for 15 minutes, then add solid sodium bicarbonate, filtered and concentrated. The rest make Toyopearl columnHW-50 (dichloromethane/ethanol in a ratio of 1:1) and containing Picatinny acceptor fraction is taken to return again in the reaction, treating it as described above. Perform sequential purification on a column of silica (toluene/acetone in a ratio of 5:4, then 1:1), obtaining the fraction of 107 mg of the compound (73) in the form will smusic / = 7/3 and the fraction of 201 mg of the compound (73) in the form of a mixture / = 9/1 with a total yield of 57% (308 mg) (see scheme 20 provided in the end of the description).

1H-NMR (deuterochloroform); (M. D.):

7,33-7,25 (m, 35H, 7 phenyl), the 5.65 (d, 3H, J=3.5 Hz, H-1 residue A, residue C, the remainder E), to 5.57 (d, 1H, J=3,9 Hz, H-1 residue (G) 5,52 (d, 1H, J= 3.3 Hz, H-1 residue I) of 5.29 (d, 1H, J=6,8 Hz, H-1 balance L) to 5.17 (t, 1H, J= 3.5 Hz, H-1 residue) 4,56 (d, 1H, J=3.5 Hz, H-1 residue M), or 4.31 (d, 3H, J=7.9 Hz, H-1 residue, the residue is D, and the remainder F) 4,27 (d, 1H, J=8.0 Hz, H-1 residue H) 4,08 (d, 1H, J=8.0 Hz, H-1 residue J), 2,80-of 2.50 (m, 4H, O(ASS="ptx2">

Preparative example 68

Methyl-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]4-O-(6-O-benzyl-2,3-di-O-methyl-D-glyukopiranozil)-(1--->4)-O- (benzyl-2,3-di-O-methyl-D-glucopyranosyloxy)-(1--->4) -O-(3,6-di-O-acetyl-2-O-benzyl- -D-glyukopiranozil)-(1--->4)- O-(benzyl-2,3-di-O-methyl-L-iodopyrazine-(1--->4)- 2,3,6-tri-O-benzyl-a-D-glucopyranosid (74)

130 mg (38,2 μmol) of compound (73) is treated according to Method 2, and the crude product is purified on a column of silica, receiving 118 mg (93%) of compound (74) (see scheme 21 provided at the end of the description).

[]D= +78(C = 0,48; dichloromethane).

ESIMS (positive ions): monoisotopic mass = 3301,49; chemical mass = 3303,65; experimental mass = 3302,40 Rel. mass. unit

1H-NMR (deuterochloroform); (M. D.):

7,33-7,25 (m, 35H, 7 phenyl), 5,64 (d, 3H, J=3.5 Hz, H-1 residue A, residue C, the remainder E), to 5.57 (d, 1H, J=3,9 Hz, H-1 residue (G) 5,52 (d, 1H, J= 3.3 Hz, H-1 residue I) of 5.29 (d, 1H, J=6,8 Hz, H-1 balance L) to 5.17 (t, 1H, J= 3.5 Hz, H-1 residue) 4,56 (d, 1H, J=3.5 Hz, H-1 residue M), or 4.31 (d, 3H, J=7.9 Hz, H-1 residue, the residue is D, and the remainder F) 4,27 (d, 1H, J=8.0 Hz, H-1 residue H) 4,08 (d, 1H, J=8.0 Hz, H-1 residue J) of 1.97 (s, 3H, acetyl), is 1.81 (s, 3H, acetyl).

Preparative example 69

Methyl-O-(2,6-di-O-is(2,6-di-O-benzyl-3-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2-O-acetyl-6-O - benzyl-3-O-methyl-D-glyukopiranozil) -(1--->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6 - tri-O-methyl - D-glyukopiranozil-(1--->4)]4-O- (6-O-benzyl-2,3-di-O-methyl-D-glucopyranosyl)-(1--->4)-O- (benzyl-2,3-di-O - methyl-a-D-glucopyranosyloxy) -(1--->4)-O- (3,6-di-O-acetyl-2-O-benzyl- -D-glyukopiranozil)-(1--->4)-O- (benzyl-2,3-di-O-methyl-L-iodopyrazine)- (1--->4)-2,3,6-tri-O - benzyl-a-D-glucopyranosid (75)

112 mg (33,9 µmol) glycosylase acceptor (74) and 59.1 mg (or 37.2 mmol) of imidate (17) (see preparative example 16) was dissolved in 2 ml of toluene. Added 42 mg of molecular sieves and stirred for 1 hour at a temperature of 25oC. the Mixture is cooled to a temperature of -20oC and added 1 M solution of tert-butyldimethylsilyl in toluene (0.20 mol/mol of their date). Stirred for 15 minutes, then add solid sodium bicarbonate, filtered and concentrated. Bring in column c ToyopearlHW-50 (dichloromethane/ethanol in a ratio of 1:1) containing acceptor, and 17-Mer. the fraction selected for back again in the reaction, treating it as described

above. Subjected to sequential purification on a column of ToyopearlHW-50 and on a column of silica, receiving 71 mg (44%) of compound (75) (see scheme 21 provided at the end of the description).

[]D= +80(C = 0,26; dichloromethane).

ESIMS (positive ions): monoisopropanolamine); (M. D.) major anomeric protons: 5,64; 5,57; 5,52; 5,48; 5,47; 5,29; 5,17; 4,56; 4,50; 4,29; 4,27; 4,08.

Preparative example 70

Methyl-2,3-di-O-methyl-6-O-tert-butyldimethylsilyl--D - glucopyranoside (77)

In argon atmosphere, 14.0 g (of 92.9 mmol) tert-butyldimethylsilyloxy, 15 ml (108 mmol) of triethylamine and 260 mg (2,13 mmol) of 4-dimethylaminopyridine added to a solution 15,84 g (from 71.3 mmol) of the compound (76) [D. Trimmell, W. M. Doane, C. B. Russel, C. E. Rist, Carbohydr. Res., 11, 497 (1969)] in 300 ml of dichloromethane. After stirring for 15 hours at room temperature the solution was diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated. The residue is purified using flash chromatography (cyclohexane/ethyl acetate in the ratio of 1.3:1), receiving 22,79 g (95%) of compound (77) (see scheme 22 provided in the end of the description) as a colourless syrup.

[]D= +87(C = 1,2; chloroform).

Preparative example 71

Methyl-2,3-di-O-methyl-6-O-tert - butyldimethylsilyl--D-Xylo-4 - hexopyranoside (78)

In an argon atmosphere and at a temperature of -70oC to 8.7 ml (123 mmol) of a solution of dimethyl sulfoxide in 20 ml of dichloromethane are added to a solution of 5.4 ml (61,9 mmol) oxalicacid in 120 ml dichlormethane 15 minutes using a magnetic stirrer add 37 ml (265 mmol) of triethylamine and after 15 minutes, leave to stand for increasing the temperature to room. Add 150 ml of water, the aqueous phase is extracted with 150 ml of di - chloromethane. The combined organic phases, washed with aqueous saturated solution of sodium chloride, dried over magnesium sulfate and concentrated. The residue is purified using flash chromatography (cyclohexane/ethyl acetate in a ratio of 9: 1, then 4:1) to give 17.3 g (93%) of compound (78) as a colourless oil (see scheme 22 provided in the end of the description).

[]D= +98(C = 1.0, chloroform).

Preparative example 72

Methyl-4-deoxy-2,3-di-O-methyl-4-C-methylene-6-O-tert - butyldimethylsilyl- -D-Xylo-4-hexopyranoside (79)

In the atmosphere of argon 75 ml of 1.6 M solution of n-utility in n-hexane was added dropwise to a suspension of 43.3 g (127 mmol) of methyltriphenylphosphonium in 250 ml of tetrahydrofuran. After keeping for 30 minutes at room temperature the mixture is cooled to a temperature of -70oC, then add a solution of 13.97 g (41,8 mmol) of the compound (78) in 60 ml of tetrahydrofuran. After keeping for 30 minutes at -70oC, the mixture is left to stand to raise its temperature to room. After 1 hour add 300 ml of aqueous saturated solution of ammonium chloride and the aqueous phase extracted with diethyl ether. Organic f (cyclohexane/ethyl acetate in a ratio of 7:1, then 4:1), receiving 8,30 g (60%) of compound (79) as a colourless oil (see scheme 22 provided in the end of the description).

[]D= +151(=1,3; chloroform).

Preparative example 73

Methyl-4-deoxy-2,3-di-O-methyl-4-C-methylene - D-Xylo - hexopyranoside (80)

Camphorsulfonate (pH = 1) are added to a solution of 8.50 g (25.6 mmol) of the compound (79) in 250 ml of a mixture of dichloromethane with methanol in the ratio of 5:1. After complete disappearance of the original product (TLC; cyclohexane/ethyl acetate in the ratio 1:1) solution is neutralized by adding triethylamine. The residue after concentration of purified using flash chromatography (cyclohexane/ethyl acetate in a ratio of 1:1, then 1:2) to give 5.32 g (95%) of compound (80) in the form of a colorless syrup (see diagram 22 provided in the end of the description).

[]D= +239(C = 1.0, chloroform).

Preparative example 74

Phenyl-2,4,6-tri-O-acetyl-3-O-methyl-1-a - selenium-D - glucopyranosid (83)

METHOD 1:

In argon atmosphere, of 5.7 ml (of 53.7 mmol) selenophene added to a solution of 13.05 g (36,0 mmol) of the compound (81) (mixture of anomers of 1:1) [E. L. Hirst, E. Persival, Methods Carbohydrate Chem., 2, 145 (1963)] in 120 ml of dichloromethane. The reaction mixture is cooled to a temperature of 0oC and added dropwise to 8.8 ml of 48 the th temperature of the reaction mixture is diluted with 100 ml dichloromethane, washed with aqueous saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered and concentrated. The crude compound (83) 8,17 g (68% in the per connection (81)) is directly used in the reaction of dezazetilirovanie (see diagram 22 provided in the end of the description).

METHOD 2:

At a temperature of 0oC and in an atmosphere of argon 510 mg (14.6 mmol) of sodium borohydride is added to a suspension of 2.27 g (7,27 mmol) diphenylsilane in ethanol. If the reaction mixture has not lost its original yellow color for 15 minutes, then add a new portion of titlefirst of boron TRIFLUORIDE. This solution in an argon atmosphere is added to the solution 4,22 g (11.0 mmol) of compound (82) [A. K. Sen, K. K. Sakar, N. Banerji, J. Carbohydr. Chem., 7, 645 (1988)] in 25 ml of dichloromethane. After boiling under reflux for three hours, the reaction mixture is allowed to cool to room temperature, filtered sodium bromide and concentrate. The residue is dissolved in 100 ml dichloromethane and washed with 50 ml of 1 M aqueous sodium hydroxide solution and 50 ml of aqueous saturated solution of ammonium chloride. The aqueous phase is extracted with dichloromethane (20 ml), the organic phase is dried over magnesium sulfate, filtered and concentrated. OS is dilatata, getting 4.35 g (86%) of compound (83) (see scheme 22 provided in the end of the description); so pl. = 101 - 102oC.

[]D= -20(C = 1.0, chloroform).

Preparative example 75

Phenyl-3-O-methyl-1-a - selenium-D-glucopyranosid (84)

32,3 g (of 84.3 mmol) of the crude compound (83) is obtained from compound (82), dissolved in 500 ml of methanol and slowly added 1.2 g of sodium. After 1 hour the solution is neutralized by adding resin IR-120 (H+), filtered and concentrated. The residue is purified using flash chromatography (cyclohexane/ethyl acetate/acetone in a ratio of 1.5:1:1) to give 22.7 g (81% in the per connection (82)) of the compound (84) in the form of syrup (see diagram 22 provided in the end of the description).

[]D= -58(C = 1.0; methanol).

Preparative example 76

Phenyl-4,4-O-benzylidene-3-O-methyl-1-selenium - D glucopyranoside (85)

In argon atmosphere, 45 mg p-toluenesulfonic acid and 5.4 ml (36,0 mmol) benzaldehydes added to a solution of 7.65 g (23,0 mmol) Tirol (84) in 150 ml of acetonitrile. After stirring for two hours at room temperature, add 1.5 g of potassium carbonate. After 30 minutes the solution is filtered, and then concentrated. The residue is purified using flash chromatog is (see circuit 22 provided in the end of the description); so pl. = 123-124oC (cyclohexane/ethyl acetate).

[]D= -38(C = 1.0, chloroform).

Preparative example 77

Phenyl-4,6-O-benzylidene-3-O-methyl-2-O-(methyl-4-deoxy-6-O - dimethylallyl-2,3-di-O-methyl-4-C-methylene-D-Xylo-hexopyranosyl)-1- - selenium-D-glucopyranosid (86)

In an argon atmosphere and at a temperature of -70oC 7,0 ml of 1.6 M solution of n-utility in (11.2 mmol) in a flask Slanka, added to a solution of 4.30 m g (10.2 mmol) of the compound (85) in 30 ml of tetrahydrofuran. After 10 minutes, add 5.0 ml (41.2 mmol) of dichlorodimethylsilane and the reaction medium is heated to room temperature. 3 hours later its concentrate and add a solution of 2.10 g (9,62 mmol) of the compound (80) and 985 mg (14.4 mmol) of imidazole in 20 ml of tetrahydrofuran. After keeping for 30 minutes at room temperature the solution is concentrated, add 50 ml of water and extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated. The sample for the analysis of compounds (86) purified using flash chromatography (mixture of toluene/acetone in a ratio of 25:1, containing 0.5% of triethylamine). Get colorless syrup with the release of 90% (see chart 22 provided at the end of the description of the 2
), of 5.24 (m, 1H, C: CH2), 5,16 (s, 1H, CH phenyl), is 4.85 (d, 1H, J=3,7 Hz, H-1), to 4.81 (d, 1H, J= 9.8 Hz, H-1'), of 4.45 (m, 1H, H-5), of 4.38 (DD, 1H, J=10,8 Hz, 4.8 Hz, H-6A), to 4.33 (DD, 1H, J=6.2 Hz, H-6b), 4,20 (m, 1H, J=9,2 Hz, H-3), of 4.05 (DD, 1H, J= 10.3 Hz, 4.9 Hz, H-6a'), a 3.87 (DD, 1H, J=8,1 Hz, H-2'), 3,52, 3,38, 3,31 3.27 (s, 3H, OCH3), 3,37 (t, 1H, J=10.3 Hz, H - 6b'), to 3.35 (t, 1H, H-4'), of 3.32 (DD, 1H, H-2), up 3.22 (DD, 1H, J=9,3 Hz, H-3'), was 3.05 (DDD, 1H, J=9,3 Hz, H-5'), of 0.38 and 0.37 (s, 3H, Si(CH3)2).

Mass spectrum: m/e 714 (M+NH4)+.

Preparative example 78

The reaction of the radical cyclization (formation of compound 87) and the splitting of simple tetraeder (88)

A solution of 6.1 ml (22.7 mmol) of tributyltinhydride and 200 mg (1,22 mmol) 2,2'-azobisisobutyronitrile in 14 ml of degassed toluene for 8 hours added to a solution of the crude compound (86), obtained from 10.2 mmol of compound (85) and 9,62 mmol of compound (80) in 850 ml of toluene.

After radical cyclization reaction solution was concentrated and the residue is dissolved in tetrahydrofuran. Add an excess (20 equivalents) of 40% aqueous solution of hydrogen fluoride. After full desirelove (TLC; toluene/acetone in a ratio of 4:1) solution is neutralized by adding solid sodium bicarbonate, filtered and concentrated. Available in a vast number of the/SUP>C.

[]D= +119(C= 1,1; chloroform).

13C-NMR (62,896 MHz; deuterochloroform); (M. D.):

137,29 (Quaternary aromatic), 128,88-125,96 (aromatic), 101,11 (CH phenyl), 97,64 (s-1), 83,52 (C-2), 82,76, 81,95, 80,84, 72,01, 71,92 and 64,31 (C-3, C-5, C-2', C-3', C-4', C-5'), 75,19 (C-1'), 69,41 (C-6'), 62,69 (C-6), 60,93, 60,70, 58,31 and 55,20 (OCH3), 38,80 (C-4), 25,58 (C methylene).

Analysis for C24H36O10H2O (502,558):

calculated, %: C 57,36 H 7,62

found, %: C 57,31 H 7,54

Preparative example 79

Methyl-6-O-acetyl-4-C-(2-O-acetyl-4,6-O-benzylidene-3-O-methyl-D-glyukopiranozil-methyl)-4-deoxy-2,3-di-O-methyl-D-glucopyranosid (89)

Connection (88) quantitatively will acetimidoyl in a mixture of acetic anhydride and pyridine in the ratio of 1:1 in the presence of catalytic amounts of 4-dimethylaminopyridine. The product obtained after concentration and chromatography was carried out (see diagram 22 provided in the end of the description).

[]D= +87(C = 1.0, chloroform).

1H-NMR (500 MHz; deuterochloroform): see Table 1.

13C-NMR (62,896 MHz; deuterochloroform); (M. D.):

170,81, 169,80 (C: O), 137,18 (C Quaternary aromatic), 128,92-125,95 (C aromatic), 101,31 (CH phenyl), 97,51 (C-1), 83,22 (C-2), 81,94, 69,25 and 63,83 (C-5, C-4', C-5'), 81,81 (C-3), 78,78 (C-3'), 72,74 (C-2'), 7 is ECtHR, m/e 586 (M+NH4)+; 569 (M+H)+; 554 (M-OMe + NH3)+; 537 (M-OMe)+.

Analysis for C28H40O12H2O (586,632):

calculated, %: C 57,33 H 7,22

found, %: C 57,28 H 7,07

The last part of the synthesis is the conversion of compound (89) imidate (90). For this benzyliden open, using cyanoborohydride sodium and hydrochloric acid. Thus liberated hydroxyl group is temporarily protected in the form of a simple p-methoxybenzylthio ether. After dezazetilirovanie primary alcohol function protects by selective introduction of tert-butyldimethylsilyl simple ester thus obtained, the connection was identified in. Oxidation under the reaction conditions Jones leads to the formation of uronic acid, which benzelius. A simple p-methoxybenzyloxy ether then otscheplaut, then this position is injected ester of levulinate acid. Used the system, which is a mixture of sulfuric acid with acetic acid and acetic anhydride leads to acetals anomeric methyl group, as well as simple benzyl ether at position 6', and get a mixture of two anomeric acetates. Selective dezazetilirovanie in position 1 is carried out with use the e (90) using trichloroacetonitrile in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene (see circuit 22 provided in the end of the description).

Preparative example 80

Ethyl-O-(2,3-di-O-benzoyl - 4,6-O-benzyliden- -D glyukopiranozil)-(1--->4)-2,3,6-tri-O-benzoyl-1-thio- -D glucopyranose (92)

To a cooled to a temperature of 0oC to a solution of 16.7 g (of 35.2 mmol) connection... [J. Westman and M. Nilsson, J. Carbohydr. Chem., 14(7), 949-960 (1995)] in 202 ml of pyridine for 20 minutes was added dropwise to 24.5 ml (211 mmol) of benzoyl chloride. The reaction mixture is stirred for 20 hours at room temperature; TLC shows a conversion of about 50%. The mixture is diluted with water and dichloromethane. After extraction the organic phase is washed with 10% sodium hydrogen carbonate solution, water, dried over magnesium sulfate and concentrated. The residue is again treated with benzoyl chloride according to the above method. The crude product is purified by chromatography was carried out on a column of silica gel, obtaining 22 g of compound (92) (see scheme 23 provided in the end of the description).

TLC; RF= 0,80 (silica gel; toluene/ethanol in a volume ratio 9:1).

Preparative example 81

O-(2,3-di-O-benzoyl-4,6-O-benzyliden- -D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-benzoyl- -D-glyukopiranozil)(1--->4)-1,6 - anhydrous-2,3-di-O-methyl-D-glucopyranose (94)

A mixture of 1.05 g (1.05 mmol) of thioglycoside (92) is Wola stirred in nitrogen atmosphere for 15 minutes. The mixture is cooled to a temperature of -20oC and enter a freshly prepared solution of 1.11 mmol N-jodatime and 0.125 mmol of triftoratsetata in 6 ml of a mixture of dichloromethane with dioxane in a volume ratio of 1: 1. After 10 minutes the reaction mixture is red filtered, diluted with dichloromethane, extracted, washed successively 10% sodium thiosulfate solution, 10% sodium hydrogen carbonate solution and water, dried over magnesium sulfate, and then concentrated in vacuo. Purification of the residue is carried out by chromatography was carried out on a column of silica gel, receiving 1,25 g of compound (94) (see scheme 23 provided in the end of the description).

TLC: RF= 0,55 (silica gel; heptane/ethyl acetate in a volume ratio of 4: 6).

Preparative example 82

O-(4,6-O-Benzyliden- -D-glyukopiranozil)-(1--->4)-O- -D-glyukopiranozil)-(1--->4)-1,6-anhydrous-2,3-di-O-methyl-D - glucopyranose (95)

To a solution of 1.24 g (1.11 mmol) of the compound (94) in 7 ml of a mixture of methanol with dioxane in a volume ratio of 1:1 add about 50 mg of potassium tert-butylate. Is stirred for one hour, then add again, 50 mg of potassium tert-butylate, after which the mixture is stirred for another 60 minutes. The reaction mixture is neutralized with help from the column with silica gel get 665 mg of compound (95) in the form of oil (see circuit 23 provided in the end of the description).

TCX: RF= 0,50 (silica gel; dichloromethane/methanol in a volume ratio 85:15).

Preparative example 83

O-(4,6-O-Benzylidene - 2,3-di-O-methyl-D-glyukopiranozil) - (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-1,6 - anhydrous-2,3-di-O-methyl-D-glucopyranose (96)

It cooled down to 5oC to a solution of 660 mg (1.1 mmol) of compound (95) in 8 ml of anhydrous tetrahydrofuran, under nitrogen atmosphere, add 387 mg (9,65 mmol) of sodium hydride, was added dropwise 0.51 ml (by 8.22 mmol) methyliodide and the mixture is stirred for 20 hours at room temperature. Excess sodium hydride is decomposed with methanol and the mixture is then poured into 50 ml ice water. After extraction 3 times with 20 ml ethyl acetate the organic phase is washed with sodium chloride solution, dried over magnesium sulfate and concentrating, getting 690 mg of pure compound (96) (see scheme 23 provided in the end of the description).

TCX: RF= 0,25 (silica gel; dichloromethane/methanol in a volume ratio 95:5).

Preparative example 84

O-(2,3-di-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (97)

690 mg (1,03 mmol) of pure compound (96) retronaut in vacuum and evaporated together with the toluene. The chromatography was carried out on a column of silica gel using mixtures of dichloromethane/ethyl acetate/methanol in a ratio of 8:1:1 allows to obtain 569 mg of compound (97) (see scheme 23 provided in the end of the description).

TLC: RF= 0,40 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 85

O-(6-O-Benzoyl)-2,3-di-O-methyl-D-glyukopiranozil)-(1--->4)- O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-1,6-anhydrous - 2,3-di-O-methyl-glucopyranose (98)

To a solution of 560 mg (0.96 mmol) of the compound (97) in dichloro methane added 227 mg (1.05 mmol) of 1-benzoyloxy-1H - benzotriazole and 1.15 mmol of triethylamine, the mixture is then stirred for 20 hours at room temperature. The reaction mixture was diluted with dichloromethane, washed with 10% sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The product was then purified by chromatography was carried out on a column of silica gel, receiving 600 mg of compound (98) (see scheme 23 provided in the end of the description).

TLC: RF= 0,50 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 86

O-(2,3-Di-O-benzoyl-4,6-O-benzyliden- -D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-Oronasal)-((1--->4)-1,6-anhydrous - 2,3-di-O-methyl-D-glucopyranose (99)

Connection (98) into a compound (99) according to the procedure described for obtaining compound (94). The reaction mix is carried out at a temperature of 5oC.

TLC: RF= 0,50 (silica gel; heptane/ethyl acetate in a volume ratio 2: 8).

Preparative example 87

O-(4,6-O-Benzyliden- -D-glyukopiranozil)-(1--->4)-O-(- D-glyukopiranozil)-(1--->4)-O-(2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-1,6 - anhydrous-2,3-di-O-methyl-D-glucopyranose (100)

Connection (99) make a connection (100) according to the same method as that described for obtaining compound (95) (see scheme 24 provided in the end of the description).

TLC: RF= 0,35 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 88

O-(4,6-O-Benzylidene-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O - methyl-D-glyukopiranozil)-(1--->4) -1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (101)

The compound (100) is converted into a compound (101) according to the same method as that described for obtaining the compound (96) (see scheme 24 provided in the end of the description).

TLC: RF= 0,50 (silica gel; dichloro the Ozil)-(1--->4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil) -(1--->4)-1,6-anhydrous-2,3-di-O-methyl-a-D-glucopyranose (102)

The compound (101) is converted into a compound (102) according to the same method as that described for obtaining compounds (97) (see scheme 24 provided in the end of the description).

TLC: RF= 0,35 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 90

O-(6-O-Benzoyl-2,3-di-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O - methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-glyukopiranozil)-(1--->4)-1,6 - anhydrous-2,3-di-O-methyl-D-glucopyranose (103)

Connection (102) into a compound (103) according to the same method as that described for connection (98) (see scheme 24 provided in the end of the description).

TLC: RF= 0,40 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 7.0:1,5:1,5).

Preparative example 91

O-(2,3-Di-O-benzoyl-4,6-O-benzylidene--D - glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O - benzoyl- -D-glyukopiranozil)-(1--->4)- O-(6-O-benzoyl-2,3-di-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) -(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4)-1,6-anhydrous-2,3-di-O-methyl-a-D - glucopyranose (104)< / BR>
The reaction mix of the compound (103) with disaccharide (2) is conducted according UB> = 0,40 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 7.0:1,5:1,5).

Preparative example 92

O-(4,6-O-Benzyliden- -D-glyukopiranozil)-(1--->4)-O- -D-glyukopiranozil)- (1--->4)-O-(2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) -1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (105)

Compound (104) is converted into a compound (105) according to the same method as that described for obtaining compound (95) (see scheme 25 provided in the end of the description).

TLC: Rf= 0,60 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 93

O-(4,6-O-Benzylidene-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)- [O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]2-1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (106)

Compound (105) into a compound (106) according to the same method as that described for obtaining the compound (96) (see scheme 25 provided in the end of the description).

TLC: RF= 0,70 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 94

nosil)-(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)- (1--->4)]2-1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (107)

A solution of 5.05 g (2.0 mmol) of the compound (106) in 50 ml of 80% acetic acid is stirred for 20 hours at a temperature of 40oC. the Mixture was concentrated in vacuo and evaporated together with the toluene. The residue is dissolved in ethyl acetate and extracted with water. The aqueous phase is extracted with dichloromethane and the organic phase is dried over magnesium sulfate, filtered and evaporated to dryness, obtaining of 2.68 g of compound (107) (see scheme 25 provided in the end of the description).

TLC: RF= 0,50 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 95

O-(6-O-Benzoyl-2,3-di-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-[O- (2,3,6-tri - O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O - methyl-D-glyukopiranozil)-(1--->4)]2-1,6-anhydrous-2,3 - di-O-methyl-a-D-glucopyranose (108)

Connection (107) into a compound (108) according to the same method as that described for connection (98) (see scheme 25 provided in the end of the description).

TLC: RF= 0,80 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 7.0:1,5:1,5).

Preparative example 96

O-(2,3-Di-O-benzoyl-4,6-O-benzyliden- -D-glyukopiranozil)-methyl- -D-glyukopiranozil)- (1--->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]2-1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (109)

A mixture of 1.97 g (2.0 mmol; 3.5 equiv.) thioglycoside (92), 0,86 g (or 0.57 mmol) Gateshead (108) and molecular sieves in powder form in 22 ml of toluene is stirred under nitrogen atmosphere for 15 minutes. Then at room temperature was added dropwise a freshly prepared solution containing 496 mg (2.2 mmol) of N-jodatime and 0,808 mmol of triftoratsetata in 12 ml of a mixture of dichloromethane with dioxane in a volume ratio of 1:1. After 10 minutes the reaction mixture is filtered, diluted with dichloromethane, extracted, washed with 10% sodium thiosulfate solution and 10% sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by chromatography was carried out on a column of silica gel, receiving 1,09 g of compound (109) (see scheme 25 provided in the end of the description).

TLC: RF= 0,80 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 6:2:2).

Preparative example 97

O-(4,6-O-Benzyliden- -D-glyukopiranozil)-(1--->4)-O-(-D - glyukopiranozil)-(1--->4) -O-(2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-[(1--->4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O - methyl-D-glyukopiranozil)]SNO the same method, as described to obtain compound (95) (see scheme 26 provided in the end of the description).

TLC: RF= 0,25 (silica gel, toluene/ethyl acetate/ethanol in a volume ratio of 5.0:2,5:2,5)

Preparative example 98

O-(4,6-O-Benzylidene-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) - a -[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)] -O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]3-1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (111)

Connection (110) into a compound (111) according to the same method as that described for obtaining the compound (96) (see scheme 26 provided in the end of the description).

TLC: RF= 0,50 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 6:2:2).

Preparative example 99

O-(2,3-Di-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O - methyl-D-glyukopiranozil)-(1--->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O - methyl-D-glyukopiranozil)-(1--->4)]3- 1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (112)

Connection (111) into a compound (112) according to the same method as that described for obtaining compounds (97) (see scheme 26 provided in the end of the description).

TLC: Rf= 0,20 (silica gel; toluene/ethyl acetate/ethanol vol is 4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6 - tri-O-methyl-D glyukopiranozil)-(1--->4)] 3-1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (113)

Connection (112) into a compound (113) according to the same method as that described for connection (98) (see scheme 26 provided in the end of the description).

TLC: RF= 0,20 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 6:2:2).

Preparative example 101

O-(6-O-Benzoyl-4-O-levulinic-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D - glyukopiranozil)-(1--->4)- [O-(2,3,6-tri-O-methyl-D glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D - glyukopiranozil)-(1--->4)]3-1,6-anhydrous-2,3-di-O-methyl-D-glucopyranose (114)

To a solution of 320 mg (0,167 mmol) of the compound (113) in 1 ml of dioxane is added 48 mg (0.25 mmol) of 1-(3-dimethylamino-propyl)-3 - ethylcarbodiimide, 29 mg (0.25 mmol) of levulinate acid and 4 mg (0,033 mmol) dimethylaminopyridine. The reaction mixture is stirred for three hours at room temperature in a nitrogen atmosphere. After that, add dichloromethane and water and, after extraction the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The crude product is purified by chromatography was carried out on a column of silica gel, getting 312 mg of the compound (114) (see scheme 26 provided at the end of the described>Preparative example 102

O-(6-O-Benzoyl-4-O-levulinic-2,3-di-O-methyl-D - glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D - glyukopiranozil)- (1--->4)-[O-(2,3,6-tri-O-methyl-D - glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D - glyukopiranozil)- (1--->4)]3-1,6-di-O-acetyl-2,3-di-O - methyl-,-D-glucopyranose (115)

A solution of 312 mg (0,155 mmol) of the compound (114) in a mixture of 2.25 ml of acetic anhydride, 50 μl of acetic acid and 0.14 ml triperoxonane acid is stirred for 4 hours at room temperature. After adding 10 ml of toluene, the mixture is concentrated and evaporated together with toluene (3 x 10 ml). After chromatography was carried out on a column of silica gel allocate 324 mg of the compound (115) (see scheme 26 provided in the end of the description).

TLC: RF= 0,65 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 6:2:2).

Preparative example 103

O- (6-O-Benzoyl-4-O-levulinic-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)- [O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)] 3-6-O-acetyl-2,3-di-O-methyl-,-D - glucopyranose (116)

A solution of 324 g (0,153 mmol) of the compound (115) and 22.3 μl (0,256 mmol) of the research in 2 ml of toluene is stirred for 4 hours at temperature the temperature of the 35oC. the Mixture is rapidly cooled with water. After extraction with dichloromethane the organic phase is washed successively with 0.1 N. hydrochloric acid and water, dried and evaporated to dryness. After chromatography was carried out on a column of silica gel allocate 280 mg of the compound (116) (see scheme 27 provided at the end of the description).

TLC: RF= 0,45 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 6:2:2).

Preparative example 104

O-(6-O-Benzoyl-4-O - levulinic-2,3-di-O-methyl-D - glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D - glyukopiranozil)-(1--->4) -[O-(2,3,6-tri-O-methyl-D - glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D - glyukopiranozil)-(1--->4)]3-6-O-acetyl-2,3-di-O-methyl-,-D-glucopyranose-trichloroacetimidate (117)

39 μl (0,39 mmol) Trichloroacetonitrile and 4.7 mg of cesium carbonate are added to a solution of 138 mg (of 0.066 mmol) of the compound (116) in 1.5 ml of dichloromethane. After stirring for two hours the mixture is filtered, concentrated and the residue chromatographic on a column of silica gel, getting 152 mg of imidate (117) (see scheme 27 provided at the end of the description).

TLC: RF= 0,35 (silica gel; toluene/ethyl acetate/ethanol in a volume ratio of 8:1:1).

Preparative example 105

Methyl-2-O-benzyl-4,6-O-gasoline is 5 ml benzylbromide. After cooling to 10oC was added dropwise a 20% aqueous sodium hydroxide solution. After stirring for 1 hour, increase the temperature to 20oC and the mixture is stirred for additional 20 hours. After this, the solution is poured into a mixture of ice water and extracted with toluene. The organic phase is concentrated and the crude product is purified by crystallization, getting 30.0 g of compound (119) (see scheme 28 provided in the end of the description).

TLC: RF= 0,60 (silica gel; toluene/ethyl acetate in a volume ratio 7: 3).

Preparative example 106

Methyl-2-O-benzyl-4,6-O-benzylidene-3-O-p-methoxybenzyl- -D-glucopyranosid (120)

of 26.4 g of Compound (119) dissolved in 211 ml of dimethylformamide and cooled to a temperature of 5oC. In an atmosphere of nitrogen was added 2.5 g of sodium hydride, and then added dropwise 13.3 g of 4-methoxybenzylamine and the mixture is stirred for 1 hour at room temperature. The mixture is diluted with ethyl acetate, washed 2 times with water and concentrated, obtaining of 40.7 g of compound (120) (see scheme 28 provided in the end of the description).

TLC: RF= 0,80 (silica gel; toluene/ethyl acetate in a volume ratio 7: 3).

Preparative example 107

Methyl-2-O-benzyl-3-O-p-methoxybenzyl- -D-GL is in a period of 4 hours at a temperature of 60oC. the Mixture is diluted with toluene and concentrated. Purification by chromatography was carried out on a column of silica gel allows you to get to 26.4 g of compound (121) (see scheme 28 provided in the end of the description).

TLC: RF= 0,07 (silica gel; toluene/ethyl acetate in a volume ratio 7: 3).

Preparative example 108

Methyl-2-O-benzyl-3-O-p-methoxybenzyl-6-O-methyl-a-D - glucopyranosid (122)

of 26.4 g of compound (121) in the atmosphere of nitrogen dissolved in 263 ml of dichloromethane. At room temperature add 11.6 g of trimethyloctadecylammonium and 17.4 g of 2,6-di - tert-butyl-4-methylpyridine. After 4 hours the mixture was poured into ice water and extracted with dichloromethane. The organic phase is washed with sodium hydrogen carbonate solution and concentrated. Purification of the crude product by chromatography was carried out on a column of silica gel allows to obtain 18.5 g of compound (122) (see scheme 28 provided in the end of the description).

TLC: RF= 0,25 (silica gel; toluene/ethyl acetate in a volume ratio 7: 3).

Preparative example 109

Ethyl-2,4,6-tri-O - acetyl-3-O-methyl-1-thio- -L - topiramate 124

48,4 g of compound (123) (1,2,4,6-Tetra-O - acetyl-3-O-methyl--L-itapiranga) [Jaurand, etc., Bio. Med. Chem. Lett., 2 897-900 (1992)] are dissolved in 175 ml of toluene. In Atmosfera add 400 ml of an aqueous solution of sodium bicarbonate and the mixture is stirred for one hour. The mixture is then poured into ethyl acetate, the organic phase is washed twice with water and concentrated. Purification by chromatography was carried out on a column of silica gel allows you to get to 29.6 g of compound (124) (see scheme 28 provided in the end of the description).

TLC: RF= 0,45 (silica gel; toluene/ethyl acetate in a volume ratio of 6: 4).

Preparative example 110

Methyl-O-(2,4,6-tri-O-acetyl-3-O-methyl-L-iodopirazol)- (1--->4)-2-O-benzyl-3-O - p-methoxybenzyl-6-O-methyl-D-glucopyranosid (125)

of 17.5 g of compound (122) and 28.2 g of compound (124) in an atmosphere of nitrogen dissolved in 525 ml of toluene. After addition of molecular sieves, the reaction mixture is cooled to a temperature of -20oC. When a continuous stream of nitrogen was added dropwise a freshly prepared 0.1 M solution of N-jodatime a (17.4 g) and triftoratsetata (1,38 ml) in a mixture of dioxane with dichloromethane in a volume ratio of 1:1. After 10 minutes the reaction mixture is red filtered and washed sequentially with an aqueous solution of sodium thiosulfate and aqueous solution of sodium bicarbonate. The organic phase was concentrated in vacuo and allocate 30.0 g of compound (125) (see scheme 28 provided in the end of the description).

TLC: RF= 0,45 (silica gel; dichloromethane/these is 1--->4)-2-O - benzyl-3-O-p-methoxybenzyl-6-O-methyl-L-glucopyranoside (126)

30.0 g of compound (125) dissolved in 460 ml of a mixture of methanol with dioxane in a volume ratio of 1:1 and add trebuchet potassium. After 15 minutes, the mixture is neutralized with resin Dowex 50WX8 (H+) and concentrated in vacuo. Purification is carried out by chromatography was carried out on a column of silica gel, getting to 17.4 g of compound (126) (see scheme 28 provided in the end of the description).

TLC: RF= 0,25 (silica gel; dichloromethane/methanol in a volume ratio 95:5).

Preparative example 112

Methyl-O-(4,6-O-isopropylidene-3-O-methyl-L-iodopirazol)- (1--->4)-2-O-benzyl-3-O-p-methoxybenzyl-6-O-methyl-D-glucopyranosid (127)

In nitrogen atmosphere of 17.4 g of compound (126) dissolved in 77 ml of dimethylformamide. Add 26 ml of 2,2-dimethoxypropane and p-toluensulfonate and the mixture is then stirred for 30 minutes. Dilution of the mixture with an aqueous solution of sodium bicarbonate, then extracted with ethyl acetate allows to obtain, after evaporation of the solvent, of 19.7 g of compound (127) (see scheme 28 provided in the end of the description).

TLC: RF= 0,45 (silica gel; dichloromethane/methanol in a volume ratio 95:5).

Preparative example 113

Methyl-O-(4,6-O - isopropylidene-2,3-di-O-methyl-L-iodopirazol)- (1--->4)-2-O-benemid and cooled to a temperature of 0oC. In an atmosphere of nitrogen was added 1.47 g (60% dispersion in oil) of sodium hydride and a 2.36 ml podmetina. After one hour the excess sodium hydride is decomposed with methanol and the mixture is extracted with dichloromethane, the extract was concentrated and get to 20.0 g of the compound (128) (see scheme 28 provided in the end of the description).

TLC: RF= 0,85 (silica gel; dichloromethane/methanol in a volume ratio 95:5).

Preparative example 114

Methyl-O-(4,6-O-isopropylidene-2,3-di-O-methyl-L - iodopirazol)-(1--->4)-2-O-benzyl-6-O-methyl-D - glucopyranosid (129)

of 18.4 g of compound (128) dissolved in 838 ml dichloromethane and 168 ml of water. Add to 7.1 g of 2,3-dichloro-5,6-dicyano-1,4 - benzoquinone and the mixture is stirred for 18 hours at a temperature of 4oC. the Mixture is then poured into aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. Concentration of the organic phase gives 12.7 g of compound (129) (see scheme 29 provided in the end of the description).

TLC: RF= 0,40 (silica gel; dichloromethane/methanol in a volume ratio 95:5).

Preparative example 115

Methyl-O-(4,6-O-isopropylidene-2,3-di-O-methyl-L - iodopirazol)-(1--->4)-2,3-di-O-benzyl-6-O-methyl-D - glucopyranosid (130)

of 10.5 g of compound (129) in the atmosphere of nitrogen dissolved in 178 ml (e) of sodium hydride, then added dropwise to 3.3 ml of benzylbromide. After 30 minutes the reaction is terminated and the excess sodium hydride is decomposed with methanol. Water is added and the mixture extracted twice with ethyl acetate. Evaporation of the solvent allows you to get to 13.6 g of compound (130) (see scheme 29 provided in the end of the description).

TLC: RF= 0,50 (silica gel; toluene/ethyl acetate in a volume ratio 1: 1).

Preparative example 116

Methyl-O-(2,3-di-O-methyl-L-iodopirazol)-(1--->4)-2,3 - di-O-benzyl-6-O-methyl-D-glucopyranosid (131)

Connection (130) dissolved in a mixture of acetic acid with water in a volume ratio of 77: 33 and stirred over night. The mixture is evaporated two times together with toluene and purified by chromatography was carried out on a column of silica gel, receiving of 11.5 g of compound (131) (see scheme 29 provided in the end of the description).

TLC: RF= 0,09 (silica gel; toluene/ethyl acetate in a volume ratio 1: 1);

RF= 0,68 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 117

Methyl-O-(2,3-di-O-methyl-L-ecoperestorika acid)- (1--->4)-2,3-di-O-benzyl-6-O-methyl-D-glucopyranosid (132)

To a solution of 11.6 g of compound (131) in 60 ml dichloromethane added 33 mg of 2,2,6,6-niharika. The mixture is cooled to a temperature of 0oC for 15 minutes, add the mixture of 44 ml of a saturated solution of sodium chloride, and 21.8 ml of a saturated solution of sodium bicarbonate and 50 ml of 1.3 M solution of sodium hypochlorite. After stirring for 1 hour the mixture is diluted with water and extracted 3 times with dichloromethane. The organic phase is washed with an aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated to dryness, obtaining a 13.4 g of crude compound (132) (see scheme 29 provided in the end of the description).

TLC: RF= 0,14 (silica gel; dichloromethane/methanol in a volume ratio 9:1).

Preparative example 118

Methyl-O-(benzyl-2,3-di-O-methyl-L-iodopyrazine) (1--->4)-2,3-di-O-benzyl-6-O-methyl-D-glucopyranosid (133)

In nitrogen atmosphere, the compound (132) is dissolved in 110 ml of dimethylformamide. Added 6.7 g of potassium bicarbonate and 10.7 ml of benzylbromide and the mixture is stirred for 90 minutes. Add ethyl acetate and water, and then after extraction the organic phase is concentrated. Purification by chromatography was carried out on a column of silica gel allows you to get to 9.9 g of compound (133) (see scheme 29 provided in the end of the description).

TLC: RF= 0,43 (silica gel; toluene/ethyl acetate in euronat)- (1--->4)-2,3-di-O-benzyl-6-O-methyl-D-glucopyranosid (134)

to 9.9 g of compound (133) is dissolved in 300 ml of methanol and refluxed in a nitrogen atmosphere. Was added dropwise to 65.2 ml of 1 M solution of sodium methylate in methanol and the mixture is stirred and refluxed for three hours. The mixture was then cooled to room temperature, add the 22.2 ml of 1 n sodium hydroxide solution and the reaction mixture was stirred for another 90 minutes. After neutralization with resin Dowex 50WX8 (H+and filtering the mixture concentrated. In an atmosphere of pure nitrogen product is dissolved in 192 ml of dimethylformamide and added molecular sieve. Add 3.2 g of potassium bicarbonate and 4.8 ml of benzylbromide and the mixture is stirred for 5 hours. After adding ethyl acetate and water, the extraction and separation of the two phases, the organic phase is concentrated. The crude product is purified by chromatography was carried out on a column of silica gel, getting to 6.19 g of compound (134) and 1.88 g of starting compound (133) (see scheme 29 provided in the end of the description).

TLC: RF= 0,55 (silica gel; toluene/ethyl acetate in a volume ratio of 4: 6).

Preparative example 120

(Methyl-O-(benzyl-4-O - levulinic-2,3-di-O-methyl-D - glucopyranosyloxy) -(1--->4)-2,3-di-O-benzyl-6-O-methyl-D - glucopyranose is incarnadined and 0.2 g of 4-dimethylamino pyridine and the mixture is stirred for two hours, in nitrogen atmosphere. Add 95 ml of diethyl ether and the precipitate filtered off. The filtrate is washed with an aqueous solution of potassium hydrosulfate, dried over magnesium sulfate, filtered and concentrated. Crystallization from a mixture of diethyl ether and heptane allows to obtain 6.2 g of the compound (135) (see scheme 29 provided in the end of the description).

TLC: RF= 0,26 (silica gel; dichloromethane/acetone in a volume ratio 95:5).

Preparative example 121

Methyl-O-(benzyl-4-O-levulinic-2,3-di-O-methyl-D - glucopyranosyloxy)-(1--->4) -1,3-di-O-acetyl-O-benzyl-6-O - methyl-,-D-glucopyranose (136)

of 6.1 g of compound (135) in the atmosphere of nitrogen dissolved in 256 ml of acetic anhydride and cooled to a temperature of -20oC. for 30 minutes was added dropwise a mixture of 4.9 ml of sulfuric acid in 49 ml of acetic anhydride. After 60 minutes, add sodium acetate up to obtain a mixture with a neutral pH. Then add ethyl acetate and water and the organic phase is concentrated. Purification by chromatography was carried out on a column of silica gel allows you to get 4.2 g of compound (136) (see scheme 29 provided in the end of the description).

TLC: RF= 0,24 (silica gel; dichloromethane/ethyl acetate in a volume ratio of 8:2).

Preil-6-O - methyl-, -D-glucopyranose (137)

of 4.2 g of compound (136) is dissolved in 42 ml of tetrahydrofuran and added to 4.1 ml of piperidine. The mixture is stirred over night at room temperature. Add ethyl acetate and the mixture washed with 0.5 N. hydrochloric acid. The organic phase is concentrated and the residue purified by chromatography was carried out on a column of silica gel, obtaining 3.2 g of the compound (137) (see scheme 29 provided in the end of the description).

TLC: RF = 0,33 (silica gel; dichloromethane/ethyl acetate in a volume ratio 1:1).

Preparative example 123

O-(Benzyl-4-O-levulinic-2,3-di-O-methyl-D - glucopyranosyloxy)-(1--->4) -3-O-acetyl-2-O-benzyl-6-O - methyl-D-glucopyranose-trichloroacetimidate (138)

of 1.59 g of compound (137) in the atmosphere of nitrogen dissolved in anhydrous dichloromethane. Add 1.1 ml of trichloroacetonitrile and 72 mg of cesium carbonate and the mixture is stirred for 1 hour. The cesium carbonate is filtered off and the filtrate concentrated. Purification by chromatography was carried out on a column of silica gel allows you to get of 1.57 g of compound (138) (see scheme 29 provided in the end of the description).

TLC: RF= 0,60 (silica gel; toluene/ethyl acetate in a volume ratio 3: 7).

Preparative example 124

Methyl-O-(Benzyl-4-O-levulinic,3-di-O-methyl-L-iodopyrazine)-(1--->4) -2,3-di-O-benzyl-6-O-methyl-D-glucopyranosid (139)

Under nitrogen atmosphere a mixture of 300 mg of the compound (133) and 455,6 mg of the compound (138) is evaporated together with toluene and dissolved in 6 ml dichloromethane. After addition of molecular sieves, the reaction mixture is cooled to a temperature of -20oC. After stirring for 20 minutes add trimethylsilyltrifluoromethane (15 mol.% with respect to the compound (138)). After 10 minutes the reaction is stopped using an aqueous solution of sodium bicarbonate. After filtering off the molecular sieve filtrate is diluted with dichloromethane, washed with water, concentrated and purified by chromatography was carried out on a column of silica gel, receiving 560 mg of the compound (139) (see scheme 30 provided in the end of the description).

TLC: RF= 0,50 (silica gel; toluene/ethyl acetate in a volume ratio 3: 7).

Preparative example 125

Methyl-O-(benzyl-2,3-di-O-methyl-D-glucopyranosyloxy)- (1--->4)-O-(3-O-acetyl-2-O-benzyl-6-O-methyl-D-glyukopiranozil)-(1--->4) -O-(benzyl-2,3-di-O-methyl--L - iodopyrazine)-(1--->4)-2,3-di-O-benzyl-6-O-methyl-a-D - glucopyranosid (140)

532,6 mg of the compound (139) dissolved in 1.9 ml of pyridine and added dropwise, at room temperature, a mixture of 2.4 ml of acetic acid, 0.3 ml of hydrazine hydrate is added 1.9 ml of pyridine. After stirring for those who nd acid, aqueous solution of sodium bicarbonate and water. The organic phase is concentrated and purified by chromatography was carried out on a column of silica gel, getting 451 mg of the compound (140) (see scheme 30 provided in the end of the description).

TLC: RF= 0,45 (silica gel; toluene/ethyl acetate in a volume ratio 3: 7).

Preparative example 126

Methyl-O-(6-O-benzoyl-4-O-levulinic-2,3-di-O-methyl - D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4) -[O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4)]3-O-(6-O-acetyl-2,3-di-O-methyl - D-glyukopiranozil)-(1--->4) -O-(benzyl-2,3-di-O-methyl-a-D - glucopyranosyloxy)-(1--->4) -O-(3-O-acetyl-2-O-benzyl-6-O - methyl-D-glyukopiranozil)- (1--->4)-O-(benzyl-2,3-di-O - methyl--L-iodopyrazine) -(1--->4)-2,3-di-O-benzyl-6-O-methyl-a-D - glucopyranosid (141)

A mixture of 144 mg (0,064 mmol) of the compound (117) and 76 g (0,058 mmol) of the compound (140) is evaporated together with toluene and the residue is dissolved in 3.0 ml mixture of dichloromethane with diethyl ether in the ratio 1:2. In an atmosphere of nitrogen was added 140 mg of molecular sieves and the mixture is cooled to a temperature of 0oC. Add 128 μl of 0.1 M solution of tributylphosphorotrithioate in dichloromethane and after 15 minutes the reaction Ave is dried and concentrated. The product was then purified first by chromatography was carried out on Sephadex LH-20 (dichloromethane/methanol in a volume ratio 1:1), then by chromatography was carried out on a column of silica gel, receiving 124 mg of the compound (141) in the form of a mixture / = 8/2 (see diagram 31 provided in the end of the description).

TLC: RF= 0,60 (silica gel; toluene/acetone in a volume ratio 1:1).

Preparative example 127

Methyl-O-(6-O-benzoyl-2,3-di-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)- (1--->4)-[O- (2,3,6-tri-O-methyl-D-glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O - methyl-D-glyukopiranozil)- (1--->4)]3-O-(6-O-acetyl-2,3-di-O - methyl-D-glyukopiranozil)- (1--->4)-O-(benzyl-2,3-di-O-methyl-D-glucopyranosyloxy)- (1--->4)-O-(3-O-acetyl-2-O-benzyl-6 - O-methyl-D-glyukopiranozil)- (1--->4)-O-(benzyl-2,3-di-O-methyl-L-iodopyrazine)- (1--->4)-2,3-di-O-benzyl-6-O-methyl-D-glucopyranosid (142)

Connection (141) into a compound (142) according to the procedure described for connection (140). Connection (142) was isolated as a mixture / = 8/2 (see diagram 31 provided in the end of the description).

TLC: RF= 0,45 (silica gel; toluene/acetone in a volume ratio 1:1).

Preparative example 128

O-(2,3,4,6-Tetra-O-acetyl-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-acetyl - is even) at a temperature of 155oC added in small portions to a suspension of 7 g (85 mmol) of sodium acetate in 70 ml of acetic anhydride. After 15 minutes a clear solution is cooled and the reaction stopped with 700 ml of ice water. After extraction with ethyl acetate the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated, obtaining of 13.1 g of compound (144) (see scheme 32 provided in the end of the description).

TLC: RF= 0,53 (silica gel; dichloromethane/ethyl acetate in a volume ratio 7:3).

Preparative example 129

Ethyl-O-(2,3,4,6-Tetra-O-acetyl- -D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-acetyl- -D-glyukopiranozil)-(1--->4)-2,3,6-tri-O - acetyl-1-thio- -D-glucopyranosid (145)

13 g (13.5 mmol) of the compound (144) is dissolved in 80 ml of toluene. In nitrogen atmosphere add 1.97 ml (26.9 mmol) of ethanthiol and 13.7 ml of 1 M solution in toluene of titlefirst of boron TRIFLUORIDE. After stirring for 60 hours, the mixture is diluted with water and dichloromethane. After extraction the organic phase is washed with 10% sodium hydrogen carbonate solution and water, dried, filtered and concentrated. The crude product is purified by chromatography was carried out on a column of silica gel, receiving 8.6 g of the compound (145) (see scheme 32 provided in the end of the description).


Ethyl-O--D-glyukopiranozil) -(1--->4)-O--D - glyukopiranozil)-(1--->4) -1-thio--D-glucopyranoside (146).

Connection (145) into a compound (146) according to the procedure described for obtaining compound (95).

TLC: RF= 0,80 (silica gel; ethyl acetate/pyridine/acetic acid/ox in a volume ratio 13:7:1,6:4).

Preparative example 131

Ethyl-O-(2,3,4,6-Tetra-O-benzoyl- -glyukopiranozil)- (1--->4)-O-(2,3,6-tri-O-benzoyl- -D-glyukopiranozil)-(1--->4) -2,3,6-tri-O-benzoyl-1-thio- -D-glucopyranosid (147)

Connection (146) into a compound (147) according to the procedure described for obtaining the compound (92).

TLC: RF= 0,50 (silica gel; toluene/ethyl acetate in a volume ratio 9: 1).

Preparative example 132

Methyl-O-(2,3,4,6-Tetra-O-benzoyl- -D-glyukopiranozil)-(1--->4)- O-(2,3,6-tri-O-benzoyl-a-D-glyukopiranozil)-(1--->4)-O-(2,3,6 - tri-O-benzoyl- -D-glyukopiranozil)-(1--->4)-O-(6-O-benzoyl-2,3 - di-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil-(1--->4)-[O-(2,3,6-tri-O-methyl-D - glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl-D - glyukopiranozil)-(1--->4)]3-O-(6-O-acetyl-2,3-di-O-methyl-D-glyukopiranozil)-(1--->4)-O-(benzyl-2,3-di-O-methyl-D - glucopyranosyloxy)-(1--->4)-O-(3-O-acetyl-2-O-benzyl-6-O - methyl-D-glyukopiranozil)-(1(of 0.066 mmol) thioglycoside (147) 55 mg (0,017 mmol) of the acceptor (142) (/ = 8/2) combine in accordance with the method described to obtain (109). The product was then purified first by chromatography was carried out on Sephadex LH-20 (dichloromethane/methanol in the ratio 1:1), then by chromatography was carried out on a column of silica gel (diethyl ether/ethyl acetate/ethanol in a volume ratio of 9:0,5:0,5) to give 49 mg of the compound (148) (see scheme 33, provided at the end of the description).

TLC: RF= 0,30 (silica gel; diethyl ether/ethyl acetate/ ethanol in a volume ratio of 85:at 7.5-7.5).

Preparative example 133

Methyl-O-(2,3,4,6-Tetra-O-benzoyl- -D-glyukopiranozil)-(1--->4)- O-(2,3,6-tri-O-benzoyl- -D-glyukopiranozil)-(1--->4)-O-(2,3,6 - tri-O-benzoyl- -D-glyukopiranozil)-(1--->4)-O-(6-O-benzoyl-2,3 - di-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil-(1--->4)-[O-(2,3,6-tri-O - methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]3-O-(6-O-acetyl-2,3-di-O-methyl-D-glyukopiranozil)-(1--->4)-O-(benzyl-2,3-di-O-methyl - D-glucopyranosyloxy acid)-(1--->4)-O-(3-O-acetyl-6 - O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3-di-O-methyl--L - ecoperestorika acid)-(1--->4)-6-O-methyl-D - glucopyranosid (149)

A solution of 47 mg (0.01 mmol) of the compound (148) in 10 ml of ethyl acetate is stirred, under nitrogen atmosphere, in the presence of 10% palladium-on-angle (90 wt.% with respect to the compound (the descriptions).

TLC: RF= 0,35 (silica gel; ethyl acetate/pyridine/acetic acid/water in a volume ratio 20:7:1,6:4).

Preparative example 134

Methyl-O--D-glyukopiranozil)-(1--->4)-O-- D-glyukopiranozil)- (1--->4)-O-(-D-glyukopiranozil) -(1--->4)-O-(2,3-di-O-methyl-D-glyukopiranozil)-(1--->4)-O-(2,3,6-tri-O-methyl-D - glyukopiranozil-(1--->4) -[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D - glyukopiranozil)-(1--->4)]3-O-(2,3-di-O-methyl-D - glyukopiranozil)-(1--->4) -O-(2,3-di-O-methyl-D - glucopyranosyloxy acid)-(1--->4) -O-(6-O-methyl - D-glyukopiranozil)-(1--->4) -O-(2,3-di-O-methyl--L - ecoperestorika acid) -(1--->4)-6-O-methyl-a-D - glucopyranosid (150)

The mixture is 0.22 ml of methanol and of 0.66 ml of 0.66 n sodium hydroxide solution is added to 41 mg (0.01 mmol) of the compound (149), then stirred for 20 hours at room temperature. The mixture is diluted with water and acidified with a 0.5 n solution of hydrochloric acid to achieve a pH of 6.5. After concentration, the pure product absoluut on a column with Sephadex G-25, using a mixture of water with acetonitrile in a volume ratio of 9:1. Containing hexadecasaccharide fractions are combined and lyophilizers, receiving 26 mg of the compound (150) in the form of a white amorphous powder (see scheme 33, provided at the end of description 8:7:1,6:4).

Preparative example 135

6-O-Tert-butyldimethylsilyl-1,2-O-isopropylidene-3-O-methyl-a-D-glucofuranose (152)

Absorb 10 grams (or 42.7 mmol) of diol (151) in 100 ml anhydrous dichloromethane and added to 7.1 g (47,3 mmol) tert-butyldimethylsilyloxy and 5.8 g (85,3 mmol) of imidazole. The reaction mixture was stirred at room temperature. After 2 hours the mixture is diluted with dichloromethane and washed with water. The organic phase is dried over magnesium sulfate, concentrated and the residue purified by chromatography was carried out on a column of silica gel (ethyl acetate/cyclohexane in a volume ratio 1:9) to give 11.9 g (80%) of the target product (152) in the form of syrup (see scheme 34 provided in the end of the description).

[]D= -34(C = 1,9; chloroform).

Preparative example 136

6-O-Tert-butyldimethylsilyl-1,2-O-isopropylidene-3-O-methyl-5-C-vinyl-a-D-glucofuranose (154)

At a temperature of -78oC in 40 ml of anhydrous dichloromethane add 3.2 ml cases (36.8 mmol) of oxalicacid and 5.2 ml (73.4 mmol) of dimethyl sulfoxide and stirred for 30 minutes. Then add 6.4 g (18.4 mmol) of the compound (152) and the mixture is stirred for 1 hour. After that add and 15.3 ml (110,0 mmol) of triethylamine and after 30 minutes the reaction mixture is diluted with dihl the th reaction. The crude ketone (153) is treated with 100 ml of anhydrous tetrahydrofuran and at a temperature of 0oC add 28 ml of 1 M solution of vinylmania (27.6 mmol) in tetrahydrofuran. After 1 hour the reaction mixture is diluted (solution) ammonium chloride and washed with water. The organic phase is dried over magnesium sulfate, concentrated and the residue purified by chromatography was carried out on a column of silica gel (ethyl acetate/cyclohexane in a volume ratio 1:9) to give 4.8 g (70%) of target compound (154) in the form of syrup (see scheme 34 provided in the end of the description).

[]D= -40(=1,3; chloroform).

Analysis:

calculated, %: C 57,72 H 9,15

found, %: C 57,77 H 9,23.

Preparative example 137

1,2,4,6-Tetra-O-acetyl-3-O-megil-5-C-vinyl - a-D - glucopyranose (156)

3.5 g (9.4 mmol) of the compound (154) add 50 ml of water, then there is added 1 g of resin IR-120 and is heated at a temperature of 80oC for 6 hours. The resin is filtered off and the filtrate concentrated. The crude product (155) acetimidoyl using 12 ml of acetic anhydride and 13 ml of pyridine. The excess acetic anhydride is decomposed with methanol and the solvents are concentrated. The residue is extracted with water and dichloromethane. The organic phase drying the Oia (ethyl acetate/cyclohexane in a volume ratio of 3: 2) to obtain 2.7 g (75%) tetraacetate connection (156) in the form of a solid substance (see circuit 34 provided in the end of the description). So pl. = 50oC.

[]D= -84(=1,6; chloroform).

Analysis:

calculated, %: C 52,47 H to 6.19

found, %: C 52,51 H to 6.19

Mass spectrometry (chemical ionization): 406 (M+NH4); 389 (M+1).

Preparative example 138

Methyl 2,3,6-tri-O-benzyl-4-O-(2,4,6-tri-O-acetyl-3-O-methyl-5 - C-vinyl-a-D-glyukopiranozil)- -D-glucopyranosid (158)

1.6 g (4.1 mmol) of the compound (156) and 2.1 g (4.5 mmol) of the compound (157) [P. J. Garegg and H. Hultberg, Carbohydr. Res., 93, C10 (1981)] are dissolved in 50 ml of anhydrous dichloromethane and added 4.0 g of molecular sieves. The reaction mixture was stirred at room temperature for one hour, then at a temperature of -78oC type of 0.95 ml (5.2 mmol) of trimethylsilyltriflate. After that, the reaction mixture is slowly brought to room temperature. After 2 hours the reaction mixture is neutralized with triethylamine and filtered through celite; the filtrate is washed with water. The organic phase is dried over magnesium sulfate, concentrated and the residue purified by chromatography was carried out on silica (ethyl acetate/cyclohexane in a volume ratio 4:1), receiving 2,77 g (85%) of target compound (158) in the form of solids (see scheme 34, provided at the end of occitano, %: C 65,14 H 6,61

found, %: C 65,09 H 6,70

Preparative example 139

Methyl 2,3,6-tri-O-benzyl-4-O-(4,6-O-isopropylidene-3-O-methyl - 5-C-vinyl-a-D-glyukopiranozil)- -D-glucopyranosid (160)

2.7 g (3.4 mmol) of the compound (158) is dissolved in 40 ml of methanol, at a temperature of 0oC add a catalytic amount of sodium and stirred at room temperature for three hours. The solvent is removed and the residue (159) is treated with 40 ml of anhydrous acetone and add 2 ml of 2,2-dimethoxypropane and a catalytic amount of p-toluenesulfonic acid. The reaction mixture was stirred at room temperature overnight. The solvent is evaporated, the residue is treated with chloroform and washed with water. The organic phase is dried over magnesium sulfate, concentrated and the residue purified by chromatography was carried out on a column of silica (ethyl acetate/cyclohexane in a volume ratio 1:1) to give 1.7 g(70%) (4', 6 '-isopropylidene-O-)-derivative (160) in the form of solids (see scheme 34 provided in the end of the description). So pl.= 55oC.

[]D= +13(C = 0.8; chloroform).

Analysis:

calculated, %: C 67,97 H 7,13

found, %: C 67,87 H 7,16

Mass spectrometry (chemical ionization): 724 (M+NH4
of 0.35 ml (4.0 mmol) of Oxalicacid and 0.57 ml (8.0 mmol) of anhydrous dimethyl sulfoxide in 10 ml of anhydrous dichloromethane is stirred for 30 minutes at a temperature of -78oC. To the solution was added 1.4 g (2.0 mmol) of the compound (160) in 10 ml of anhydrous dichloromethane and stirred for another 45 minutes. The reaction mixture is neutralized by adding 1.7 ml (12,0 mmol) of anhydrous triethylamine, then diluted with dichloromethane. After washing the reaction mixture with water, the organic phase is dried over magnesium sulfate, concentrated and the residue (161) are immediately used without purification in the next reaction. Ketone (161) add 15 ml of anhydrous tetrahydrofuran and at a temperature of -78oC add 4 ml of 1 n solution of superseded (4.0 mmol) in tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 hour and then add 2 ml of 5% sodium hydroxide solution and 1 ml of hydrogen peroxide. The solvent is evaporated and the residue treated with ethyl acetate and washed with water. The organic phase is dried over magnesium sulfate, concentrated and the residue purified by chromatography was carried out (ethyl acetate/cyclohexane in a volume ratio of 2:1) to give 1.0 g (70%) of compound (162) (see scheme 34 provided in the end of the description).

Preparative example 141

Methyl 2,3,6-tri-O-benzyl-4-O-(2-O-acetyl-3-O-methyl-5-C-vinyl - a-D-mannopyranosyl)- -D-glucopyranosid (164)

940 mg (1.3 mmol) of the compound (162) dissolved in 3 ml of pyridine and add 0.3 ml of acetic anhydride. The reaction mixture was stirred at room temperature for three hours. The excess pyridine and acetic anhydride were removed and the residue (163) directly used to remove isopropylidene protective group with 5 ml of 80% acetic acid at a temperature of 60oC for two hours. The excess acetic acid is removed by evaporation and the residue purified by chromatography was carried out on a column of silica gel (ethyl acetate/cyclohexane in a volume ratio 4:1) to give 660 mg (70%) of the diol (164) in the form of solids (see scheme 34 provided in the end of the description). So pl. = 53oC.

[]D= -10(C = 0.8; chloroform).

Mass spectrometry (chemical ionization): 726 (M+18); 709 (M + 1).

Preparative example 142

Methyl 2,3,6-tri-O-benzyl-4-(2-O-acetyl-3-O-methyl-6-O-tosyl - 5-C-vinyl-a-D-mannopyranosyl)- -D-glucopyranose (165)

600 mg (0.9 mmol) of the compound (164) dissolved in 3 ml of pyridine and added 240 mg (1.3 mmol) of Teilhard. The reaction mixture peforma and washed with water. The organic phase is dried over magnesium sulfate, concentrated and the residue purified by chromatography was carried out on a column of silica gel (ethyl acetate/cyclohexane in a volume ratio 1: 1) to give 297 mg (80%) totalrevenue connection (165) in the form of syrup (see scheme 34 provided in the end of the description).

[]D= -26(C = 0.8; chloroform).

Preparative example 143

Methyl 2,3,6-tri-O-benzyl-4-(2,6 - anhydrous-3-O-methyl-5-C-vinyl - a-D-mannopyranosyl)- -D-glucopyranosid (166)

550 mg (0.6 mmol) of the compound (165) add 3 ml of ethanol and then add 5 ml of 0.1 n sodium hydroxide solution in ethanol. The reaction mixture is heated at a temperature of 70oC for three hours, then neutralized with resin IR-120 (form H+) and filtered through celite. The residue after concentration purified by chromatography was carried out on a column of silica gel (ethyl acetate/cyclohexane in a volume ratio 1:1) to give 292 mg (70%) of the compound (166) in the form of syrup (see scheme 34 provided in the end of the description).

[]D= +13(C = 0,5; chloroform).

Mass spectrometry: 666 (M+18).

Preparative example 144

Methyl 2,3,6-tri-O-benzyl-4-(benzyl-3-O-methyl-2-O-5-C - methylidene- -L-icaperiorat)- -D-glucopyranose -78oC, then for 30 seconds pass by ozonation ozone. The colour of the solution becomes pale yellow. To the solution was added dimethyl sulfide, then the reaction mixture is washed with water. The organic phase is dried over magnesium sulfate, and concentrate without further purification directly used in the next reaction. The crude aldehyde contribute in 16 ml of tert-butanol and add 5 ml of 2-methylbut - 2-ene and 16 ml of water. Then, to the mixture are added successively 700 mg NaH2PO4and 700 mg of NaClO2. The suspension is intensively stirred over night at room temperature, diluted with water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, concentrated, and then directly used in the next reaction. The crude acid contribute in 25 ml of dimethylformamide and added 0.7 g (2.0 mmol) of tetrabutylammonium, 0.25 g (2.5 mmol) of potassium bicarbonate and 0,250 ml (2.1 mmol) of benzylbromide. The reaction mixture was stirred at room temperature for 5 hours, then extracted with water and diethyl ether. The ether phase is dried over magnesium sulfate, concentrated and the residue purified by chromatography was carried out on a column of silica gel (ethyl acetate/cyclohexane in a volume ratio of 2:1) getting 236 ª (chemical ionization): 774 (M + 18).

EXAMPLES

Example 1

Methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo- -D-glyukopiranozil)-(1--->4)- O-(3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)-(1--->4)-[O- (3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)-(1--->4) -O-(3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)-(1--->4)6-O- (2,3-di-O-methyl-6-O - sulfo--D)-(1--->4)-O- (2,3-di-O-methyl-a-D glucopyranosyloxy acid)-(1--->4)-O-(2,3,6-tri-O - sulfo- -D-glyukopiranozil)-(1--->4) -O-(2,3-di-O-methyl--L - ecoperestorika acid)-(1--->4)-2,3,6-tri-O-sulfo--D - glucopyranoside in the form of sodium salt (168)

The compound (31) is treated according to Method 5, when receiving the connection (168) (80%, based on a three stage).

[]D= -41(C = 0,8; water).

ESIMS (negative ions): monoisotopic mass = 7133,26; chemical mass = 7138,90; experimental mass = 7137,26 0.0 Rel. mass. unit

1H-NMR (D2O): (M. D.) major anomeric protons: 5,71; 5,48; 5,46; 5,44; 5,17; 5,08; 4,81; 4,78; 4,67.

An identical procedure allows one to obtain compound (169) and (170) (see tab. I).

Example 4

Methyl-O-(2,3-di-O-methyl-4,6-di sulfo- -D - glyukopiranozil)-(1--->4) -[O-(2,3-di-O-methyl-6-O-sulfo- -D - glyukopiranozil)-(1--->4)]15-O-(2,3-di-O-methyl-D - glucopyranosyloxy acid)-(1--->4)-O-(2,3,6-tri-O - sulfo- -D-glycoproteins salt (171)

55 mg (10.5 mmol) of the compound (51) is treated according to Method 5, getting after lyophilization 50 mg (77%, based on a three stage) sulfated product (171).

[]D= +107(s = 0,52; water).

ESIMS (negative ions): monoisotopic mass = 6194,16; chemical mass = 6198,83; experimental mass = 6195,33 1,79.

1H-NMR (D2O): (M. D.) major anomeric protons: 5,71; 5,67; 5,48; 5,43; 5,17; 5,10; 4,68.

An identical procedure allows one to obtain compound (172) and (173) (see tab. II).

Example 7

Methyl-O-(3-O-methyl - 2,4,6-tri-O-sulfo- -D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)- (1--->4)-O-(3-O-methyl-2,6-di-O-sulfo- -D-glyukopiranozil)- (1--->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4)]4-O-(2,3-di-O - methyl-6-O-sulfo- -D-glyukopiranozil)-(1--->4)-O-(2,3-di-O - methyl-D-glucopyranosyloxy acid-(1--->4)-O-(2,3,6-tri - O-sulfo- -glyukopiranozil)-(1--->4) -O-(2,3-di-O-methyl-L - ecoperestorika acid)-(1--->4)-2,3,6-tri-O-sulfo--D - glucopyranoside in the form of sodium salt (174)

Connection (75) is treated according to Method 5, get a connection (174) (84% in the calculation of the three stages).

1H-NMR (D2O): (M. D.) major anomeric protons: 5,69; 5,63; 5,57; 5,46; 5,44; 5,41; 5,15; 5,06; 4,79; 4,66; 4,62; 4,41.

Following the procedure of example 7 and using adequate intermediate products, get compounds of examples 8-12, described in table. III.

Example 13

Methyl-O-(2,3,4,6-Tetra-O-sulfo- -D-glyukopiranozil)-(1--->4)-O- (2,3,6-tri-O-sulfo- -D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri - O-sulfo- -D-glyukopiranozil)-(1--->4) -O-(2,3-di-O-methyl-6-O - sulfo- -D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1--->4) -[O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4) -O-(2,3,6-tri-O-methyl - D-glyukopiranozil)-(1--->4)]3-O-(2,3-di-O-methyl-6-O-sulfo--D - glyukopiranozil)-(1--->4) -O-(2,3-di-O-methyl-D - glucopyranosyloxy acid) -(1--->4)-O-(6-O-methyl - 2,3-di-O-sulfo--D-glyukopiranozil)-(1--->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid)-(1--->4)-6-O-methyl-2,3-di-O-sulfo- -D-glucopyranosid (180)

26 mg (0,0084 mmol) hexadecasaccharide, which completely removed the protective group, is dissolved in 0,87 ml of dimethylformamide. In an atmosphere of nitrogen was added 125 mg (0.67 mmol, 80 EQ.) complex of sulfur trioxide with triethylamine and the mixture is stirred for 16 hours at a temperature of 50oC. the Mixture is cooled to ambient temperature the volume and applied to a column of Sephadex G-25, elwira with a mixture of water with acetonitrile in a volume ratio of 9:1. The appropriate fraction is separated, concentrated to a small volume, making a column of ion exchange resin Dowex XW4 (Na+) (water) and the eluate lyophilizer, receiving 37 mg of the compound (180) in the form of a white powder (see diagram 35 provided in the end of the description).

[]D= +67,6(c = 1; water).

ESIMS: molecular weight is 4370,6 (H+-form).

C128H222O113S16(theoretically calculated molecular mass = 4370,14).

NMR; the shift of the anomeric proton (M. D.): residue 1: 5,17; rest 2: 5,03; the remainder is 3: 5,41; the remainder is 4: 4,42; the remainder is 5: 5,49; the remainder is 6: 4,66; residues 7, 9 and 11: 5,67; residues 8, 10 and 12: 4,46; the remainder 13: 5,61; the remainder 14: 4,94; the remainder 15: 5,59; the remainder 16: 5,69.

Biological tests

Biological test on antithrombotic activity was carried out as follows.

Rats were injected intravenously, the compounds and determined the value of the ED50(effective dose) on the model of venous stasis and induction of the device according to the method described in J. Reyers and others in Trombosis Research, 1980, 18, 669-674. This figure was determined on a model of arterial thrombosis induced by implan the ost., 1978, 39, 74-83.

The results are given in table. IV.

An example of a composition in the form of the solution:

The compound of example 7 40 mg

water up to 0.4 ml

Upon receipt of the pharmaceutical compositions using traditional methods, depending on the desired formulation. In this case, get the solution of the current start by dissolving the compound in the form of sodium salt, available in powder form, soluble in water.

1. Synthetic polysaccharide of formula I

< / BR>
the wavy line represents a relationship that is located either above or below the plane of the pyranose cycle

< / BR>
means polysaccharide Ro containing n identical or different monosaccharide units linked to its anomeric carbon with D;

< / BR>
is a schematic illustration of the monosaccharide residue with pyranose structure selected among the hexoses, and this residue is linked to its anomeric carbon to another monosaccharide residue and the hydroxyl group of this residue is substituted by an identical or different groups X selected among (C1-C6)- alkyl groups, and sulfo; h = 2;

n means an integer from 10 to 25;

Re means polysaccharide structure:

< / BR>
GA R1the value of, or with the oxygen atom to which it is attached and with the carbon atom containing carboxyl function in the same cycle, form the group-CH2-O;

R means (C1-C6)-alkyl group;

W denotes an oxygen atom or a methylene group; or one of its salts, in particular pharmaceutically acceptable salt.

2. Salt of the polysaccharide under item 1, in which the cation is chosen among cations of alkali metals, especially of sodium and potassium.

3. Polysaccharide and salt according to any one of p. 1 or 2 of formula I.

< / BR>
where

< / BR>
means a special family of polysaccharides Ro related to its anomeric carbon with PE, as indicated in formula I;

< / BR>
is specified for formula I;

OH have specified for formula I value and, in the case of the same monosaccharide, may be the same or different;

the monosaccharides contained in [ ]mform a repeating m times the disaccharide; monosaccharides contained in [ ]tform repeated t times the disaccharide;

m = 1 - 8; t = 0 to 5; R = 0 - 1, provided that 5 m + t 12;

and its salts, in particular pharmaceutically acceptable salts.

4. Polysaccharide and salt according to any one of p. 1 or 2 of the formula II.And
Re, therefore, as indicated in the case of formula I;

< / BR>
is specified for formula I;

OH have specified for formula I value and, in the case of the same monosaccharide, may be the same or different;

the monosaccharide contained in [ ]mis repeated m times; the monosaccharide contained in [ ]trepeated t' time; the monosaccharide contained in [ ]prepeated R', times;

m' = 1 to 5; t' = 0 to 24; p' = 0 to 24, provided that 10 m' +t'++p' 25;

and their salts, in particular pharmaceutically acceptable salts.

5. Sol according to any one of p. 1 or 2, the anion of which corresponds to the formula I. 1

< / BR>
where t = 5,6 or 7, the cation is a pharmaceutically acceptable monovalent cation

as well as their corresponding acids.

6. Sol according to any one of p. 1 or 2, the anion of which corresponds to the formula I. 2

< / BR>
where t = 5, 6 or 7, the cation is a pharmaceutically acceptable monovalent cation

as well as their corresponding acids.

7. Sol according to any one of p. 1 or 2, the anion of which corresponds to the formula I. 3

< / BR>
where m = 1, 2, or 3; t = 2, 3, 4 or 5, the cation is a pharmaceutically acceptable monovalent cation

as well as their corresponding acids.

8. Polysaccharides under item 1, select the media is-glyukopiranozil)-(1->4)-[O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)]4-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)]5-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)]6-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(2,3-di-O-methyl-4,6-di-O-cryosanua acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of a sodium salt;< / BR>
-methyl-O-(2,3-di-O-methyl-4,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)-(1->4)] 13-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(2,3-di-O-methyl-4,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)-(1->4)] 15-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)

(1->4)]2-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)]2-[O-(2,3-di-O-methyl-6-O--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(3-O-is ULFO--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)] 2-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)] 3-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)] 4-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)- (1->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)] 3-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)Teal--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)]4-[O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salts;

-methyl-O-(3-O-methyl-2,4,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(3-O-methyl-2,6-di-O-sulfo--D-glyukopiranozil)-(1->4)-[O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)-O-(2,3,6-tri-O-methyl-D-glyukopiranozil)-(1->4)]5-O-(2,3-di-O-methyl-6-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl-D-glucopyranosyloxy acid)-(1->4)-O-(2,3,6-tri-O-sulfo--D-glyukopiranozil)-(1->4)-O-(2,3-di-O-methyl--L-ecoperestorika acid)-(1->4)-2,3,6-tri-O-sulfo--D-glucopyranoside in the form of sodium salt.

9. The compound of formula II.1

< / BR>
where T1and Tnidentical or different, denote Deputy, selected from acetyl, benzyl, trityl, allyl, parametersbodily or 2-(trimethylsilyl)ethyl;

Z represents a protective group of the hydroxyl function selected from levulinic and parameterstyle formula III.1

< / BR>
where T1and Tnidentical or different, denote Deputy, selected from acetyl, benzyl, trityl, allyl, parametersbodily or 2-(trimethylsilyl)ethyl;

Z represents a protective group of the hydroxyl function selected from levulinic and parametersbodily; or

OZ andnform together a group of 4,6-O-benzyliden or 4,6-O-isopropylidene.

11. Pharmaceutical composition having anticoagulant or antithrombotic activity, containing as an active start polysaccharide or salt according to any one of paragraphs.1 - 8, in the form of a salt with a pharmaceutically acceptable base or acid form, in combination or in a mixture with inert, non-toxic pharmaceutically acceptable excipients.

12. The pharmaceutical composition according to p. 11, in the form of single doses, in which the active principle is mixed with at least one pharmaceutical excipient.

13. The composition according to p. 12, in which each single dose contains 0.1 to 100 mg of active beginning.

14. The composition according to p. 13, in which each single dose contains 0.5 - 50 mg of active beginning.

15. The polysaccharide or salt on PP. 1 - 8 to obtain medicines are suitable in the case of pathologies,

 

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