2-sharonlee or 4,5,6,7-tetrahydro-2 - sharinaletisha-phosphonates or phosphinate and pharmaceutical composition based on them

 

(57) Abstract:

New 4-R1-R2-R3-2 - sharonlee-, 4 -, R4-4-R5-6-R6- 4,5,6,7-tetrahydro-2-sharonlee - and 4.7-C-4,5,6,7-tetrahydro-2-sharinaletisha, phosphonates, and phosphinate formulas I and II and IIA, respectively, intended for the treatment of degenerative values; compositions containing them; and methods of their use for the treatment of degenerative diseases; and how to obtain these compounds by reaction of the corresponding 2-halogenoalkanes phosphate, phosphonate or phosphinic acid of formula III in the presence of an acid acceptor. 2 S. p. f-crystals, 5 Il., 8 table.

The invention relates to 2-sharonlee - 4,5,6,7 - tetrahydro-2-sharinaletisha-phosphonates and-Phosphinates, inhibiting enzymatic activity; to compositions containing these compounds, their use and the treatment of disruptive disorders, and to methods for their preparation.

Inhibition of proteolytic enzymes using non-toxic reagents used in the treatment of disruptive disorders, such as emphysema, rheumatoid arthritis, and pancreatitis, which are based on proteolysis. In biomedical assermentos are serine proteases. On the basis of their substrate specificity, some serine proteases belong to the group of chymotripsin or elastase.

Chymotrypsin and chymotrypsin these enzymes break down the peptide bonds in proteins in those sections, to the carboxy end there is usually a Tip, Tyr, Phe, Met, Leu or another amino acid residue, which contains an aromatic or large alkyl side chains. Elastase and elastase-like enzymes usually break down the peptide bonds in those areas where the carboxyl side of a relationship, there is Ala, Val, Ser, Leu, or other similar, smaller amino acids. The chymotrypsin - and elastase such enzymes have been detected in leukocytes, mast cells, and pankreaticescom juice at higher organisms, and are secreted by many types of bacteria, yeast and parasites.

In the publication of Japanese patent 72/00419 reveals a number of 2-sharingilluminatis, including 2-sharinaletisha per Se and 2-sharonlee 2,4-dichlorobenzoate, and 4-nitrobenzoate. These compounds possess strong activity against pyricularia rice, Rhizoctonia rice, Helminthosporium rice and chaff leaves of rice.

Sunkel and other J. Med. Chem. 31, 1886-1890 (1988) disclose a series of 2-saharinen-lower alkyl-1,4-digitool activity.

In U.S. patent (Chen) discloses various 2-aroyl-methylcholine used as photographic chemicals and film components.

In U.S. patent 4195023 (Mulvey and others) revealed R1-2-R2CO-1,2-benzisothiazol-3-ones, where R1is halogen, alkoxy, alkylamino, dialkylamino, alkoxy-carbonyl, amino, nitro, or hydrogen in benzoinum ring, and R2is hydrogen, alkyl, alkenyl, quinil, cycloalkyl, halogenfree, heteroaryl, or replaced by heteroaryl; and R1-2-A-CO-sacharine, where R1has values similar to the values of the substituents bentinho rings 1,2-benzisothiazol-3-ons, and A is alkyl, alkenyl, quinil, cycloalkyl, florfenicol, heteroaryl or substituted by heteroaryl. These compounds are capable of inhibiting elastase, and used for the treatment of emphysema. Zimmerman and others (J. Biol Chem. 255 (20), 9848-9851 (1980)) open N-acylcholine, where the acyl group is furoyl, phenol, benzoyl, cyclopropanol, ethylbutyryl and acryloid, which have the ability to inhibition of serine proteases.

In Chemical Abstracts 81, 22249 (1974) discloses 4-were-2-shorinjiryukata with bactericidal and full protease. For example, in U.S. patent 4659855 (Powers) discloses derivatives of arylsulfonate used as inhibitors of elastase. In U.S. patent 4547371, 4623645, (Doherty and others) reveal cephalosporinase and sulfoxidov, respectively, which, as shown, are strong inhibitors of elastase and used for the treatment of inflammatory diseases, in particular arthritis, and easely.

In the work Jeshima and other J. Biol. Chem. 257(9). 5085-5091 (1982) presents the results of studies of serine proteases (elastase of human leukocytes, pancreatic elastase pigs, cathepsin G, and bovine chymotrypsin A)) using 4-nitrophenylamino and thioesters of N-crittercontrol.com, 2-substituted-4H-3,1-benzoxazin-4-ones, 2-substituted-4-khinazolinov and 2-substituted-4-chloropyrazole.

In the work of Cha (Biochem Pharmacol, 24, 2177-2185 (1975) describes the kinetic approaches to the study of the binding of inhibitors with macromolecules, such as enzymes, and methods for determining parameters such as the inhibition constants, reaction rate, and the concentration of bound and unbound enzymes.

In U.S. patent 4276298 (Jones and others) discloses 2-R-1,2-benzisothiazolinone-1,1-dioxides, where R is phenyl, substituted is ylamino, alkylsulfonyl, N, N-dialkylamino, trifluromethane, trifloromethyl, triftormetilfullerenov and trifluromethanesulfonate, or pyridium, substituted in the same way as R in the case when R is phenyl, except that the pyridyl can be mono-nitrosamines. These compounds possess the ability to inhibit proteolytic enzyme, in particular, elastase, and are used to treat emphysema, rheumatoid arthritis and other inflammatory diseases.

Powers and others (Biochem. 24, 2048 2058 (1985) describe studies of inhibition of four chymotrypsin-like enzymes such as, cathepsin G, protease I and II of the fat cells of rats, chymase human skin, and chymotrypsin Ausing N-forarchive and N-(2,4-dicyanovinyl)saccharin.

Svoboda and others (Coll. Czech. Chem. Commun. 51, 1133 1139 (1986)) disclose obtain 4-hydroxy-2H-1,2 - benzothiazin-3-carboxylates by intramolecular condensation of Dickman esters 2H-1,2-benzisothiazol-3-one-2-acetate-1,1-dioxide.

U.S. patents 4350752 and 4363865 (Reczek and others) and U.S. patent 4410618 (Vanmeter and others) are photoreagent (Reczek 4350752 and Vanmeter and others) and photographic dyes (Reczek 4363865) and reveal various 2-substituted-sacharine used Inoi protecting group (Reczek 4350752), and diffundere in the media, photographic dyes, related to the nitrogen atom of imida by 1,1-alkalinous group (Reczer 4363865); and N-arylmethylidene that are disclosed blocked photoreagent having a group of organic photoreagent containing heteroatom through which it communicates with a protective group (Vanmeter).

In U.S. patent 3314960 (Freed and others) discloses 2-(1,1,3-trioxo-1,2-benzisothiazol-2-yl)glutarimide, which, as indicated, can be used as selalunya funds.

In French patent 1451417, 2-chloromercuri disclosed as an intermediate compound to obtain the N-metalshark d1-TRANS-chrysanthemate used as an insecticide, and in U.S. patent 3002884 (L0) discloses 2-chloro-2-bromo and 2-iodometrically used as fungicidal funds.

In PCT application WO 90/13549 (Dunlap and others) revealed a series of derivatives of 2-substituted sharenow used as inhibitors of proteolytic enzymes.

The invention relates to 4-R1-R2-R3-2-saccharin-ylmethyl-, 4 -, R4-4-R5-6-R6-4,5,6,7-tetrahydro-2-sharonlee-, 4,7-C-4,5,6,7-tetrahydro-2-sharinaletisha-phosphonates is Yu to proteolytic enzyme, and which can be used for the treatment of disruptive disorders.

The invention also relates to compositions for the treatment of degenerative disorders, which include pharmaceutical carrier and an effective amount of a compound of formulas I, II or IIA, inhibitory proteomically enzyme.

In addition, the invention relates to a method of using compounds of formula I, II or IIA for the treatment of degenerative disorders, which is that the patient in need of such treatment, enter the product containing an effective amount of a compound of formulas I, II or IIA required for inhibition of proteolytic enzyme.

The invention also relates to a method for obtaining compounds of formula I, II or IIA, which is that the 4-R1-R2-R3-2-halogenoalkanes, 4-R4-4-R5-6-R6-4,5,6,7-tetrahydro-2-halogenoalkanes or 4.7-C-4,5,6,7-tetrahydro-2-halogenmethyl saccharin is subjected to reaction with phosphate, phosphonate or phosphinic acid of formula III (see below) in the presence of an acid acceptor.

In particular, the invention relates to 4-R1-R2-R3-2-sharonlee - and 4-R4-4-R5-6-R6-4,5,6,7-tetrahy hydrogen, halogen, lower alkyl, Perfora-lower alkyl, perchloro-lower alkyl, lower alkenyl, lower quinil, cyano, amino, lower alkylamino, di-lower alkylamino, carboxamido, lower alkoxy, benzyloxy, hydroxy, lower alkoxycarbonyl or phenyl;

R2and R3independently represent hydrogen or a substituent in any of the appropriate 5-, 6 - or 7-positions selected from the group comprising halogen, cyano, nitro, N B, 1-lower alkyl-2-pyrrolyl, lower alkylsulfonyl, polyflora-lower alkylsulfonyl, polychloro-lower alkylsulfonyl, aminosulfonyl, lower alkyl, polyflora-lower alkyl, polychloro-lower alkyl, cycloalkyl, lower alkoxy, hydroxy, carboxy, carboxamido, hydroxy-lower alkyl, formyl, aminomethyl, polyflora-lower alkylsulfonyl, polychloro-lower alkylsulfonyl, lower alkylsulfonamides, lower alkoxycarbonyl-lower alkylamino, lower alkylcarboxylic, lower alkoxy-poly-lower alkylene, cycloalkane, hydroxy-lower alkoxy, polyhydroxyalkane, or its acetal or ketal, polyalkoxyalkyl, (lower alkoxy)2P(O)-O-, -SR, -SOR, -SO2R, -OCOR, -O-(C1-10-alkylene)-COOR, -O-(C1-10-alkylene)-COOH, and-O-(C2-10alkylen)-N B, where R is selected from lower alkyl, lower alkoxy, or halogen, and N B, in any case, represents amino, lower alkylamino, di-lower alkylamino, 1-azetidine, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinil, 4-lower-alkyl-1-piperazinil, 4-benzyl-1-piperazinil, 1-imidazolyl, or (carboxy-lower alkyl)amino;

or R2and R3together represent a 3-atomic or 4-atom unsubstituted or methylated saturated bridge connecting the carbon atoms in the 5,6 - or 6,7-positions, and the atoms of the bridge consist of one of two carbon atoms and two identical or different heteroatoms selected from oxygen atoms, sulfur and nitrogen;

R4is hydrogen, lower alkyl or phenyl;

R5is hydrogen or primary lower alkyl; or R4and R5taken together are ethylene;

R6is hydrogen or lower alkoxy;

m and n are independently 0 or 1;

if m and n are 1, A and B independently represent hydrogen, lower alkyl, phenyl, lower alkoxyphenyl or benzyl; or together they represent:

< / BR>
where R7and R8independently represent hydrogen or chlorine, and each of R9and R10is hydrogen, LIC represent lower alkyl, phenyl, benzyl or 2-pyridinyl; and

if m and n are equal to 0, then A and B independently represent lower alkyl, phenyl or lower alkoxyphenyl.

< / BR>
where C represents a methylene, ethylene, or dimethylmethylene, and preferably methylene, and A, B, m, and n are as defined for formulas I and II.

Preferred compounds of formula I are compounds in which:

R1represents hydrogen, lower alkyl, preferably C1-4-alkyl, and more preferably propyl, isopropyl or sec-butyl; or lower alkoxy, preferably methoxy or ethoxy;

R2represents lower alkoxy, in particular, C1-3-lower alkoxy, more preferably methoxy or isopropoxy; polyalkoxyalkyl, in particular 2,3-dimethoxypropane; lower alkoxy-poly-lower alkylene, in particular, methoxy-lower alkylenediamine; or polyhydroxyalkane or its ketal or acetal, and preferably 2,3-dihydroxypropane, or dimethylacetal;

R3represents hydrogen or lower alkoxy, in particular methoxy;

m and n are both equal to 0 or 1;

if m and n are equal to 1, then A and B independently represent hydrogen, lower alkyl, phenyl, lower al="ptx2">

Other preferred compounds of formula I are compounds in which:

R1represents hydrogen; lower alkyl, in particular C1-4-alkyl, preferably isopropyl or sec-butyl; or lower alkoxy, in particular methoxy or ethoxy;

R2represents hydrogen, hydroxy or lower alkoxy, in particular methoxy or ethoxy; or polyhydroxyalkane or ketal or acetal, in particular, dihydroxyacetone or ketal or acetal, and preferably 2,3-dihydroxypropane or dimethylacetal;

R3is hydrogen;

m and n are both 0 or 1;

if m and n are 1, then A and B are independently preferably both hydrogen, lower alkyl, in particular C1-4-lower alkyl, and more preferably, stands, ethyl, isopropyl or bootrom, phenyl, lower alkoxyphenyl or benzyl; and

if m and n are 0, then A and B is independently, preferably both, lower alkyl, in particular C1-4-lower alkyl, and more preferably, bootrom, phenyl or lower alkoxyphenyl, in particular methoxyphenyl, and more preferably 4-methoxyphenyl.

Preferred compounds of formula II are soutputfile methyl;

R5represents hydrogen or methyl;

R6represents hydrogen or lower alkoxy;

m and n are both 0 or 1;

if m and n are equal to 1, then A and B independently are hydrogen, lower alkyl, phenyl or benzyl; and

if m and n are equal to 0, then A and B are independently lower alkyl, phenyl or lower alkoxyphenyl.

Other preferred compounds of formula II are compounds in which:

R4represents lower alkyl, preferably methyl;

R5is a primary lower alkyl, preferably methyl;

R6represents hydrogen or lower alkoxy, preferably hydrogen;

m and n are both 0 or 1, preferably 1;

A and B independently are preferably both, lower alkyl, in particular C1-4is lower alkyl.

Especially preferred compounds of formula II are compounds in which:

R4represents hydrogen or lower alkyl; and

R5represents hydrogen or a primary lower alkyl, or R4and R5taken together, represent ethylene.

It should be noted that in the chemical literature, joints, spine, these connections are often referred to as derivatives of saccharin, and this name will be used when describing the compounds of the invention and their biological properties.

Used in the description, the terms "lower alkyl", "lower alkoxy" and "lower alkane" means a monovalent aliphatic radicals, including branched radicals circuit, consisting of 1-10 carbon atoms, for example, lower alkyl (or lower alkanol) these groups can be methyl, ethyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl, 1,1,3,3-TETRAMETHYLBUTYL, 1,1-dimethyloctyl etc.

Used in the description the terms "cycloalkyl and cycloalkene" means radicals having from 3 to 7 carbon atoms, examples of which can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy.

Used in the description of the term "halogen" means fluorine, chlorine, bromine or iodine.

Used in the description, the terms "lower alkenyl" or "lower quinil" means a monovalent unsubstituted radicals ), 1-(2-butenyl), 1-(1-methyl-2-propenyl), 1-(4-methyl-2-pentenyl), 4,4,6-trimethyl-2-heptenyl, 1-ethinyl, 1-(2-PROPYNYL), 1-(2-butenyl), 1-(1-methyl-2-PROPYNYL), 1-(4-methyl-2-pentenyl), etc.

Used in the description of the term C2-10alkylene means a divalent saturated radicals, including radicals branched chain containing 2 to 10 carbon atoms, which are free valences on different carbon atoms; and the term C1-10means a divalent saturated radicals, including radicals branched chain containing 1-10 carbon atoms, which have a free valence on the same or free carbon atoms. Examples of such radicals can serve as 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1-methyl-1,2-ethylene, 1,8-octile, etc. and in the case of only C1-10then the methylene, ethylene, propylidene etc.

Used in the description, the term lower alkoxy-poly-lower alkylene means such radicals in which the lower alkoxy has the values given above, poly means 2-4, and the lowest alkylen in the lower-alkylene means divalent radicals, including branched radicals containing from 2 to 5 carbon atoms. For example, this term includes: CH3(OCH2CH2)pO-

CH

Used in the description of the term polyalkoxyalkyl means a monovalent aliphatic alkoxy radicals with 3 to 5 carbon atoms, substituted 2 4 methoxy or ethoxy groups, neither of which is associated with the same or a C-1 carbon atom.

Compounds of the invention inhibit the activity of serine prostheses, in particular, leukocyte elastase person and chymotrypsin-like enzymes, and therefore can be used in the treatment of diseases associated with degenerative conditions, such as emphysema, rheumatoid arthritis, pancreatitis, cystic fibrosis, chronic bronchitis, respiratory distress syndrome in adults, inflammatory bowel disease, psoriasis, disease, and deficiency of inhibitor - trypsin 1.

Compounds of formulas I, II and IIA are obtained by the reaction of 4-R1-R2-R3-2-halogenoalkane, 4-R4-4-R5-6-R6-4,5,6,7 - tetrahydro-2-halogenoalkane or 4.7-C-4,5,6,7-tetrahydro-2-halogenoalkane respectively with complex fluids phosphoric acid, complex monoufia phosphorlation, if m and n are equal to 1, then A and B are not hydrogen. This reaction can be carried out in the presence of an acid acceptor, such as a carbonate of an alkali metal, Trinity alkylamino, or 1,8-diazabicyclo[5.4.0]undec-7-ene (hereinafter referred to DBU). This reaction is carried out in an organic solvent, which is inert at the reaction conditions, for example, such as acetone, methyl ethyl ketone (MEK), acetonitrile, tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), N-organic, methylenechloride (YFC), xylene, toluene, or lower alkanols, at a temperature ranging from room temperature to the boiling point of the used solvent.

Compounds of formulas I, II and IIA, where m n is equal to 1, and A and B are hydrogen, is obtained by hydrogenolysis of the corresponding compounds in which m and n are equal to 1, and A and B are benzyl.

4-R1-R2-R3-2-halogenoalkane required to obtain compounds of formula 1 are obtained by the methods described D Alelio and other J. Macromol. Sci-Chem. A3(5), 941 (1969) and Saari, etc. I. Hct. chem. 23. 1253 (1986). In the method described Saari methyl ester of the corresponding entrylevel acid get traditional method of substituted Anthranilic acid and diazotize sulphonylchloride, which, in turn, is subjected to reaction with concentrated ammonium hydroxide, and get substituted derivatives of saccharin of formula IV. After the reaction of these derivatives with formaldehyde in nisselbaum solvent receive a 4-1-R2-R3-2-hydroxy-methylcholine formula V, which are then subjected to reaction with toniguy.com or trihalide phosphorus, resulting in a gain corresponding derivatives of 4-R1-R2-R3-2-halogenoalkane formula VI.

4-R1-R2-R3-2-halogenoalkane formula VI, where R1, R2, R3have the meanings given above and X is chlorine or bromine, can be obtained by reaction of the corresponding 4-R1-R2-R3-2-phenyldimethylsilane with sulfurylation in an inert organic solvent, for example, MDS, ethylene dichloride (ejh) or carbon tetrachloride, at a temperature of from about 0oC to about 30oC. 4-R1-R2-R3-2-phenyldimethylsilane, in turn, are obtained by the reaction of 4-R1-R2-R3-saccharin of formula IV with halogennitroalkanes in an inert organic solvent, such as toluene, xylene, DMF, or YFC, at a temperature in devlina through reaction of galogensoderjashimi or tallic salt derived saccharin of formula IV (obtained by reaction of a derivative of saccharin with a lower alkoxide of thallium in the lower alkanol), or di-lower alkylammonium salt derived saccharin (obtained as described below) in the presence of halide Tetra-lower alkylamine, such as tetrabutylammonium bromide (BTBA); or saccharin derivative of formula VI per se in the presence of halide Tetra-lower alkylamine or saccharin derivative of formula IV per se in the presence of halide Tetra-lower-alkylamine and lower alkoxide of an alkali metal, such as t-piperonyl potassium.

Sacharine formula IV can also be converted into chlorotriazine formula VI where X is chlorine using a one-step reaction with an excess of formaldehyde or an equivalent amount of formaldehyde, such as paraformaldehyde or 1,3,5-trioxane, and CHLOROSILANES, preferably by chlorotrimethylsilane, in the presence of a Lewis acid, preferably a catalytic amount of tin chloride, in an inert solvent, preferably 1,2-dichloroethane (ethylene dichloride, ejh).

The described methods are illustrated below, with R1, R2and R3have the meanings given above, Alk is lower alkyl, X is halogen and pH is phenyl.

The compounds of formula IV can also be obtained by reaction of an alkali metal, such as lithium, optionally in the presence of a Tetra-lower-alkylamidoamines, and in an inert organic solvent, for example THF, and reaction of the obtained alkali metal salt either with sulfur dioxide at a temperature in the range from -50 to -80oC with subsequent reaction of the resulting sulfonate alkali metal with hydroxylamine-O-sulfonic acid in the presence of aqueous base, or sulfanilamide, then with ammonia. If you choose method using dioxide-hydroxylamin-O-sulfonic acid, prior to adding sulfonate alkali metal, hydroxylamine-O-sulfonic acid, it is desirable to neutralize the base, preferably one equivalent of aqueous sodium hydroxide. The obtained 2-R1-R2-R3-6-amino-sulfonyl-N, N-di-lower-alkylbenzene then heated in an acidic environment for the implementation of its cyclization to obtain di-lower-alkylammonium salt of the desired 2-R1-R2-R3-saccharin of formula IV, which can be used directly in subsequent reactions, or if necessary, can be hydrolyzed in dilute acid; and allocate the free saccharin. The cyclization is preferably carried out in glacial acetic acid at nugrowth values, defined above, and the alkali metal is lithium.

< / BR>
The compounds of formula IV, where R1is either the primary or secondary lower alkyl, which can be used as intermediates for producing compounds of formula I, described above, will receive one of the following ways.

The compounds of formula IV, where R1is a primary lower alkyl, get through the reaction of 4-methyl-R2- R3-saccharin (formula IV, where R1is CH3) with two molar equivalents of a lower-alkylate in an inert organic solvent, for example THF, and reaction of the obtained lithium salt with one molar equivalent of a lower-alkylhalides; moreover, both the reaction is carried out at a temperature in the range from about -50 to -80oC.

The compounds of formula IV, where R1is a primary lower alkyl, and R2and R3are not hydrogen, or R1is secondary lower alkyl, and R2and R3are as defined for formula I, get through the reaction of 2-primary-lower-alkyl - R2-R3-N,N-di-lower-alkylbenzene (formula VII, where R1is not the primary lower alkyl) od is slim-alkylamino lithium optionally in the presence of a Tetra-lower-alkylamidoamines, in an inert organic solvent, for example THF, and reaction of the obtained lithium salt with one molar equivalent of a lower alkylamine at a temperature in the range from about -50 to -80oC. the Obtained 2-primary or secondary lower alkyl-R2-R3-N,N-di-lower alkyl-benzamide then converted into the compounds of formula IV, where R1is primary or secondary lower alkyl, through the same sequence of reactions described above, i.e. by reaction of the 2-primary or secondary-lower-alkyl-R2-R3- N,N-di-lower alkylbenzene with one molar equivalent of a lower alkylate; reaction of the obtained lithium salt either with sulfur dioxide and then with hydroxylamine-O-sulfonic acid in the presence of base, or with sulfanilamides, and then with ammonia; and cyclization of the target 4-primary or secondary-lower-alkyl-R2-R3- saccharin of formula IV.

If the original material is 2-lower alkyl-R2-R3-N,N-lower-alkylbenzene, 2-lower alkyl group is stands, after alkylation receive connections 2-lower alkyl group is either straight or ruleno chain. On the other hand, if the original material is 2-lower alkyl group contains more than one carbon atom, the alkylation occurs on the carbon atom adjacent to the benzene ring, and gives products with secondary lower alkyl group in the 2-position.

A preferred method of preparing compounds IV, where R1is n-lower alkyl, and R2and R3are hydrogen, includes a reaction block benzyl protons of the starting material VII trialkylsilyl group that allows you to enter the lithium in the 6-position, and to obtain the sulfonamide described above. This method (where R11-CH2is n-lower alkyl) is illustrated below.

< / BR>
2-n-lower-alkylbenzene are solirovanie with the formation of the benzyl anion, using alkylate or preferably dialkylamide lithium (DAL), in an inert solvent, preferably THF, and treated with the appropriate chlorotriethylsilane, preferably by chlorotrimethylsilane. Saccharin was synthesized as described above, and the silyl group is removed by treatment with a source of fluoride anion, preferably cesium fluoride in DMF), or a fluoride, Tetra-n-butylamine in an inert solvent.

< / BR>
If you want to get 4,5,6,7-tetrahydrofuran formula VIII, may be used with the following modification (Fig. 2).

5-chloro-2-benzyl-2H-isothiazol-3-one 1-oxide can be oxidized with a suitable oxidizing agent, preferably hydrogen peroxide in acetic acid, to obtain 1,1-dioxide, which is then subjected to reaction under typical conditions Diels Alder with the corresponding diene and reduced to obtain 2-benzylhydroxylamine, which is then subjected to hydrogenolysis as described above, obtaining tetrahydrofuran VIII, which in turn can be converted into an intermediate compound, 2-halogenmethyl derived, by the way, described above to obtain compound VI from compound IV.

Alternatively, the compounds of formula I, where R1is lower alkyl or phenyl, and R2and R3are hydrogen, can be synthesized from 2-cyclohexenone (Fig.3)

2-Cyclohexene subjected to reaction with cuprate (R1)2

4,5,6,7-tetrahydrofurane, which are the starting materials for preparing compounds of formula II, where R6represents hydrogen, synthesized in a manner analogous to the previous method (Fig. 4).

3-lower alkyl-2-cyclohexene subjected to reaction with an appropriate di(lower alkyl)litecure in ethereal solvent, preferably in diethylether, -50 +20oC, preferably at about 0oC, and the resulting adduct is treated in situ medicinetramadol and hexamethylphosphoramide. Thus obtained 6,6-di-(lower alkyl)-2-oxocyclohexyl carboxylate is subjected to reaction with benzylmercaptan, as described above, and a mixture of 2-(benzylthio)cyclohexanecarbonyl chlorosulfonated esters, which is then treated with ammonia, as described above, and receive targeted 4,4-di(lower alkyl)-4,5,6,7-tetrahydrofuran VIIIA, which can then be converted in the intermediate 2-halogenmethyl derived as described earlier.

It should be noted that the above-described each of the transformations saccharin IV 2-halogenoalkanes VI may be equally applicable to the conversion of tetrahydrocanabinol VIII and VIIIA in the corresponding 2-galactocerebroside.

Phosphonates, phosphates and phosphinic acid of the formula III belong to a well-known class of phosphorus compounds. These classes of phosphorus compounds, and methods for their preparation are dedicated many works, for example, M. Regitz, Organische Phospoh Acidic I and II, Hauben-Weyl, Methods Der Organischen Chemie, Vilrte Edition, Erweiterungs-Und-Folge-Bande, Bande E1 and E2, Georg Fhieme Verlag, Stuttgart-new York, 1982; Robert Engel, Ph. D. Synthesis of Carlon-Phosphorus Bonds, CRC Press, Inc. Boca Raton, Florida, 1988; J. Jankowska and other Synthesis (1984); 408; K. Nagasawa, Chem. and Pharm. Bull. 7, 397 (1959); and J. G. Moffatt and others, J. Am. Chem. 79, 1194 (1957).

For changes of functional groups in the compounds of the invention can be used simple chemical transformations which are conventional and well known in the art. For example, can be made the connection; oxidation of sulfides or sulfoxidov with obtaining relevant sulfoxidov or sulfones; saponification of esters to the corresponding carboxylic acids; catalytic dibenzylamine phenolic ethers, benzylamino or benzylphosphonic the corresponding phenols, dibenzylamine amines and dibenzylamine phosphate; or the reaction of phenol with an alkylating agent in the presence of a base or an alcohol in the presence of a binding agent to obtain the desired ethers.

Standard procedures of biological tests, which were subjected to the characteristic compounds of the invention have shown that these compounds have activity of inhibiting the leukocyte elastase human, and therefore can be used for the treatment of degenerative disorders, such as emphysema, rheumatoid arthritis, pancreatitis, fibreboard cystic fibrosis, chronic bronchitis, respiratory distress syndrome in adults, inflammatory bowel disease, psoriasis, disease and deficiency of inhibitor-trypsin 1.

Compounds of the invention having the basic functions can be transformed into additive acid salt through reaction of the base with the acid is this cold salt of a weak aqueous base, for example, such as a carbonate of an alkali metal and a bicarbonate of an alkali metal. Thus obtained, the base can then be subjected to interaction with the same or a different acid to obtain the same or a different acid additive salt. Thus, the bases and their acid additive salts are easily vzaimoprevrascheny.

Similarly, the compounds of the invention having acid functions (i.e., carboxylic acid and phosphate), can be converted into their salt form by reaction of the acid or phosphate with a base, such as hydroxides of alkali metal or ammonium, or organic bases, such as alkyl-, dialkyl - or trialkylamine, and Vice versa, acids and phosphates can be obtained from their salts by treatment of the salts aqueous acids.

Compounds of the invention and their salts have inherent pharmacological activity, the type of which will be more fully described below. This specific activity can be used for pharmaceutical purposes through the use of free bases or free acids of these compounds, or salts formed from their pharmaceutically acceptable acids and bases (that esvny doses such that the predominant properties inherent in the basic structural molecule, presents a free base or free acid are not subjected to the adverse effects side effects attributed to the anions or cations.

In case of using this pharmacological activity of the salt, it is obvious that it is preferable to use pharmaceutically acceptable salts. Although the insolubility in water, high toxicity, or lack of crystalline properties can make some specific types of salts unacceptable or less desirable for use in this pharmaceutical composition, however, these water-insoluble or toxic salts can be converted into their corresponding pharmaceutically acceptable bases by decomposition of these salts with aqueous base or aqueous acid as described above; or, alternatively, they can be converted to any desired pharmaceutically acceptable salt by double decomposition reaction using anion or cation, for example, by using ion-exchange procedures.

In addition, regardless of their pharmaceutical value, these salts can be used as kharakterizujuschie in the procedures for isolation or purification. Like all salts, these derivatives salts used for characterization or purification may be, if necessary, used to restore the pharmaceutically acceptable free bases or free acids via reaction of the salts with aqueous base or aqueous acid, or, alternatively, they can be turned into any pharmaceutically acceptable salt, for example, by using ion-exchange reactions.

A new distinctive feature of the compounds of the invention, in this case, is the idea of getting free bases and acids, as well as cationic and anionic forms of these compounds with basic and/or acidic functions, and not any particular acid or base or anion of the acid or base cation associated with the salt forms of the compounds; rather, we can say that the acidic or basic parts, anions or cations, which can be associated with the salt forms are in themselves neither new nor critical, and therefore, they can be any of the acid anions or cations of bases capable of forming salts with bases or acids.

Compounds of the invention can be obtained dlli capsules for oral administration, containing the active compound either in pure form or combined with suitable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, Arabic gum, etc. in Addition, the compound of the present invention can be used as drugs for oral and parenteral administration, or for aerosol inhalation, which may be made in the form of aqueous solutions of water-soluble salts of the compounds of the present invention or in the form of aqueous solutions of alcohols, glycols or oily solutions, or emulsions of the type oil-water containing these compounds; and, these drugs can be manufactured using traditional techniques obtain drugs.

The percentage of active ingredient in these preparations may vary in accordance with the dose that must be obtained. The dose necessary for introduction to a patient will depend on the clinical assessment that includes the following factors: mode of administration, duration of treatment, the physical data and the patient's condition, the reactivity of the active component and the susceptibility of the patient to this drug streetmachine all of these factors and use of best clinical evaluation from the point of view of the interests of the patient.

The molecular structure of the compounds of the invention were established on the basis of study of their infrared and NMR spectra. These patterns were confirmed by the calculated and found values for the elementary analysis. All melting points are given without amendment.

Obtaining raw materials.

Preparation I. Crushed potassium hydroxide (7.4 g, 0,132 M) was mixed with dimethyl sulfoxide (DMSO) (100 ml) and the mixture was stirred for 5 minutes Then to the mixture was added 6-methylanthranilic acid (10.0 g, of 0.066 M) was added drop by drop iodomethane (4.52 ml, 0,073 M). The reaction mixture was stirred for 30 min at room temperature, then diluted with 250 ml of simple ether, washed with water (I ml), dried with magnesium sulfate and concentrated. The crude product was filtered through a pad of silica gel [with a flash grade (32 of 63)] suirable a simple mixture of ether and hexane (1:9), which was awarded to 4.23 g (39%) of methyl 6-methylanthranilate in the form of an oily substance.

Thus obtained methyl 6-methylanthranilate (to 4.23 g, 0,026 M) was dissolved in 25 ml of acetic acid and the solution was cooled to 0oC. Then was added concentrated hydrochloric acid and 45 ml and obtained a suspension of brown-defined orange solution stirred 1 h at 0oC, and then added 6 portions to a mixture of 2.18 g (0,013 M) chloride dihydrate, copper and sulfur dioxide (6.3 g) in 33 ml of acetic acid and 6 ml of water at 0oC. the Dark green solution was stirred at room temperature overnight, poured into 300 ml ice water and the separated solid was collected and dried by suction, resulting in a received 1,11 g of methyl 2-chlorosulfonyl-6-methylbenzoate, which was immediately added to 100 ml of ice-cold ammonium hydroxide and stirred at room temperature overnight. Then the solution was acidified to pH 1 with concentrated hydrochloric acid, and the precipitate was collected and dried by the air, resulting in a received 729 mg (12%) 4-methylcholine, so pl. 224 226oC.

A mixture of 1.0 g (0.005 M) 4-methylcholine, 0.33 g (0.001 M) BTBA and 1.2 g (0,0075 M) chloromethylthiazole in 25 ml of toluene was heated under reflux for about 16 h, then cooled, diluted with ethyl acetate and the solution washed with aqueous bicarbonate and water. The organic layer was drained dry and got 0.74 g of 2-phenylthiomethyl-4-methylcholine.

The resulting solution (0.74 g, of 0.002 M) was dissolved in 25 ml of YFC, and the solution, stirring, was treated drop by drop over about 2 hours with a solution of 0.47 g (0,003 M) saravali and dried, as a result, were received and 0.46 g of 2-chloromethyl-4-methylcholine in the form of a pale yellow solid.

Preparation 2. In accordance with the procedure described in preparation 1, 5.0 g (0,029 M) 6-chlorantraniliprole acid and 2.75 ml (0,044 M) iodomethane were subjected to reaction in the presence 4,08 g (0,073 M) of powdered potassium hydroxide, resulting in a received 4,22 g (78%) of methyl 6-chloroacrylate in the form of an oily substance.

4-Chlorosarin was obtained by the same method as 4-metalshark using 4,22 g (0,023 M) of methyl 6-chloroacrylate in 22 ml of acetic acid and 40 ml of concentrated hydrochloric acid and 1.68 g (0,024 M) of sodium nitrite in 7 ml of water, resulting in the obtained diazonium salt which was added to 1,93 (0,011 M) chloride dihydrate, copper and 6.5 g of sulfur dioxide in 30 ml of acetic acid and 5 ml of water. The obtained methyl 2-chloro-sulfonyl-6-chlorobenzoate was treated with 150 ml of ammonium hydroxide, as described above, resulting in received of 3.07 g (62%) 4-chlorosarin in the form of a pale yellow solid, so pl. 245-246oC.

Hydroxymethyl-4-chlorosarin was obtained by heating a solution of 1.00 g (0,0046 M) 4-chlorosarin and 3.22 ml of aqueous 37% formaldehyde solution in ethanol. All attempts to crystallize viscous melanocytoma stage without characterization.

Thus obtained crude 2-hydroxymethyl-4-chlorosarin (609 mg, 0,0025 M) was mixed with 5 ml of diethyl ether, was added 3 ml of thionyl chloride. The resulting mixture was heated until complete dissolution, then stirred overnight at room temperature, diluted with 20 ml simple ether, filtered through a layer of zeolite coated on top of the sand and suirable simple ether. The solvent was removed, resulting in a received 430 mg of crude derived chlormethyl. Part of the obtained product (225 mg) was deleted for the following reactions. The residue (205 mg) was subjected to flash chromatography on silica gel and was suirable 40% ether/pentane, resulting in received 137 mg of 2-chloromethyl-4-chlorosarin, so pl. 135-136oC.

Preparation of 3. To a suspension of 6.0 g (0.03 M) of copper iodide in 100 ml of TRF was added 25 ml of dimethyl sulfide, and the resulting yellow solution was cooled to -78oC and one drop was treated with a solution of 23 ml (0,06 M) 3.0 M solution of panelbased magnesium in diethyl ether. The obtained pale yellow-orange solution was stirred at -78oC in nitrogen atmosphere for 1 h, and then processed to 3.02 g (0.03 M) 2-cyclohexenone in 10 ml of THF. The resulting mixture was heated to 0oC for 2 h, was again cooled to -78

The compound obtained (3.0 g, of 0.013 M), 4.8 g (0,039 M) benzylmercaptan and 1.0 g of resin Amberlyst-15 (Rohm and Haas.) in chloroform was heated under reflux for 20 h, then the mixture was treated with 1.5 g of the resin was heated for another 4 hours Then the mixture was cooled to room temperature, filtered, the filtrate was dried to dryness in vacuo, the residue was pereirae with hexane, and the solid substance was collected by filtration, resulting in a received 0,85 g (19%) of a mixture of methyl 2-benzylthio-6-phenylcyclohexyl-2-ene-carboxylate and methyl 2-benzylthio-6-phenylcyclohexane-1-ene of carboxylate, 0.6 g (0,0018 M) which was heated with 2.0 g of 2,3-sodium dichloro-5,6-dicyanobenzoquinone in 25 ml of toluene was stirred in nitrogen atmosphere for 24 hours the Mixture was filtered through a layer of silica gel, elwira mixture YFC and hexane (2:1), and the eluate was dried to dryness, resultierende in 10 ml of YFC, was diluted with 20 ml of acetic acid and 5 ml of water, then the mixture was cooled to -10oC, and after this mixture was barbotirovany gaseous chlorine until then, until an exothermic reaction begins to diminish. After that, the mixture was stirred 10 min, and dried to dryness in vacuo, resulting in a received 0,41 g (85%) of methyl 2-chloro-sulfonyl-6-phenylbenzoate, which was dissolved in 10 ml THF and added to 25 ml of concentrated ammonium hydroxide solution, cooling in a bath of ice/acetone. The reaction mixture was extracted with YFC, the organic phase was discarded, and the aqueous layer was acidified to pH 1 with concentrated hydrochloric acid and was extracted with YFC. The organic extracts were washed with saline, dried and evaporated to dryness, resulting in the obtained 0.33 g (97%) 4-fenilalanina.

In accordance with the procedure described in preparation 1, 4-phenylalanin (0.33 g, 0,0012 M) were subjected to reaction with 0.3 g (0,0019 M) chlorocarbonylsulfenyl in 15 ml of toluene in the presence of 0.08 g (0,0025 M) TBAB, and the product, 2-phenylthiomethyl-6-phenylalanin (0,48 g, 100%), were treated with sulfurylchloride in YFC, which was obtained 0.36 g (95%) of 2-chloromethyl-4-fenilalanina.

Preparation 3B. To a suspension of anhydrous CuCN (2.16 g, 0.025 M) in anhydrous about the tion for 1 h at -78oC m 30 min at -45oC, the reaction mixture was again cooled to -78oC. Then the solution was added cyclohexanone (2.4 g, 0.025 M) in the simple ether (25 ml) and continued stirring for 15 min at -78oC and 30 min at -45oC. the resulting mixture was again cooled to -78oC, and added HMPA (10 ml) in a simple ether (25 ml). After 5 min was added medicinepharmacy (2.55 g, 0.03 M) in the simple ether (25 ml) and the reaction mixture was heated to 0oC for 2 h the resulting mixture was extinguished 2 N. HCl (100 ml), the layers were separated and the organic phase was washed with saturated solution of NH4Cl (g ml), water (I ml), brine (g ml) and dried (Na2SO4). The solvent was removed in vacuo and was purified by distillation Kygelrohr (bath temperature 100 115oC at 0.6 mm), which was obtained 4.7 g (88%) of methyl 2-(1,1-dimethylethyl)-cyclohexane-6-he carboxylate.

Cyclohexanone (4,6, of 0.022 M) was mixed with benzylmercaptan (2,95 g 0,024 M), acidic montmorillonite clay (7.5 g in anhydrous toluene (7.5 g). The mixture was heated under reflux in an atmosphere of nitrogen with azeotropic removal of water for 6 h, cooled to room temperature and left over night. The solids were filtered off and washed with simple ether. Objedl in vacuum, the residue was purified using flash chromatography on silica gel (10% ether in hexano), and received a mixture of 4.4 g (66%) of methyl 2-benzylthio-6-(1,1-dimethylethyl)-cyclohex-2-ene-carboxylate and 2-benzylthio-6-(1,1-dimethylethyl)cyclohex-1-EN-carboxylate, which was stirred with DDH (17.5 g, 0,077 M) in toluene (50 ml) for 16 hours the Red reaction mixture was filtered through a 15 cm layer of silica gel, elwira mixture of hexanol; YFC: simple ether (6:3:1) (1000 ml). Eluate washed with 10% NaOH solution, water, saline solution, and dried. The solvent was removed in vacuo and was purified by chromatography on silica gel (5% ether in hexano), which was obtained 1.6 g (40%) of methyl 2-benzylthio-6-(1,1-dimethylbenzoyl).

Entitiesthat (1.3 g, 0,004 M) dissolved in YFC (5 ml) was diluted with acetic acid (25 ml) and water (2 ml), the mixture was cooled to -10oC, and treated with gaseous chlorine until then, until an exothermic reaction begins to diminish. Then the mixture was stirred 10 min drained to dryness in a vacuum. The residue was purified using flash chromatography on silica gel (1:1 hexane: YFC), and was obtained 0.8 g (67% ) of methyl 2-chlorosulfonyl-6-(1,1-dimethylethyl)benzoate, which was dissolved in THF (5 ml) was added to a solution of concentrated hydroxy the reaction mixture was concentrated in vacuo and acidified to pH 2 N. HCl. Separated solids were collected by filtration and was led from simple ether, resulting in received 0, 64 g (95%) of 4-(1,1-dimethylethyl)-saccharin, so pl. 185-187oC.

4-(1,1-dimethylethyl)saccharin (0.025 g, 1.0 mm) was mixed with chloromethylthiazole (0.25 g, 1.5 mm) and tetrabutylammonium ammonium (0.2 g, 0.6 mm) in toluene (25 ml) and was heated under reflux in nitrogen atmosphere for 16 hours the mixture was cooled to room temperature, evaporated to dryness and purified via chromatography on silica gel (80%) YFC in hexane, which was obtained 0.35 g (98%) 2-phenylthiomethyl-4-(1,1-dimethylethyl)saccharin, who were treated with sulfurylchloride (0.25 g, 1.8 mm) in YFC and was obtained 0.21 g (75%) 2-chloromethyl-4-(1,1-dimethylethyl)saccharin.

Preparation 4. The mixture 3,22 g (0,012 M) 4-bromoaniline [Japanese Pat. Desclosure 58/79, 0,34: C. A. 100, 7773 W (1984)] 1.63 g (0,015 M) t-butoxide potassium 0.39 g (0,0012 M) TBAB and 3.0 ml (0,022 M) chloromethylthiazole in 100 ml of toluene was heated under reflux in nitrogen atmosphere for 8 h and then stirred at room temperature for about 16 hours, the Reaction mixture was diluted with ethyl acetate, the organic layer was washed with water, dilute potassium carbonate and brine, drained sulfate mage is Tate which received 3,86 g (84%) 4-bromo-2-phenyldimethylsilane, so pl. of 174.5-178oC.

To the obtained solution of 3.27 g, 0,0085 M) in 85 ml of YFC was added drop by drop under stirring, of 1.02 ml (0,0127 M) sulfurylchloride. This mixture was stirred at room temperature for one and a half hours, concentrated in vacuo and the residue was pereirae with hexane, resulting in received 2,61 g crude product, which was recrystallize from toluene-hexane, and received 2.24 g (85%) 2-chloromethyl-4-bromoaniline, so pl. 157-159oC.

Preparation 5. To a solution of 8.0 ml (0,053 M) of tetramethylethylenediamine (TMEDA) in 350 ml of THF at -70oC was added 42 ml (0,055 M), 1.3 M solution of sec-utility in cyclohexane and the mixture was stirred for 15 minutes To this solution was added drop by drop under stirring solution 10,36 g (0,050 M) 2-methoxy-N,N-diethylbenzamide in 150 ml of THF, maintaining at this temperature at 60oC or below. After stirring for 20 min, the reaction mixture was barbotirovany sulfur dioxide, while maintaining the reaction temperature below -50oC, until then, until the reaction mixture will not give an acid reaction when wetted with litmus paper. This mixture was stirred at room temperature for 2 h, diluted with 450 ml of hexane, and the selected solid material was collected, restoratin-O-sulfonic acid. Selected white solid was collected and dried, resulting in received? 7.04 baby mortality g (49%) 2-aminosulfonyl-6-methoxy-N, N-diethylbenzamide, so pl. 190-194,5oC.

A mixture of the obtained product (4.3 g, of 0.015 M) in 75 ml of dioxane and 25 ml of concentrated hydrochloric acid was heated on a steam bath for 70 hours, then cooled, concentrated in vacuo, diluted with water and ice, and the mixture was made strongly basic with concentrated sodium hydroxide. After that, the mixture was washed YFC, the aqueous layer was acidified with diluted hydrochloric acid and was extracted with YFC. The extracts were dried with magnesium sulfate and dried to dryness, resulting in a received 1.29 g (40%) 4-methoxycoumarin. An alternative and preferred procedure for cyclization of 2-aminosulfonyl-6-methoxy-N, N-diethylbenzamide 4-methoxycoumarin with 65% yield was carried out by heating in glacial acetic acid for 6,5 hours

Repeating the procedure described in preparation 4 (see above), 1,14 g (0,0053 M) 4-methoxycoumarin was subjected to reaction with 1.31 ml (0,0097 M) chloromethylthiazole in toluene in the presence 0,72 g (0,0064 M) t-butoxide potassium and 174 mg (0,00054 M) of tetrabutylammonium bromide, and got to 1.23 g (69% ) 4-methoxy-2-phenyldimethylsilane, so is DH, and received 282 mg (36%) 2-chloromethyl-4-methoxycoumarin, so pl. 169-174oC.

Preparation of 6A. To a solution 4,74 ml (0,031 M) of tetramethylethylenediamine in 300 ml of THF (which to use was passed through alumina) was added 5.8 g (0.03 M) 2-ethyl-N,N-diethylbenzamide. This solution was cooled to -78oC and treated with a solution 34,9 ml (0,031 M) 0.9 M solution in-utility in cyclohexane. After adding the above solution, and the mixture was stirred 20 min and then was treated with a solution of 3.2 ml (0.04 M) of ethyliodide, while maintaining the temperature at -78oC. Then the temperature was raised to room temperature, the mixture was stirred for about 16 h and poured into water. The obtained oily product was separated and was chromatographically on silica gel, elwira a mixture of 10% ethyl acetate and hexane, resulting in received 2.86 g (43%) 2-sec-butyl-N,N-diethylbenzamide in the form of a yellow oily product.

In accordance with the procedure described in preparation 5 (see above), 2-sec-butyl-N, N-diethylbenzamide (10,45 g 0,045 M) dissolved in 70 ml of THF, was added to a solution of 39.2 ml (0,047 M) 1.2 M solution of sec-utility in cyclohexane and 7.1 ml (0,047 M) tetramethylaniline in 250 ml of THF, maintaining the temperature at -78oC. After the addition, the mixture is PE is atoi temperature. After that, the mixture was dried to dryness in vacuo, and the residue was dissolved in water and, stirring, was added to a cold solution of 15.2 g (0,134 m) of hydroxylamine-O-sulfonic acid and 15.4 ml (0,134 M) 35% sodium hydroxide, and received a 10.1 g (72%) 2-aminosulfonyl-6-sec-butyl-N,N-diethylbenzamide.

The compound obtained (6,83 g 0.22 M) was dissolved in 100 ml of glacial acetic acid, and the solution was heated under reflux for 13 h, and then dried to dryness. The residue was pereirae with diethyl ether, and collected by filtration, which was obtained 5.7 g (83%) diethylammonium salt 4-second-Boticaria.

The compound obtained (3.0 g, 0,0096 M) were subjected to reaction with 1.13 ml (0,012 M) chloromethylthiazole in toluene, resulting in a received 3,47 g (100%) 2-phenylthiomethyl-4-second-Boticaria.

The obtained relation (3.2 g, 0,0097 M) were subjected to reaction with 2.3 ml (0,029 M) sulfurylchloride in 20 ml of YFC and received 2.4 g (87%) 2-chloromethyl-4-second-Boticaria.

Preparation of 6B. 2 using a procedure similar to that described in preparation 6A, and 9.2 g (32,9 mm) of 3,4-dimethoxy-2-propyl-N,N-diethylbenzamide was subjected to reaction with sulfur dioxide and 5.6 g (49,4 mm) of hydroxylamine-O-sulfonic acid, and was received with 7.4 g (63%) of 2-aminosweet the om and phenyldimethylsilane with the use of 1.42 ml (15 mm) chloromethanesulfonyl, and received 4,07 g of 5,6-dimethoxy-2-phenylthio-4-propylalanine. 3,59 g (8.8 mm) phenylthiourea was subjected to reaction with a 2.12 ml (36,4 mm) sulfurylchloride and received 2,84 g (97%) 2-chloromethyl-5,6-dimethoxy-4-propylalanine.

3,4-dimethoxy-2-propyl-N, N-diethylbenzamide were obtained using the following procedure:

To a solution of 0,216 M n-utility in 250 ml of simple ether at room temperature was added drop by drop 138,2 g (0,216 M) veratrole in 100 ml of simple ether and 32.6 ml (0,216 M) TMEDA. The reaction mixture was stirred at room temperature for 14 h and 21.9 ml (0,225 M) n-propyl for 1 h at room temperature and treated with an aqueous solution of 1 N. HCl, resulting in a received 14 g (36% ) of 2,3-dimethoxy-benzodiapine that bromisovali using 14,52 g (81,6 mm) N-bromosuccinimide 36 g Kieselgel in 400 ml of CCl4in accordance with the method Hisatoshi and others [Bull. Chem. Soc. Jap 32, 591-593 (1989)] which was received at 19.6 g (98%) of 6-bromo-2,3-dimethoxybenzamide.

Bromobenzoyl (14.2 g, 54,8 mm) was dissolved in 200 ml of simple ether was cooled to -78oC, and added to 25.2 ml (63 mm) 2.5 N n-utility in hexane. The reaction mixture was heated to 0oC, was kept for 1 h, cooled to -70oC and was added 9 ml (71,2 mm) diethylcarbamazine. React was led from hexane, and got 9.5 g (62%) of 3,4-dimethoxy-2 - propyl-N,N-diethylbenzamide, so pl. 65-67oC.

Preparation 6C. In accordance with the procedure described in preparation 6B, of 10.75 g (30 mm) 2-aminosulfonyl-4,5-dimethoxy-6 - isopropyl-N,N-diethylbenzamide was cyclically, and got to 6.43 g of 5,6-dimethoxy-4-isopropylaniline (so pl. 186-188oC simple ether-hexane), 5 g (17.5 mm) which was subjected to phenyldimethylsilane using 2,48 ml (26,3 mm) phenyldimethylsilane in accordance with the procedure described in the getting 5, and chlorination of 3 equivalents of sulfurylchloride obtaining 2-chloromethyl-5,6-dimethoxy-4 - isopropylaniline, exit 85% so pl. 117-119oC after crystallization and ethyl acetate-hexane.

Required benzamide was obtained from 2,3-dimethoxy- --methylbenzoate by the synthesized with subsequent carbamylcholine, as described in the preparation of 6B, resulting in a received intermediate compound 3,4-dimethoxy-2-isopropyl-N, N-diethylbenzamide. A solution of 66 ml of 0.96 M Deut-utility added to 16,1 g (57,6 mm) benzamide 400 THF at -78oC in nitrogen atmosphere. After stirring for 1 h, the orange anion was Coulibaly in excess of sulfur dioxide at -60oC. the Reaction was brought to room temperature is nnow the mixture evaporated. Sulphonylchloride was extracted in EtOAc-simple ether, washed with water, dried and evaporated. The residue was dissolved in 80 ml of THF, was added 17 ml conc. NH4OH at 0oC. the Reaction mixture was rapidly stirred at room temperature, evaporated, and pereirae simple ether-hexane (2:1), resulting in a received 12,89 g (62%) 2-aminosulfonyl-4,5-dimethoxy-6-isopropyl-N, N-diethylbenzamide, so pl. 138-140oC. 2 Preparation 7. To a solution of 9.3 ml (0,058 M) of tetramethylethylenediamine in 340 ml of THF at -78oC was added 52 ml (1.1 M) solution (0,067 M) Deut-utility in cyclohexane. Then this solution was treated with a solution 11,37 g (0,052 M) 2-propyl-N,N-diethylbenzamide in 75 ml of THF at -78oC, and the resulting solution was stirred 15 min, and then treated with a solution of 8.3 ml (0.104 g M) ethyliodide in THF. After this solution was stirred for 1.5 h at -78oC, and then extinguished by adding one drop of a saturated ammonium chloride at -78oC. the resulting mixture was heated to room temperature, diluted with diethyl ether, then washed with diluted hydrochloric acid, water, saturated sodium bicarbonate, and brine, and then dried to dryness, resulting in a received 12,91 g crude product which p is l)-N,N-diethylbenzamide in the form of a yellow oily substance.

In accordance with the procedure described in preparation 5 (see above), 2-(3-pentyl)-N, N-diethylbenzamide (3,05 g, 0,0115 M) in THF was subjected to reaction with 10.5 ml (0,126 M) 1.2 M solution of sec-utility in cyclohexane in the presence of 2.1 ml of 0.014 M) tetramethylaniline. Then the obtained lithium salt was subjected to reaction at first with sulfur dioxide and then with hydroxylamine-O-sulfonate sodium, resulting in received of 1.97 g (52%) of 2-aminosulfonyl-6-(3-pentyl)-N, N-diethylbenzamide in the form of pale yellow crystals, so pl. 118-120oC (softening at 102oC), 1.84 g (0,0056 M) which was cyclically in 22 ml of glacial acetic acid, at reflux, resulting in a received 1.28 g (70% ) diethylammonium salt of 4-(3-zentel)saccharin, so pl. 107,5-109,5oC.

The compound obtained 0,0037 M was subjected to reaction from 0.74 ml (0,0055 M) chloromethylthiazole in the presence of 166 mg (0,0004 M) BTBA in 45 ml of toluene, and received of 1.93 g of 2-phenylthiomethyl-4-(3-pentyl)saccharin as a pale yellow oily substance, of 1.93 g (0,0037 M) which was subjected to reaction with a 0.59 ml (0,0073 M) sulfurylchloride in 37 ml of YFC, which was obtained 1.2 g of 2-chloromethyl-4-(3-pentyl)saccharin as a pale yellow oily substance.

Preparation 8. A solution of 50.0 g (0.27 M) is, then cooled and the excess thionyl chloride drove away. The obtained 2,4-dimethoxybenzoate was dissolved in 150 ml of YFC and the resulting solution was treated with a solution of 68 ml (48 g, 0.66 M) diethylamine 500 ml YFC, and then was cooled to 0oC. After complete addition, the mixture was stirred for 15 h at room temperature, then washed with saturated sodium bicarbonate, water, brine and was dried to dryness and the residue person to distil under vacuum, resulting in a received 44,78 g (69%) of 2,4-dimethoxy-N,N-diethylbenzamide, so Kip. 155-163 C/0,4 mm

In accordance with the procedure described above in preparation 5, 10.0 g (0,042 M) product in 250 ml of THF was subjected to reaction with 40,57 ml of a 1.1 M solution (0,044 M) Deut-utility in cyclohexane and 6.35 ml (0,042 M) of tetramethylethylenediamine in THF. The obtained lithium salt was first subjected to reaction with approximately 40 ml of sulfur dioxide and then with an aqueous solution of 0.13 m) of hydroxylamine-O-sulfonate sodium, resulting in received compared to 8.26 g of 2-aminosulfonyl-4,6-dimethoxy-N,N-diethylbenzamide, 7.0 g (0,022 M) which was cyclically in 80 ml of glacial acetic acid, heated under reflux, resulting in a received 6.6 g (94%) diethylammonium salt of 4,6-dimethoxyaniline, which was used as talvacchia with 3,82 ml (0,028 M) chloromethylthiazole in the presence 0,611 g (0,0019 M) BTBA in 200 ml of toluene, the result that was obtained 6.2 g (89%) 2-phenylthiomethyl-4,6-dimethoxyaniline, of 5.82 g (0,016 M), which was subjected to reaction 3.23 grams (0,0019 M) sulfurylchloride in 100 ml of YFC, and received 4,63 g (100%) 2-chloromethyl-4,6-dimethoxyaniline, so pl. 185-187oC.

Preparation of 9A-9C. In accordance with the procedure described above in preparation 5, replacing used in this procedure, 2-methoxy-N,N-diethylbenzamide the corresponding 2-R1-R2-R3- substituted-N,N-diethylbenzamide, resulting in the use of intermediate compounds, 2-phenyldimethylsilane, received 4-R1-R2-R3-2-halogenopyrimidines presented in table A, where in each case R3is hydrogen. In the specified table for each 2-unsubstituted saccharides, 2-phenylthiomethyl-sharenow and 2-chloromethyloxirane are, wherever possible, the melting temperature (198>C), the solvent for the recrystallization and output in the columns entitled "so pl. /rest." and "Exit". In all cases, intermediate compounds, namely 2-phenyldimethylsilane were used directly in the next stage without further characterization or purification.

Preparation 10. In accordance with the procedure described is 2-hydroxymitragynine. The compound obtained (25 g, 0,117 M) were subjected to reaction from 63.3 g (0,234 M) tribromide phosphorus in diethylether, resulting received 29,8 g (92%) 2-bromoethylamine, so pl. 155 157oC.

Preparation 11. To a solution of 4 g (0,0175 M) 6-nitrosourea in 240 ml of ethanol, was added 4.4 g (0,175 M) ethoxide thallium, and the resulting mixture was left at room temperature for 1 h, then cooled to about 16 hours and the resulting solid is collected and dried, resulting in a received 7.6 g (100%) tallic salt of 6-nitrosourea. The resulting product is suspended in 50 ml of DMF, and the mixture was processed 3,07 grams (0,0194 M) chlorocarbonylsulfenyl, and then the mixture was heated at about 63oC for 5 h and left at room temperature for about 16 hours, after which it was poured into ice-cold water. The crude product obtained by filtration, stirred in YFC and filtered to remove tallic salt. This filtrate was removed of the solvent, and the resulting pale yellow solid was treated with ultrasound using the heat of ethanol, and again collected and dried, resulting in a received 4.6 g (75%) of 6-nitro-2-phenyldimethylsilane, so pl. 161-163oC. the compound Obtained was subjected to reaction with sulfurylchloride in YFC, rosamarina.

Preparation 12. A solution of 49.8 g (0,199 M) 2-hydroxy-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoic acid in 200 ml of methanol was heated to 50oC and then was treated with one drop of approximately 80 g of sulfuric acid, at least to maintain the reaction at a temperature of distillation. Then this reaction mixture was heated under reflux for another 11 hours, after which it was cooled and distributed between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, and drained dry, resulting in received 48.6 g (92%) of methyl 2-hydroxy-5-(1,1,3,3-TETRAMETHYLBUTYL)-benzoate.

The compound obtained, dissolved in 250 ml of DMF, was treated first of 40.4 g (0,36 M) of 1,4-diazabicyclo[2,2,2]-octane, and then of 33.4 grams (0,27 M) N, N-dimethylthiocarbamate in 100 ml of DMF. This reaction mixture was heated at 45oC for about 8 h, cooled, poured into ice-cold water, concentrated hydrochloric acid, and then extracted with ethyl acetate. The combined organic extracts were washed with diluted hydrochloric acid, sodium bicarbonate, and then brine, and then dried to dryness and received 48,2 g (76%) of methyl 2-(N,N-dimethylthiocarbamate)-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoate, kouya a mixture of ethyl acetate and toluene (1:9), the result that was obtained 3.6 g (14%) of methyl 2-(N,N-dimethylcarbamate)-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoate.

A solution of the obtained compound (0,025 M) in 40 ml of YFC processed, stirring, 80 m glacial acetic acid, and then adding 16 ml of water. The reaction mixture was cooled to 0oC, and after the reaction mixture was barbotirovany chlorine for approximately 5 minutes while maintaining the temperature between 5 and 24oC. the Reaction mixture was stirred for another 30 min, concentrated in vacuo and the remaining solution was poured into ice-cold water. After extraction of the mixture with ethyl acetate and extraction of product from the combined organic extracts was obtained 6.8 g (78%) of methyl 2-chlorosulfonyl-5-(1,1,3,3-TETRAMETHYLBUTYL)-benzoate.

The product obtained 9.0 g (0,026 M) was dissolved in THF and added to 100 ml of concentrated ammonium hydroxide with cooling in an ice bath. The resulting solution was stirred for about 16 hours, then concentrated in vacuo, and the concentrated solution was acidified to pH 3 with concentrated hydrochloric acid. The resulting mixture was stirred for several hours, and the separated solid was collected, washed with water and dried, resulting in a received 9.0 g of 5-(1,1,3,3-TETRAMETHYLBUTYL)saccharin, etc. 213 215oC.

Preparation 13. In accordance with the procedure described above in preparation 12, 15.5 g (0,086 M) ethyl 2-hydroxy-6-methylbenzoate was subjected to reaction with 15.9 g (0,129 M) N,N-dimethylthiocarbamate in the presence of 19.3 g (0,172 M) of 1,4-diazabicyclo [2,2,2]octane in DMF, and received 22.1 g (96%) of ethyl 2-(N,N-dimethylthiocarbamate)-6-methyl-benzoate, which was heated at 220oC about 10 o'clock the Obtained product was purified by chromatography on silica gel in YFC, resulting in the obtained ethyl 2-(N,N-dimethylcarbamate)-6-methylbenzoate in the form of a red-brown oily substance.

A solution of the obtained compound (22,6 g, 0,0844 M) in 170 ml of YFC processed 340 m glacial acetic acid and 68 ml of water, cooling in a bath of ice and acetone, and after the reaction mixture was barbotirovany chlorine for 10 to 15 minutes Of the reaction vessel was removed excess chlorine and YFC, and the mixture was poured into water and distributed between YFC and water. The organic layer vtorogo was subjected to reaction with concentrated ammonium hydroxide in THF, and got to 6.1 g (67%) 4-methylcholine.

In accordance with the procedure described in preparation 11, the resulting product (10.1 g, 0,0512 M) was turned into a lithium salt through reaction with 12.8 g (0,0512 M) ethoxide thallium in ethanol and the resulting tallic salt was subjected to reaction with 6.7 g (0,0427 M) chloromethylthiazole in DMF, resulting in received 6.85 g (50%) 2-phenylthiomethyl-4-methylcholine.

The obtained compound (6.7 g 0,021 M) were subjected to reaction with sulfurylchloride in YFC, and obtained 4.9 g (95%) 2-chloromethyl-4-methylcholine.

Preparation of 14A. A mixture of 75 g (0,36 M), 3,3-dithiobisnitrobenzoic acid, 102 ml of thionyl chloride and a catalytic amount of pyridine was stirred for about 24 h and then evaporated to dryness in a vacuum. The residue was treated using YFC and again evaporated to dryness to remove residual thionyl chloride and anhydride, resulting in the received 87 g (98%) of the corresponding bis-acid chloride, with 44.8 g (0,18 M) which was dissolved in THF and added drop by drop to the solution 77,16 g (0,72 M) benzylamine in THF. The resulting mixture was stirred 2 h at 40 45oC, cooled, and the precipitated solid was collected, washed with water and dried, resulting in a received 59 g (84%) 3,3 dithiobisnitrobenzoic acid N,N'-Deeb is 6 M) sulfurylchloride in YFC and received a mixture of 2-benzyl-2H-isothiazol-3-one and 5-chloro-2-benzyl-22-isothiazol-3-one, which are separated from each other, mainly with the use of ultrasound in YFC (which was solubilizers, for the most part, the first connection). Undissolved material was collected by filtration and was chromatographically on silica gel using YFC. Thus obtained 5-chloro-2-benzyl-2H-isothiazol-3-one, so pl. 58 68oC.

A solution of 10 g (0,044 M) the compounds obtained in YFC was cooled to 0oC and the solution was treated with 7.6 (0,044 M) 3-chloroperbenzoic acid, the resulting mixture was stirred 10 minutes and then was treated with the second part of 7.6 g perbenzoic acid. Then this reaction mixture was filtered, the filter washed YFC, the filtrate was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, and then drained to dryness, then the residue was chromatographically in YFC on silica gel and the product was suirable with a mixture of hexane and YFC (50:50), resulting in a received 7,15 g (46%) of 5-chloro-2-benzyl-2H-isothiazol-3-one-oxide.

A solution of 1.1 g (0,045 M) of the obtained compound in 8 ml of benzene was treated with 0.55 g (0,0051 M) 2-methoxyfuran, was heated in a pressure vessel at 70oC for one and a half hours, and then cooled and the resulting solid was collected, washed SUP>oC.

A mixture of the obtained product (1.85 g, 0,006 M), 2,48 g (0,018 M) of potassium carbonate and 1.70 g (0,012 M) under the conditions in acetone was heated under reflux for 1.5 h, then cooled and poured into water. Selected solid substance was collected by filtration, washed with water, and dried, resulting in a received 1.70 g (89%) of 2-benzyl-4,7-dimethoxybenzoate-3-one-1-oxide, 1.13 g (0,0035 M) which was oxidisable of 1.20 grams (0,007 M) 3-chloroperbenzoic acid in YFC using the procedure described above, and received of 1.03 g (88%) of 2-benzyl-4,7-dimethoxycoumarin.

The mixture 2,07 g (0,0062 M) obtained yield of 1.37 g (0,02 M) format ammonium and 1.5 g of 10% palladium charcoal in 80 ml of methanol was heated under reflux for 1 h, then cooled and filtered, and the filtrate was dried to dryness, and received 0,92 g (57%) ammonium salt of 4,7-dimethoxycoumarin.

A solution of 1.11 g (0,0042 M) ammonium salt was dissolved in DMF, was added to 0.67 g (0,0042 M) chloromethylbenzene, and then was heated under reflux for 8 h, cooled, and poured into ice-cold water. The selected solid is collected, washed with water and dried, resulting in a received 0.50 g (33%) 2-phenylthiomethyl-4,7-dimethoxycoumarin.

Police in preparation 4, resulting received 0,22 g (58%) 2-chloromethyl-4,7-dimethoxycoumarin.

Cooking 14B and 14C.

In accordance with the procedure described in the preparation of 14A, other derivatives of 2-chloromethyloxirane received as follows:

Preparation 14B. 5.8 g (0,024 M) 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide was subjected to reaction from 3.76 g (0,0335 M) 2-toxiferine, and received 3,05 g (40%) of 2-benzyl-4-ethoxy-7-hydroxybenzotriazole-3-one-1-oxide, 5.7 g of which was subjected to reaction with 3.6 g (0,0197 M) 2-(2-methoxyethoxy)ethylbromide in the presence of 4.95 g (0,0358 M) potassium carbonate in 125 ml of ketone and 25 ml of DMF, which was obtained 7.0 g (93%) of 2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy] benzisothiazol-3-one 1-oxide, which was oxidisable, as described previously, using 3-chloroperbenzoic acid in YFC, and obtained 2-benzyl-4-ethoxy-7(2-(2-methoxyethoxy)ethoxy]saccharin. 6.6 g (0,015 M) of the obtained compound was dibenzylamine 3,34 g (0,053 M) format ammonium in the presence of 6.4 g of 10% palladium charcoal in methanol, and was obtained ammonium salt of 4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy] saccharin, which was subjected to the reaction of 2.38 g (0,015 M) chloromethylthiazole in 100 ml of DMF, resulting in received of 1.46 g (21%) 2-phenylthiomethyl-4-ethoxy-[2-(2-methoxyethoxy)etocrylene in YFC, and got to 1.16 g of 100% 2-chloromethyl-4-ethoxy-7-[2-(2-methoxyethoxy)-ethoxy]saccharin.

Preparation of 14C. 3.03 g (0.01 M) 2-benzyl-7-hydroxy-4-methoxybenzothiazole-3-one-1-oxide preparation of 14A was subjected to reaction with a 2.01 g (0,011 M) 2-(2-methoxyethoxy)ethylbromide in methyl ethyl ketone in the presence of 2 g (0,015 M) of potassium carbonate, and received 2.58 g (64%) of 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy] benzisothiazol-3-one-1-oxide, which was oxidisable using 1.1 g (0,0063 M) 3-chloroperbenzoic acid in YFC, and obtained 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy] saccharin. 0.25 g (0,0006 M) of the obtained product was dibenzylamine with the use of 0.13 g (0,0021 M) format ammonium in methanol in the presence of 0.25 g of 10% pallidipennis coal, which was obtained 0.21 g (100%) of the ammonium salt of 4-methoxy-7-[2-(methoxyethoxy)-ethoxycoumarin. 1.4 g (0,004 M) ammonium salt was subjected to reaction from 0.63 g (0,004 M) chloromethylthiazole in DMF, and received 2-phenylthiomethyl-4-methoxy-7-[2-(2-methoxy-ethoxy)ethoxy] saccharin, which was subjected to reaction with sulfurylchloride in YFC resulting received of 0.53 g (35%) 2-chloromethyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.

Preparation 15. A solution of 1.89 g (0,011 M) diethylaminoacetate sulfur (DATS) in 20 ml of YFC was added to WM the ptx2">

This reaction mixture was stirred at -78oC for 1 h the temperature was slowly brought to room temperature and the resulting mixture was stirred 16 h and then poured into ice-cold water. The organic layer was separated and washed with water, dried with magnesium sulfate and drained dry, the result was obtained 2.2 g of product which was recrystallize from ethyl acetate, which was obtained 1.6 g (74%) 2-foramerican, so pl. 96-98oC.

Preparation of 16A. To a solution of 0.5 g (0,0025 M) 4-methylcholine in THF, cooled to -78oC in a dry bath of ice and acetone, was added drop by drop, was stirred, a solution of 5.2 ml of a 1.3 M solution of sec-butyl lithium in cyclohexane. The resulting mixture was stirred for another 1 h at -78oC and then was treated with 0.16 ml (0,025 M) under the conditions for 1.5 h the mixture was stirred for 1 h and 45 min, extinguished in 25 ml of 1 N. hydrochloric acid, after which the reaction mixture was made strongly basic, aqueous mixture was extracted with chloroform, acidified, and then extracted with ethyl acetate. The combined organic extracts washed with 10% sodium thiosulfate, then brine, and dried dry sodium sulfate, resulting in the received product, PFP-range which was found the th above in preparation 4, the raw material (0,47 g, 0,0022 M) were subjected to reaction from 0.24 ml (0,0028 M) chloromethylthiazole in toluene, in the presence of tetrabutylammonium bromide, and the product was chromatographically on silica gel, elwira YFC, and 5 ml fractions were collected. The first 420 ml of the eluate was discarded. After evaporation of the following 20 fractions, obtained 0.07 g of material, mostly 2-phenylthiomethyl-4,7-dimethylalanine, which was rejected. The following 25 fractions gave 0,37 g 2-phenylthiomethyl-4-acylcholine, which was subjected to reaction with sulfurylchloride in YFC, resulting received 0,19 g (66%) 2-chloromethyl-4-acylcholine.

Preparation of 16B. In accordance with the procedure described in the preparation of 16A, 10 g (0,051 M) 4-methylcholine in THF was subjected to reaction with 86 ml (0.10 M) Of 1.18 M solution of sec-utility in cyclohexane, and the resulting solution was treated with 4.5 ml (0,050 M) ethyliodide, resulting received 10,15 g (89%) of 4-propylalanine, which was subjected to reaction with 5,32 ml (0,056 M) chloromethylthiazole in toluene, in the presence of tetrabutylammonium bromide, and obtained crude mixture, of which using flash chromatography on silica gel was allocated 2-phenylthiomethyl-4 - propylalanine in the form of oily substance, 1.8 g (0,0052 M) which was subjected to the CLASS="ptx2">

Preparation 16C. The preferred alternative for the preparation of 16A is as follows:

To a solution 5,13 g (25 mm) of N,N,2-triethylbenzene in THF (50 ml) at -78oC was added LDA (Aldrich 2.0 M, 15,63 ml, 31,25 mm). The resulting solution was heated to -10oC in ice water for 1 h, then was cooled to -78oC in a dry bath of ice and acetone. TM SCl (6,34 ml, 50 mm) was added at about -78oC and then the reaction mixture was brought to room temperature within 1 h This reaction mixture is extinguished saturated NH4Cl, were extracted by a simple ether (CH ml), dried MgSO4, evaporated, and the residue person to distil in a Kugelrohr (130 - 140oC, 0.65 mm), resulting in a received 6,51 g (94%) of N, N-diethyl-2-(1-(trimethylsilyl)ethyl]benzamide.

To a solution of sec-utility (0,97 M, 5,10 ml, 4,96 mm), TMEDA (0.75 ml, 4,96 mm) in THF at -78oC was added excessive amount of SO2, and was heated to room temperature. THF was removed in vacuum, and then subjected to reaction at 0oC with two equivalents of sodium hydroxide solution (1:1) (0.36 g, 9.0 mm) and hydroxylamine-O-sulfonic acid (1.0 g, 9.0 mm) in H2O. the resulting reaction mixture was stirred at room temperature for 4 h and was extracted with EtOAc and subjected to the and 0.62 g (47%) 2-aminosulfonyl-N,N-diethyl-6-[1-(trimethylsilyl)ethyl]-benzamide. Benzamide (0.95 g, 2.66 M) was heated under reflux in glacial acetic acid (20 ml) for 18 h, evaporated to dryness, pereirae with hot cyclohexane (30 ml) and with tracking number EtOAc (3 ml), and cooled by loosening and filtration. Thus received 0,81 g(85%) 4-[1-(trimethylsilyl)ethyl]saccharin, so pl. 123 125oC.

To trimethylsilylmethylamine (0.25 g, 0.70 mm) in DMF (9 ml) at room temperature was added H2O (1 ml) and cesium fluoride (0.75 g, 4,94 mm, 7 equivalents). After 7 h the reaction mixture was poured into 5% NaOH and was extracted using EtOAc. The aqueous layer was acidified 12hHCl, and was extracted with Et2O EtOAc (1:1), dried Na2SO4, filtered and evaporated, resulting in the obtained colorless solid in quantitative yield. This substance was recrystallized from 5% Et2O-hexanol, resulting received 0,091 g (64%) 4-acylcholine, so pl. 183-185oC.

Preparation 17. 0.07 g sample of the compound obtained in the early fractions in the chromatographic separation described above in the preparation of 16A, and consisting mainly of 2-phenylthiomethyl-4,7-dimethylalanine, were subjected to reaction with 0.05 ml of sulfurylchloride in YFC and product paracrystallineoC.

Preparation of 18A. To a solution of 40.0 g (0,174 M) 2-isopropyl-4-methoxypropanol in 600 ml of diethylether at 0oC was added 103,68 ml (0,175 M 1,69 M solution of utility in diethylether. After complete addition, the resulting solution was cooled to 0oC for 1 h and stirred for another 5 h at room temperature, and then was cooled to -78oC and treated with a solution 23,68 g (0,175 M) N, N-diethylcarbamoyl in 80 ml of diethylether. The resulting solution was stirred for about 12 h, the reaction temperature was then raised, and the reaction was suppressed by using a saturated solution of ammonium chloride. Water and the organic layer was separated, the aqueous layer was subjected to reverse extraction with ethyl acetate, and the resulting combined organic extracts were washed once with saline, and then dried to dryness, resulting in the obtained crude product, which was subjected to flash chromatography on silica gel, elwira 30% ethyl acetate/hexane, and received 34.4 g (79%) of 2-isopropyl-4-methoxy-N,N-diethylbenzamide in the form of an oily substance, which was used as such in the subsequent stage without further purification. The oily substance may be, if necessary, subjected to distillation, so the pile compound (15.0 g, to 0.060 M) in 100 ml of diethylether, were subjected to reaction with 77,8 ml (0,784 M) 1.2 M solution of sec-utility in cyclohexane in the presence 6,98 g (0,06 M) of tetramethylethylenediamine. The obtained lithium salt was subjected to reaction at first with 50 ml of sulfur dioxide and then with 0,181 M hydroxylamine-O-sulfonate sodium, and obtained 11.6 g (59%) 2-aminosulfonyl-6-isopropyl-4-methoxy-N, N-diethylbenzamide, so pl. 103-105oC (from ethyl acetate/hexane), and 11.0 g (0,034 M) which was cyclically in 200 ml of glacial acetic acid, heated under reflux, which was obtained 10.3 g diethylammonium salt of 4-isopropyl-6-methoxycoumarin, so pl. 132-135oC.

The compound obtained (0,030 M) were subjected to reaction from 6.14 ml (7,25 g 0,046 M) chloromethylthiazole in the presence of 0.98 g (0,003 M) BTBA in 250 ml of toluene, and received a 10.1 g (88%) 2-phenylthiomethyl-4-isopropyl-6-methoxycoumarin, in the form of oily substance, 9.7 g (0,026 M) which was subjected to reaction with 3.1 ml (a total of 5.21 g, 0,039 M) sulfurylchloride in YFC, resulting received 6,9 g (88% ) 2-chloromethyl-4-isopropyl-6-methoxycoumarin, so pl. 151-152oC.

Preparation of 18V. An alternative procedure is the following:

To a solution of 300 ml of N,N,N',N'-tetramethylethylenediamine (TMEDA) (1,99 M) in 4 l of anhydrous simple EPE is min, one drop of solution was added 454,2 g 2-isopropyl-4-methoxy-N,N-diethylbenzamide (1,82 M) in 300 ml of anhydrous simple ether. During the addition, the temperature was maintained at -60oC or below. After complete addition, the reaction mixture was stirred PI -70oC for 1 h and warmed up to -50oC. After maintaining the temperature at -50oC for 30 min the mixture was again cooled to -70oC. To this stirred solution was added via cannula a solution of 200 g of SO2200 ml of dry simple ether, pre-cooled to -40oC, at a positive pressure of nitrogen for 20 minutes the Temperature of the reaction mixture during the addition was maintained below -40oC. a White powdery precipitate of sulfinate argillite separated almost immediately. After the addition, the ice bath was removed, and the reaction mixture was stirred at room temperature for 2 hours Then it was cooled to -5oC and to this stirred solution was added to 190 ml of sulfurylchloride (2.36 M) drop by drop, over 15 min, maintaining the temperature during addition below 10oC. After an additional 30 minutes of stirring at 0-5oC, white insoluble precipitate was filtered and washed with 2-liters of anhydrous question is Akanistha substances. This crude sulphonylchloride was dissolved in 1.4 liters of THF, cooled to -10oC, was added in portions during 15 min, 540 ml of concentrated NH4CH (28%) (for adding maintained the temperature at the 15oC or below). After stirring for 15 min at room temperature. THF and excess ammonia was removed under vacuum, the result has been a dark oily substance, which was diluted to 6.0 l of water and acidified 3 N. HCl to pH 1. The obtained light-yellow substance was collected by filtration and washed with 800 ml of water. The obtained solid substance was dried at 60oC in vacuum for 18 h, and recrystallized from a mixture of 800 ml of ethyl acetate and 3 l of hexane, resulting in received 429 g of 2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzene, and so pl. 122-125oC.

The solution 429,6 g diethylbenzamide (1,31 M) in 1.5 l of acetic acid was heated under reflux for 20 hours Then cooled to room temperature and the solvent was removed in vacuum. The oily residue was dissolved in 6 liters of water and brought to pH 1 6 N. hydrochloric acid. The resulting crude product was collected by filtration and washed with 2 l of water. The obtained solid was dried in vacuum at 60oC is toxicaria, so pl. 188oC.

To a suspension of 24 g of paraformaldehyde (0.8 M) and 86.4 g of chlorotrimethylsilane (1.6 M) in 200 ml of 1,2-dichloroethane was added 0.8 ml of anhydrous tin chloride (IV), and the resulting solution was stirred on a steam bath for 1 h At the end of this period, to a transparent solution was added 51 g (0.2 m) of 4-isopropyl-6-methoxycoumarin, and the reaction mixture was heated under reflux for another 18 hours Then it was cooled to room temperature, poured into water, and the obtained organic layer was separated and washed with 50 ml of 2 n sodium hydroxide solution. This organic layer was dried with anhydrous magnesium sulfate and concentrated in vacuo, resulting in the obtained crude product. After that, it was purified by crystallization from ethyl acetate and hexane, and received 57 g (87%) 2-chloromethyl-4-isopropyl-6-methoxycoumarin, so pl. 151oC.

Preparation 19. To a solution of 1.0 g (0,0039 M) 4-isopropyl-6-methoxy-saccharin in 15 ml of YFC, was added at room temperature 1.28 g (5,12 ml) of 1 M solution tribromide boron in YFC. After complete addition, the reaction mixture was heated under reflux for 5 h, then cooled and dried to dryness, and the residue was treated with ice and saturated sodium bicarbonate. Pathiramanal hydrochloric acid. After extracting the mixture with ethyl acetate/diethyl ether (8:2), drying of the organic extracts and removal of the solvent in vacuo, was obtained 0.9 g (96%) of 6-hydroxy-4-isopropylaniline in the form of a white crystalline solid, which was used as such in the subsequent stage.

Also used an alternative procedure. To a stirred suspension 62,74 g (0,47 M) AlCl3in 500 ml of chloroform at 0oC, was added 43,9 g (0.7 M) ethanethiol. Within a few minutes had formed a clear solution. To this solution for 30 min was added to 20.0 g (0,078 M) 4-isopropyl-6-methoxycoumarin in 550 ml of chloroform. This solution was heated to room temperature and stirred for 3-4 h at 60oC. After cooling, the mixture was poured into ice water and acidified with diluted HCl. Selected solid substance was collected by filtration, washed with water and dried, resulting in received of 18.4 g (97%) of 6-hydroxy-4-isopropylaniline.

In accordance with the procedure described in preparation 4, 6-hydroxy-4-isopropylaniline (0,004 M) were subjected to reaction and 0.61 ml (0,00416 M) chlorotrimethylsilane in toluene in the presence of 0.133 g (0,004 M) BTBA, which was obtained 0.32 g (21%) 6-girlfrined in YFC, and received 1.2 g (84%) 2-chloromethyl-6-hydroxy-4-isopropyl-saccharin, so pl. 149-150oC.

Preparation of 19A. In accordance with the procedure described above in preparation 19, 4-methoxycoumarin can be converted sequentially in 4-hydroxycoumarin, 4-hydroxy-2-phenylthiomethyl and 2-chloromethyl-4-hydroxycoumarin.

Preparation 20. 2 5 g (0,0207 M) 6-hydroxy-4-isopropylaniline was dissolved in 150 ml of methanol, after which was added 3.4 g (0,0104 M) CS2CO3. The resulting mixture was stirred at room temperature for 3-4 hours, the Excess amount of methanol was removed under reduced pressure and the resulting residue was dried under high vacuum for 2 hours After that, the residue was dissolved in 110 ml of DMF, was added 0.32 g (0,0209 M) chloromethanesulfonyl. Stirred the mixture was heated at 70-75oC for 12 h, and then cooled, treated with ice water and was extracted with 600 ml of a mixture of ethyl acetate and ether (4:1). The organic layer was washed with water and saturated NaCl, and then dried. The solvent was removed under reduced pressure. The obtained residue was purified using flash chromatography using 20% ethyl acetate in YFC. The result of this procedure received a 4.5 (60%) of 6-hydroxy-4 - isopropyl-2-Hairdryer and procedure, described in preparation 19, and received 2-chloromethyl-6-hydroxy-4-isopropylaniline, as specified in the preparation of 19.

Preparation 21. To a solution of 5-chloro-2-benzyl-4-isothiazolin-3-one (J. Hlt. Chem. 8, 571, 1971) (9.4 g, 0.04 M) in YFC (100 ml) was added in one portion 80-85% 3-chloroperoxybenzoic acid (10.8 g, 0,06 M), and the resulting mixture during the night was stirred in nitrogen atmosphere. The precipitated solid was filtered and washed YFC (50 ml). The combined filtrate is evaporated almost to dryness, and the residue was distributed between ethyl acetate (300 ml) and saturated NaHCO3(100 ml). The resulting layers were separated and the organic phase was washed with saturated NaHCO3(G ml), brine (g ml) and drained. After removal of solvent in vacuo, was obtained 10.0 g (99%) 5-chloro-2-benzyl-4-isothiazolin-3(2H)-one-1-oxide as a pale yellow oily substance.

1-oxide (10.0 g, 0.04 M) in glacial acetic acid (200 ml) was treated with 30% H2O2(100 ml, 0,88 M) and heated in a steam bath for 2 hours, during which was added 30 ml (0,26 M) 30% H2O2. After an additional 1 h of heating on the steam bath, the reaction mixture was cooled to room temperature, and poured into cold water (1 l) and stirred. Besieged terate which was obtained 4.8 g (45%) of 5-chloro-2-benzyl-4-isothiazolin-3(2H)-she 1,1-dioxide as colorless solid product.

Dioxide (1.2 g, 4,7 mm) was mixed with 2.02 g (11 mm) 2-trimethylsiloxy-5-methylhexan-1,3-diene (obtained from 5-metrex-3-ene according to the method of E. J. Cozey and other Tet. Lett. 495, 1984) in toluene (50 ml) and was heated under reflux for 20 h under nitrogen atmosphere. The resulting mixture was cooled to room temperature and concentrated in vacuum. The residue was dissolved in THF (25 ml) and was treated with 2 N. HCl (10 ml). After 10 minutes of stirring at room temperature in a nitrogen atmosphere, was added a simple ether (100 ml) and the layers were separated. The organic phase is washed with water, brine, then dried and evaporated to dryness, resulting in the obtained pale-yellow foam. This foam was dissolved in toluene (30 ml) was added DBU (1.5 ml) and stirred 2 h at room temperature. After this was added YFC (100 ml) and 2 N. HCl (50 ml) and continued to stir for another 5 minutes the Layers were separated and the organic phase is washed with water and brine, and dried off. After removal of the solvent in vacuo and purification of the residue via flash chromatography on silica gel (Hexane:YFC:simple ether 5:4:1), was obtained 0.6 g (39%) of 2-benzyl-4 - isopropyl-6-oxitetraciclina in the form of a pale yellow foam.

This tetrahydrofuran (0,59 g, 1.7 mm) was dissolved in toluol refrigerator with azeotropic removal of water for 96 hours During the 96-hour period, every 12 h was added an additional amount of dimethylaminohydrolase (0.8 g, 10.0 mm) and 4A sieves, and after this time the reaction mixture was cooled to room temperature and filtered. The filter residue was washed with deethylation (100 ml) and the combined filtrates were concentrated in vacuo, resulting in a received 0,63 g (99%) of 2-benzyl-4-isopropyl-6-dimethylamino (4,5-Dihydrocodeine in the form of a pale yellow solid.

To a solution of dihydrocoumarin (to 0.63 g, 1.7 mm) in boiling under reflux chloroform 850 ml), parts for 4 h added activated manganese dioxide (4.3 g, 59.5 mm 59.5 mm). After adding the last portion of the manganese dioxide, the reaction was heated under reflux for another 1 h, then cooled to room temperature, and filtered through a pad of Super-Cel, elwira with ethyl acetate. United eluate was concentrated in vacuo, and the residue was purified using flash chromatography on silica gel (elwira mixture of hexanol, YFC and simple ether, 5:4:1), which was obtained 0.32 g (50%) of 2-benzyl-4-isopropyl-6-dimethylamino-saccharin in the form of a colorless solid.

2-bensisahar (0.32 g, 0.9 mm) methane (20 ml) was treated with the m, then the mixture was cooled to room temperature and filtered through a pad of Super-Cel, elwira methanol (100 ml). United eluate concentrated in vacuum. The residue was dissolved in YFC (10 ml), then thereto was added glacial acetic acid (0.25 ml), stirred 5 min, and evaporated to dryness in a vacuum, the result was obtained 0.25 g (100%) 4-isopropyl-6-diethylaminocoumarin in the form of a colorless foam.

In accordance with the procedure described in preparation 1, a mixture of 4-isopropyl-6-diethylaminocoumarin (0.27 g, 1.0 mm), chloromethylbenzene (0.32 g, 2.0 mm) and tetrabutylammonium bromide (0.1 g, 0.2 mm) in toluene was converted into 0,22 g (56%) 2-phenylthiomethyl-4 - isopropyl-6-diethylaminocoumarin, which were treated with sulfurylchloride (of 1.86 ml, 0.31 in ml, 0,31 M solution, 0.6 mm), which was obtained 0.15 g of a yellow gum, which contained 25% (as determined by NMR) 2-chloromethyl-4-isopropyl-6-dimethylamino-7-chlorosarin.

Preparation 22. 31 g of 4-isopropyl-1,2-dimethoxybenzene was treated with N-bromosuccinimide, and then butyllithium and diethylcarbamazine, as in getting 6B, the result of which was obtained 15.2 g of 2-isopropyl-4,5-dimethoxy-N, N-diethylbenzamide in the form of a viscous oily substance. Received benzamin result was obtained 4.5 g sulfonamida with so pl. 181-182o(After crystallization from ether). The compound obtained was cyclically in acetic acid according to the procedure of preparation 18B, and received in the result of 2.86 g of 6,7-dimethoxy-4-isopropylaniline, so pl. 210-212oC (ETHYLACETYLENE).

To a solution of 0.5 g of 4-isopropyl-6,7-dimethoxycoumarin in 3 ml of DMF was added 0.5 ml of diisopropylethylamine at room temperature. After 15 min was added 0.35 g of chloromethanesulfonyl, and the resulting mixture was heated at 80oC for 16 hours the Reaction mixture was poured into EtOA, and washed with an aqueous solution of Na2CO3, aqueous solution 2 N. HCl, and saturated aqueous NaCl. The organic layer was dried with sodium sulfate, and the solvent was removed. The result chromatography using YFC, was obtained 0.35 g of the target product, which is then immediately used. 0.35 g sample phenyldimethylsilane in 3 ml of YFC was treated with 0.1 ml of sulfurylchloride for 30 min at 20oC, followed by removal of solvent and rubbing with hexane and was obtained 0.3 g of 2-chloro-methyl-6,7-dimethoxy-4 - isopropylaniline.

Preparation 23. To a solution of 5.7 g of methylpiperidine in 20 ml of dry ether was added 30 ml of 3.0 methylacrylamide simple ether in tacheny. The organic layer was dried with sodium sulfate, the solvent was removed, and obtained 5.6 g of crude 3,4-dimethoxy-(1'-hydroxy-1'-methylethyl/benzene. This product was immediately processed in 50 ml of acetic acid with 1 g of 10% Pd/c for 20 h with the addition of hydrogen to 50 psi (344,7 kPa). After removal of catalyst by filtration and removal of solvent, was obtained 4.5 g of 5-isopropyl-1,3-benzodioxole. The resulting isopropylindole were subjected to bromirovanii, amidation, sulfating and cyclization according to the procedure described in preparation 22, resulting in a received 700 mg of 4-isopropyl-6,7-methylenedioxyaniline with so pl. 226-228oC (from ethyl acetate/hexane). In accordance with the procedure of preparation 22, 500 mg of saccharin were subjected to chloromethylpyridine, and received the 300 mg 2-chloromethyl-4-isopropyl-6,7-methylenedioxyaniline, so pl. 174-176oC.

Preparation 24. In accordance with the procedure described in preparation 18A, 5 g of 2-bromo-N,N-dimethylamine were converted into 3.5 g of N,N-diethyl-2-dimethylaminobenzoate. The obtained amide was subjected to reaction by the method described in preparation 18B, and received 65 mg of 4-diethylaminocoumarin, etc., 228-229oC (from ether-hexane).

In the reaction of 4-dimethyl is whether 4-dimethylamino-2-phenylthiomethyl. As a result of the reaction of the obtained compound with sulfurylchloride in YFC received 4-dimethylamino-2-chloro-metalshark. Alternatively, reaction of 4-diethylaminocoumarin with paraformaldehyde and chlorotrimethylsilane in the presence of catalytic amounts of tin chloride in ethylene dichloride was obtained 4-dimethylamino-2-chloromercuri.

Preparation 25. To a solution of 1.0 g (2,75 mm) 6-hydroxy-4-isopropyl-2-phenyldimethylsilane in THF was added 0.73 g (2,78 mm) of triphenylphosphine, 0.14 g (3.04mm) of ethanol and of 0.48 g (was 2.76 mm) of diethylazodicarboxylate at room temperature. The resulting mixture was stirred for 10-12 hours the Reaction was repeated, according to 3.73 g (10,28 mm) 6-hydroxy-compounds. The reaction mixture was combined, and subjected to flash chromatography on silica gel, elwira with ethyl acetate in hexane (10% and then 15%), resulting in a received 4,37 g (85%) 6 ethoxy-4-isopropyl-2-phenyldimethylsilane, so pl. 111,5-112,5oC, which is then converted into 2-chloromethyl-6-ethoxy-4-isopropylaniline with the release of 91% (so pl. 127-128oC) in accordance with the procedure described in the preparation of 18A.

Other 4-R1-R2-R3-sacharine formula IV used as intermediates for obtaining connection is oinoi acid with thionyl chloride, resulting gain 2-cryptomathematical, after the reaction of which with diethylamino get 2-trifloromethyl-N,N-diethylbenzamide. In accordance with the procedure described in preparation 5, in the reaction of the obtained compound with a second-butyllithium, and the reaction of the obtained lithium salt with sulfur dioxide and then with hydroxylamin-O-sulfonate sodium, received 2-trifluoromethyl-6-aminosulfonyl-N, N-diethylbenzamide, after heating which in glacial acetic acid, was obtained 4-cryptomaterial.

Similarly, in the reaction of 2-trichloromethylbenzene acid with thionyl chloride was obtained 2-trichloromethylbenzene, which was then subjected to reaction with diethylamine and got 2 trichloromethyl-N,N-diethylbenzamide. In accordance with the procedure described in the getting 5, amide obtained was subjected to reaction with the second-butyllithium, and the resulting lithium salt was subjected to reaction with sulfur dioxide and then with hydroxylamine-O-hydroponicum sodium, resulting in received a 2-trichloromethyl-6-aminosulfonyl-N, N-diethylbenzamide, and after heating in glacial acetic acid, was obtained 4-trichloromethylthio.

In the reaction of 4-cyclohexylbenzene Kistler-N, N-diethylbenzamide. Then, in accordance with the procedure described in preparation 5, was carried out by reaction of the obtained compound with a second-butyllithium, with subsequent reaction of the obtained lithium salt with sulfur dioxide and then with hydroxylamine-O-sulfonate sodium, resulting in the received 4-cyclohexyl-2-aminosulfonyl-N,N - diethylbenzamide, after heating which in glacial acetic acid, was obtained 6-cyclohexylaniline.

In the result of benzylidene 6-PetroChina received 2-benzyl-6-nitrofuran, which was then subjected to a reduction reaction using tin chloride and water florodora, and obtained 2-benzyl-6-aminocoumarin. After the reaction of this compound with methanesulfonamido, triftormetilfullerenov or trichlorocarbanilide in YFC in the presence of pyridine, followed by hydrogenolysis of 2-benzyl-protective groups were, respectively, 6-methylsulfonylmethane, 6-triftormetilfullerenov, or 6-trichlorotrifluoroethane.

In the diazotization of 6-aminocoumarin using nitrous acid in acidic medium and decomposition of the obtained diazonium salt in the presence of copper cyanide or copper chloride, Diwali, accordingly, 6-cyanoalanine, 6-chlorosulfonylphenyl, 6-methylcoumarin or 6-cryptanalytical. After the reaction for 6-chlorosulfonylphenyl in situ with ammonia or methanesulfonamido received, respectively, 6-aminosulphonylphenyl and 6-methanesulfonylaminoethyl. In the oxidation of 6-methylthiopurine and 6-cryptanalytically using two molar equivalents of 3-chloroperbenzoic acid was obtained 6-methylsulfonylamino and 6-triftormetilfosfinov, respectively.

As a result of hydrolysis of 6-cyanoalanine when heated with aqueous sodium hydroxide solution were given saccharin-6-carboxylic acid. After N-benzylidene 6-cyanoalanine received 2-benzyl-6-cyanoalanine. After alkaline hydrolysis of this compound was obtained 2-bensisahar-6-carboxylic acid which was then converted to the chloride 2-bensisahar-6-Karabanovo acid through reaction with thionyl chloride and subsequent exhaustive hydrogenation in the presence of palladium charcoal, received 6-hydroxymitragynine. After oxidation of this compound using pyridine-trichloride chromium, 2:1" (Collins Reagent) in YFC received 6-formicary, which is then subjected to restore the

After the reaction of 4-trichoroethylene acid with thionyl chloride were obtained chloride 4-trifluromethanesulfonate, which was then subjected to reaction with diethylamine in the 4-trifluoromethyl-N,N-diethylbenzamide. In accordance with the procedure described in preparation 5, was carried out by reaction of the obtained compound with a second-butyllithium, and reaction of the resulting lithium salt with sulfur dioxide and then with hydroxylamine-N,N-sulfonate sodium, resulting in the received 4-trifluromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which is then heated in glacial acetic acid and was obtained 6-cryptomaterial.

In the reaction of 4-trichloromethylbenzene acid with thionyl chloride was obtained 4-trichloromethylbenzene, which was then subjected to reaction with diethylamine and received 4-trichloromethyl-N,N-diethylbenzamide. In accordance with the procedure described in preparation 5, the compound obtained was subjected to reaction in the second-butyllithium, and the resulting lithium salt was subjected to reaction with sulfur dioxide and then hydroxyamine-O-sulfonate sodium, resulting in the received 4-trichloromethyl-2-aminosulfonyl-N,N-diethylbenzamide, after heating which in glacial acetic acid, was obtained 6-trichlorosilane, and after the reaction of this compound with diethylamine received 2-ethinyl-N,N-diethylbenzamide. The compound obtained was subjected to reaction with the second-butyllithium, and the resulting lithium salt was subjected to reaction with sulfur dioxide and then with hydroxylamine-O-sulfonate sodium, resulting in a received 2-ethynyl-6-aminosulfonyl-N, N-diethylbenzamide, after heating which in glacial acetic acid was obtained 4-itinerarary.

In the reaction of 2-ethynyl-6-aminosulfonyl-N, N-diethylbenzamide with bromine was obtained 2-(1,2-dibromoethyl)-6-aminosulfonyl-N, N-diethylbenzamide, which was subjected to reaction with Amida sodium in ammonia, and received the 2-ethinyl-6-aminosulfonyl-N,N-diethylbenzamide, after heating which in glacial acetic acid was obtained 4-ethnischen.

Ethyl 2-aminobenzoate was subjected to reaction with two molar equivalents of benzylchloride in acetone potassium carbonate was obtained ethyl 2-(N,N-dibenzylamino)-benzoate, which is then subjected saponified in an aqueous ethanol solution of potassium hydroxide and the obtained product was isolated from the neutral environment, resulting in a received 2-(N,N-dibenzylamino)-benzoic acid.

The resulting acid was subjected to reaction with thionyl chloride, and ethylbenzamide. This compound was subjected to reaction with the second-butyllithium, and the resulting lithium salt was subjected to reaction with sulfur dioxide and then with hydroxylamine-O-sulfonate sodium, resulting in a received 2-(N, N-dibenzyl)-6-aminosulfonyl-(N, N-diethylbenzamide), after heating which in glacial acetic acid was obtained 4-N,N-dibenzylamino saccharin, which is then subjected to catalytic dibenzylamino in the atmosphere of hydrogen and in the presence of palladium charcoal, resulting in a received 4-aminocoumarin. After reductive alkylation of this compound, which was carried out by using one molar equivalent of formaldehyde in formic acid, was obtained 4-methylaminoethanol.

Was carried out by selective N-benzylidene cesium salt of 6-hydroxy-4-isopropylaniline (preparation 19) using benzylbromide, and the reaction of 2-benzyl-6-hydroxy-4-isopropylaniline with N,N-diethylthiocarbamate in DMF according to the procedure described in preparation 12, resulting in a received 2-benzyl-4-isopropyl-6-(N, N-diethylthiocarbamate)saccharin, which is then subjected to heating and rearrangement of obtaining 2-benzyl-4-isopropyl-6-(N, N-diethylcarbamyl)saccharin. After gidrol reaction with methyliodide and exchange hydrogenolysis, the result that was obtained 4-isopropyl-6-methylcoumarin. This compound was oxidized with one or two molar equivalents of 3-chlorbenzoyl acid and was obtained 4-isopropyl-6-methylsulfonylamino and 4-isopropyl-6-methylsulfonylamino.

In the reaction of 2-isopropyl-4-foramtting acid with thionyl chloride was obtained 2-isopropyl-4-forensicare, which was then subjected to reaction with diethylamine, and was obtained 2-isopropyl-4-fluorescent-N,N-diethylbenzamide. After the reaction of this compound with second-butyllithium, and the reaction of the obtained lithium salt with sulfur dioxide and then with hydroxylamine-O-sulfonate sodium was obtained 2-isopropyl-4-fluorescent-2-aminosulfonyl-N,N-diethylbenzamide, after heating which in glacial acetic acid was obtained 4-isopropyl-6-pterosaurian.

The compound obtained was subjected to reaction with thiophenols, 4-methylphenylimino, 4-methoxybenzylidene, 4-chlorophenylsulfonyl, 1-mercapto-4-methylnaphthalene or 1-mercaptoethanol followed by heating the reagents in DMF, and was obtained 4-isopropyl-6-penaltyshall, 4-isopropyl-6-(4-methylphenylthio)saccharin, 4-isopropyl-6-(4-methoxy-phenylthio)saccharin, 4-isopropyl-6-(4-course is what these compounds were subjected to oxidation reaction in each case with one or two molar equivalents of 3-chlorbenzoyl acid, and was obtained 4-isopropyl-6-phenylsulfinyl-saccharin, 4-isopropyl-6-phenolsulfonephthalein, 4-isopropyl-6-(4-methylphenylsulfonyl) saccharin, 4-isopropyl-6-(4-methylphenylsulfonyl)saccharin, 4-isopropyl-6-(4-methoxybenzenesulfonyl)saccharin, 4-isopropyl-6-(4-methoxybenzenesulfonyl)saccharin, 4-isopropyl-6-(4-chlorophenylsulfonyl)saccharin, 4-isopropyl-6-(4-chlorophenylsulfonyl)saccharin, 4-isopropyl-6-(4-methyl-1-naphthylmethyl)saccharin, 4-isopropyl-6-(4-methyl-1-naphthylmethyl)saccharin, 4-isopropyl-6-(1-naphthylmethyl)saccharin, 4-isopropyl-6-(1-naphthylmethyl)saccharin.

2-benzyl-6-hydroxy-4-isopropylaniline was subjected to reaction with one molar equivalent of acetic anhydride, benzoyl chloride, or chloride 1-naftilaminom acid, followed in each case, the exchange hydrogenolysis, resulting received, respectively, 4-isopropyl-6 - acetoxyacetyl, 4-isopropyl-6-benzoyloxy-saccharin and 4-isopropyl-6-(1-naphthyl-carbonyl-oxy)saccharin.

After heating 4-isopropyl-6-pterosauria in DMF with azetidinol, pyrrolidine, piperidine, morpholine, 1-benzylpiperazine, 1-methylpiperazine, imidazole, t-butyl-alpha-amino-acetate or ammonia were obtained, respectively, 4-isopropyl-6-1-azetidine saccharin, 4-Joel-6-(4-benzyl-1-piperazinil)saccharin, 4-isopropyl-6-(4 - methyl-1-piperazinil)saccharin, 4-isopropyl-6-(1-1H-imidazolyl)saccharin, 4-isopropyl-6-(t-butoxycarbonyl-methylamino)saccharin, 4-isopropyl-6-aminocoumarin.

4-Isopropyl-6-(4-benzyl-1-piperazinil)saccharin was subjected to catalytic dibenzylamino in the atmosphere of hydrogen and in the presence of palladium charcoal, resulting in a received 4-isopropyl-6-(1-piperazinil)saccharin.

4-Isopropyl-6-(t-butoxycarbonylmethylene)saccharin was subjected to hydrolysis using dilute hydrochloric acid, whereupon the product was isolated from the neutral environment and has obtained 4-isopropyl-6 - carboxymethylaminomethyl.

After the reaction of 4-isopropyl-6-aminocoumarin with one molar equivalent of acetylchloride received 4-isopropyl-6-acetaminoohen.

Using alkaline hydrolysis reaction of saponification of 4-carbomethoxyamino (preparation 9D) to obtain the corresponding saccharin-4-carboxylic acid, which through reaction with thionyl chloride was converted into the acid chloride, and after the reaction indicated the acid chloride with ammonia received saccharin-4-carboxamide.

After diazotization aminocoumarin with nitrous acid in an acidic environment and decomposition obtained diazo methylcholine formula VI, presented in table. 2, where, in each case, R3is hydrogen, and X is Cl, can be obtained by the reaction of 4-R1-R2-R3-sharenow, which, in turn, is obtained using chloromethylthiazole in the presence of t-butoxide potassium and tetrabutylammonium bromide, followed by reaction of the obtained 4-R1-R2-R3-2-phenyldimethylsilane with sulfurylchloride in YFC; and/or by the reaction of 4-R1-R2-R3-sharenow who receive using paraformaldehyde and chlorotrimethylsilane in the presence of catalytic amounts of tin chloride in ethylene dichloride.

Preparation 87. Isothiazol-6-carboxaldehyde was subjected to reaction with 3-(triphenylphosphonio)propanoate lithium standard Wittig conditions, and obtained 4-(5-isothiazole)-3-butenova acid, which was then restored and cyclically using aluminium chloride, resulting in the received 4-oxo-4,5,6,7 - tetrahydro-1,2-benzisothiazole, 4-oxo-compound was subjected to reaction with methyltriphenylphosphonium standard Wittig conditions, and the obtained 4-methylene compound through the reaction of the Simmons-Smith was injected methylene, as a result, poluchila received 6,7-dihydrospiro[3-oxo-1,2-benzisothiazol-4(5H), 1'-cyclopropane 1,1-dioxy] 4-spirocyclopropane-4,5,6,7-tetrahydrofuran). This compound was subjected to chloromethylpyridine in accordance with the procedure described in preparation 1, and received 2-chloromethyl-4-spirocyclopropane-4,5,6,7-tetrahydrofuran.

Preparation 88. 2-Benzyl-4-isopropyl-6-oxitetraciclina preparation 21 was subjected to restore using sodium borohydride and methylation with use under the conditions in the presence of sodium hydride, resulting in a received 2-benzyl-4-isopropyl-6 - methoxyethylmercury. This compound was dibenzylamine and chlormethiazole in accordance with the description in preparation 21, and received a 2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrofuran.

Preparation 89. To the freshly distilled cyclopentadiene 25 ml) at 0oC was added 4-bromo-2-(tert-butyl)isothiazol-3(2H)-1,1-dioxide (Helu. Chim. Acba. 72, 1416, 1989) (7.9 g, 0,03 M). The resulting mixture was stirred 16 h at 0oC, and then concentrated in vacuum. The residue was purified by filtration through silica gel, elwira hexane (500 ml) and then with 20% ethyl acetate in hexane (500 ml) and again 20% ethyl acetate in hexane (500 ml). Eluate was concentrated in vacuum, and received of 9.8 g (100%) narbonense and the society.

This adduct (0.4 g, 1.2 mm) in 25 ml of ethyl acetate containing 5% Pd on CaCO3(0.2 g), stirred in an atmosphere of hydrogen for 4 h, and the resulting reaction mixture was filtered through a pad of silica gel, elwira with ethyl acetate (100 ml). Eluate was concentrated in vacuo, and the residue was led from hexanol, resulting received 0.4 g (100%) bromocarbons, 3A-bromo-2-t-butyl-3A, 4,5,6,7,7-hexahydro-4,7-methane-1,2-benzisothiazol-3(2H)-1,1-dioxide, in the form of a white crystalline substance.

To a solution of bromobenzene (3.7 g, to 0.011 M) in toluene 825 ml) at 0oC was added diazabicyclo (1,37 g to 0.011 M) in toluene (10 ml). After 20 minutes stirring at 0oC, the reaction mixture was added silica gel (25 g). The resulting suspension was loaded on top of a 15 cm pad of silica gel and was suirable 20% ethyl acetate in hexano (800 ml). Eluate was concentrated in vacuum, and obtained 2.8 g (100%) dehydrobrominated connection, 2-t-butyl-4,5,6,7-tetrahydro - 4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, in the form of a white solid.

This dehydrobrominated compound (2.8 g, to 0.011 M) in triperoxonane acid (30 ml) was heated under reflux for 48 h and left at room temperatute was dissolved in simple ether (100 ml) and washed with saturated NaHCO3(G ml). The layers were separated, and the aqueous phase was acidified to pH 1 using 2 N. HCl was extracted with YFC (g ml). The combined organic extracts were dried and concentrated in vacuum, the result was obtained 0.9 g (42%) bicyclo[2.2.1]some saccharine derived, 4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-1,1-dioxide (4,5,6,7-tetrahydro-4,7-methane-saccharin), in the form of a white solid.

The mixture derived bicyclo(2.2.1)saccharin (0.9 g, 5 mm), chloromethylbenzene (0.07 g, 7 mm) and tetrabutylammonium bromide (0.36 g, 0.16 mm) in toluene (50 ml) was heated under reflux in nitrogen atmosphere for 16 h, cooled to room temperature, and evaporated to dryness in a vacuum. The residue was purified using flash chromatography on silica gel (100 g) using 100% YFC as eluent, and received of 1.05 g (72%) of the corresponding 2-phenylthiomethyl derived in the form of a viscous oily product.

This product (1,05 g, 3 mm) in dichloromethane (100 ml) was treated with sulfurylchloride (0.66 g, 5 mm) and stirred for 2 h the yellow solution was diluted YFC (100 ml), washed with saturated solution of NaHCO3and concentrated in vacuum. The residue was purified using flash chromatography on silica gel (33% ) YFC in hexa is aromatic-4,5,6,7-tetrahydro-4,7-melanocharis).

Preparation 90 and 91. In accordance with the procedures described in preparation 89, obviously, cyclohexadiene or 1,1-dimethyl-cyclopentadiene may be subjected to reaction with 4-bromo-2-(t-butyl)isothiazol-3(2H)-1,1-dioxide with receiving, respectively, 3A-bromo-2-t-butyl-3A,4,7,7-tetrahydro-4,7-ethano or 4.7-dimethylamino-1,2-benzisothiazol-3(2H)-1,1-dioxide, which can be hydrogenosomal obtaining 3A-bromo-2-t-butyl-3A, 4,5,6,7,7-hexahydro-4,7-ethano (or 4,7-dimethylamino)-1,2-benzisothiazol-3(2H)-1,1-dioxide, which, in turn, can be dehydrobrominated obtaining 2-t-butyl-4,5,6,7-tetrahydro-4,7-ethano (or 4,7-dimethylamino)-1,2-benzisothiazol-3(2H)-1,1-dioxide, which can then be dalkiran obtaining 4,5,6,7-tetrahydro-4,7 - ethano (or 4,7-dimethylamino)-1,2-benzisothiazol-3(2H)-1,1-dioxide, which, in turn, can be subjected to reaction with chloromethanesulfonyl obtaining 2-phenylthiomethyl-4,5,6,7-tetrahydro-4,7-ethano (or 4,7-dimethylamino)-1,2-benzisothiazol-3(2H)he 1,1-dioxide, which can then be subjected to reaction with sulfurylchloride obtaining 2-chloromethyl-4,5,6,7-tetrahydro-4,7-ethano (or 4,7-dimethylamino)-1,2-benzisothiazol-3(2H)-it, i.e., 2-chloromethyl-4,5,6,7-tetrahydro-4,7-etnosfera (sentence is 92E-94E. A common way to obtain methyl 2-alkylcyclohexane-6-noncarboxylic.

To a suspension of anhydrous Cul (10 mm) in anhydrous THF (100 ml) were added Me2S (10 mm), and the resulting solution was cooled to -78oC. Then, within 15 min, was added the Grignard reagent (allylbromide magnesium) (20 mm). After 1 hour stirring at -78oC, was added a solution of cyclohexanone (10 mm) in THF, and continued to stir for another 15 minutes To the mixture was added HMPA (5 ml) and after 15 min was added methylcyclopropyl (30 mm) in THF (20 ml), after which the reaction mixture was heated to room temperature and stirred over night. Then, the reaction mixture was extinguished with the help of 2 N. HCl (50 ml). The layers were separated, and the aqueous phase was extracted with Et2O (g ml). The combined organic extracts were washed with saturated solution of NH4Cl (g ml), water (I ml), brine (CH ml), and dried with sodium sulfate (Na2SO4). After removal of the solvent in vacuo and purification, or by distillation in a Kugelrohr or using flash chromatography, has been the target of methyl 2-alkylcyclohexane-6-noncarboxylic (PL. C).

A common way to obtain methyl 2-benzylthio-6 - alkylcyclohexane-2-incorporate and methyl 2-benzylthio-6-alkyl is a (1,1 EQ. ) and acidic montmorillonite clay KSF (weighing 1.5 times the mass of methyl 2-alkylcyclohexane-6-noncarboxylic) in anhydrous toluene (50-100 ml) was heated under reflux in an atmosphere of nitrogen with azeotropic removal of water for 12-14 h, and then cooled to room temperature. The obtained solid was filtered and washed with simple ether. The combined filtrate washed with 10% Na2CO3, water, saline solution, and dried off. After removal of the solvent in vacuo and purification of the residue via flash chromatography on silica gel (10% ether in hexane), was obtained a mixture of methyl 2-benzylthio-6-alkylcyclohexane-2-enecarboxylate and methyl 2-benzylthio-6-alkylcyclohexane-1 enecarboxylate (PL. D), which are then used in the next stage in the form of a mixture.

A common way to obtain 4-alkyltetrahydrofuranes.

A solution of methyl 2-benzylthio-6-alkylcyclohexane-2-enecarboxylate and methyl 2-benzylthio-6-alkylcyclohexane-1 enecarboxylate (1-10 mm mixture) in 10 ml of YFC bred 20-50 ml of glacial acetic acid and 1-5 ml of water, the mixture was cooled to -10oC, and after this mixture was barbotirovany gaseous chlorine until then, until an exothermic reaction begins to diminish. The mixture is then raznyx-2-enecarboxylate and methyl 2-chlorosulfonyl-6-alkylcyclohexane-1 enecarboxylate, which was dissolved in 10 ml THF and added to 25 ml of concentrated ammonium hydroxide, cooling, while in the bath with ice and acetone. After 2-hour stirring, the reaction mixture was concentrated in vacuo, and the residue was dissolved in water, acidified to pH 1 using 2 N. HCl, and was extracted with YFC. The organic phase was dried and concentrated in vacuum, which received a mixture of methyl 2-aminosulfonyl-6-alkyl-cyclohex-2-enecarboxylate and methyl 2-chlorosulfonyl-6-alkylcyclohexane-1 enecarboxylate, which was dissolved in 10 ml THF and added to 25 ml of concentrated ammonium hydroxide, cooling, while in the bath with ice and acetone. After 2-hour stirring, the reaction mixture was concentrated in vacuo, and the residue was dissolved in water, acidified to pH 1 using 2 N. HCl, and was extracted with YFC. The organic phase was dried and concentrated in vacuum, which received a mixture of methyl 2-aminosulfonyl-6-alkylcyclohexane-2-enecarboxylate and methyl 2-aminosulfonyl-6-alkylcyclohexane-1 encorporate. The resulting mixture was dissolved in methanol and added to a freshly prepared solution of sodium methoxide (10-50 mm), and then stirred at room temperature for 12 hours, Reactio braciale, and the aqueous phase was acidified to pH 1 with concentrated HCl and was extracted with YFC. The organic extracts were washed brine, drained them evaporated to dryness, resulting in the received 4-alkyl-4,5,6,7-tragida-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (4-alkyl-4,5,6,7-tetrahydrofuran) (table. E).

A mixture of 4-alkyl-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-1,1-dioxide (4-alkyl-4,5,6,7-tetrahydrofuran) (1.0 EQ. ), chloromethylbenzene (1.5 equiv.) and tetrabutylammonium bromide (0.2 EQ.) in toluene (25 ml/g of saccharin) was heated under reflux in nitrogen atmosphere for 16 to 24 h, and then cooled to room temperature. The resulting mixture was evaporated to dryness and the residue was chromatographically on silica gel, elwira with a mixture of hexane and YFC (1:1 1:3), resulting in a received corresponding 2-phenylthiomethyl-4-alkyl-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-1,1-dioxide (2-phenylthiomethyl-4-alkyl-4,5,6,7-tetrahydrofuran) (table. F).

A solution of 2-phenylthiomethyl-4-alkyl-4,5,6,7-tetrahydrofuran (1.0 EQ.) handled sulfurylchloride (1.5 equiv.) and stirred for 2 h Obtained yellow solution was drained dry, and received 2-chloromethyl-4-alkyl-4,5,6,7-tetrahydrofuran. In the resulting compounds, the alkyl is stands (92E), is isgotovlenia V-V E-E, and using as starting material methylcyclohexane-6-noncarboxylic, has consistently received: a mixture of methyl 2-benzyltoluene-1 (and 2)-ene-carboxylate (yield 40%); a mixture of methyl 2-chlorosulfonyl-cyclohex-1-(2)-enecarboxylate; a mixture of methyl 2-aminosulfonates-1-(2)-enecarboxylate, 4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-1,1-dioxide 4,5,6,7-tetrahydrofuran (yield 50% ), 2-phenylthiomethyl-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-1,1-dioxide-2-phenylthiomethyl-4,5,6,7-tetrahydrofuran (yield 40%) and 2-chloromethyl-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-1,1-dioxide (2-chloromethyl-4,5,6,7-tetrahydrofuran).

Preparation 96. Methyl 2,2-dimethylcyclohexane-6-it-carboxylate.

To a suspension of anhydrous Cul (70,0, 0,37 M) in anhydrous ether (500 ml) at 0oC was added metallice in free form (520 ml of 1.4 M solution in ether, 0.73 M). After 15 minutes stirring at 0oC, was added a solution of 3-methyl-2-cyclohexenone (20,0 g, 0.18 M) in ether (50 ml) and continued stirring for another 1 hour To the mixture was added THF (50 ml) and HMPA (25 ml) and after 15 min was added methyl-cyanoformate (45,0 g, 0,53 M) in THF (20 ml), after which the reaction mixture was heated to room temperature and stirred for 3 h the Reaction mixture was hacky washed with saturated solution of NH4Cl (g ml), water (I ml), brine (g ml) and was dried with sodium sulfate. After removal of the solvent in vacuo and purification by distillation in a Kugelrohr, got 34,0 g (99%) of methyl-2,2-di-methylcyclohexane-6-he carboxylate, so Kip. 80-84oC/0.6 mm which was then turned into a 2-chloromethyl-4,4-dimethyl-4,5,6,7-tetrahydrofuran in accordance with the General methods described in preparations W-W E-E.

The final products.

Example 1. A solution of 2-bromoethylamine (2.0 g, 7.2 mm), dietilfosfat (to 2.29 g, 10,9 mm) and N,N-diisopropylethylamine (1,41 g 10,9 mm) in 40 ml of methylenechloride stirred at room temperature for 48 hours the Reaction mixture was concentrated, and the residue was subjected to flash chromatography on silica gel, elwira 30% ethyl acetate in hexano, resulting received 2,35 g (80%) dibutil 2-sharinaletisha in the form of a colorless oily product.

Example 2. A solution of 2-chloromethyl-4-ethoxycoumarin (2.0 g, 7,3 mm), diethylphosphate (1.68 g, 10,9 mm), and triethylamine (1,53 ml, 10,9 mm) in 25 ml of methylenechloride was heated under reflux for 58 hours After cooling, the reaction mixture was concentrated, and the residue was subjected to flash chromatography on silica gel, elwira mixture is to maintain oily product.

Example 3. To a solution of dibenzylamine (0,69 g, 2,48 mm) in 30 ml of methanol at room temperature was added cesium carbonate (0,403 g, 1,24 mm). After 2-hour stirring, the solvent evaporated, and the residue was dried in high vacuum and suspended in 10 ml of N,N-dimethylformamide. To the suspension was added 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.5 g, 1.6 mm), and the mixture was stirred 24 h in an oil bath at 50oC. After cooling, the mixture was diluted with ice water and was extracted with 200 milliliters simple mixture of ether and ethyl acetate (4:1). The organic layer was separated and sequentially washed with water and then saturated saline solution. The extract was dried with magnesium sulfate, filtered, concentrated, and the residue was subjected to flash chromatography on silica gel, elwira a mixture of ethyl acetate and hexane, resulting in received 0,46 g (52%) dibenzyl 4-isopropyl-2-sharinaletisha in the form of an oily substance, which was crystallized after conditioning, so pl. 75,5-76,5oC.

In accordance with the procedures described above in examples 1 to 3 (hereinafter referred to methods 1 and 3), were obtained the compounds of formula I are given below in table. 1. In each of examples 4 to 9, to obtain products used 2 bromo"ptx2">

In examples 1 to 17 and 20, to obtain the compounds as raw materials used phosphate and phosphine acid, which was a commercial material. Diisopropylphenol used in examples 18, 19 and 21, were received as follows:

A mixture of diisopropylfluorophosphate (10 g, 50 mm) (see R. A. Melvor, etc. Can. J. Chem. 34, 1819 (1956)) in 10 ml of distilled water and stirred in an oil bath at 80oC for 2 h the mixture was concentrated in vacuo and the remaining water was removed by azeotropic distillation with benzene (g ml). After drying in high vacuum was obtained 8.8 g (97%) of Diisopropylamine in the form of an oily material, which is then used without purification.

Example 22. Aminobutiramida 6-(2,2-dimethyl-1,3-dioxane-4-yl)methoxy-4-isopropyl-2-Sakhalinenergo.

Diethylazodicarboxylate (0.96 g, 5,55 mm) was added to the mixture aminobutiramida 6-hydroxy-4-isopropyl-2-sharinaletisha (2.37 g, 5,44 mm), triphenylphosphine (1.44 g, 5.5 mm) and glyceryltrinitrate (2,2-dimethyl-1,3-dioxolane-4-methanol) (0,79 g, 5,98 mm) in 40 ml of THF, and the mixture was stirred 15 h at room temperature. Excess solvent was removed under reduced pressure, and the residue was subjected to flash chromatography (SiO

Example 23. 2-Sakhalinenergo.

Dibenzyl 2-Sakhalinenergo (1.1 g) dissolved in 50 ml of methanol was subjected to hydrogenation in the presence of 10% palladium charcoal (0.3 g) for approximately 6 hours at normal melting. The solution was concentrated under reduced pressure, and obtained 2-Sakhalinenergo in the form of a thick oily residue which was then dissolved in methanol and treated with cyclohexylamine (0,59 ml). After keeping at room temperature were salt crystals, which were collected by filtration, washed with a mixture of methanol and ether, and dried, resulting in a received 0,503 g (43,9% ) dicyclohexylamine salt of the target compound, so square (shrinkage at 214-215oC).

Example 24. a) Methyl 2,2-dimethylcyclohexane-6-noncarboxylic.

To a suspension of anhydrous Cul (50.0 g, 0,37 M) in anhydrous ether (500 ml) at 0oC added free motility (520 ml of 1.4 M solution in ether, 0.73 M). After 15 minutes stirring at 0oC, was added a solution of 3-methyl-2-cyclohexen-1-it (20,0 g, 0.18 M) in ether (50 ml), and continued to stir for 1 h To the mixture was added is whether to room temperature and stirred 3 hours Then the reaction was suppressed using 2 N. HCl (50 ml). The layers were separated, and the aqueous phase was extracted with Et2O (g ml). The combined organic extracts were washed with saturated rip NH4Cl (g ml), H2O (g ml), brine (CH ml), and dried with sodium sulfate. After removal of the solvent in vacuo and purification by distillation (Kugelrohr), received 34,0 g (99%) of methyl 2,2-dimethylcyclohexane-6-noncarboxylic; so bales. 0,6 80-84oC.

b) Methyl-2-benzylthio-6,6-dimethylcyclohex-2--carboxylate and methyl-2-benzylthio-6,6-dimethylcyclohex-1-ene-carboxylate.

An acidic resin Amberlyst-15 (Amberlyst-15) (25,0 g) was mixed with polyphosphoric acid (3.0 g) and phosphoric acid (3.0 g) and heated in vacuum at 60oC for 2 h the resulting resin was mixed with methyl 2,2-dimethylcyclohexane-6-it-carboxylate (34,0 g, 0.18 M), benzylmercaptan (50.0 g, 0.40 M) and crushed sieve 4 A (20,0 g) in anhydrous dichloroethane (700 ml) was heated under reflux in nitrogen atmosphere for 18 h and cooled to room temperature. The solid was filtered, the filtrate was concentrated in vacuum and the excess benzylmercaptan drove away. The residue was purified by chromatography (YFC:hexane 2:1), and obtained 11.3 g (21%) of a mixture of methyl 2-benzylthio c) the mixture (11.3 g, 0.04 M) was dissolved in YFC (25 ml), diluted glacial acetic acid (65 ml) and then water (10 ml) was cooled to -10oC, and after the mixture was barbotirovany gaseous chlorine until then, until the exothermic reaction ceases. After the mixture is stirred 10 minutes and drained dry, which received a mixture of methyl 2-chlorosulfonyl-6,6-dimethylcyclohex-2-enecarboxylate and methyl 2-chlorosulfonyl-6,6-dimethylcyclohex-1 enecarboxylate, which was then dissolved in 10 ml THF and added to 25 ml conc. hydrocity ammonium cooling in a bath of ice and acetone. After 2-hour stirring, the reaction mixture was concentrated in vacuo, the residue was dissolved in water, acidified to pH 1 using 2 N. HCl, and was extracted with YFC. The organic phase was dried and concentrated in vacuum, which received a mixture of methyl 2-aminosulfonyl-6,6-dimethylcyclohex-2-enecarboxylate and methyl 2-aminosulfonyl-6,6-dimethylcyclohex-1 enterobacteria. The resulting mixture was dissolved in methanol (25 ml) and added to a freshly prepared solution of sodium methoxide (0.20 M), and then stirred for 12 h at room temperature. The reaction mixture was concentrated in vacuum, diluted with water and was extracted with simple ether the organic extracts were washed with saline, was dried and evaporated to dryness, resulting in a 3.5 g (42%) of 4,4-dimethyl-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-1,1-dioxide (4,4-dimethyl-4,5,6,7-tetrahydrofurane).

d) a Mixture of 4,4-dimethyl-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-1,1-dioxide (1.0 g, 4,7 mm), chloromethylbenzene (1.1 g, 7.0 mm) and tetrabutyrate ammonium (0.3 g, 0,93 mm) in toluene (25 ml) was heated under reflux in nitrogen atmosphere for 16 to 24 h, and then cooled to room temperature. The resulting mixture was evaporated to dryness and the residue was chromatographically on silica gel, elwira with a mixture of hexane and YFC (1:1 1:3), which was obtained 1.0 g (67%) 2-phenylthiomethyl-4,4-dimethyl-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-1,1-dioxide (2-phenylthiomethyl-4,4-dimethyl-4,5,6,7-tetrahydrofuran).

e) a Solution of 2-phenylthiomethyl-4,4-Limeil - 4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-she 1,1-dioxide (0.8 g, 2.4 mm) were treated with sulfurylchloride (of 0.48 g, 3.5 mm), and stirred 2 h Obtained yellow solution was drained to dryness, diluted simple ether (100 ml) and washed with saturated solution of NaHCO3and a salt solution. The organic phase was dried and concentrated in vacuo, resulting in a received 0.6 g (95%) 2-chloromethyl-4,4-dimethyl-4,5,6,7-tetrahydro-4,4-benzisothiazol-3(2H)-she triethylamine (0.7 g, 6.9 mm) in dichloroethane (15 ml) at 50oC for 16 h, and then cooled to room temperature. The resulting mixture was dried to dryness and purified using flash chromatography on silica gel (40% hexane in ethyl acetate), which was obtained 0.18 g (21%) diethyl-4,4-dimethyl-4,5,6,7-tetrahydro-3-examiniation-2-ylmethyl 1,1-di-oxitocina (diethyl-4,4-dimethyl-4,5,6,7-tetrahydro-2-Sakhalinenergo) as a colorless oily product.

Example 25. Aminobutiramida 6 ethoxy-4-isopropyl-2-saharinen-metaphosphate (example 19) can be also obtained by the method described in example 22, that is, using the reaction aminobutiramida 6-hydroxy-4 - isopropyl-2-sharinaletisha with triphenylphosphine, ethanol and diethylazodicarboxylate.

If you repeat the procedure of example 22, but instead of glyceryltrinitrate to use the appropriate alcohol, you can get aminobutiramida 4-R1-R2-R3-2-sharinaletisha (PL. 2).

2,3-dimethoxy-1-propanol, which was used in example 29 was synthesized as follows.

A solution of 10.0 g (0,055 M) DL----O-benzyl glycerol in a small amount of THF was added to the suspension 15,38 g (0,137 M) tert-butoxide potassium in 300 ml of THF. The mixture is stirred at technerdia substance. The reaction stirred 10 h at room temperature, then cooled, carefully diluted with sodium chloride solution and was extracted with ether. The organic layer was washed with water, then 5% HCl, again with water, and saturated NaCl, then dried off. The solvent was removed and the residue was purified using flash chromatography, resulting in the received 1-benzyloxy-2,3-dimethoxypropane 9,16 g 79% in the form of an oily product.

A solution of 8.8 g (0,042 M) of the obtained product in 200 ml of MeOH was subjected to hydrogenation using 1.1 g of 10% Pd/C under a pressure of 50 pounds per square inch (344,7 kPa). Then the catalyst was removed by filtration and the solvent evaporated under reduced pressure, resulting in a received 4.4 g (87%) of 2,3-dimethoxy-1-propanol.

Example 33. Through reaction aminobutiramida 6-hydroxy-4-isopropyl-2-sharingmetadata (1 M) in YFC with anhydride triftormetilfullerenov acid (1.3 M) in the presence of triethylamine (3 M) at 0oC can be obtained after standard processing and purification, aminobutiramida 4-isopropyl-6-tripterocalyx-2-chainmailvest.

Example 34. By reaction of the product of example 33 (1 M) in nitrogen atmosphere and in p-dioxane with 1-methyl-2-tributylstannyl-pyrrole (1.6 M) in prisutstvennye under reflux and after standard treatment and purification, can be obtained aminobutiramida 4-isopropyl-6-[2-(1-methylpropenyl)]-2-chainmailvest.

Example 35. By reaction of the product of example 33 (1 M) in THF with 40% aqueous dimethylamine (4,4 M) at room temperature and after standard treatment and purification, can be obtained aminobutiramida-6-dimethylamino-4-isopropyl-2-chainmailvest.

Example 36. Through reaction aminobutiramida 6-hydroxy-4-isopropyl-2-sharingmetadata in toluene di-(fluorine-butoxymethyl)methylamine at 80oC and after standard treatment and purification can be obtained ester aminobutiramida 4-isopropyl-8-methyl-2,3,7,8-tetrahydro-9H-1,3-oxazino-[6,5-g]-3-oxybisethanol-2-ylmethyl 1,1-dioxide phosphoric acid.

Example 37. By processing aminobutiramida 6-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy-4-isopropyl-2-sharinaletisha (example 22) (1 M) monohydrate p-toluensulfonate acid (0.8 M) in methanol - chloroform at room temperature, after standard processing and purification, can be obtained aminobutiramida 6-(2,3-dihydroxypropane)-4-isopropyl-2-catherinemstelmanver.

Example 38. Through reaction aminobutiramida 6-hydroxy-4-isopropyl-2-sharinaletisha (1 M) in acetone with tert-butylbromide and cleaning, can be obtained aminobutiramida 6-(2-tributoxy-2-oksidoksi)-4 - isopropyl-2-Sakhalinenergo.

Example 39. In accordance with the procedure of example 38, but using the benzyl bromoacetate instead of tert-butylbromide can be obtained aminobutiramida 6-(2-benzyloxy-2-oksidoksi)-4-isopropyl-2-Sakhalinenergo, which can then be converted into aminobutiramida 6 carboxymethoxy-4-isopropyl-2-Sakhalinenergo by hydrogenation in the presence of palladium charcoal.

Example 40. In accordance with the procedure described in example 3, but using 2-chloromethyl-4-hydroxycoumarin instead of 2-chloromethyl-4-isopropyl-6-methoxycoumarin, can be obtained dibenzyl 4-hydroxy-2-Sakhalinenergo.

Example 41. In accordance with the procedure described in example 22, dibenzyl 4-hydroxy-2-Sakhalinenergo may be subjected to reaction with diethyldithiocarbamate, triphenylphosphine and benzyl alcohol to obtain dibenzyl 4-benzyloxy-2-sharinaletisha.

In accordance with the procedure described in example 3, each of the 4-R1-R2-R3-2-chlorotriazine preparations 1-86; 4-R4-4-R5-6-R6-chloromethyl-4,5,6,7-tetrahydrocanabinol preparations 87, 88, 9 is, may be subjected to the reactions of each of the complex di-esters of phosphoric acid, complex mono-esters of phosphoric acid and phosphinic acids of the formula III, are presented in table. 3 and in Fig. 5, to obtain the corresponding compounds of formulas I, II and IIA, respectively.

Complex mono(2-methylpropyl)-ether of methylsulfonic acid and complex monopoloy ester of methylphosphonic acid in the table. 3 can be obtained by hydrolysis of (2-methylpropyl) ester methylphosphonochloridate and phenyl ester methylphosphonochloridate, respectively.

Etilenoprovodov acid and isopropylphenoxy acid in the table. 3 can be obtained by traditional O-alkyl cleavage of the corresponding methyl ethers, for example, by reaction with trimethylsilylpropyne [(CH3)3SiBr] and hydrolysis formed so difficult trimethylboron ether.

Traditional acid hydrolysis of compounds resulting from each of the reactions hlorofilovykh compounds of preparations 1-96, with a compound of formula III, where A and B together are:

< / BR>
where R9and R10together represent isopropylidene (Fig. 5) gives the relevant soedin (leukocyte elastase-inhibitory complex has been described for the constants true reversible inhibition, related to competitive inhibitors [Cha, Biochem. Pharmacol. 24, 2177-2185 (1975)] However, the compounds of the present invention do not form a truly reversible inhibitory complexes, and to some extent absorbed by the enzyme. Therefore, in this experiment, instead of that which was calculated as the ratio , i.e. the ratio of the rate of reactivation of the enzyme in the rate of inactivation of the enzyme. First, measured values , and then calculate .

The rate of inactivation, the enzyme activity of the tested compounds was determined by measuring the enzymatic activity of the corresponding enzyme as a function of time after addition of test compounds. By constructing a curve of the logarithm of enzyme activity from the time received, the observed rate of inactivation, which can be represented in the form where t 1/2 is the time required for the enzyme activity decreased by 50% Thus, the rate of inactivation is:

< / BR>
where [1] represents the concentration of inhibitory compounds.

Similarly defined constant reactivation, after which calculated the inhibition constant as:

< / BR>
Values determined 0,035.

1. Sharonlee or 4,5,6,7-tetrahydro-2-sharinaletisha-phosphonates or phosphinate General formula I

< / BR>
where M represents a group of the formula

< / BR>
or

< / BR>
R1hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, lower alkenyl, lower quinil or amino group;

R2hydrogen, hydroxy, halogen, lower alkyl, lower alkoxyl;

R3hydrogen, halogen, lower alkyl, cycloalkyl, lower alkoxy or carboxypropyl or 1,3-deoxythymidine alkoxyl;

m and n are 0 or 1;

A and B are hydroxy,

lower alkyl, benzyl or phenyl, or their acidic additive or basic additive salt.

2. The pharmaceutical composition inhibiting the proteolytic enzyme containing the active principle derived 2-substituted sharenow and pharmaceutically acceptable filler, characterized in that the active agent it contains 2-sharonlee or 4,5,6,7-tetrahydro-2-Sakhalinenergo, -phosphonate or phosphinate formula I under item 1 or acidic additive or basic additive salt in an effective amount.

 

Same patents:

The invention relates to new derivatives methylenephosphonic acid of General formula I

< / BR>
in which R1, R2, R3and R4independently are C1-C10the alkyl straight or branched chain, optionally unsaturated, C3-C10-cycloalkyl, optionally unsaturated, aryl, aralkyl, silicom SiR3or hydrogen, in formula I, at least one of the groups R1, R2, R3and R4is hydrogen and at least one of the groups R1, R2, R3and R4different from hydrogen

The invention relates to a technology for obtaining esters vinylphosphonic acid, which finds wide use as a reactive flame retardants and plasticizers in the production of various polymer materials

The invention relates to the chemistry of phosphorus - organic compounds, and in particular to a new method of obtaining S-triphenylcarbinol esters of dealkylation and tetrathiofulvalene acids of General formula (I)

(RX)SGePh3where R is lower alkyl; X Is 0, S

The invention relates to new phosphorylated to Surinam General formula

R-- OCH2-COOH,

(I) where R is a saturated or unsaturated aliphatic hydrocarbon residue with a straight or branched chain, containing 6-30 carbon atoms which may be substituted with halogen, -OR, - SR1or-NR1R2group, where R1and R2lowest alkali

The invention relates to organic chemistry and can be used to obtain phosphonates, which can be used to reduce the Flammability of polymer materials

The invention relates to the chemistry of organophosphorus compounds with s-R connection, namely to a new connection, 4-trimethylsilylethynyl-2-trimethylsiloxy-C-2-cyanobutane formula I

CH< / BR>
(I) which can be used as an intermediate product to obtain 4-methylhydroxypropyl-2-aminobutane - howl acid (phosphinotricin) formulas II

CHO)CH2CHOOH

(II) with high herbicide activity and finds application in agriculture (in the form of monoammonium salt) as a contact herbicide continuous spectrum, and the means of obtaining it

The invention relates to the chemistry of organophosphorus compounds with s-R connection, namely to a new connection - 4-trimethylsilylethynyl-2-trimethylsiloxy--2-butenonitrile formula I

MeCH=where Me is methyl, which can be used as an intermediate for obtaining 4-methylhydroxypropyl-2-clobutinol acid of the formula II

MeO)CH2CH-COOH with high herbicide activity and finds application in agriculture as a systemic herbicide (1), and the method of its production

The invention relates to new 2-sharonlee heterocyclic carboxylates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, to a method of their use for the treatment of diseases associated with degeneration of the tissues, and to a method of production thereof

The invention relates to the production of heterocyclic compounds containing two cyclic selftimer grouping in a single aromatic nucleus such as diimide 4,6-Desulfovibrio acid (dithio-m-bisharin), formulas

HNNH,

which can be used as a monomer for the synthesis of new geterotsiklicheskikh heat-resistant polymers, new polymers with a system of conjugate relations, as well as new reactive oligomers
The invention relates to medicine and can be used to treat breast cancer stage III - IV
The invention relates to gynecology and could be used for the treatment of uterine and ovarian cancer stage III - IV
Up!