8-chloro-6-sulfonylacetanilide acid and the method of their derivation, their ethers and method of production thereof, the ester of 6,8 - dichlorocinnamic acid and method of production thereof, a method of obtaining 6,8-dichlorocinnamic acids and the method of obtaining- lipoic acid (the comparisons)

 

(57) Abstract:

The present invention relates to a method for producing 8-chloro-6-sulfonylacetanilide acids of formula I and, respectively, their alkyl esters of formula II, and 6,8-dichlorocinnamic acid and its alkyl esters of the formula III as intermediates in the synthesis of the enantiomers-lipoic acid, as well as methods of conversion of enantiomers of 8-chloro-6-hydroxyoctanoic acid enantiomers-lipoic acid. The method of obtaining enantiomers-lipoic acid is that 8-chloro-hydroxyoctanoic acid etherification education alilovic esters, which are then subjected to reaction with sulphonylchloride and tertiary nitrogenous base and get alkalemia esters of 8-chloro-6-sulfonylacetanilide acids that interact with the alkali metal disulfides, sulfur is transferred to dihydrolipoic acid oxidation which get-lipoic acid. This way using the new intermediate products allows you to get enantiomer-lipoic acid with a theoretical yield of 100%. 15 C. and 3 h.p. f-crystals.

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The technical field

The invention relates to a method for-lipowy what's acid of formula VI enantiomeric purity. The invention includes description of new (+)- and (-)-8-chloro-6 - sulfonylacetanilide acids of formula I and their alkyl ethers of the formula II enantiomeric purity, the new esters of (+)- and (-)-6,8 - dichlorocinnamic acid of the formula III and methods for their preparation, and methods of obtaining lipovich acids and dihydrolipoic acid enantiomeric purity.

-Lipoic acid - 3-(4-carboxybutyl)-1,2-ditiolan (thioctic acid).

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Art

R-enantiomer-lipoic acid is a natural substance that is present in small quantities in almost all tissues of animals and plants. As a coenzyme-lipoic acid is involved in the reaction of oxidative decarboxylation of-keto acids (e.g., pyruvic acid). -Lipoic acid is of interest to pharmacology, because it has anti-inflammatory, analgesic and cytoprotective effect. Important medical indication is treatment-lipoic acid diabetic polyneuritis. According to the latest data (CA 116: 207360) -lipoic acid may be useful in the treatment of diseases caused by viruses HIV-1 and HTLV III BC

As for your is from the racemate, The R-enantiomer has a predominantly anti-inflammatory, and S-enantiomer is mainly analgesic effect (EP 0427247, 08.11.90). As a consequence, the synthesis of pure enantiomers, in particular the R-form, is of great practical importance.

Known methods for producing-lipoic acid enantiomeric purity include the splitting of the racemate of the final product or its predecessors, asymmetric synthesis using chiral compounds and reagents, enantiospecific syntheses based on natural optically active precursors, as well as microbiological synthesis (review: J. S. Yadav et al., J. Sci. Ind. Res. 1990, 49, 400; and also: A. G. Tolstikov et al., Bioorg.chem., 1990, 16, 1670; L. Dasaradhi et al., J. Chem.Soc., Chem. Commun. 1990, 729: A. S. Gopalan et al. , J. Chem.Perkin Trans. 1 1990, 1897: A. S. Gopalan et al., Tetrahedron Lett. 1989, 5705; EP 0487986 A2, 14.11.91).

Of these the most practical methods to date remains the method of splitting of the racemate, based on the formation of diastereomeric salts-lipoic acid with optically active-methylbenzylamine (DE-OS 4137773.7, 16.11.91). The disadvantages of the method include the fact that the splitting of the racemate is carried out only at the last stage of the synthesis, when the side enantiomer is impossible to raamisolatie or Intesa, only one enantiomer can be used to obtain the target product (-lipoic acid enantiomeric purity), and therefore, theoretically, the output can be achieve only 50% (E. Walton et al., J. Am. Chem.Soc. 1955, 77, 5144; D. S. Acker, W. J. Wayne, J. Am.Chem.Soc., 1957, 79, 6483; L. G. Chebotarev, A. M. Yurkevich, Chem. Pharm. W., 1980, 14, 92).

The invention

The aim of the present invention is to develop a method of obtaining-lipoic and dihydrolipoic acid enantiomeric purity, when the splitting of the racemate is carried out at the earliest possible stages of the synthesis, and transformation of both side of the enantiomers of 8-chloro-6-hydroxyoctanoic acid in the target enantiomer-lipoic acid occurs with a theoretical yield of 100% without additional racemization and inversion.

In schemes 1 and 2, presents the sequence of reactions leading to the R-(+)- and S-(-)- -of lipovich acids. In the diagram, R is predominantly a linear or branched C1-C4is an alkyl group, including methyl-, ethyl-, n-propyl, ISO-propyl, n-butyl, ISO-butyl, tert-butyl, mainly methyl; R' is predominantly methyl-, p-tolyl group.

The original connection of racemic 8-chloro-6-hydroxyoctanoic acid of formula VI had known what="ptx2">

Optically pure (+)-8-chloro-6-hydroxyoctanoic acid and (-)-8-chloro-6 - hydroxyoctanoic acid was obtained by interaction of racemic 8-chloro-6-hydroxyoctanoic acid with optical antipodes-methylbenzylamine, education diastereomeric salt pairs and allocation of poorly soluble salts, followed by decomposition of the pure diastereomeric salts of (+)-8-chloro-6-hydroxyoctanoic acid and R-(+)- -methylbenzylamine and, respectively, ( -)-8-chloro-6-hydroxyoctanoic acid and S-(-)- -methylbenzylamine. The decomposition of salts spent acids, e.g. mineral acids or bases, such as hydroxides of alkali metals.

The purpose of the invention is achieved by the fact that both enantiomers of 8-chloro-6-hydroxyoctanoic acid of formula VI is directly transferred to R-lipoic acid of formula (+)-IV according to the following sequence of reactions: (+)-8-chloro-6-hydroxyoctanoic acid and its alkyl esters, the process sulfochloride with retention of configuration, and (-)-8-chloro-6-hydroxyoctanoic acid and its alkyl esters, glorious treatment configuration. Subsequent introduction into the molecule of sulfur atoms all intermediate compounds in the quality of the final product P CLASS="ptx2">

Of enantiomers of 8-chloro-6-hydroxyoctanoic acid of the formula VI can stereospecific with retention of configuration in the presence of catalytic amounts of HCl to obtain alkyl esters of the formula VIII, predominantly methyl ether.

Then from alkyl-(+)-8-chloro-6-hydroxyoctanoic formula (+)-VIII enantiomeric purity can save the configuration to get alkyl-(+)-8-chloro-6-sulfonylmethane formula (+)-II from which to synthesize (-)-dihydrolipoic formula (-)-V or (+)- dihydrolipoic formula (+)-V acid.

However, (+)- 8-chloro-6 - hydroxyoctanoic acid of formula (+)-VI directly through intermediate obtain (+)-8-chloro-6-sulfonylacetanilide acid of formula (+)-I high yield stereospecific directionally translate (-)-dihydrolipoic formula (-)-V or R-lipoic formula (+)-IV acid. In this case, the synthesis of formula (+)-I is carried out in the presence of 2.0-2.2 mol. EQ. sulfochloride and 1.5 to 2.5, preferably of 2.0 and 2.1 mol. EQ., tertiary nitrogenous base, preferably triethylamine.

The method of obtaining optical isomers-lipoic acid of the formula IV from dihydrolipoic acids optical purity by oxidation with air oxygen in the presence of catalytic-8-chloro-6-hydroxyoctanoic formula (-)-VIII enantiomeric purity by reaction with thionyl chloride in the presence of catalytic amounts of pyridine with the address configuration get alkyl-(+)-6,8-dichloroquinoline formula (+)-III. Subsequent introduction into the molecule of sulfur atoms by tonirovaniem using Na2S2leads to the formation of R-lipoic acid of formula (+)-IV high optical purity.

Similarly from (-)-8-chloro-6-hydroxyoctanoic acid of formula (-)-VI with high yield (+)-6,8 - dichlorooctane acid of formula (+)-VII, if the chlorination carried out in the presence of 1.5-5, preferably 2.0 to 2.5 mol.EQ. thionyl chloride, and then to carry out the hydrolysis of the reaction mixture with aqueous solutions of bases, preferably sodium hydroxide. Subsequent translation of (+)-6,8-dichlorocinnamic acid with Na2S2in R-lipoic acid is described in the literature (D. S. Acker, W. J. Wayne, J. Am. Chem.Soc., 1957, 79, 6483).

(+)- and (-)-dihydrolipoic acid can also be obtained by hydrogenation of S(-)- - and, respectively, R(+)- -of lipovich acids by known methods.

All these reactions are carried out in suitable organic solvents. As the organic solvent can be, for example, used the hydrocarbons containing in the chain from 3 to 10 carbon atoms, liquid aromatic hydrocarbons, esters of aliphatic and cycloaliphatic carboxylic acids containing from 2 to 6 uglerodnaya and glimepirid, or a homogeneous mixture of these solvents. Most preferred are ethyl acetate, cyclohexane, toluene, ethanol, and made of them a homogeneous mixture.

The degree of purity of the optical isomers and the diastereomeric salts was determined by the value of the specific optical rotation. While the relative content of the optical isomer of 8-chloro-6 - hydroxyoctanoic acid of formula VI and a-lipoic acid of the formula IV was determined by HPLC on optically active sorbents with accuracy of 0.5%. Optical purity alkyl-(+)-8-chloro-6 - hydroxyoctanoic formula VIII is additionally determined by the method of 1H-NMR of its ester (hydroxy group) with (S)-(+)-O-acetylindole acid.

The present invention allows to obtain the enantiomers-lipoic acid is a simple and effective way, with high chemical and optical yield.

Information confirming the possibility of carrying out the invention

Summary of the invention the following examples.

Example 1

and 39.9 g (204 mmol) of racemic 8-chloro-6 - hydroxyoctanoic acid (+)/(-)-VI was dissolved in 4oC in 155 ml of a mixture of ethyl acetate/cyclohexane (1:1). Within 10 min of the portions was added 13.5 g (112 mm is an ethyl acetate/cyclohexane (1:1) and 30 ml of cyclohexane. Salt recrystallize twice from 400 ml of a mixture of ethyl acetate/cyclohexane (3:1) and dried in vacuum at 40oC. Got to 20.5 g (+)(+)- diastereomer salt, []20D= +22,7o(C=1; ethanol).

Salt suspended at 20oC in 220 ml of diethyl ether. While cooling and stirring was slowly acidified with 3 N. hydrochloric acid to pH 1, and the salt went into solution. After 30 min, the separated organic phase, once washed 20 ml of 2 N. HCl, twice with 20 ml water and dried with magnesium sulfate. After removal of the solvent in vacuum obtained 10.8 g (54% of theory.) (+)-8-chloro - 6-hydroxyoctanoic acid (+)-VI; []20D= +24,5o(C= 1, ethanol), taking into account the error definition: > 99% (HPLC), so pl. 29-30oC.

Example 2

33,9 g (173 mmol) of racemic 8-chloro-6 - hydroxyoctanoic acid (+)/(-)-VI was dissolved at 40oC in 130 ml of a mixture of ethyl acetate/cyclohexane (1:1). Within 10 min of the portions was added to 11.5 g (95 mmol) of S-(-)- -methylbenzylamine. After 2 h, cooled to 20oC, the precipitate was separated by filtration, washed with 17 ml of a mixture of ethyl acetate/cyclohexane (1:1) and 25 ml of cyclohexane. Salt recrystallize twice from 340 ml of a mixture of ethyl acetate/cyclohexane (3:1) and dried in vacuum at 40oC. Received and 17.2 g (-)(-)-dia is 0 ml of diethyl ether. While cooling and stirring was slowly acidified with 3 N. hydrochloric acid to pH 1, and the salt went into solution. After 30 min, the separated organic phase, once washed with 17 ml of 2 N. HCl, twice with 20 ml water and dried with magnesium sulfate. After removal of the solvent in vacuo got 9.1 g (53% of theory.) (-)-8 - chloro-6-hydroxyoctanoic acid (-)-VI; []20D-24,5o(C=1, ethanol), taking into account the error definition: > 99% (HPLC), so pl. 29-30oC.

Example 3

6.4 g (32,9 mmol) of (+)-8-chloro-6-hydroxyoctanoic acid (+)-VI boiled under reflux in 100 ml of absolute methanol in the presence of 0.4 ml of conc. hydrochloric acid for 2 hours Then the solvent was distilled in vacuum. Received 6.6 g (97% of theory.) methyl-(+)-8-chloro-6-hydroxyoctanoic (+)-VIII (R=Me) [] 20D= +24,5o(C=1, ethanol), taking into account the error definition: > 99% (1H-NMR).

Example 4

7.7 g (to 39.5 mmol) of (-)-8-chloro-6-hydroxyoctanoic acid (-)-VI boiled under reflux in 120 ml of absolute methanol in the presence of 0.5 ml of conc. hydrochloric acid for 2 hours Then the solvent was distilled in vacuum. Got 7.9 g (97% of theory.) methyl-(-)-8-chloro-6-hydroxyoctanoic (-)-VIII (R=Me) [] 20D= -24,5o(c=1, ethanol), taking into account errors ODA is 4.1 g (40 mmol) of triethylamine were mixed in 80 ml of toluene. When cooled (10-15oC) was slowly added 3.5 g (30,6 mmol) methanesulfonamide. Was stirred for 30 min, was added 25 ml of water and again stirred for 30 min, separated the organic phase and dried with magnesium sulfate. The solvent was evaporated in vacuum. Obtained 3.8 g (69% of theory.) (+)-8-chloro-6 - methyloxycarbonyl acid (+)-I (R'=Me), []20D= +32,9o(C=1; ethanol).

Example 6

6.6 g (34 mmol) of (-)-8-chloro-6-hydroxyoctanoic acid (-)-VI and 7.0 g (68 mmol) of triethylamine were mixed in 140 ml of toluene. When cooled (10-15oC) was slowly added 6.0 g (52,6 mmol) methanesulfonamide. Was stirred for 30 min, was added 40 ml of water and again stirred for 30 min, separated the organic phase and dried with magnesium sulfate. The solvent was evaporated in vacuum. Got 6.5 g (70% of theory.) (-)-8-chloro-6 - methyloxycarbonyl acid (-)-I (R'=Me), []20D= -32,8o(C=1; ethanol).

Example 7

4.0 g (19.2 mmol) of methyl-(+)-8-chloro-6 - hydroxyoctanoic (+)-VIII (R=Me) and 1.97 g (19.2 mmol) of triethylamine were mixed in 90 ml of toluene. When cooled (10-15oC) was slowly added 2,63 g (23,0 mmol) methanesulfonamide. Was stirred for 30 min, was added 30 ml of water and again stirred for 30 min, and separated organizescooperation (+)-II (R=R'=Me), []20D= +31,2o(C=1; ethanol).

Example 8

2.1 g (10 mmol) of methyl-(-)-8-chloro-6 - hydroxyoctanoic (-)-VIII (R=Me) and 1.0 g (10 mmol) of triethylamine were mixed in 40 ml of toluene. When cooled (10-15oC) was slowly added 1.4 g (12 mmol) of methanesulfonamide. Was stirred for 30 min, was added 25 ml of water and again stirred for 30 min, separated the organic phase and dried with magnesium sulfate. The solvent was evaporated in vacuum. Received 2.5 g (86% of theory.) methyl-(-)-8-chloro-6-methylacetanilide (-)-II (R=R'=Me), []20D= -31,3o(C=1; ethanol).

Example 9

To a solution of 2.4 g (11.0 mmol) of methyl-(+)-8-chloro-6 - hydroxyoctanoic (+)-VIII (R= Me) and 0.04 g (0.5 mmol) of pyridine in 8 ml of toluene was slowly added a solution of 1.6 g (13.5 mmol) of thionyl chloride in 5 ml of toluene. Boiled under reflux for 1 h After cooling to room temperature was added to the reaction mixture 20 ml of ice water, the separated organic phase was washed with 10 ml water and dried with magnesium sulfate. The solvent was evaporated in vacuum. Received 2.0 g (81% of theory.) methyl-(-)-6,8-dichloroquinoline (-)-III (R=Me) [] 20D= -30,0o(c=1; benzene).

Example 10

To a solution of 2.9 g (13,2 mmol) methyl-(-)-8-chloro-6 - hydroxyoctanoic (-)-VIII (R= Me) and 0.05 g (0,6 the under reflux for 1 h After cooling to room temperature was added to the reaction mixture of 25 ml of ice water, the separated organic phase was washed with 10 ml water and dried with magnesium sulfate. The solvent was evaporated in vacuum. Received 2.4 g (81% of theory.) methyl-(+)-6,8 - dichloroquinoline (+)-III (R=Me) [] 20D= +30,1o(c=1; benzene).

Example 11

To a solution of 2.4 g (12.3 mmol) of (+)-8-chloro-6 - hydroxyoctanoic acid (+)-VI and 0.05 g (0.6 mmol) of pyridine in 30 ml of toluene was slowly added to 3.3 g (27.7 mmol) of thionyl chloride. Boiled under reflux for 1 h After cooling to room temperature was added to the reaction mixture 50 ml of ice water, the separated organic phase was washed with 20 ml water and stirred 4 h with 30 ml of 2 N. NaOH. Separated aqueous phase was acidified 3 N. HCl to pH 1, extracted with diethyl ether (2x20 ml). The combined extract was dried with magnesium sulfate. The solvent was evaporated in vacuum. Obtained 2.1 g (80% of theory.) (-)-6,8 - dichlorocinnamic acid (-)-VII, []20D= -30,6o(c= 1: benzene).

Example 12

To a solution of 3.0 g (15,4 mmol) of (-)-8-chloro-6-hydroxyoctanoic acid (-)-VI and 0.06 g (0.8 mmol) of pyridine in 40 ml of toluene was slowly added 4.1 g (to 34.4 mmol) of thionyl chloride. Boiled under reflux for 1 h Poslaju, washed with 20 ml water and stirred 4 h with 35 ml of 2 N. NaOH. Separated aqueous phase was acidified 3 N. HCl to pH 1, extracted with diethyl ether (2x20 ml). The combined extract was dried with magnesium sulfate. The solvent was evaporated in vacuum. Obtained 2.6 g (80% of theory.) (+)-6,8 - dichlorocinnamic acid (+)-VII, []20D= +30,5o(C= 1; benzene).

Example 13

A mixture of 4.6 g (19 mmol) of nonahydrate of sodium sulfide (Na2S9H2O) and 0.61 g (19 mmol) of sulfur in 40 ml of ethanol was boiled under reflux for 15 minutes After 2 h at a temperature of 20oC was added a solution of 4.9 g (17 mmol) of methyl-(+)-8-chloro-6-methylacetanilide (+)-II (R=R'=Me) in 5 ml ethanol and was stirred for 3 hours Then added 24 ml of 10% NaOH and was stirred for 2 h at 25oC. After evaporation of the ethanol under vacuum to the reaction mixture for 10 min at 25oC was added a solution of 0.37 g (9.7 mmol) of detribalized in 10 ml of 1% NaOH, while stirring slowly heated to 100oC, stirred at this temperature for 1 h, After cooling, the reaction mixture was acidified using conc. HCl to pH 1 and extracted with diethyl ether (2x20 ml). The organic phase is dried with sodium sulfate, the solvent was evaporated in vacuum. Obtained 2.8 g (79% of theory.) (-)-dihydrolipoic Calatafimi sodium and 0.41 g (13 mmol) of sulfur in 25 ml of ethanol was boiled under reflux for 15 minutes After 2 h at a temperature of 20oC was added a solution of 3.3 g (11 mmol) of methyl-(-)-8-chloro-6 - methylacetanilide (-)-II (R=R'=Me) in 5 ml ethanol and was stirred for 3 hours Then added 15 ml of 10% NaOH and was stirred for 2 h at 25oC. After evaporation of the ethanol under vacuum to the reaction mixture for 10 min at 25oC solution was added 0.25 g (6.6 mmol) of detribalized in 10 ml of 1% NaOH, while stirring slowly heated to 100oC, stirred at this temperature for 1 h, After cooling, the reaction mixture was acidified using conc. HCl to pH 1 and extracted with diethyl ether (CH ml). The organic phase is dried with sodium sulfate, the solvent was evaporated in vacuum. Received of 1.9 g (83% of theory.) (+)- dihydrolipoic acid (+)-V []20D= +13,7o(or=1.5; ethanol).

Example 15

A mixture of 1.5 g (6.3 mmol) of nonahydrate of sodium sulfide and 0.2 g (6.3 mmol) of sulfur in 15 ml of ethanol was boiled under reflux for 15 minutes After 2 h at a temperature of 20oC was added a solution of 1.5 g (5.5 mmol) of (+)-8-chloro-6-methyloxycarbonyl acid (+)-I in 4 ml of ethanol and was stirred for 3 hours Then added 15 ml of 10% NaOH and was stirred for 2 h at 25oC. After evaporation of the ethanol under vacuum to the reaction mixture for 10 min at 25< 100oC, stirred at this temperature for 1 h, After cooling, the reaction mixture was acidified using conc. HCl to pH 1 and extracted with diethyl ether (2x10 ml). The organic phase is dried with sodium sulfate, the solvent was evaporated in vacuum. Obtained 0.8 g (70% of theory.) (-)-dihydrolipoic acid (-)-V []20D= -13,5o(C= 1.0, ethanol).

Example 16

A mixture of 1.8 g (7.6 mmol) of nonahydrate of sodium sulfide and 0.24 g (7.6 mmol) of sulfur in 18 ml of ethanol was boiled under reflux for 15 minutes After 2 h at a temperature of 20oC was added a solution of 1.8 g (6.6 mmol) of (-)-8-chloro-6-methyloxycarbonyl acid (-)-I in 5 ml of ethanol and was stirred for 3 hours Then added 18 ml of 10% NaOH and was stirred for 2 h at 25oC. After evaporation of the ethanol under vacuum to the reaction mixture for 10 min at 25oC was added a solution of 0.14 g (3.8 mmol) of detribalized in 5 ml of 1% NaOH, while stirring slowly heated to 100oC, stirred at this temperature for 1 h, After cooling, the reaction mixture was acidified using conc. HCl to pH 1 and extracted with diethyl ether (2x10 ml). The organic phase is dried with sodium sulfate, the solvent was evaporated in vacuum. Received 1.0 g (73% of theory.) (+)-dihydrolipoic acid (+)-V []sodium and 0.08 g (2.6 mmol) of sulfur in 10 ml of ethanol was boiled under reflux for 15 minutes After 1 h at a low boil added a solution of 0.55 g (2.4 mmol) of methyl-(+)-6,8 - dichloroquinoline (+)-III (R=Me) in 5 ml of ethanol. Was stirred for 15 min, drove 8 ml of ethanol. Then added 10 ml of 0.5 N. NaOH and was stirred for 12 h at 25oC. After acidification of the reaction mixture conc. HCl until pH 1 was extracted with diethyl ether (2x20 ml), the organic phase is dried with sodium sulfate, the solvent was evaporated in vacuum. After recrystallization from cyclohexane obtained 0.28 g (57% of theory.) R - (+) - a-lipoic acid (+)-IV, so pl. 44-46oC, taking into account the error definition: > 99% (HPLC).

Example 18

A mixture of 0.87 g (3.6 mmol) of nonahydrate of sodium sulfide and 0.11 g (3.6 mmol) of sulfur in 15 ml of ethanol was boiled under reflux for 15 minutes After 1 h at a low boil added a solution of 0.77 g (3.4 mmol) of methyl-(-)-6,8 - dichloroquinoline (-)-III (R=Me) in 7 ml of ethanol. Was stirred for 15 min, drove 12 ml of ethanol. Then added 14 ml of 0.5 N. NaOH and was stirred for 12 h at 25oC. After acidification of the reaction mixture conc. HCl until pH 1 was extracted with diethyl ether (2x20 ml), the organic phase is dried with sodium sulfate, the solvent was evaporated in vacuum. After recrystallization from cyclohexane got 0,38 g (54% of theory.) S-(-)- - -lifeevanecense acid of the formula I

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where R' is a linear or branched C1-C4is an alkyl group.

2. (+)- and (-)-8-chloro-6-sulfonylacetanilide acid of the formula I on p. 1, characterized in that they are intended for use as intermediates in obtaining enantiomers-lipoic acid.

3. Esters of (+)- and (-)-8-chloro-6-sulfonylacetanilide acids of the formula II

< / BR>
where R and R' represent linear and branched C1-C4is an alkyl group.

4. Alkalemia esters of (+)- and (-)-8-chloro-6-sulfonylacetanilide acids of the formula II under item 3, characterized in that they are intended for use as intermediates in obtaining the enantiomers, lipovich acids.

5. Esters of (+)- and (-)-6,8-dichlorocinnamic acid of the formula III

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where R is a linear or branched C1-C4is an alkyl group.

6. Alkalemia esters of (+)- and (-)-6,8-dichlorocinnamic acids of the formula III under item 5, characterized in that they are intended for use as intermediates in obtaining enantiomers-lipoic acid.

7. The way to obtain (+)- or (-)-8-chloro-6-sulfonylacetanilide acids of the formula I in p. 1, characterized in that (+)- or (-)-8-chloro-6-gidroochistke base at a temperature of 0-30oWith in an organic solvent.

8. The method of obtaining alilovic esters of (+)- or (-)-8-chloro-6-sulfonylacetanilide acids of the formula II in paragraph 3, characterized in that alkalemia esters of (+)- or (-)-8-chloro-6-hydroxyoctanoic acid is subjected to interaction with 1.0 to 1.5 mol. EQ. sulphonylchloride and 1.0 to 1.5 mol. EQ. tertiary nitrogenous base at 0-30oWith in an organic solvent.

9. The method of obtaining alilovic esters of (+)- or (-)-6,8-dichlorocinnamic acid of the formula III in paragraph 5, characterized in that alkalemia esters of (+)- or (-)-8-chloro-6-hydroxyoctanoic acid is subjected to interaction with 1.0 to 2.0 mol. EQ. thionyl chloride in the presence of catalytic amounts of pyridine at 60-130oWith in an organic solvent.

10. The way to obtain (+)- or (-)-6,8-dichlorocinnamic acid, characterized in that the corresponding (+)- or (-)-8-chloro-6-hydroxyoctanoic acid is subjected to interaction with 1.5 to 5.0 mol. EQ. thionyl chloride in the presence of catalytic amounts of pyridine at 60-130oWith in an organic solvent.

11. The way to obtain R-(+)--lipoic acid, wherein (+)-8-chloro-6-hydroxyoctanoic acid is subjected to interaction with sulphonylchloride and tertiary nitrogenous Vij with disulfides alkali metal and sulfur is transferred to (-)-dihydrolipoic acid, oxidation which receive the target connection.

12. The way to obtain R-(+)--lipoic acid, wherein (+)-8-chloro-6-hydroxyoctanoic acid etherification education alilovic esters, which are then subjected to reaction with sulphonylchloride and tertiary nitrogenous base and get alkalemia esters of (+)-8-chloro-6-sulfonylacetanilide acid of formula (+)-II in paragraph 3 that the interaction with the disulfides of alkali metals and sulfur translate (-)-dihydrolipoic acid oxidation which receive the target connection.

13. The way to obtain S-(-)--lipoic acid, wherein (-)-8-chloro-6-hydroxyoctanoic acid is subjected to interaction with sulphonylchloride and tertiary nitrogenous base to obtain (-)-8-chloro-6-methyloxycarbonyl acid of formula (-)-I in paragraph 1, which then interact with the disulfides of alkali metals and sulfur is transferred to (+)-dihydrolipoic acid oxidation which receive the target connection.

14. The way to obtain S-(-)--lipoic acid, wherein (-)-8-chloro-6-hydroxyoctanoic acid etherification education alilovic esters, which are then subjected to reaction with sulphonylchloride and tertiary nitrogenous Sodeistvie with disulfides alkali metal and sulfur is transferred to (+)-dihydrolipoic acid, oxidation which receive the target connection.

15. The way to obtain R-(+)--lipoic acid, wherein (-)-8-chloro-6-hydroxyoctanoic acid is subjected to interaction with thionyl chloride in the presence of pyridine to obtain (+)-6,8-dichlorocinnamic acid, which then interact with the disulfides of alkali metals and sulfur is transferred to the target connection.

16. The way to obtain R-(+)--lipoic acid, wherein (-)-8-chloro-6-hydroxyoctanoic acid etherification education alilovic esters, which are then subjected to reaction with thionyl chloride in the presence of pyridine and get alkilany ether (+)-6,8-dichlorocinnamic acid of formula (+)-III in paragraph 5, which by interaction with the disulfides of alkali metals and sulfur is transferred to the target connection.

17. The way to obtain S-(-)--lipoic acid, wherein (+)-8-chloro-6-hydroxyoctanoic acid is subjected to interaction with thionyl chloride in the presence of pyridine to obtain (-)-6,8-dichlorocinnamic acid, which then interact with the disulfides of alkali metals and sulfur is transferred to the target connection.

18. The way to obtain S-(-)--lipoic acid, wherein (+)-8-chloro-6-guide what analgorithm in the presence of pyridine and get alkilany ether (-)-6,8-dichlorocinnamic acid of formula (-)-III p. 5, which by interaction with the disulfides of alkali metals and sulfur is transferred to the target connection.

 

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