8-halogen-6-hydroxyoctanoic acid, their esters, salts and methods for their preparation

 

(57) Abstract:

The invention relates to new (+) or (-)-8-halogen-6-hydroxyoctanoic acids of the formula I, where X denotes Cl, Br, I, alkyl esters of formula II and their salts with methylbenzylamino formula III. The method of obtaining isomers of 8-halogen-6-hydroxyoctanoic acid of formula I by decomposition of the pure diastereomeric salts of the formula III by treatment with inorganic or organic acids or bases. The method of obtaining alilovic esters 8-halogen-6-hydroxyoctanoic acid of formula II by transferring 8-halogen-6-hydroxyoctanoic acid of formula I to compound of formula II in the presence of catalytic amounts of Hcl at a temperature of 50 - 100oC, preferably at 60oSince, in the solvent used, the corresponding alcohol, and the reaction takes place stereospetsifichno with retention of configuration. The method of obtaining salts of formula III by treating the racemic mixture of (+)-8-halogen-6-hydroxyoctanoic acid and (-)-8-halogen-6-hydroxyoctanoic acid or any mixture of isomers (+) and (-)-8-halogen-6-hydroxyoctanoic acid enantiomers-methylbenzylamine in the solution and then spend the recrystallization of the diastereomeric compounds. TechNet. 7 C. and 3 h.p. f-crystals.

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The invention relates to new (+) and (-)- 8-halogen-6-hydroxyoctanoic acids (halogen = chlorine, bromine and iodine) of the formula I, their alkyl esters of formula II and their salts with optically active-methylbenzylamino formula III, which in turn are used as intermediates for obtaining lipovich acid enantiomeric purity of the formula IV, and dihydrolipoic acid enantiomeric purity of the formula V-Lipoic acid - 3-(carboxybutyl)-1,2-ditiolan (thioctic acid).

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Prior 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 sour/P> As for the properties of optically pure isomers-lipoic acid (R - and S-enantiomers, i.e., R-lipoic and S--lipoic acid), in contrast to 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 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 and others, 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 Ozmone to raamisolatie or invert. In other known methods, when the splitting of the racemate is performed on the preliminary stages of the synthesis, in each case 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. Waltonet 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. J., 1980, 14, 92).

The invention

The aim of the invention is the synthesis of intermediate products to obtain-lipoic and dihydrolipoic acid enantiomeric purity, which can be used to obtain the desired enantiomer-lipoic acid or dihydrolipoic acid with the release of 100% of theory.

Starting compound for the synthesis of intermediate products is racemic 8-chloro-6-hydroxyoctanoic and 8-bromo-6 - hydroxyoctanoic acid of formula I (X= Cl,Br) are obtained in a known manner, gidrolizu their racemic alkyl esters of formula II (X= Cl, Br) (Y. Deguchi, and K. Nakanishi, Yakugaku Zasshi 1963, 83, 701). Racemic 8-iodine-6-hydroxyoctanoic acid of formula I (X= I) are obtained in high yield by treating the racemic 8 - chloro-6-hydroxyoctanoic acid of formula I (X=Cl) sodium iodide in acetone.

For isomerase-methylbenzylamine isomers is dissolved in a suitable solvent at high temperatures, for example, 30oC to 100oC, preferably from 40oC to 60oC, and 10oC - 30oC, preferably at 20oC and using crystallization allocate net diastereomer salt. As a solvent along with water used aliphatic hydrocarbons with the length of the hydrocarbon chain of from 3 to 10 carbon atoms, liquid aromatic hydrocarbons, esters, aliphatic and cycloaliphatic carboxylic acids with 2-6 carbon atoms and aliphatic and cycloaliphatic alcohols with 2 to 6 carbon atoms, aliphatic and cycloaliphatic alcohols with 1 to 6 carbon atoms, ethers, and esters of glycol or a homogeneous mixture of all the above-listed solvents. The most preferred solvents are ethyl ether, acetic acid, cyclohexane, toluene and the homogeneous mixture.

It should be noted that diastereomeric salts of these compounds show a significant difference in solubility, which can be used during the processing of a racemate 8-halogen-6 - hydroxyoctanoic acids of formula I are optically pure isomer-methylbenzylamine for the selective extraction of one diastereomeric salt of formula III. And for selective receipt of a specific isomer of n-0.6 mol-EQ pure enantiomer-methylbenzylamine. To improve the content of the corresponding enantiomer of 8-halogen-6-hydroxyoctanoic acid, currently in stock solution in excess, can adding another enantiomer-methylbenzylamine. This method is applicable for continuous way to obtain (+)-8-halogen-6-hydroxyoctanoic acid and (-)- 8-halogen-6-hydroxyoctanoic acids, both pure enantiomers can be obtained with a large output without losses. For these additional purification of the diastereomeric salts using recrystallization of pure abovementioned solvents or homogeneous mixtures.

The decomposition of pure salts of the formula III (+)-8 - halogen-6-hydroxyoctanoic acid and R-(+) - methylbenzylamine and, respectively, (-)-8-halogen-6-hydroxyoctanoic acid and S-(-)--methyl-benzylamine obtained by the above methods, conduct or acids such as mineral acids or bases, such as hydroxides of alkali metals, followed by extraction emit pure (+)-8-halogen-6-hydroxyoctanoic acid and (-)-8-halogen-6-hydroxyoctanoic acid.

According to the invention the enantiomers of 8-halogen-6 - hydroxyoctanoic acids of formula 1 can stereospetsifichno translate to save the ical quantities of HCl. The treatment is carried out at a temperature of from 50oC to 100oC, preferably at 60oC, the solvent used, the corresponding alcohol.

The optical purity of the isomers and the diastereomeric salts is determined by the value of the specific optical rotation. The relative content of the optical isomers of 8-halogen-6-hydroxyoctanoic acids of formula I and --lipoic acid of formula IV is determined by HPLC on optically active sorbents with accuracy of 0.5%. In addition, determination of the optical purity of the alkyl esters of 8-halogen-6 - hydroxyoctanoic acid of formula II is carried out using the method 1H-NMR, the pre-turning their treatment (5)-(+)-O - acetylindole acid in a mixture of diastereoisomeric esters.

This invention allows to obtain (+)- and (-)-8-halogen-6 - hydroxyoctanoic acid (halogen = chlorine, bromine and iodine) of the formula I, their alkalemia esters of the formula II and their salts with optically active-methylbenzylamino formula III, which are intermediates in obtaining lipovich acids of the formula IV enantiomeric purity, as well as dihydrolipoic acids of formula V enantiomeric purity in a simple and effective way, with high chemical and optical the slots or dihydrolipoic acid enantiomeric purity of the intermediate products in accordance with this invention. Separate stages of transformation of the corresponding racemates can be performed by known methods (see diagram at the end of the description).

In a similar way we obtain S(-)-lipoic acid, and in the circuit shown on the left using the(-)-8-chloro-6 - hydroxyoctanoic acid and right - (+)-8-chloro-6 - hydroxyoctanoic acid. Optically pure dihydrolipoamide acid is obtained by recovering the optically pure of lipovich acids by known methods.

Information confirming the possibility of carrying out the invention

Summary of the invention the following examples.

Example 1.

of 1.94 g (10 mmol) of (+)-8-chloro-6-hydroxyoctanoic acid (+)-1 (X=Cl) was dissolved at 60oC in 30 ml of a mixture of ethyl acetate: cyclohexane (1:1). Within 5 min was added to 1.21 g (10 mmol) of R-(+) - methylbenzylamine. After 1 hour the mixture was cooled to 20oC. the Precipitate was filtered and washed with a mixture ethyl acetate: cyclohexane (1: 1) (2x3 ml). The salt was dried in vacuum at 40oC. Received 3.12 g (99% of theory) of the salt of (+)-8-chloro-6-hydroxyoctanoic acid and R-(+) - methylbenzylamine (+)/(+)-III (X=Cl), []20D= +22,7(C=1; ethanol), E. E. (taking into account the errors of determination): > 99% (HPLC). Solubility in a mixture of ethyl acetate-cyclohexane (1: 1) and 0.09% (0 mmol) of (-)-8-chloro-6-hydroxyoctanoic acid (-)-I (X=Cl) was dissolved at 60oC in 30 ml of a mixture of ethyl acetate: cyclohexane (1:1). Within 5 min was added to 1.21 g (10 mmol) of (+) - methylbenzylamine. After 1 hour the mixture was cooled to 20oC. the Precipitate was filtered and washed with a mixture ethyl acetate: cyclohexane (1:1) (2x3 ml). The salt was dried in vacuum at 40oC.

Got 3,05 g (97% of theory) of the salt of (-)-8-chloro-6 - hydroxyoctanoic acid and R-(+) - methylbenzylamine (-)/(+)-III (X=Cl), []20D= +10,3(C=1; ethanol), E. E. : > 99% (HPLC). Solubility in a mixture of ethyl acetate-cyclohexane(1: 1) - 0,30% (20oC), ethyl acetate-cyclohexane(3:1) - 0.54% (20oC), so pl. 94-95oC.

Example 3.

of 1.94 g (10 mmol) of (-)-8-chloro-6-hydroxyoctanoic acid (-)-I (X=Cl) was dissolved at 60oC in 30 ml of a mixture of ethyl acetate: cyclohexane (1:1). Within 5 min was added to 1.21 g (10 mmol) of S-(-) - methylbenzylamine. Then spent processing as described in example 1. Received 3.11 g (99% of theory) of the salt of (-)-8-chloro-6-hydroxyoctanoic acid and S-(-)-a-methylbenzylamine (- ) /(- ) III (X= Cl), []20D= -22,7(C= 1; ethanol), E. E.: > 99% (HPLC). Solubility in a mixture of ethyl acetate-cyclohexane(1: 1) - 0,09% (20oC), ethyl acetate-cyclohexane(3:1) - 0.16% (20oC), so pl. 122-124oC.

Example 4.

of 1.94 g (10 mmol) of (+)-8-chloro-6-hydroxyoctanoic Bismol) S-(-) - methylbenzylamine. Then spent processing as described in example 1.

Received 3.04 from g (97% of theory) of the salt of (+)-8-chloro-6 - hydroxyoctanoic acid and S-(-) - methylbenzylamine (+) /(- ) III (X=Cl), []20D= -10,3(C=1; ethanol), E. E. : > 99% (HPLC). Solubility in a mixture of ethyl acetate-cyclohexane(1: 1) - 0,30% (20oC), ethyl acetate-cyclohexane(3:1) - 0.54% (20oC), so pl. 94-95oC.

Example 5.

39,9 r (204 mmol) of racemic 8-chloro-6-hydroxyoctanoic acid (+)/(-)-I (X= Cl) was dissolved at 40oC in 155 ml of a mixture of ethyl acetate: cyclohexane (1:1). Within 10 min was added portions of 13.5 g (112 mmol) of R-(+) - methylbenzylamine. Then after 2 h, cooled the reaction mixture to 20oC, the precipitate was separated by filtration, washed with 20 ml of a mixture of 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 = +22,7(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 divided phase and the organic phase is once washed 20 ml of 2 N. Sol is 10.8 g (54% of theory) of (+)-8-chloro-6-hydroxyoctanoic acid (+)-I (X=Cl); []20D= +24,5(C=1; ethanol), e.e. > 99% (HPLC), so pl. 29-30oC.

Example 6.

33,9 g (173 mmol) of racemic 8-chloro-6-hydroxyoctanoic acid (+)/(-)-I (X= Cl) was dissolved at 40oC in 130 ml of a mixture of ethyl acetate: cyclohexane (1: 1). Within 10 min was added portions of 11.5 g (95 mmol) of S-(-) - methylbenzylamine. Then after 2 h, cooled the reaction mixture 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 of (-)-(-)-diastereomer salt = -22,7(C=1; ethanol).

Salt suspended at 20oC in 190 ml of diethyl ether. While cooling and stirring slowly acidified with 3 N. hydrochloric acid to pH 1, and the salt went into solution. After 30 min divided phase and the organic phase is once washed with 17 ml of 2 N. hydrochloric acid, twice 20 ml of water and dried with magnesium sulfate. After removal of the solvent in vacuo got 9.1 g (53% of theory) []20D= -24,55(C=1; ethanol), e.e. > 99% (HPLC), so pl. 29-30oC.

Example 7.

6.4 g (32,9 mmol) of (+)-8-chloro-6-hydroxyoctanoic acid within 2 hours Then the solvent was distilled in vacuum. Received 6.6 g (97% of theory) of methyl ester of (+)-8-chloro-6-hydroxyoctanoic acid (+)-II (X=Cl, R=Me)] 20D= +24,5(C=1; ethanol), E. E. > 99% (1H NMR).

Example 8.

7.7 g (to 39.5 mmol) of (-)-8-chloro-6-hydroxyoctanoic acid (-)-I (X=Cl) was 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) of methyl ether of (-)-8-chloro-6-hydroxyoctanoic acid (-)-II (X=Cl, R=Me)] 20D= -24,5(C=1; ethanol), E. E. > 99% (1H NMR).

Example 9.

9.0 g (46,3 mmol) of racemic 8-chloro-6 - hydroxyoctanoic acid I (X= Cl) and 10.6 g (70,0 mmol) of sodium iodide were dissolved in 100 ml of acetone and boiled under reflux for 12 hours the Precipitate was filtered in vacuum, washed with 10 ml of acetone and the obtained filtrate was concentrated to 30 ml and Then added 100 ml of diethyl ether, washed with 10 ml water and dried with sodium sulfate. The solvent was distilled in vacuum. Got to 12.1 g (91% of theory) of racemic 8-iodine-6 - hydroxyoctanoic acid I (X=I).

Example 10.

2.85 g (10 mmol) of (+)-8-iodine-6-hydroxyoctanoic acid ((+) - methylbenzylamine. After 1 hour the mixture was cooled to 20oC. the Precipitate was filtered and washed with a mixture ethyl acetate: cyclohexane (1:1) 2 times in 3 ml Salt was dried in vacuum at 40oC. Got to 4.01 g (99% of theory) of the salt - (+)-8 - iodine-6-hydroxyoctanoic acid and R-(+) - methylbenzylamine (+)/(+)-III (X=J), []20D= +23,65(C=1; ethanol), E. E. : > 99% (HPLC). Solubility in a mixture of ethyl acetate-cyclohexane(1:1) 0,07% (20oC), so pl. 108-111oC.

Example 11.

2.85 g (10 mmol) of (-)-8-iodine-6-hydroxyoctanoic acid (-)-I (X=I) was dissolved at 60oC in 30 ml of a mixture of ethyl acetate: cyclohexane (1:1). Within 5 minutes added to 1.21 g (10 mmol) of R-(+) - methylbenzylamine. After 1 hour the mixture was cooled to 20oC. the Precipitate was filtered and washed with a mixture ethyl acetate: cyclohexane (1: 1) (2x3 ml) Salt was dried in vacuum at 40oC. Received 3,93 g (97% of theory) of the salt of (-)-8-iodine-6 - hydroxyoctanoic acid and R - (+) - methylbenzylamine (-)/(+)-III (X=I), []20D= -14,25(C=1; ethanol), E. E.: > 99% (HPLC). Solubility in a mixture of ethyl acetate-cyclohexane(1:1) 0,50% (20oC), so pl. 84-86oC.

Example 12.

2.85 g (10 mmol) of (-)-8-iodine-6-hydroxyoctanoic acid (-)-I (X=I) was dissolved at 60oC in 30 ml of a mixture of ethyl acetate: cyclohexane (1:1). Within 5 minutes added to 1.21 g of (-)-8-iodine-6-hydroxyoctanoic acid and S-(-) - methylbenzylamine (- ) /(- ) III (X= I), []20D= -23,65(C=1 in ethanol), E. E.: > 99% (HPLC). Solubility in a mixture of ethyl acetate-cyclohexane(1:1) - 0,07% (20oC), so pl. 108-111oC.

Example 13.

2.85 g (10 mmol) of (+)-8-iodine-6-hydroxyoctanoic acid (+)-l (X=I) was dissolved at 60oC in 30 ml of a mixture of ethyl acetate: cyclohexane (1:1). Within 5 minutes added to 1.21 g (10 mmol) of S-(-) - methylbenzylamine. Then spent processing as described in example 10. Got 3,90 g (96% of theory) of the salt of (+)-8-iodine-6-hydroxyoctanoic acid and S-(-) - methylbenzylamine (+) /(- ) III (X= I), []20D= +14,2(C= 1; ethanol), E. E.: > 99% (HPLC). Solubility in a mixture of ethyl acetate-cyclohexane(1:1) - 50% (20oC), so pl. 84-86oC.

Example 14.

of 8.1 g of salt (+)-8-iodine-6-hydroxyoctanoic acid and (R)-(+) - methylbenzylamine (+)/(+)-III (X= I) suspended at 20oC in 90 ml of diethyl ether. While cooling and stirring slowly acidified with 3 N. hydrochloric acid to pH 1, and the salt went into solution. After 30 min divided phase and the organic phase is once washed with 10 ml 2 N. hydrochloric acid, twice 10 ml of water and dried with magnesium sulfate. After removal of the solvent in vacuo received 5.2 g (90% of theory) of (+)-8-iodine-6 - hydroxyoctanoic acid (+)-I (X=I); []20oC in 90 ml of diethyl ether. While cooling and stirring, slowly acidified with 3 N. hydrochloric acid to pH 1, and the salt goes into solution. After 30 min share phase and the organic phase is washed once with 10 ml 2 N. hydrochloric acid, twice 10 ml of water and dried with magnesium sulfate. After removal of the solvent in vacuo gain of 5.1 g (89% of theory) of (-)- 8-iodine-6-hydroxyoctanoic acid (-)-I (X=I); []20D= -24,7(C=1; ethanol), e.e. > 99%.

Example 16.

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

Example 17.

A mixture of 3.1 g (13 mmol) of nonahydrate of sodium sulfide and 0.41 g (13 mmol) of sulfur in 25 ml of ethanol is refluxed for 15 minutes After 2 h at a temperature of 20oC add a solution ablaut 15 ml of 10% NaOH and stirred for 2 h at 25oC. After evaporation of the ethanol under vacuum to the reaction mixture for 10 min at 25oC add a solution of 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 is acidified with conc. HCl to pH 1 and extracted with diethyl ether (CH ml). The organic phase is dried with sodium sulphate, the solvent evaporated in vacuum. Gain of 1.9 g (83% of theory.) (+)-dihydrolipoic acid (+)-V []20D= +13,7(or=1.5; ethanol).

Example 18.

To a solution of 2.9 g (13,2 mmol) methyl-(-)-8-chloro-6 - hydroxyoctanoic (-)-VIII (R=Me) and 0.05 g (0.6 mmol) of pyridine in 10 ml of toluene is added slowly a solution of 1.9 g (16.2 mmol) of thionyl chloride in 6 ml of toluene. Refluxed for 1 h After cooling to room temperature, add to the reaction mixture of 25 ml of ice water, the organic phase is separated, washed with 10 ml of water and dried with magnesium sulfate. The solvent is evaporated in vacuum. Obtain 2.4 g (81% of theory.) methyl-(+)-6,8 - dichloroquinoline (+)-III (R=Me) [] 20D= +30,1(C=1; benzene).

Example 19.

A mixture of 0.62 g (2.6 mmol) of nonahydrate of sodium sulfide and 0.08 g (2,6 IMO the t solution of 0.55 g (2.4 mmol) of methyl-(+)-6,8-dichloroquinoline (+)-III (R= Me) in 5 ml of ethanol. Stirred for 15 min, 8 ml of distilled ethanol. Then add 10 ml of 0.5 N. NaOH and stirred for 12 h at 25oC. After acidification of the reaction mixture conc. HCl to pH 1 extracted with diethyl ether (2x20 ml), the organic phase is dried with sodium sulphate, the solvent evaporated in vacuum. After recrystallization from cyclohexane obtain 0.28 g (57% of theory.) R-(+)--lipoic acid (+)-IV, so pl. 44-46oC, taking into account the error definition: > 99% (HPLC).

1. (+) or (-)- 8-halogen-6-hydroxyoctanoic acid of the formula I

< / BR>
where X denotes Cl, Br, I.

2. (+) or (-)-8-halogen-6-hydroxyoctanoic acid of the formula I on p. 1, characterized in that they are intended for use as intermediates in obtaining the enantiomers, lipovich acids, as well as enantiomers dihydrolipoic acids.

3. Esters (+) or (-)-8-halogen-6-hydroxyoctanoic acid of the formula II

< / BR>
where X denotes CL, Br, I,

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

4. Alkalemia esters (+) or (-)-8-halogen-6-hydroxyoctanoic acids of the formula II under item 3, characterized in that they are intended for use as intermediates in obtaining enantio is selected from salts of (+)-8-halogen-6-hydroxyoctanoic acid and R-(+) - methylbenzylamine, (+)-8-halogen-6-hydroxyoctanoic acid and S-(-) - methylbenzylamine, (-)-8-halogen-6-hydroxyoctanoic acid and R-(+) - methylbenzylamine, (-)-8-halogen-6-hydroxyoctanoic acid and S-(-) - methylbenzylamine, where halogen represents chlorine, bromine or iodine.

6. Salt of the formula III under item 5, characterized in that they are intended for use as intermediates in obtaining the enantiomers, lipovich acids, as well as enantiomers dihydrolipoic acids.

7. A method of obtaining optically pure isomers of 8-halogen-6-hydroxyoctanoic acids of the formula I, where X denotes CL, Br, I, by decomposition of the pure diastereomeric salts of the formula III, where X denotes CL, Br, I, p. 5, characterized in that the net diastereomer salt under item 5 is decomposed by treatment with inorganic or organic acids or bases, respectively.

8. A method of obtaining optically pure isomers alilovic esters 8-halogen-6-hydroxyoctanoic acid of formula II, where X denotes Cl, Br, I, R is a linear or branched1-C4is an alkyl group, characterized in that the optically pure isomers of 8-halogen-6-hydroxyoctanoic acid of the formula I, where X denotes Cl, Br, I, transferred to the compounds of formula II in prte solvent used, the corresponding alcohol, moreover, the reaction takes place stereospetsifichno with retention of configuration.

9. Way acquisition and allocation of salts of the formula III, where X denotes Cl, Br, I, p. 5 of optically pure isomers of 8-halogen-6-hydroxyoctanoic acid and the enantiomers of methylbenzylamine, characterized in that the racemic mixture of (+)-8-halogen-6-hydroxyoctanoic acid and (-)-8-halogen-6-hydroxyoctanoic acid or any mixture of isomers (+) and (-)-8-halogen-6-hydroxyoctanoic acid is treated with enantiomers of methylbenzylamine in the solution and then spend the recrystallization of the diastereomeric compounds, and halogen denotes chlorine, bromine or iodine.

10. Continuous method of obtaining pure diastereoisomeric salt of formula III, where X denotes CL, Br, I, comprising the reaction of interaction of racemates 8-halogen-6-hydroxyoctanoic acid or a mixture of isomers (+) and (-)-8-halogen-6-hydroxyoctanoic acid with optically pure-methylbenzylamino, characterized in that after the reaction of precipitated salt is filtered off and the mother liquor is treated, and halogen denotes chlorine, bromine or iodine.

 

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FIELD: industrial organic synthesis.

SUBSTANCE: method comprises contacting vapor-phase mixture at 150-205°C with alkali and/or alkali-earth metal carboxylate dispersed on activated carbon resulting in conversion of alkyl iodides into corresponding carboxylic acid esters, while iodine becomes bound in the form of inorganic iodide.

EFFECT: facilitated freeing of carboxylic acid product from organic iodine compounds.

4 cl, 2 tbl, 32 ex

FIELD: chemical technology.

SUBSTANCE: invention relates to technology for synthesis of acetic acid by the cabonylation reaction of methanol with carbon monoxide. Method involves preparing the productive flow in the reaction section containing acetic acid, acetaldehyde, water and other impurities. In the cleansing treatment the reaction products are subjected for treatment wherein acetaldehyde impurities are oxidized to either acetic acid after its isolation and recovered to the reaction zone or to carbon dioxide and water that removed from the system. As result, method provides excluding the negative effect of acetaldehyde at step for separation of the reaction products. Oxygen, air or their mixtures, ozone, carbon peroxide or peracetic acid are used as oxidant. As possible variants of the method, the productive flow is fed to distillation column wherein flow of light products or heavy products are isolated under condition that each of these flow involves acetic acid, acetaldehyde and water. Then "light" or "heavy" flow is subjected for oxidation as said above to reduce the concentration of acetaldehyde. As a variant of the method the flow of heavy products can be treated by extraction with water followed by oxidation of acetaldehyde-containing aqueous phase. Invention provides improvement of method due to exclusion of the necessity of purification of the end product from acetaldehyde impurity.

EFFECT: improved treatment method.

20 cl, 3 tbl, 35 ex

FIELD: industrial production of methacrylic acids at reduced amount of industrial wastes.

SUBSTANCE: proposed method is performed by catalytic oxidation of propane, propylene or isobutylene in vapor phase at separation of final product and forming of high-boiling mixture as by-product which contains (according to Michaels addition) water, alcohol or methacrylic acid added to methacrylic group. By-product is decomposed in thermal decomposition reactor at simultaneous distillation of decomposition products in distilling column from which methacrylic acid is taken in form of distillate. Flow of liquid decomposition residue is forced for peripheral direction by means of mixing blades before withdrawal from reactor. Peripheral direction is obtained with the aid of liquid fed from the outside of decomposition reactor; to this end use is made of initial high-boiling material or flow of liquid discharged from decomposition reactor. If necessary, etherification stage is performed through interaction with alcohol for obtaining methecrylic ester. Decomposition of by-product formed at obtaining methacrylic acid by oxidation of propylene or isobutylene or at obtaining methacrylic acid by interaction of acid with alcohol by alcohol through introduction of by-product into thermal decomposition reactor provided with distilling column which has plates made in form of disks and toroids for simultaneous decomposition and distillation. Plant proposed for realization of this method includes thermal decomposition reactor and distilling column, level meters and lines for discharge of liquid containing easily polymerized compounds. Level indicator mounted at area of accumulation of liquid shows pressure differential. Line for detecting the side of high pressure of this level meter is connected with accumulated liquid discharge line.

EFFECT: updated technology; increased yield of target products.

38 cl, 14 dwg, 2 tbl, ex

FIELD: carbon materials and hydrogenation-dehydrogenation catalysts.

SUBSTANCE: invention relates to improved crude terephthalic acid purification process via catalyzed hydrogenating additional treatment effected on catalyst material, which contains at least one hydrogenation metal deposited on carbonaceous support, namely plane-shaped carbonaceous fibers in the form of woven, knitted, tricot, and/or felt mixture or in the form of parallel fibers or ribbons, plane-shaped material having at least two opposite edges, by means of which catalyst material is secured in reactor so ensuring stability of its shape. Catalyst can also be monolithic and contain at least one catalyst material, from which at least one is hydrogenation metal deposited on carbonaceous fibers and at least one non-catalyst material and, bound to it, supporting or backbone member. Invention also relates to monolithic catalyst serving to purify crude terephthalic acid, comprising at least one catalyst material, which contains at least one hydrogenation metal deposited on carbonaceous fibers and at least one, bound to it, supporting or backbone member, which mechanically supports catalyst material and holds it in monolithic state.

EFFECT: increased mechanical strength and abrasion resistance.

8 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to the perfection of the method of regulating quantities of dissolved iron in liquid streams during the process of obtaining aromatic carboxylic acids or in the process of cleaning technical aromatic carboxylic acids, characterised by that, to at least, part of the liquid stream for regulating the quantity of dissolved iron in it, at least one peroxide with formula R1-O-O-R2 is added. Here R1 and R2 can be the same or different. They represent hydrogen or a hydrocarbon group, in quantities sufficient for precipitation of the dissolved iron from the liquid. The invention also relates to the perfection of the method of obtaining an aromatic carboxylic acid, through the following stages: A) contacting the crude aromatic material which can be oxidised, with molecular oxygen in the presence of an oxidising catalyst, containing at least, one metal with atomic number from 21 to 82, and a solvent in the form of C2-C5 aliphatic carboxylic acid in a liquid phase reaction mixture in a reactor under conditions of oxidation with formation of a solid product. The product contains technical aromatic carboxylic acid, liquid, containing a solvent and water, and an off-gas, containing water vapour and vapour of the solvent; B) separation of the solid product, containing technical aromatic carboxylic acid from the liquid; C) distillation of at least part of the off gas in a distillation column, equipped with reflux, for separating vapour of the solvent from water vapour. A liquid then forms, containing the solvent, and in the upper distillation cut, containing water vapour; D) returning of at least, part of the liquid from stage B into the reactor; E) dissolution of at least, part of the separated solid product, containing technical aromatic carboxylic acid, in a solvent from the cleaning stage with obtaining of a liquid solution of the cleaning stage; F) contacting the solution from the cleaning stage with hydrogen in the presence of a hydrogenation catalyst and under hydrogenation conditions, sufficient for formation of a solution, containing cleaned aromatic carboxylic acid, and liquid, containing a cleaning solvent; G) separation of the cleaned aromatic carboxylic acid from the solution, containing the cleaning solvent, which is obtained from stage E, with obtaining of solid cleaned aromatic carboxylic acid and a stock solution from the cleaning stage; H) retuning of at least, part of the stock solution from the cleaning stage, to at least, one of the stages B and E; I) addition of at least, one peroxide with formula R1-O-O-R2, where R1 and R2 can be the same or different, and represent hydrogen or a hydrocarbon group, in a liquid from at least one of the other stages, or obtained as a result from at least one of these stages, to which the peroxide is added, in a quantity sufficient for precipitation of iron from the liquid.

EFFECT: controlled reduction of the formation of suspension of iron oxide during production of technical aromatic acid.

19 cl, 1 dwg, 6 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method, by which the carboxylic acid/diol mixture, that is suitable as the initial substance for the manufacture of polyester, obtained from the decolourised solution of carboxylic acid without actually isolating the solid dry carboxylic acid. More specifically, the invention relates to the method of manufacturing a mixture of carboxylic acid/diol, where the said method includes the addition of diol to the decolourised solution of carboxylic acid, which includes carboxylic acid and water, in the zone of the reactor etherification, where diol is located at a temperature sufficient for evaporating part of the water in order to become the basic suspending liquid with the formation of the specified carboxylic acid/diol mixture; where the said carboxylic acid and diol enter into a reaction in the zone of etherification with the formation of a flow of a complex hydroxyalkyl ether. The invention also relates to the following variants of the method: the method of manufacture of the carboxylic acid/diol mixture, where the said method includes the following stages: (a) mixing of the powder of damp carboxylic acid with water in the zone for mixing with the formation of the solution of damp carboxylic acid; where the said carboxylic acid is selected from the group, which includes terephthalic acid, isophthatic acid, naphthalenedicarboxylic acid and their mixtures; (b) discolourisation of aforesaid solution of damp carboxylic acid in the zone for reaction obtaining the decolourised solution of carboxylic acid; (c) not necessarily, instantaneous evaporation of the said decolourised solution of carboxylic acid in the zone of instantaneous evaporation for the removal of part of the water from the decolourised solution of carboxylic acid; and (d) addition of diol to the decolourised solution of carboxylic acid in the zone of the reactor of the etherification, where the said diol is located at a temperature, sufficient for the evaporation of part of the water in order to become the basic suspending liquid with the formation of the carboxylic acid/diol mixture; where the aforesaid carboxylic acid and diol then enter the zone of etherification with the formation of the flow of complex hydroxyalkyl ether; and relates to the method of manufacture of carboxylic acid/diol, where the said method includes the following stages: (a) the mixing of the powder of damp carboxylic acid with water in the zone for mixing with the formation of the solution of carboxylic acid; (b) discolourisation of the said solution of damp carboxylic acid in the reactor core with the formation of the decolourised solution of carboxylic acid; (c) crystallisation of the said decolourised solution of carboxylic acid in the zone of crystallisation with the formation of an aqueous suspension; and (d) removal of part of the contaminated water in the aforesaid aqueous solution and addition of diol into the zone of the removal of liquid with the obtaining of the said carboxylic acid/diol mixture, where diol is located at a temperature sufficient for evaporating part of the contaminated water from the said aqueous suspension in order to become the basic suspending liquid.

EFFECT: obtaining mixture of carboxylic acid/diol.

29 cl, 4 dwg

FIELD: chemistry.

SUBSTANCE: method of obtaining product - purified carboxylic acid, includes: (a) oxidation of aromatic initial materials in primary oxidation zone with formation of raw carboxylic acid suspension; where raw carboxylic acid suspension contains terephthalic acid; where said oxidation is carried out at temperature within the range from 120°C to 200°C; (b) withdrawal of admixtures from raw suspension of carboxylic acid, removed at temperature from 140°C to 170°C from stage of oxidation of paraxylol in primary oxidation zone and containing terephthalic acid, catalyst, acetic acid and admixtures, realised in zone of solid products and liquid separation with formation of mother liquid flow and product in form of suspension; where part of said catalyst in said suspension of raw carboxylic acid is removed in said mother liquid flow; and where into said zone of solid products and liquid separation optionally additional solvent is added; (c) oxidation of said product in form of suspension in zone of further oxidation with formation of product of further oxidation; where said oxidation is carried out at temperature within the range from 190°C to 280°C; and where said oxidation takes place in said zone of further oxidation at temperature higher than in said primary oxidation zone; (d) crystallisation of said product of further oxidation in crystallisation zone with formation of crystallised product in form of suspension; (e) cooling of said crystallised product in form of suspension in cooling zone with formation of cooled suspension of purified carboxylic acid; and (i) filtration and optionally drying of said cooled suspension of purified carboxylic acid in filtration and drying zone in order to remove part of solvent from said cooled suspension of carboxylic acid with obtaining of said product - purified carboxylic acid.

EFFECT: purified carboxylic acid with nice colour and low level of admixtures, without using stages of purification like hydration.

8 cl, 1 tbl, 1 dwg, 1 ex

FIELD: organic chemistry, in particular stereoselective method for production of dihydroxyesters and derivatives thereof.

SUBSTANCE: disclosed is method for production of compound having formula 1, wherein R and R' represent optionally substituted hydrocarbon groups; X represents hydrocarbon linker group. Claimed method includes either stereoselective ketogroup reducing to dihydroketo precursor followed by selective etherification of primary hydroxyl or selective etherification of primary dihydroketo precursor hydroxyl followed by stereoselective ketogroup reducing.

EFFECT: compounds useful in production of pharmaceutical compositions.

19 cl, 1 tbl, 4 ex

FIELD: biologically active substances.

SUBSTANCE: invention relates to improved method of obtaining total amount of phenol acid including following steps: (a) multi-rooted sage is extracted with water and filtered; (b) filtrate is placed in polyamide column and washed with water to neutral reaction, wash water is removed, and polyamide column is eluted with weak aqueous alkali solution, and obtained fractions are connected; (c) alkali fractions obtained in step (b) are acidified and placed in absorption column with macroporous resin, column is washed to neutral state, wash water is removed, column is eluted with aqueous or anhydrous lower alcohol, eluent is collected, evaporated at reduced pressure to remove alcohol, and dried. Yield of final product exceeds 4% based on amount of crude drug and content of total amount of phenol acid exceeds 80%. Thus obtained total amount of phenol acid can be used as drug for prevention and treatment of brain vessel diseases.

EFFECT: enlarged resource of vegetable material for preparation of vascular drugs.

15 cl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method for synthesis of alkyl(meth)acrylates which are used in synthesis of polymers and copolymers with other polymerisable compounds, involving a step for re-esterification of alkyl ester of α-hydroxycarboxylic acid with (meth)acrylic acid, accompanied by formation of alkyl(meth)acrylates and α-hydroxycarboxylic acid, and a step for dehydration of α-hydroxycarboxylic acid, accompanied by formation of (meth)acrylic acid.

EFFECT: method enables to obtain a product with high selectivity.

22 cl, 2 tbl, 2 dwg, 38 ex

FIELD: medicine.

SUBSTANCE: invention relates to applications of compound 11-deoxyprostaglandin of general formula (IV) for obtaining composition for treatment of central nervous system disorder and for obtaining composition for protection of endothelial cells of brain vessels, to pharmaceutical composition based on said compounds, to method of treating central nervous system disorder, as well as to method of treating central nervous system disorder, as well as to compounds of general formula (IV) or their pharmaceutically acceptable salts, esters or amides, on condition that compound is not 11-desoexy-13,14-dihydro-15-keto-16,16-difluor- PGE1. , where L represnts hydroxy, lower alkanoyloxy or oxo; A represents -COOH or its pharmaceutically acceptable salt, ester or amide; B represents -CH2-CH2 or -CH=CH-; Z represents , or , where R4 and R5 represent hydrogen or hydroxy. R4 and R5 cannot represent hydroxy simultaneously; X1 and X2 represent similar or different halogen atoms; R1 represents saturated or unsaturated bivalent lower or middle aliphatic hydrocarbon; R2 represents single bond or lower alkylene and R3 represents linear lower alkyl.

EFFECT: increase of treatment efficiency.

14 cl, 7 ex, 6 tbl, 20 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to an improved continuous method of producing esters of alpha-hydroxy carboxylic acids, in which an amide of alpha-hydroxy carboxylic acid reacts with alcohol as the starting components in the presence of a catalyst to obtain a mixture of products containing esters of alpha-hydroxy carboxylic acids, ammonia, unreacted amide of alpha-hydroxy carboxylic acid, as well as alcohol and a catalyst, in which a) streams of starting components containing amide of alpha-hydroxy carboxylic acid, alcohol and catalyst as the starting components are fed into a high-pressure reactor; b) the streams of starting components react with each other in the high-pressure reactor at pressure from 1 bar to 100 bar; c) the mixture of products obtained at step b), which contains esters of alpha-hydroxy carboxylic acids, unreacted amide of alpha-hydroxy carboxylic acid and catalyst, is removed from the high-pressure reactor; and d) alcohol and ammonia content in the mixture of products is reduced, where ammonia is removed by distillation under pressure which is constantly kept higher than 1 bar without recourse to additional cleaning agents. The continuous method is especially expedient when used on an industrial scale.

EFFECT: improved continuous method of producing esters of alpha-hydroxy carboxylic acids.

30 cl, 12 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, represented by the following formula (I) and their pharmaceutically acceptable salts, where values for groups R1, R4-R6, Ra, m, n, Y, X are determined in the invention formula. Said compounds are used as preparations for enhancing growth of axons and prevention of diseases associated with histone diacetases, in particular tumours or diseases associated with cell proliferation.

EFFECT: compounds in accordance with the claimed invention can be used as anti-cancer, antidiabetic agents and anti-neurodegenerative agents in case of diseases such as Alzheimer's disease, Huntington's disease, spinocerebral ataxia and spinal muscular atrophy in people.

18 cl, 44 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to improved method of obtaining polyols, which includes the following stages: a) oxidation of unsaturated natural fats, unsaturated natural fatty acids and/or esters of fatty acids with dinitrogen oxide; b) interaction of the product, obtained at stage a), with hydrating reagent in presence of catalyst, which contains, at least, one transition metal from groups from 6 to 11; c) interaction of the reaction product from stage b) with alkylene oxides in presence of multimetalcyanide catalyst. Invention also relates to method of obtaining polyurethanes, which includes oxidation of unsaturated natural fats, unsaturated natural fatty acids and/or esters of fatty acids with dinitrogen oxide, interaction of the obtained product with hydrating reagent in presence of catalyst, which contains, at least, one transition metal from groups from 6 to 11, interaction of the reaction product with alkylene oxides in presence of multimetalcyanide catalyst with obtaining polyols, interaction of polyisocyanates with polyols as compounds, which have two hydrogen atoms, reactionable with respect to isocyanate groups.

EFFECT: simple methods make it possible to obtain wide spectrum of products without application of expensive initial reagents.

10 cl, 8 ex

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