DD129442B3 - PROCESS FOR THE PREPARATION OF CAPTOPRIL AND CONTRACTUAL SALTS - Google Patents

Abstract

The present invention relates to a process for the preparation of captopril of the formula I, as well as its physiologically tolerated salts. The invention

Description

in which Y has the meaning given for R ₂ in claim 2 or represents a protective group, acylated in a manner known per se, giving the intermediate of general formula X ',

CH., YS-CH ₂ -CH-CO-N} COR < ^X ') ц

in which R has the meaning given in claim 2, and, after optionally saponifying the group COR to the free carboxyl group, the group Y is cleaved by known methods and the resulting compound is optionally reacted with a base to form a salt.

5. The method according to claim 4, characterized in that one uses a mercaptocarboxylic acid of the general formula IX in which Y is the radical R ₅ CO-, which is then cleaved off by ammonolysis.

Field of application of the invention

The invention relates to a process for the preparation of the novel proline derivative captopril and its physiologically acceptable salts of the formula I.

CH-, - I -

I ³ (D.

HS-CH, CH 2 CO 3 CH-COOH

In the following general formulas, R represents a hydroxyl group or a lower alkoxy group, R _{2 represents} a hydrogen atom, a phenyl group or one through one of the radicals

ο μ μ

R ₅ -C-, R ₅ -MC-, _or R ₅ -NH-C-,

substituted phenyl group wherein R _{5 represents} a lower alkyl group, a phenyl group or a phenyl-substituted lower alkyl group and M represents an oxygen or sulfur atom.

In Formula I, the asterisks designate asymmetric carbon atoms. The compounds of the formula I can therefore be present as stereoisomers or as racemates. The invention relates to both the separated isomers and their racemic mixtures. The enantiomers in which the asymmetric carbon atom of the amino acid proline is in the L-configuration are preferred. Also preferred are the enantiomers in which the a-carbon atom in the acyl side chain, i. H.

the carbon atom bearing the methyl group is in the D form.

The salts may be derived from inorganic bases such as ammonia, alkali metals, for example sodium and potassium, or alkaline earth metals, for example calcium and magnesium or from organic bases, such as dicyclohexylamine, Ν, Ν'-dibenzylethylenediamine, N-methyl-D-glycamin, N, N'-bis (dehydroabietyl) ethylenediamine, or derive from amino acids such as arginine or lysine.

Non-toxic, physiologically acceptable salts are preferred, but other salts, such as the salts with dicyclohexylamine, can be used advantageously for the isolation and purification of the products.

The "lower alkyl radicals" are unbranched or branched hydrocarbon radicals having at most 7 carbon atoms.

Specific examples are the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and isopentyl groups. The lower alkoxy radicals also contain at most 7 carbon atoms. Specific examples are the methoxy, ethoxy,

Propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy. Preferred lower alkyl or alkoxy radicals contain at most 4 carbon atoms. Particularly preferred are the radicals having 1 or 2 carbon atoms. The preferred phenyl-substituted lower alkyl radical is the phenylmethyl group.

The substituted phenyl radicals preferably carry the substituent in the 4-position.

Particularly preferred are the stereoisomers in which the proline is in the L-form.

Characteristic of the known technical solutions

Technical solutions related to the present invention are currently unknown.

Object of the invention

The aim of the invention is the development of new, valuable drugs.

Explanation of the essence of the invention

The invention has for its object to provide a process for the preparation of captopril and its physiologically acceptable salts.

Captopril can be prepared by various methods.

In general, captopril is obtained by acylating compounds of general formula III

(III)

HN CH COR

with a carboxylic acid of general formula IV

R ₂ S CH ₂ CHCOOH ^(IV)

or their chemical equivalent. This means that they can be prepared not only by direct acylation with a carboxylic acid of general formula IV, but also via suitable intermediates, for example by acylation with

(a) an ω-halocarboxylic acid of the general formula V

X CH ₂ CHCOOH ^(v)

in which X represents a chlorine, bromine or iodine atom, or

(b) a p-tosyloxycarboxylic acid, d. H. in the general formula V, X represents a p-tosyloxy radical

{c) a substituted acrylic acid of formula Vl

CH

• ^J (VI)

CH ₂ = C - COOH

The resulting acylation products are then subjected to a displacement or addition reaction with the anion of a thiol or a thioacid of general formula VII.

R ₂ -SH (VII)

The acylation can also be carried out with a thiolactone of the general formula VIII

CH

(VIII)

or with a mercaptocarboxylic acid of the general formula IX

Y S -CH

CH

COR

(IX),

in which Y has the meaning given for R ₂ , or a protective group, such as

CH "O

CH.

A ^ _n

CH ₃ CONHCH ₂ ,

ROC-CH-CH ₂ -S

represents done. The protecting group can be cleaved by known methods, for example by treatment with hot trifluoroacetic acid, cold trifluoromethanesulfonic acid, mercuric acetate, sodium in liquid ammonia or with zinc and hydrochloric acid. An overview of the known processes for the removal of the protective group is in Houben-Weyl, Methods of Organic Chemistry, Vol. 15, Part 1,1974, S.736ff. contain.

When using carboxylic acids of general formula IV as the acylating agent, the acylation may be carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide, or the carboxylic acid may be converted to its mixed anhydride, symmetrical anhydride, acid chloride, ester or by using the Woodward reagent K, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline are activated. An overview of the known acylation is contained in Houben-Weyl, Methods of Organic Chemistry, Vol. XV, Part II, 1974, pages 1 ff.

According to a preferred preparation process, captopril is prepared by reacting proline or its ester of general formula III with a halocarboxylic acid of general formula V in which X represents a halogen atom, preferably a chlorine or bromine atom. This reaction can be carried out according to one of the known methods, wherein the carboxylic acid of the general formula V before conversion with the compound of the general formula III by conversion into a mixed anhydride, symmetrical anhydride, acid chloride, an active ester or by using the Woodward reagent Bait of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline is activated. The reaction described gives a compound of general formula X.

CH.

• CH

CO

(X)

CH-COR

The compound of the general formula X can be reacted, for example, with the anion of a thioacid of the general formula VII to captopril. If R ₂ in the thioacid is R ₅ -CO, captopril can be prepared by ammonolysis of the resulting product. If R _{2 is} a protecting group, it may be cleaved by any of the methods described above. If R in the resulting compound is an ester radical, for example a tert-butoxy group, this can be eliminated by reaction with trifluoroacetic acid and anisole. This gives the corresponding free carboxylic acid. Other alkoxy moieties can be converted to the carboxyl group by alkaline hydrolysis.

In another embodiment, the acylation can be carried out with a substituted acrylic acid of the general formula VI. For this purpose, the acrylic acid is first converted into the acid halide, and then with a compound of general formula III to give a compound of general formula XI

CH ₃

H ₂ C

= C

CO

CH.

CH-COR

(XI)

which is then treated as described above with the thiol or thioacid of general formula VII.

As acylating agent may also be a 3-p-tosyloxy-2-methylpropionic acid of the formula XIII

(XIL)

COOH

be used. The resulting intermediate product is treated further as described above.

In a further embodiment, the substituted acrylic acid of general formula VI can first with the thioacid of general formula VII to give a compound of general formula XIII

(XIII) R ₂ -S-CH ₂ -CH-COOH

be reacted thereon, for example, with thionyl chloride in their acid halide and then reacted with a compound of general formula IM.

The compounds of general formula III can also be protected by a ω-mercaptocarboxylic acid of general formula XIV

Rg-S - CH ₂ - CH-COOH

(XIV)

be acylated, in which R _{8 represents} one of the protective groups described above. After the acylation, the protecting group can be removed by one of the known methods described above.

Further suitable acylating agents are thiolactones, such as β-propiolothiolactone or α-methyl-β-propiolothiolactone.

In a particularly preferred embodiment of the process according to the invention, the compounds of general formula III are reacted with a halocarboxylic acid halide of general formula XV

CH

^{1 J} (XV)

x - CH ₂ - си-сох

acylated, in which X represents a halogen atom, preferably a chlorine or bromine atom. This reaction is carried out in the presence of a base such as dilute caustic, alkali metal bicarbonate or carbonate solution at low temperature, for example at about 0 to 15 ° C. The resulting intermediate is also reacted in the presence of a base, preferably an alkali metal carbonate solution with the anion of a thiol or a thioacid of general formula VII, and then worked up in a known manner.

If R2 in the resulting compound the group R ₅ -CO-group, they can be prepared by ammonolysis, for example with concentrated ammonia or with a solution of ammonia in an alcohol, or by alkaline hydrolysis, are converted, for example, with a metal hydroxide in Captopril.

In another embodiment, an ester, preferably the tert-butyl ester, of general formula III is added to my anhydrous medium, such as methylene chloride, tetrahydrofuran or dioxane, with a thiocarboxylic acid of the general formula

cooH ^(XVI)

reacted in the presence of dicyclohexylcarbodiimide, Ν, Ν'-carbonylbisimidazole, ethoxyacetylene, diphenylphosphorylazide or a similar coupling agent at a temperature of about 0 to 10 ⁰ C. The ester residue can then be cleaved off, for example, by treatment with trifluoroacetic acid and anisole at room temperature.

The reaction of an ester of general formula III in which R represents a lower alkoxy radical, preferably a tert-butoxy group, with a thiolactone such as β-propiothiolactone or α-methyl-β-propiothiolactone can be carried out in an anhydrous solvent such as tetrahydrofuran, dioxane or methylene chloride, be carried out at temperatures of about 0 ⁰ C to room temperature .. The ester residue can be cleaved as described above with trifluoroacetic acid and anisole.

In another embodiment, captopril may also be prepared by reacting a carboxylic acid of general formula XX

M CH-

Il I J

R ₅ -NH-CS - CH ₂ CH-COOH

(XX)

be prepared with a compound of general formula III.

In the preparation processes described above, the starting compounds can be used as racemates or as separate enantiomers. When using the racemates, the products obtained can be cleaved by conventional chromatographic methods or by fractional crystallization in the stereoisomers.

The salts are prepared in a known manner by reacting the free acids with at least one equivalent of the corresponding base in a solvent in which the salt is insoluble or in water, the water passing through

Freeze-drying is removed. The salts may in turn be converted to the free acids or, if desired, to other salts with a cation exchanger in the H ⁺ form, for example a polystyrenesulfonic acid resin, or with a dilute acid and subsequent extraction with an organic solvent such as ethyl acetate or methylene chloride ,

Captopril is a valuable drug. It prevents the conversion of the decapeptide angiotensin I into angiotensin II and therefore reduces or eliminates angiotensin-induced hypertension. Angiotensin I is produced by the action of the enzyme renin on angiotensinogen, a pseudoglobulin in blood plasma. Angiotensin I is converted to angiotensin II by the angiotensin converting enzyme (ACE).

The latter is an active hypertensive compound responsible for various forms of hypertension in, for example, rats and dogs.

The captopril prepared by the process according to the invention engages in the reaction sequence angiotensinogen (renin) - * angiotensin I -> angiotensin My by blocking the angiotensin converting enzyme and thereby reducing or eliminating the formation of the hypertensive compound angiotensin II. The administration of captopril or its physiologically acceptable salts thus mitigates angiotensin-induced hypertension. A single dose, or preferably two to four divided daily doses of about 0.1 to 100 mg, preferably from about 1 to 50 mg / kg / day, is suitable for lowering blood pressure, as described in the article by SL Engel, TR Schachfer, MH Waugh and B. Rubin, Proc.

Soc. Exp. Biol. Med., Vol. 143, 1973, p. 483).

Captopril and its physiologically acceptable salts can be administered orally or parenterally in conventional dosage forms.

embodiments

Example 1 L-proline tert -butyl ester

230 g of L-proline are dissolved in a mixture of 1 liter of water and 400 ml of 5N sodium hydroxide solution. The resulting solution is cooled in an ice bath and then added with vigorous stirring 460 ml of 5 η sodium hydroxide solution and 340 ml of benzyloxycarbonyl chloride over ^1/2 Hour added in five equal portions. The mixture is then stirred for 1 hour at room temperature, then extracted twice with diethyl ether and acidified with concentrated hydrochloric acid. The resulting precipitate is filtered off and dried. Yield 442g, mp 78 to 80 ⁰ C.

180 g of the obtained benzyloxycarbonyl-L-proline are dissolved in a mixture of 300 ml of methylene chloride, 800 ml of liquid isobutylene and 7.2 ml of concentrated sulfuric acid. The resulting solution is shaken for 72 hours in a pressure vessel. The pressure is then released, the isobutylene evaporated and the remaining solution washed with a 5% sodium carbonate solution and with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure. Yield: 205 g of benzyloxycarbonyl-L-proline tert-butyl ester.

205 g of this compound are dissolved in 1.2 liters of anhydrous ethanol and hydrogenated using 10 g of 10% palladium on carbon at atmospheric pressure until only traces of carbon dioxide in the exiting hydrogen gas are detected (24 hours). Thereafter, the catalyst is filtered off and the filtrate is evaporated under a pressure of 30 Torr. The residue obtained is distilled under reduced pressure. The title compound is obtained from Kp · іт _О гг50 to 51 ° C.

Example 2 S-acetylthio-methylpropionic acid

A mixture of 50 g of thioacetic acid and 40.7 g of methacrylic acid is heated on the steam bath for 1 hour and then stored at room temperature for 18 hours. Subsequently, it is determined by NMR spectroscopy that the methacrylic acid has completely reacted. The reaction mixture is then distilled under reduced pressure. Yield 64 g of the title compound of bp. 128.5 to 131 ⁰ C 2.6 Torr.

Example 3 3-Benzoylthio-2-methylpropionic acid

Example 2 is repeated with the modification that thiobenzoic acid is used instead of thioacetic acid. It will get the title connection.

Example 4 3-phenylacetylthio-2-methylpropionic acid

Example 2 is repeated with the change that instead of thioacetic acid thiophenylacetic acid is used. It will get the title connection.

Example 5

1 - (3-Acetylthio-2-methylpropanoyl) -L-proline tert-butyl ester

5.1 g of L-proline tert-butyl ester are dissolved in 40 ml of methylene chloride. The resulting mixture is stirred with cooling in an ice bath, treated with a solution of 6.2 g of dicyclohexylcarbodiimide in 15 ml of methylene chloride and immediately afterwards with a solution of 4.9 g of 3-acetylthio-2-methylpropionic acid in 5mi of methylene chloride. Subsequently, the resulting mixture is stirred for 15 minutes in an ice bath and then for 16 hours at room temperature. The resulting precipitate is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue obtained is dissolved in ethyl acetate and washed until neutral. The organic phase is separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue obtained is purified by chromatography on a silica gel column using chloroform as eluent. Yield 7.9 g of the title compound.

Example 6 HS-acetylthio-methylpropanoyo-L-proline

Method A:

7.8 g of the prepared according to Example 5 iO-acetylthio - ^ - methylpropanoyl-L-proline tert-butyl ester are dissolved in 55 ml of anisole and 110 ml of trifluoroacetic acid. The resulting mixture is kept for 1 hour at room temperature, then the solvent is distilled off under reduced pressure and the residue is reprecipitated several times from a mixture of diethyl ether and hexane. Subsequently, 6.8 g of the residue are dissolved in 40 ml of acetonitrile and treated with 4.5 ml of dicyclohexylamine. The resulting crystalline precipitate is filtered off and boiled with 100 ml of freshly distilled acetonitrile. Thereafter, the mixture is cooled to room temperature and filtered off. Yield: 3.8g from mp. (165) 187-188 ° C. The compound is recrystallized from isopropanol. It has a specific rotation [a] _D of -67 ° (C 1,4, ethanol). The crystalline dicyclohexylamine salt is suspended in a mixture of 5% potassium bisulfate solution and ethyl acetate. Thereafter, the organic phase is separated, washed with water and evaporated to dryness. The residue obtained is recrystallized from a mixture of ethyl acetate and hexane in the 2 D form. The title compound is obtained, mp 83-85 ° C, [a] g ⁵ : -162 ° (с 1.7, ethanol).

Method B:

A suspension of 8.1 g of 3-acetylthio-2-methylpropionic acid and 7 g of thionyl chloride is stirred for 16 hours at room temperature. Thereafter, the reaction mixture is evaporated to dryness and distilled under reduced pressure (bp. 80 ⁰ C). 5.4 g of the obtained S-acetylthio ^ -methylpropionsäurechlorides and 15 ml of 2 η sodium hydroxide solution are added to a solution of 3.45 g of L-proline in 30 ml of 1 N sodium hydroxide solution, which was cooled in an ice-water bath. The mixture is then stirred for 3 hours at room temperature and then extracted with diethyl ether. The aqueous phase is acidified and extracted with ethyl acetate. Then the organic phase is dried over magnesium sulfate and evaporated to dryness. There is obtained the 1- (3-acetylthio-2-DL-methylpropanoyl) -L-proiin.

Method C:

A solution of 3.45 g of L-proline in a mixture of 100 ml of water and 12 g of sodium bicarbonate is cooled in an ice-water bath and treated with vigorous stirring with 4.16 g of methacrylic chloride. Thereafter, the resulting mixture is stirred for 2 hours at room temperature and then extracted with diethyl ether. The aqueous phase is acidified with 1 η hydrochloric acid and extracted with ethyl acetate. The organic phase is evaporated to dryness under reduced pressure, the residue is mixed with 3.5 g of thiolacetic acid, admixed with a few crystals of azobisisobutyronitrile and heated for 2 hours on a steam bath. Thereafter, the reaction mixture is dissolved in a 75:25 by volume mixture of benzene and acetic acid and chromatographed on a silica gel column with the same solvent. There is obtained the 1- (3-acetylthio-2-DL-methylpropanoyl) -L-proline.

Example 7

1- (3-Benzoylthio-2-trimethylpropanoyl) -L-pro-ni-tert-butyl ester

Example 5 is repeated with the modification that 3-benzoylthio-2-methylpropionic acid is used instead of 3-acetylthio-2-methylpropionic acid. It will get the title connection.

Example 8 1- (3-Phenylacetylthio-2-methylpropanoyl) -L-proline tert -butyl ester

Example 5 is repeated with the change that instead of 3-acetylthio-2-methylpropionic acid, the S-phenylacetylthio ^ - methylpropionic acid is used. It will get the title connection.

Example 9 1- (3-Benzoylthio-2-methylpropanoyi) -L-proline

Example 6, method A, is repeated with the modification that instead of 1- (3-acetylthio-2-methylpropanoyl) -L-proline tert -butyl ester of 1- {3-benzoylthio-2-methylpropanoyl) -L-proline tert-butyl ester is used. It will get the title connection.

Example 10 i-fS-Phenyfacetylthio ^ -methylpropanoyo-L-proline

Example 6, process A, is repeated with the modification that instead of 1- (3-acetylthio-2-methylpropanoyl) -L-proline tert-butyl ester of 1-P-phenylacetylthio ^ -methyl-propanoyl-L-proline tert-butyl ester is used. It will get the title connection.

Example 11 1- (3-Mercapto-2-D-methylpropanoyl) -L-proline

1- (3-Mercapto-2-methylpropanoyl) -L-proline is prepared from the products of Examples 6, 9 and 10 as follows: Dissolve 0.85 g of the thioester in a 5.5n solution of ammonia in methanol and at room temperature for 2 hours kept. Thereafter, the solvent is distilled off under reduced pressure and the residue is dissolved in water. The resulting solution is passed through a cation exchanger in the H ⁺ form and eluted with water. The positive thiol reaction fractions are collected and lyophilized. The residue obtained is recrystallized from a mixture of ethyl acetate and hexane. Yield: 0.3 g. The title compound has a melting point of 103 to 104 ⁰ C and a [a] _D of -131 ° (C 2, ethanol).

Example 12 HS-ethoxycarbonyl-O-thio-α-methylpropanoylH-proline

A solution of 1- (3-mercapto-2-methylpropanoyl) -L-proline in 30 ml of 1 N sodium bicarbonate solution is treated with ethyl chloroformate. The resulting mixture is stirred vigorously for 1 hour at 5 ° C. and then for 2 hours at room temperature. Then the reaction mixture is acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water, dried over magnesium sulfate and evaporated to dryness. It will get the title connection.

Example 13 1- (3-Ethyldithio-2-methylpropanoyl) -L-pro-methyl ester

A) A solution of ethyl thiosulphate in 100 ml of methanol is treated with 1- (3-mercapto-2-methylpropanoyl) -L-proline. The resulting mixture is stirred vigorously for 4 hours at room temperature. Thereafter, the methanol is distilled off under reduced pressure. The compound 1- [3- (ethyldithio) -2-methylpropanoyl] -L-proline is obtained.

B) A solution of 1- (3-mercapto-2-methylpropanoyl) -L-proline in water is maintained at a pH of 6-7 by careful addition of sodium hydroxide and treated with a solution of ethyl thiosulfinate in 50 ml of ethanol. The resulting mixture is vigorously stirred at room temperature until negative reaction to thiol groups. Thereafter, the reaction mixture is diluted with water, adjusted to a pH of 8 and extracted with ethyl acetate. The aqueous phase is then acidified to pH 3 and extracted again with ethyl acetate. The latter ethyl acetate extract is washed with water, dried and evaporated to dryness. The compound 1 - [3- (ethyldithio) -1-methylpropanoyl-L-proline is obtained.

A solution of 1- [3- (ethyldithio) -2-methylpropanoyl] -L-proline in ethyl acetate is treated with a solution of diazomethane in diethyl ether until a yellowish color persists. Thereafter, the mixture is added with a few drops of acetic acid until the yellow color disappears, and the solvents are distilled off under reduced pressure. It will get the title connection.

Example 14 3 - [{4-Methoxyphenyl) methylthio] -2-methylpropionic acid

A solution of 8.6 g (0.1 mol) of methacrylic acid in 50 ml of 2N sodium hydroxide solution is mixed with 15.4 g (0.1 mol) of p-methoxy-a-toluolthiol. Thereafter, the resulting mixture is heated for 3 hours on the steam bath and then refluxed for 2 hours. After cooling, the reaction mixture is extracted with diethyl ether. The layers are separated and the aqueous layer is acidified with concentrated hydrochloric acid and extracted with methylene chloride. The acidic extracts are then washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting semi-solid residue is taken up in 50 ml of methylene chloride, diluted with 50 ml of hexane and quenched. Yield: 5.5 g of the title compound as a colorless crystalline solid of mp. 74 to 82 ° C.

Example 15 1- [3- (4-IVethoxyphenyl) -nethylthio] -2-methylpropanoyl-L-proline tert-butyl ester 3.6g (0.015 mol) of 3 - [(4-methoxyphenyl) methylthio] -2-methylpropionic acid , 2.6g (0.015 mol) of L-proline tert-butyl ester and 3.1 g (0,015MoI) of dicyclohexylcarbodiimide are stirred in.50ml gelöst'und methylene chloride at a temperature of 0 ⁰ C for 30 minutes. Thereafter, the cooling bath is removed and the mixture is stirred for about 16 hours. The resulting suspension is filtered. The filtrate is washed with 5% potassium bisulfate-saturated sodium bicarbonate and brine, then dried over magnesium sulfate and evaporated under reduced pressure. The resulting clear oil is chromatographed on a 250 ml silica gel column with a mixture of ethyl acetate and hexane in a volume ratio of 20:80 as the eluent. The main fraction of R _f value 0.70 (silica gel, ethyl acetate) is evaporated. Yield 5.5 g (93%) of the title compound as a clear oil of R _r 0.70 (silica gel, ethyl acetate) and R _r 0.60 (silica gel, diethyl ether).

Example 16 1- (3-Mercapto-2-methylpropanoyl) -L-proline

1.2 g (0.003 mol) of the product obtained according to Example 15, 5 ml of anisole and 0.5 ml of trifluoromethanesulfonic acid are dissolved under nitrogen as a protective gas in 20 ml of trifluoroacetic acid and stored for 1 hour at room temperature. Thereafter, the solution is evaporated under reduced pressure. The resulting red residue is taken up in ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated again. The residue obtained is then treated repeatedly with hexane. The residual hexane is evaporated leaving 0.4 g of oil. A 180 mg portion of this oil is subjected to 2 mm silica gel plates with a 75:25 by volume mixture of benzene and acetic acid as the mobile phase of preparative thin-layer chromatography. The band giving the strongest positive reaction to nitroprusside (R, value: 0.40) is recovered. Yield: 135 mg of the title compound as an oil. The thin-layer chromatogram with 75:25 by volume of benzene and acetic acid shows an R _f value of 0.40 and an R _f value of 0.62 with a 50:40:10 mixture of chloroform, methanol and acetic acid.

Example 17 1- (3-Mercapto-2-D-methylpropanoyl) -L-proline

10.0 g of 1- [3- (acetylthio) -2-D-methylpropanoyl] -L-proline are slurried at 150 ° C. under an argon shower in a temperature of 10 ° C. in 150 ml of water. Thereafter, the resulting mixture is mixed with 5 η sodium hydroxide solution and the pH of the solution kept at 13 for 1.5 hours. Thereafter, the addition of caustic soda is stopped and the solution is acidified with concentrated sulfuric acid to a pH of 2.0. Then the resulting aqueous solution is extracted three times with 150 ml of methylene chloride. The methylene chloride extracts are combined and evaporated. The resulting oil is taken up in ethyl acetate and filtered off. Then, the resulting filtrate is diluted with 30 ml of hexane. After 2 hours, additional hexane is added and

the mixture was cooled to 1O ⁰ C for 1 hour. The resulting crystals are filtered off, washed twice with 25 ml of hexane and dried to constant weight. Yield: 6.26 g of the title compound as colorless crystals of mp 100 to 102X.

Example 18 1 - (- Tosyloxy-2-methylpropanoyl) -L-proline

Example 6, process B, is repeated with the modification that instead of S-acetylthio ^ -methylpropionsäurechlorid the S-tosyloxy ^ -methylpropionsäurechlorid is used. It will get the title connection.

Example 19 1- (3-Acetylthio-2-methylpropanoyl) -L-proinine

A solution of 1.14 g of thiolacetic acid and 3.5 ml of triethylamine in 20 ml of ethyl acetate is added with 3.5 g of 1- (3-tosyloxy-2-methylpropanoyl) -L-proline. Thereafter, the resulting mixture is heated to 50 ⁰ C for 3 hours, then cooled, diluted with 100 ml of ethyl acetate and washed with dilute hydrochloric acid. The organic layer is separated, dried and evaporated to dryness under reduced pressure. Then the residue obtained is dissolved in acetonitrile and treated with dicyclohexylamine. The crystalline precipitate is filtered off and recrystallized from isopropanol. The dicyclohexamine salt of the title compound is obtained, mp 187-188 ° C, [α] ": -67 ° (C 1.4, ethanol) The salt can be converted to the free acid of melting point 83-85 ° C When the solution is seeded in the crystallization with a refractory compound, an isomorphic form of mp 104-105 ⁰ C is obtained.

Example 20 Methacryloyl-L-proline

23.0 g (0.2 mol) of L-proline are dissolved in 100 ml of water and stirred with cooling in an ice bath. The resulting solution is dropwise in 3 hours with 19.6m! (0.2 mol) of methacryloyl chloride in 25 ml of methyl isobutyl ketone. At the same time, 2N sodium hydroxide solution is added and the pH of the reaction mixture is kept at 7.0. The sodium hydroxide solution is added after completion of the addition of the acid chloride for a further 4 hours. Thereafter, the reaction mixture is adjusted to pH 5 with concentrated hydrochloric acid and extracted with ethyl acetate. The aqueous layer is then acidified to pH 2.5 and carefully extracted with ethyl acetate. The acidic extracts are washed with brine and dried over magnesium sulfate. The ethyl acetate solution is treated with 40 ml of dicyclohexylamine and cooled for about 15 hours. The resulting colorless precipitate is filtered off and dried. Yield: 29 g (39%) of a colorless solid of mp 202 to 21O ⁰ C. The product is recrystallized from 1.5 liters of a mixture of acetonitrile and isopropanol in the volume ratio 3: 1. Yield: 19.7 g of dicyclohexylamine salt of the title compound as fine colorless needles melting at 202-210 ⁰ C. The resulting salt is dissolved in a mixture of water and ethyl acetate and acidified with concentrated hydrochloric acid. Thereafter, the resulting suspension is filtered off to remove a fine colorless precipitate, which is washed thoroughly with ethyl acetate. Thereafter, the filtrate is saturated with sodium chloride and extracted thoroughly with ethyl acetate. The ethyl acetate extracts are combined, washed with brine, dried over magnesium sulfate and evaporated. The resulting clear oil which solidifies is recrystallized from a mixture of ethyl acetate and hexane. Yield: 7.5 g (83%) of the title compound as a colorless crystalline solid of mp 89-93 ° C

After further recrystallization, a sample melts at 95 to 98 ^° C.

Example 21 1- (3-Acetylthio-2-D-methylpropanoyl) -L-proline

183 mg (0.001 mol) of methacryloyl-L-proline are dissolved in 0.5 ml of thiolacetic acid and stored for 16 hours at room temperature. Thereafter, the solution is evaporated under reduced pressure. The resulting yellow residue is subjected to preparative thin-layer chromatography on a silica gel column with a 90: 5: 5 by volume mixture of methylene chloride, methanol and acetic acid. The main fraction is 240 mg of a clear oil. The thin layer chromatogram with a mixture of methylene chloride, methanol and acetic acid in the volume ratio 90: 5: 5 shows that the 1- (3-acetylthio-2-DL-methylpropanoyl) -L-proline, corresponding to the product of Example 29, method B, with an R _r value of 0.35 and using 75:25 by volume benzene and acetic acid at an R, value of 0.38.

The oil obtained above is dissolved in 3m acetonitrile, treated with dicyclohexylamine until basic reaction of the solution and cooled. Thereafter, the resulting colorless crystalline precipitate is filtered off. Yield 106mg, mp 175-181 ⁰ C. By recrystallization from isopropanol, the dicyclohexylamine salt of the title compound, melting is obtained 187-188 ° C. It is identical to the product of Example 29, method A.

Example 22 3-Benzylthio-2-methylpropionic acid

Example 14 is repeated with the change that instead of p-methoxy-a-toluolthiol the a-Toluolthiol is used. It will get the title connection.

Example 23 1- [3- (Benzylthio) -2-methylpropanoyl] -L-proline tert -butyl ester

Example 15 is repeated with the change that 3-benzylthio-2-methylpropionic acid is used instead of 3 - [(4-methoxyphenyl) methylthio] -2-methylpropionic acid. It will get the title connection.

Example 24 1- [3- (Benzylthio) -2-methylpropanoyl] -L-proline 7.8 g of 1- [3- (benzylthio) -2-methylpropanoyl] -L-proline tert -butyl ester are added to a mixture of 55 ml Anisole and 110ml trifluoroacetic acid dissolved. The resulting solution is kept for 1 hour at room temperature. Thereafter, the solvent is distilled off under reduced pressure, the residue taken up in diethyl ether, washed several times with saturated brine, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The title compound of R _f value 0.5 (silica gel, benzene, acetic acid, 3: 1) or (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1) is obtained.

Example 25 i-P-Mercapto-methylpropanoylo-L-proline 0.1 g of 1- [3- (benzylthio) -2-methylpropanoyl] -L-proline is suspended in 10 ml of boiling liquid ammonia. The suspension is added with stirring with small portions of sodium until a blue color persists. Thereafter, the solution is removed by adding some ammonium sulfate crystals. The ammonia is evaporated under a nitrogen atom. Then, the residue obtained is dissolved in a mixture of dilute hydrochloric acid and ethyl acetate. The organic layer is separated, dried and evaporated to dryness under reduced pressure. The title compound of Rf 0.35 (silica gel, benzene, acetic acid, 3: 1) or of R, value O, 5 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water 14: 1: 2: 1) is obtained, which is identical to the product of Example 34.

Example 26 S-Triphenylmethylthio-methylpropionic acid A solution of 1.2 g of 3-mercapto-2-methylpropionic acid and 2.9 g of trityl chloride in 50 ml of methylene chloride is kept at room temperature for 2 hours, then heated on the steam bath for 20 minutes and then dried to dryness under reduced pressure evaporated. The residue obtained is dissolved in saturated sodium bicarbonate solution and washed with ethyl acetate. The aqueous phase is then acidified to pH 3 and extracted with ethyl acetate. The organic layer is separated, dried and evaporated to dryness. The title compound of Rf value 0.8 (silica gel, benzene, acetic acid 3: 1) is obtained.

Example 27 1- [3- (Triphenylmethylthio) -2-methylpropanoyi] -L-proline tert-butyl ester Example 15 is repeated with the modification that instead of 3 - [(4-methoxyphenyl) methylthio] -2-methylpropionic acid the 3-triphenylmethylthio-2-methylpropionic acid is used. It will get the title connection.

Example 28 1- [3- (Triphenylmethylthio) -2-methylpropanoyl] -L-proline 1.8 g of 3-triphenylmethylthio-2-methylpropionic acid and 0.8 g of Ν, Ν'-carbonyldiimidazole are dissolved in 10 ml of tetrahydrofuran with stirring at room temperature. After 20 minutes, the resulting solution is added to a mixture of 0.6 g of L-proline and 1.0 g of N-methylmorpholine in 20 ml of dimethylacetamide. The resulting mixture is stirred at room temperature for about 15 hours, then evaporated to dryness and the residue taken up in a mixture of ethyl acetate and 10% potassium bisulfate solution. The organic layer is separated, dried and evaporated to dryness under reduced pressure. The title compound of R _f value 0.4 (silica gel, benzene, acetic acid 3: 1) or of R _f value 1.0 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water 14: 1: 2: 1) is obtained.

Example 29 1- {3-Mercapto-2-methylpropanoyl) -L-proline 5g of 1- [3-triphenylmethylthio) -2-methylpropanoyl] -L-proline tert -butyl ester are dissolved in a mixture of 55 ml of anisole and 110 ml of trifluoroacetic acid and kept at room temperature for 1 hour. Thereafter, the solvents are distilled off under reduced pressure. The resulting residue is chromatographed on a silica gel column in equilibrium with a 75:27 by volume mixture of benzene and acetic acid with the same solvent as eluent. The fractions with the compound of R _f 0.40 (silica gel with the same solvent) are collected and evaporated to dryness. The title compound of R _f 0.62 (silica gel, chloroform / methanol: acetic acid, water, 50:40:10) is obtained which is identical to the product of Example 34.

Example 30 3- (Tetrahydropyran-2-ylthio) -2-methylpropionic acid A solution of 2.4 g of S-mercapto-1-methylpropionic acid and 1.9 g of freshly distilled 2,3-dihydro-4H-pyran in 60 ml of benzene is charged with 2.8 g Bortrifluoridätherat added. The resulting mixture is treated after 2 hours with 4g potassium carbonate, stirred and filtered off. The filtrate is then evaporated to dryness. It will get the title connection.

Example 31 1- [3- (Tetrahydropyran-2-ylthio) -2-methylpropanoyl] -L-proline Example 28 is repeated with the modification that, instead of S-triphenylmethylthio-methylpropionic acid, 3- (tetrahydropyran-2-ylthio) 2-methylpropionic acid is used. The title compound of R _f value 0.8 (silica gel, benzene, acetic acid, 3: 1) or of R _r value 0.75 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1) is obtained. receive.

Example 32 143-mercapto-2-methylpropanoyl) -L-proline

A solution of 1 g of 1- [3- (tetrahydropyran-2-ylthio) -2-methylpropanoyl] -L-proline in a mixture of 25 ml of methanol and 25 ml of concentrated hydrochloric acid is kept for 30 minutes at room temperature. Thereafter, the solvents are distilled off under reduced pressure. The title compound of Rf 0.35 (silica gel, benzene, acetic acid, 3: 1) or R _f value 0.5 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1) is obtained which is identical to the product of Example 34.

Example 33 S-acetamidomethylthio-methylpropionic acid

2.4 g of S-mercapto ^ -methylpropionic acid and 1.8 g of N-hydroxymethylacetamide are dissolved in trifluoroacetic acid and stored for 1 hour at room temperature. Thereafter, the trifluoroacetic acid is distilled off under reduced pressure. The residue obtained is dried under reduced pressure over potassium hydroxide; the title compound is obtained.

Example 34 1- [3- (Acetamidomethylthio) -2-methylpropanoyl] -L-proline

Example 31 is repeated with the modification that 3-acetamidomethylthio-2-methylpropionic acid is used instead of 3- (tetrahydropyran-2-ylthio) -2-methylpropionic acid. The title compound of R _f value 0.2 (silica gel, benzene, acetic acid, 3: 1) or of Rf value 0.3 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1) is obtained. receive.

Example 35 1- {3-Mercapto-2-methylpropanoyl) -L-proline

1.4 g of 1- [3- (acetamidomethylthio) -2-methylpropanoyl] -L-proline and 1.93 g of mercuric acetate are dissolved in a mixture of 25 ml of acetic acid and 25 ml of water and stirred on the steam bath for 1 hour. Thereafter, the hydrogen sulfide is introduced into the solution until the mercury sulfide has completely precipitated. The mixture is filtered off, the precipitate is washed with ethanol and the filtrate is evaporated to dryness under reduced pressure. The title compound is Rf 0.35 (silica gel, benzene, acetic acid, 3: 1) or R, 0.5 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1). obtained, which is identical to the product of Example 1.

Example 36 T43-mercapto-2-methylpropanoyl) -L-proline tert -butyl ester

A solution of 1.2 g (10 mM) 2-mercapto-2-methylpropionic acid and 1.7 g (10 mM) L-proline tert-butyl ester in 25 ml of methylene chloride is cooled to a temperature of 5 ° C. and treated in portions with a solution of 2 , 26g dicyclohexylcarbodiimide in 5 ml of methylene chloride. Then the resulting mixture is kept for 2 hours at room temperature and then treated with 5 drops of acetic acid. The mixture is filtered off and the filtrate evaporated to dryness. The resulting oily residue is taken up in 20 ml of a mixture of petroleum ether and ethyl acetate in a volume ratio of 3: 1 and chromatographed in a petroleum ether-filled 150 ml silica gel column. The fraction eluted with a mixture of petroleum ether and ethyl acetate in the volume ratio 1: 1 contains 0.6 g of the title compound. It is dried under reduced pressure over phosphorus pentoxide for 12 hours.

Rf value 0.6 (silica gel, benzene, acetic acid, 3: 1) or of R _r value 0.8 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1).

Example 37 1- (3-Mercapto-2-methylpropanoyl) -L-proline

Dissolve 1- (3-mercapto-2-methylpropanoyl) -L-proline tert-butyl ester in a mixture of 20 ml anisole and 45 ml trifluoroacetic acid. The resulting mixture is stored for 1 hour under argon as a protective gas at room temperature and then evaporated to dryness under reduced pressure. The residue is reprecipitated several times from a mixture of ethyl acetate and hexane. The residue is dissolved in 30 ml of ethyl acetate and treated with 1.85 ml of dicyclohexylamine. The resulting crystalline precipitate is filtered off and recrystallized from isopropanol.

To convert the salt to the free acid, the crystals are dissolved in a mixture of 100 ml of 5% potassium bisulfate solution and 300 ml of ethyl acetate. The organic phase is separated, washed once with water, dried over magnesium sulfate and evaporated to dryness under reduced pressure.

The title compound of Rf 0.35 (silica gel, benzene, acetic acid, 3: 1) or R _f value 0.5 (silica gel, methyl ethyl ketone, acetic acid, pyridine, water, 14: 1: 2: 1) is obtained which is identical to the product of Example 11.

Claims (4)

Claim: CH ₃ j HS - CH ₂ - CH - CO - N CH - CCOH and its basic salts, characterized in that proline III (III) CH - СОО'Ы or its lower alkyl ester, with the carboxylic acid IV , ³ (IV) HS - CH ₂ - CH - COOH or their chemical equivalent acylated in a conventional manner, optionally saponified the proline-lower alkyl ester in a conventional manner to the free acid and the resulting compound is optionally reacted with a base to form a salt. 2. The method according to claim 1, characterized in that the proline III or its lower alkyl ester with a carboxylic acid of the general formula! V CH ₃
X - CH ₂ - CH - COOH ^(V V in which X is a chlorine, bromine or iodine atom or a tosyloxy group, acylated in a conventional manner and the resulting intermediate X. CH ₃ H ₂ c CH- X - CH ₂ - CH - CO - N CH - COR in which R denotes a hydroxyl group or a lower alkoxy radical, then with the anion of a thiol or a thioacid of the general formula VII R ₂ -SH (VII), in the R _{2 is} a hydrogen atom, a phenyl group or by one of the radicals OM M Il II " R ₅ -C, R ₅ -MC or R ₅ -NH-C- substituted phenyl group, wherein R _{5 is} a lower alkyl, a phenyl group or a phenyl-substituted lower Alkyirest and M is an oxygen or sulfur atom, treated, and optionally saponifying the proline-lower alkyl ester in a conventional manner to the free acid and the resulting compound optionally reacted with a base to a salt. 3. The method according to claim 1 for the preparation of captopril, characterized in that the proline III or its lower alkyl ester with methacrylic acid Vl CH ₃ CH ₂ = c-C00h or a chemical equivalent acylated in a conventional manner and the resulting intermediate product Xl ? ^H 3 "II - (XI), CH _{2 = C-} CO - N CH-COR in which R has the meaning given in claim 2, then reacted with the anion of a thiol or a thioacid of general formula VII, and optionally saponifying the proline-lower alkyl ester in a conventional manner to the free acid and the resulting compound optionally with a base converted to a salt. 4. The method according to claim 1 for the preparation of captopril, characterized in that the proline III or its lower alkyl ester with a mercaptocarboxylic acid of the general formula IX CH ₃ (IX ') YS-CH ₂ -CH-COOH '