DD263757A5 - PROCESS FOR PREPARING 1- [3-MERCAPTO- (2S) -METHYL-PROPIONYL] -PYRROLIDIN- (2S) CARBON ACID - Google Patents

Abstract

According to the invention, compounds of formula (I) are prepared or pharmaceutically acceptable salts thereof. According to the invention, an omega-halo-acylproline of the formula (III) or a salt thereof is reacted with thiourea in an organic dipolar aprotic solvent and the resulting isothiuronium compound of the formula (II) or a hydrogen acid salt thereof formed with hydrogen halide - optionally after isolation - hydrolyzed , Formulas (I) - (III)

Description

Field of application of the invention

The invention relates to a novel process for the preparation of 1 - [3-murcapto (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid of the formula

OH S)

j 3 ^ ⁰ 'COOH

(S)

or the pharmaceutically acceptable salts thereof.

The compound of the formula I is known by the name captopril and has valuable hypotensive action.

Characteristic of the known state of the art

According to UK Pat. No. 1576161, the halogen atom of an omega-halo-acylproline can be converted into a mercapto group by means of various reaction agents. The reaction is carried out with the anion R - S "in which R is a hydrogenator.i, a C 1 -C 4 -alkyl group, a phenyl-C 1 -C 4 -alkyl group, a triphenyHC 1 -alkyl group or a group of the forms

R ₁ -O-0

means _(worhi R, is a C | ₄ is alkyl group or a phenyl group..

Only those R-S "anions are useful for the preparation of captopril in which the substituent of the sulfur atom can be removed from the compound formed in the substitution reaction of the halogen atom, i.e., treated as a protecting group.

The simplest case where R represents a hydrogen atom has not been taught in UK Patent No. 1576161.

If R is a tert-butyl group, a benzyl group or a trityl group, the reaction agent used would be tert-butyl mercaptan, benzyl mercaptan or trityl mercaptan. The listed reagents are dangerous, carcinogenic or toxic compounds.

To duichführung the substitution of the halogen atom, the carboxyl group of the proline must be provisionally provided by a protective group. Furthermore, the yield is unacceptably low. K. Hofmann and coworkers described an analogous procedure with benzylmercaptan (.1. Am. Chem. Soc., 71, 1253 [1949]): a 4-chlorobutyl derivative is reacted with the sodium salt of benzylmsrcnptane, and from which with a yield of 66% of the theory obtained S-benzyl-4-mercapto-butyl derivative is the protecting group - ie dio benzyl group - with sodium removed in ethanol The yield is only 347 »of the theory.

Even worse results can be expected with the use of tert-butyl mercaptan and trityl mercaptan because the spatial disability is much higher for the two compounds. The protecting groups of this type are generally introduced into the molecules in reverse order: the already formed mercapto compound is reacted with isobutylene or thionyl chloride (T.W.Greene, Protective Groups in Organic Synthesis, p.193, [1981]).

If R is a group of the formula

stands, the captopril can be made extremely uneconomical. According to one example of UK Patent No. 1576161, the analogous 1- (1-mercapto-acetyl) proline is prepared by thiobenzoic acid. The yield calculated on the proline is only 15% of theory.

The case where R is a Wasr atom is described in UK Patent No. 2,065,643: N- [3-halo (2S) -methyl-propionyl] - (S) -proline is combined with a sodium aqueous solution of sodium hydrosulfide changed. The reaction requires long-term heating, and also the corresponding disulfide is formed in an amount of E mol-7o. This byproduct is then to be reduced in a besor stage in the presence of an acid with zinc. The yield of Reduktior is 71 % of theory If the sodium hydrosulfide is dissolved in Ν, Ν-dimethyl-formamide, the yield decreases to 65% c or theory. It appears that the best result is obtained by the use of an aqueous solution of ammonium hydrosulfide, but the reaction product and the by-products formed can only be chromatographically isolated. In this way, a mixture of 92% captopril, 6% disulfide and 0.5% symmetry: hem sulfide is obtained. The formation of the last impurity is irreversible, ie it can by no means be converted into captopril. Furthermore, the sulfide and the captopril have an almost similar solubility, so they simply can not be separated. The above-mentioned disadvantages are reinforced by an article by M. Shiwazaki and co-workers (Chem. Pharm. Bull., 30, 329 [1982] ). Thus, the latter method is unsuitable for the production of captopril on an industrial scale. According to US Pat. No. 4,332,725, the halogen atom is converted by means of sodium thiosulfate into the mercapto group. In this case, a so-called Buntesche S3lz is formed, which is heated with concentrated hydrochloric acid and thus converted into captopril. The absorbency is 70% of theory.

The CE OS Nr.3526023 N- [3-halo (2S) -methylpropionyl] is - (S) -proline with thiourea in water, e nem reacted alcohol or an aqueous alkanol at 60 to 100 ⁰ C. A compound of the formula

? ^H 3 (S) I OOH

G-S-GH₂-GH-CO-Kf ^{! IV)}.

wherein X represents a halogen atom is obtained, which is hydrolyzed without isolation in the reaction mixture with an alkali metal hydroxide or carbonate. However, it would be virtually impossible to rework this known method.

'iel the invention

The object of the invention is to provide an improved process for the preparation of 1- [3-mercapto (2S) -methyl-propionyl) -pyrrolidine (2S) -carboxylic acid, with which the desired compound ai finely and economically on an industrial scale in high yield can be won.

Explanation of the essence of the invention

The invention has for its object to find suitable reactants and reaction conditions. ate dl ·

CH-

It has been found that the compound of formula I is from; an omega-halo-acylproline of the formula

³ (8) QOC) H

, -CH-CO- (S)

X-OH ₂ -GH-CO-H

wherein X is a halogen atom, can be produced economically, when reacting the omega-halo-acylproline of the formula III or a salt thereof in an organic dipolar aprotic solvent with thiourea, the obtained isothiuronium compound of the formula

H ₉ N. 9 ^H 3

\ I

CS-CH ₂ -CH-CO-N

(S)

or an acid addition salt thereof formed with hydrogen halide, optionally after isolation, and if desired, salifying or liberating the product of formula I from a salt.

The free carboxyl group of the compound of the formula I can be converted into a salt with an inorganic or organic base. When a salt of the compound of formol I is obtained in the process according to the invention, it can be converted into the free carboxylic acid in a manner known per se.

In formula III, X represents a halogen atom, preferably a bromine atom.

The reaction of the compound of formula III or a salt thereof with thiourea proceeds only in an organic dipolar aprotic solvent such as Ν, Ν-dinethyl-formamide, Ν, Ν-dimethyl-acetamide or dimethyl sulfoxide. In general, the reaction is carried out at a temperature of 20 to 80 ⁰ C, advantageously from 50 to 70 ° C under atmospheric pressure. As usual, the reaction is complete after 15 to 25 hours. Although an acid binder, for. B. an organic base is present in the reaction mixture, the compound of formula II is obtained in a solid state. In the absence of an acid binder, the acid addition salt formed with the corresponding hydrogen halide is obtained. If desired, the compound of formula II before the next reaction step - the hydrolysis - isolated. In general, the acid addition salt formed with the hydrogen halide of the compound of formula II remains in solution, as a result of which it is usually hydrolyzed without isolation.

The isothiuronium compound of formula II or the acid addition salt aen dersel is advantageous expedient hydroüsiert in the presence of a base such as hydrazine at a temperature of 0 to 30 ^c 'C of 10 to 15 ° C under atmospheric pressure. The product of formula I is from the reaction mixture in a conventional manner z. B. isolated by extraction and evaporation.

According to the invention, the isothiuronium compound of the formula II is prepared with an almost theoretical bulge and converted into captopril by hydrolysis. Even if the final product is recrystallized, a total yield of over 80% of theory is obtained. The captopril obtained according to the invention contains neither the corresponding disulfide nor the symmetrical sulfide as impurity, therefore the iodometrically determined purity of captopril is 99.5%.

embodiment

The invention is further illustrated by the following examples, but is not limited to these examples. Preparation of the starting compound: 1- [3-bromo (2S) -methyl-propionyl) -pyrrolidine (2S) -carboxylic acid-IV-monohydrate

3.34 g (0.02 mole) of 3-bromo-2-methylpropionic acid and 4.60 g (0.02 mole) of Sj-proline benzyl ester hydrochloride are dissolved in 20 ml of anhydrous dichloromethane and the resulting solution is added to the mixture of 1 , 9g of triethylamine and 5ml of anhydrous Dichlormetran and then 3,92g (0.019 moles) dissolved in 20ml unc Dichlormothan N, N'-dicyclohexylcarbodiimide at ⁰ ° C with stirring? cooling added. The reaction mixture is further? hours at ⁰ ° C. The reaction mixture is filtered and the filtrate is extracted with 20 ml of 9% hydrochloric acid solution, 20 ml of water, 5% sodium bicarbonate solution and finally 20 ml of water The organic phase is dried over anhydrous magnesium sulfate 6,40g (95% of theory) of 1-.beta.-bromo-2-methyl-2-methyl-4-amidylbenzylbenzylbenzylester are obtained in the form of helium-3-lm oil.

Thin layer chromatography (silica gel, 3 parts benzene, 1 part glacial acetic acid): R ₁ = 0.44 and 0.48, corresponding to a diastereomer ratio of 1: 1.

The resulting oil is dissolved in 60 ml of ethyl acetate, and 0.6 g of 10% palladium / carbon catalyst is added to the solution. The! Bus board is hydrogenated at room temperature and under atmospheric pressure. When the aliquot compound can no longer be detected by thin-layer chromatography, the catalyst is filtered, washed with ethyl acetate, the organic solvent is evaporated off and the residue is recrystallized from water. So 2.00g title compound are obtained, which melt at 69 to 72 ⁰ C !. The yield is 42.5% of theory. [α1έ ^! · = - 88.1 ° (c = 1, ethanol)

example 1

1- [3Mercapto- (2S) -methylpropionyll-pyrrolidine- (2S) -carboxylic acid

10.56 g (0.0374 mole) of 1- [3-bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid and 3.04 g (0.040 mole) of thiourea are dissolved in 30 m! Dissolved Ν, Ν-dimethylacetamide under nitrogen, and the reaction mixture is stirred at 60 ⁰ C under nitrogen for 5 to 20 hours. The solvent is evaporated under reduced pressure and the residue is dissolved in 50 ml of distilled water. To the resulting solution, 6.00 g (0.12 mole) of hydrazine hydrate are added with cooling with ice-water and Stielt material, and the reaction mixture is stirred for 30 minutes with cooling with ice water and a further 30 minutes at room temperature. To the reaction mixture is added 100 ml of 5% sulfuric acid solution, and the white precipitate is filtered, washed with water and then with dichloromethane. The filtrate is extracted with dichloromethane 30 ml each four times, the combined organic solutions are washed twice with 20 ml of water twice, and the organic phase is extracted twice with 15 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. 7.54 g (99% of theory) of oil remain behind, which is recrystallized from 25 ml of trichlorethylene.

Thus, 6.10 g of title product are obtained, which melts at 104 to 106 ⁰ C. The yield is 80% of theory.

[ala ⁵ = -129.5 ° (c = 2, ethanol)

Example 2

1- [3-mercapto (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid

2.64 (0. (0.01 mol) of 1- [3-bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid and 0.76 g (0.01 mol) of thiourea are dissolved in methanol dimethylsulfoxide, and the solution C is stirred for 24 hours at 60 to 7O ^0, then treated with 30ml 10% sodium hydroxide solution and stirred for an additional hour. The pH value is adjusted with 20% hydrochloric acid solution under cooling with ice water to 1 and the solution is extracted four times with 20 ml of dichloromethane each time, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure, the residual oil being recrystallised from trichloroethyl ether.

Thus 1.64 g of the title compound was obtained, which melts at 104 to 106 ⁰ C. The yield is 81% of theory. [α] έ ⁵ = -129.5 ° (c = 2, ethanol)

Example 3

1- | 3-i / lercapto- (2S) -methylpropionyl) pyrrolidine (2S) -carbonsäui ( "

5.28 ci (0.02 mole) of 1- [3-bromo (2 S) -methylpropionyl] -pyrrolictine (2S) -carboxylic acid and 1.67 g (0.022 mole) of thiourea are dissolved in 15 mL of Ν, Ν-dimethylformamide dissolved, and the resulting solution is stirred at 6OX for 24 hours. The solvent is evaporated under reduced pressure, the residue dissolved in 30 ml of distilled water, the resulting solution treated with 6.00 g of 50% i 3er hydrazine solution under cooling with ice water and stirred for a further hour with cooling. 50 ml of 5% strength sulfuric acid solution are added to the reaction mixture, the precipitated precipitate is filtered, washed with water and then with dichloromethane. 10 g of sodium chloride are added to the aqueous phase, and the mixture is extracted four times with 30 ml of dichloromethane each time. The combined organic solutions are dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The remaining oil is recrystallized from 20 ml of trichlorethylene.

Thus, 3.33 g of title compound are obtained, which melts at 104 to 106 ⁰ C. The yield is 82% of theory. [ate ⁵ = -129.5 ⁰ Ic = 2; ethanol)

Example 4

A. 1 - ¹ (2S) -Methyl-3-isothiouroniumpropionylj-pyrrolidine (25) -carboxylate

5.64 ij (0.02 mole) of 1- [3-bromo (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid monohydrate are dissolved in 50 ml of dichloromethane and the resulting solution w> rc! stirred with 5 g of anhydrous magnesium sulfate for one hour. The drying agent is filtered, washed with 10 ml of dichloromethane, the organic solutions are combined and evaporated under reduced pressure. The residue is dissolved in 15 ml of anhydrous Ν, Ν-dimethylacetamide, treated with 1.52 g (0.02 mol) of anhydrous thi lamstoff and stirred under nitrogen for 24 hours. During the reaction, the flask containing the reaction mixture is kept in an oil bath of 7'0 "C. Then, the mixture is cooled with ice-water and diluted with 150 ml of acetonitrile To the resulting mixture is added 2.8 ml (0.02 mol) of triethylamine The reaction mixture is stirred for a further 2 hours, the precipitate is filtered, suspended in 20 ml acetonitrile, filtered, redissolved in 20 ml / acetonitrile, filtered and dried to give 4.2 g of the title compound, melting at 187-189 ° C .: The yield is 81% of theory. [aβ ⁵ = - 1J7 to 111 ⁰ C (c = 1, Essigsä jre)

TLC:

(6 parts of a mixture of pyridine, water and glacial acetic acid in a ratio of 20: 11: 6.4 parts of ethyl acetate. R, = 0.41. (A mixture of butanediol, glacial acetic acid and water in a ratio of 7: 1: 3) Rf = 0.2.

B. 1- [3-mercapto (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid

2mi (0.02 mole) of 50% hydrazine is added to the stirred and ice-cooled solution of 2.59 g (0.01 mole) of 1 - [(2S) -methyl-3-isothiuronium-propionyl] -pyrrolidine (2S) -carboxylate added dropwise in 25 ml of water under nitrogen. The reaction mixture.

is stirred under cooling for additional 30 minutes, then the cooling bath is removed and the mixture is stirred for a further 30 minutes. The reaction mixture is again cooled to a temperature below 10 ° C, treated with the g-mixture of 2 ml of concentrated hydrochloric acid and 2 ml of water, and stirred for 30 minutes. After the addition of 6 to 10 g of sodium chloride, the product is extracted three times with 20 ml of dichloromethane each time. The organic solutions are combined, washed with 1bml of water and the aqueous phase is extracted with 5 ml of dichloromethane. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The (2.03 g) oily residue is recrystallized from 10 ml of trichlorethylene, the crystals are washed with η-hexane and dried.

Thus, 1.62 g title compound is obtained, which melts at 103 to 104 C ^c. The yield is 80% of theory.

[a] f = -129 to 13O '(c = 2, Äthar.ol)

Claims (8)

A process for the preparation of 1- [3-mercapto (2S) -methyl-propionyl-pyrrolidine (2S) -carboxylic acid of the formula CH, ³ (S) HS-CH ₀ -CH-CO-Nr "" COOH "Π-Ι_ΓΠ_Μ t ^ (S) or the pharmaceutically acceptable salts thereof, from an omega-halo-acylproline of the formula T ^H 3 (S) X-CH ₂ -CH-CO-N ρ, .00OH
UU -IN r ^ (S) characterized in that the omega-halo-acylproline of the forms! Reacting III or a salt thereof in an organic dipolar aprotic solvent with thiourea, the obtained isothiuronium compound of the formula H ₂ N _x ^ CH ₃ (S) or an acid addition salt thereof formed with hydrogen halide - optionally after isolation - hydrolysed and, if desired, the product of formula I is converted into a salt or released from a salt. 2. The method according to claim 1, characterized in that reacting the omega-halo-acylproline of the formula III or a salt thereof in an organic dipolar aprotic solvent with thiourea, the obtained, formed with hydrogen halide acid addition salt of the isothiuronium compound of the formula II - If appropriate, after isolation - hydrolyzed and, if desired, the product of formula I is converted into a salt or from a salt * / eisetzt. 3. The method according to claim 1, characterized in that reacting the omega-halo-acylproline of the formula III or a salt thereof in an organic dipolar aprotic solvent with thiourea, the resulting isothiuronium compound of the formula II is isolated, then hydrolyzed, and if desired the product of formula I is converted into a salt or released from a salt. 4. The method according to claim 1, 2 or 3, characterized in that one uses as a dipolar aprotic solvent Ν, Ν-dimethyl-formamide, N, N-dimethyl-acetamide or dimethyl sulfoxide. 5. The method according to claim 1,2 or 3, characterized in that the reaction with the thiohb. r> material at 20 to 8O ⁰ C, advantageously at 50 to 7O ⁰ C performed. 6. The method according to claim 1, 2 or 3, characterized in that one carries out the reaction with the thiourea in the presence of an acid binder. 7. The method according to claim 1,2 or 3, characterized in that one hydrolyzes the isothiuronium compound in the presence of hydrazine. 8. The method of claim 1, 2, 3 or 6, characterized in that one hydrolyzes the isothiuronium compound at 0 to 30 ⁰ C, advantageously at 10 to 15 ° C.