FI87770C - Process for the preparation of mercaptoacylproline - Google Patents

Description

87770

Process for the preparation of mercaptoacylproline i f

The invention relates to a new process for the preparation of the formula (S) ®H3

HS -CHrt-CH-CO-ΙΊ- / I

2 <3, O

for the preparation of 1- [3-mercapto- (2S) -methylpropionyl] pyrrolidine - (2S) -carboxylic acid or a pharmaceutically acceptable salt thereof according to

The compound of formula I is known under the international non-proprietary name captopril and has valuable antihypertensive activity.

According to GB 1,576,161, the halo atom of a haloacylproline can be converted to a mercapto group by various reagents. The reaction is carried out with the anion RS-, where R represents hydrogen, C 1-4 alkyl, phenyl (C 1-4 alkyl), triphenyl- (C 1-2 alkyl) or a group of formula R 1 - ΟΙ ... 0, in which R, represents C 1-4 alkyl or phenyl.

Of the various R-S anions, only those suitable for the preparation of captopril in which the substituent of the sulfur atom of the compound formed in the halo atom substitution reaction can be removed, i. it is like a protecting group. The following meanings of the residue R belong to this category: hydrogen, tert-butyl, benzyl, triphenylmethyl (trityl) and R'-Cr o wherein the residue R has the meaning given above.

2 87770 «

For the simplest case where R is hydrogen, nothing is shown.

If R represents tert-butyl, benzyl or trityl, the reagent used may be tert-butyl mercaptan, benzyl mercaptan or trityl mercaptan, each of which is a hazardous, carcinogenic and toxic compound. To effect halogen substitution, the carboxyl group of proline must be temporarily protected. Further, the yield of such a reaction is very low. For example, K. Hofmann et al. show a close analogy in the case of benzyl mercaptan [J. Am. Chem. Soc., 71, 1253 (1949)]: The 4-chlorobutyl derivative is reacted with the sodium salt of benzyl mercaptan to give the S-benzyl-4-mercaptobutyl derivative in 66% yield. The protecting group is removed with the resulting hydrogen produced with sodium in ethanol. Thus the total yield is 34%. Even worse results can be expected with tert-butyl mercaptan and trityl mercaptan, as in both cases the etheric inhibition is much higher. In general, such protecting groups are attached to the molecules in the opposite way: existing mercapto compounds are reacted with isobutylene or thionyl chloride [T.W. Greene, Protective Groups in Organic Synthesis, pp. 193, 1981].

If R represents a group of formula R 1 - (jj-, captopril: O

can be prepared in very low yields.

According to an example of GB Patent Publication No. 1,576,161. . the analogous 1- [2-mercaptoacetyl] -proline is prepared using thiobenzoic acid in 15% yield based on proline.

GB 2,065,643 discloses a case where R is hydrogen: N- [3-halo- (2S) -methylpropionyl] - (S) -proline is reacted with an aqueous solution of sodium hydrogen sulfide 3,87770. The reaction product is formed after long heating. However, the corresponding disulfide is also formed in an amount of 5 moles - *. This by-product must be reduced with zinc in a separate step in the presence of an acid. The yield is 71%. If sodium hydrogen sulfide is dissolved in Ν, Ν-dimethylformamide, the above yield is reduced to 65%. In fact, the best result is obtained with aqueous ammonium hydrogen sulfide solution, but the reaction product and the by-products present can be separated only by column chromatography. Also in this way a mixture of 92% captopril, 6% disulfide and 0.5% symmetrical sulfide is obtained. The latter impurity by-product is formed irreversibly, i. it cannot be converted to captopril. In addition, the solubility of sulfide is the same as that of captopril. Thus, they cannot be distinguished in a simple preparative manner. The above facts are confirmed by the article by M. Shimazaki et al. [Chem. Pharm. Bull., 30, 3120 (1982) J. Thus, the latter process cannot be used in industrial scale manufacturing.

According to U.S. Patent 4,332,725, the halo atom is converted to a mercapto group with sodium thiosulfate. In this case, a so-called Bunte salt heated with concentrated hydrochloric acid to give captopril in 70% yield.

According to DE-A-35 26 023, N- [3-halo- (2S) -methylpropionyl] - (S) -proline is reacted with thiourea in water, alkanol or aqueous alkanol at 60-100 ° C to give N ? h3 <s) cocii

C - S - CU2 - CU - CO - II-f IV

A compound according to I (S) x "4 87770, wherein X represents a halo atom. This compound is hydrolyzed in the reaction mixture without isolation with alkali metal hydroxide or carbonate.

However, it has proved virtually impossible to replicate the latter known process. By following the method of Example 5 of said publication, we obtained in our experiments a product which did not crystallize and therefore its melting point could not be determined. TLC analysis of the oily product showed that the product contained about 50% thiourea and 15% captopril. Its optical activity in ethanol was: [α] 25 = -27 ° (c = 1.7; ethanol) The NMR spectrum of this crude product was not determined.

By the method of Example 6 of the same DE publication, we also obtained an oily product which did not crystallize. The product was subjected to TLC analysis based on 25% captopril, along with five other compounds.

The optical activity of this oil was as follows: ... [a] u25 = -35 ° (c = 1.7; ethanol) _ Since no pure crystalline material was obtained, the melting point could not be determined either and NMR analysis was not meaningful •. · To do.

In conclusion, the process for the preparation of captopril described in DE-A-35 26 023 is not ·. : industrially applicable.

It has now been found that a compound of formula I can be produced. economically formula 5 87770 CH, <s>

I 3 COOH

Λ · “* CJ ^ - CH - CO - IJ—— S XXX

An omega-haloacylproline of formula (S) wherein X represents a halo when the omega-haloacylproline of formula III or a salt thereof is reacted with a thiourea in an organic dipolar aprotic solvent to give HI (3)

™ 3 COOH

c - S - CH, - CH- CO -] J- / II

An isothiouronium compound according to EH (1) (3) or a hydrohalide thereof, which after optional isolation is hydrolysed and ... if desired, the product of formula I is converted into a salt or liberated from a salt.

More specifically, the method according to the invention is mainly characterized by what is set forth in the characterizing part of claim 1.

The free carboxyl group of a compound of formula I may be: converted to a salt with an inorganic or organic base.

If a salt of a compound of formula I is obtained in the process of the invention, the free carboxylic acid can be liberated in a manner known per se.

In formula III, X represents a halogen atom, preferably a bromine atom of 6,87770.

The reaction of a compound of formula III or a salt thereof with a thiourea takes place only in an organic dipolar aprotic solvent such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide or dimethyl sulfoxide. In general, the reaction is carried out at 20 to 80 ° C, especially 50 to 70 ° C at atmospheric pressure. The reaction time is usually 15 to 25 hours. If an acid scavenger such as an organic base is also used, the compound of formula II is obtained as a solid. Without the acid scavenger, the corresponding hydrohalide addition salt is formed. If desired, the compound of formula II is isolated before the next reaction step, i. before hydrolysis. Regularly, the hydrohalide addition salt of a compound of formula II remains in solution, as a result of which it generally hydrolyzes without isolation.

The isothiouronium compound of formula II or a hydrohalide addition salt thereof is preferably hydrolyzed in the presence of a base such as hydrazine at 0-30 ° C, suitably at 10-15 ° C at atmospheric pressure. The product of formula I is isolated from the reaction mixture in a manner known per se, e.g. by extraction or evaporation.

The isothiouronium compound of formula II is obtained and hydrolyzed to captopril in almost quantitative yield. Even if the latter product is recrystallized, the yield is more than 80%. The resulting captopril does not contain · 1 the corresponding disulfide or symmetrical sulfide, so it is almost 99.5% pure (determined by iodometry).

: The process according to the invention is explained in more detail by the following non-limiting examples.

7 B7770 Preparation of 3.34 g (0.02 moles) of 3-bromo-2-methylpropionic acid and 4.60 g of the starting compound, 1- [3-bromo- (28) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid monohydrate (0.02 mol) of benzylpyrrolidine (2S) carboxylate hydrochloride is dissolved in 50 ml of anhydrous methylene chloride. To the resulting stirred mixture is added 1.9 g of triethylamine in 5 ml of anhydrous methylene chloride under cooling at 0 ° C, then 3.92 g (0.019 mol) of N, N'-dicyclohexylcarbodiimide in 20 ml of methylene chloride are added at the same temperature. The reaction mixture is stirred at 0 ° C for 2 hours, then at room temperature for a further 12 hours. The filtered mixture is extracted with 20 ml of 9% hydrochloric acid, 20 ml of water, 20 ml of 5% aqueous sodium hydrogen carbonate solution, then 20 ml of water. The organic layer is dried over ignited magnesium sulfate and evaporated. 6.40 g (95%) of benzyl 1- [3-bromo-2-methylpropionyl] pyrrolidine (2S) carboxylate are obtained in the form of a pale yellow oil.

Thin layer chromatography (silica gel, benzene / glacial acetic acid 3: 1), two spots, Rf = 0.44 and 0.48, corresponding to a 1: 1 ratio of diastereomers.

The oil is dissolved in 60 ml of ethyl acetate and 0.6 g of 10% palladium-on-carbon catalyst is added to the resulting solution. The reaction mixture is hydrogenated at atmospheric pressure until no ester is present in the thin layer chromatography. The catalyst is removed by filtration, washed with ethyl acetate, the organic solvent is distilled off and the residue is recrystallized from water. In this way, 2.00 g (42.5%) of the title compound are obtained, m.p. 69-72 ° C.

- - | [α] 25 D = -88.1 ° (c = 1, ethanol).

8 87770

Example 1 1- [3-Mercapto- (28) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid 10.56 g (0.0374 moles) of 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine- 2S) -Carboxylic acid and 3.04 g (0.040 mol) of thiourea are dissolved in 30 ml of N, N-dimethylacetamide and the reaction mixture is stirred at 60 [deg.] C. under a nitrogen atmosphere for 15-20 hours. The organic solvent is removed under reduced pressure and the residue is dissolved in 50 ml of distilled water. To the resulting solution is added 6.00 g (0.12 moles) of hydrazine hydrate under a nitrogen atmosphere while cooling the flask with ice water. The reaction mixture is stirred for 30 minutes under cooling, then for a further 30 minutes at room temperature. 100 ml of 5% sulfuric acid are added, the white precipitate is filtered off, washed with water and then with methylene chloride. The filtrate is extracted with 4 x 30 ml of methylene chloride, the organic solutions are combined, washed with 2 x 20 ml of water and the aqueous phase is extracted with 2 x 15 ml of methylene chloride. The organic phases are combined, dried over ignited magnesium sulphate, filtered and evaporated under reduced pressure.

7.54 g (99%) of the residual oil are crystallized from 25 ml of trichlorethylene. In this way, 6.10 g (80%) of ... the title compound are obtained. Sp. 104-106 ° C.

. [α] D 25 = -129.5 ° (c = 2, ethanol).

Example 2 1- (3-Mercapto- (28) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid 2.64 g (0.010 mol) of 1- [3-bromo- (2S) -methylpropionyl] - * · 'pyrrolidine- The (2S) -carboxylic acid and 0.76 g (0.10 mol) of thiourea are dissolved in 10 ml of dimethyl sulfoxide, the solution is stirred at 60-70 ° C for 24 hours, then 30 ml of 10% aqueous sodium hydroxide solution are added and the mixture is stirred for a further hour and the mixture is acidified with 20% hydrochloric acid under cooling to pH 1, then extracted with 4 x 20 ml of methylene chloride The organic solutions are combined, dried over ignited magnesium sulphate and evaporated under reduced pressure The residual oil is crystallized from trichlorethylene to give 1.64 g (81%) of the title compound, mp 104-106 ° C.

[α] D 2 = -129.5 ° (c = 2, ethanol).

Example 3 1- [3-Mercapto- (2S) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid 5.28 g (0.02 mol) of 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine- ( 2S) -Carboxylic acid and 1.67 g (0.022 mol) of thiourea are dissolved in 15 ml of N, N-dimethylformamide and the mixture is stirred at 60 ° C for 24 hours. The solvent is distilled off under reduced pressure and the residue is dissolved in 30 ml of distilled water. To the ice-cooled solution, 6.0 g of 50% hydrazine is added, and the reaction mixture is stirred for 1 hour under ice-water cooling. 50 ml of 5% sulfuric acid are then added, the precipitate is filtered off, washed with water and methylene chloride. 10 g of sodium chloride are added to the aqueous phase and it is extracted with 4 x 30 ml of methylene chloride. The organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the solvent is removed under reduced pressure. The residual oil is crystallized from 20 ml of trichlorethylene. This gives 3.33 g (82%) of the title compound. Sp. 104-106 ° C.

[α] 25 D = -129.5 ° (c = 2, ethanol).

Example 4 A. 1 - ((28) -methyl-3-isothiouronium propionyl] -pyrrolidine (28) -carboxylate 5.64 g (0.02 mol) of 1- [3-bromo- (2S) -methylpropionyl] - · The pyrrolidine (2S) -carboxylic acid monohydrate is dissolved in 50 ml of methylene chloride and the resulting solution and 5 g of ignited magnesium sulphate are stirred for 1 hour. The residue is dissolved in 15 ml of anhydrous N, N-dimethylacetamide, treated with 1.52 g (0.02 mol) of thiourea and stirred under a nitrogen atmosphere for 24 hours while maintaining the flask containing the reaction mixture at 70 ° C with an oil powder. The mixture is cooled with ice water and diluted with 150 ml of acetonitrile, and 2.8 ml (0.02 mol) of triethylamine in 20 ml of acetonitrile are added dropwise over 30 to 40 minutes with stirring. n for a further 2 hours, the precipitate formed is filtered, suspended in 20 ml of acetonitrile, filtered, resuspended in 20 ml of acetonitrile, filtered and dried. 4.2 g (81%) of the title compound are obtained. Sp. 187-189 ° C.

[α] D 25 = -107 ...- 111 0 (c = 1, acetic acid).

Thin layer chromatography (6 parts of a 20: 11: 6 mixture of pyridine, water and glacial acetic acid, 4 parts of ethyl acetate): Rf = 0.41, (7: 1: 3 mixture of butanol, glacial acetic acid and water): Rf = 0.2 .

B. 1- [3-Mercapto- (28) -methylpropionyl] -pyrrolidine- (28) -carboxylic acid 2 ml (0.02 mol) of 50% hydrazine are added dropwise to a stirred solution of 2.59 g (0, 01 moles) of 1-t (2S) -methyl-3-isothiouronium propionyl] -pyrrolidine (2S) -Y * j carboxylate in 25 ml of water under a nitrogen atmosphere and cooling with ice water. The mixture is stirred for a further 30 minutes under cooling, then the cooling bath is removed and stirring is continued for a further 30 minutes. The reaction mixture is cooled: again to a temperature below 10 ° C and treated with a mixture of ... 2 ml of concentrated hydrochloric acid and 2 ml of water.

The mixture is stirred for 30 minutes, then 6-10 g of YY sodium chloride are added and the product is extracted with 3 x 20 ml of methylene chloride. The organic solutions are combined, washed with 15 ml of water and the aqueous phase is extracted with 5 ml of methylene chloride. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. 2.03 g of the residual oil are crystallized from 10 ml of trichlorethylene. The product is washed with n-hexane and dried. 1.62 g (80%) of the title compound are obtained.

Sp. 103-104 ° C.

[α] D = -129 ...- 130 ° (c = 2, ethanol).

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Claims (3)

12 87770 Claim: A process for the preparation of CH (S) I 3 COOH 113. CH2-Oil-00-N- (1- (3-mercapto- (2S) -methylpropionyl] -pyrrolidine- (2S) -carboxylic acid or pharmaceutically acceptable salts thereof according to the method of formula III OH (3) r113 oooii X - CII2-Oli - 00 - IS III (S) kj omega-haloacylproline, in which X represents a halogen atom, is reacted with thiourea in a solvent to give the formula; ) I, Cη3 C00H Isotiouronium compound of the formula Nc-S - OHo - CH - CO - Hf-II 2 (s) to be hydrolysed, characterized in that the reaction of the omega-halo: acylproline of the formula III with the thiourea is carried out in an organic dipolar aprotic solvent, preferably in dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide, followed by hydrolysis of the isothiouronium compound of formula II or a salt thereof with hydrohalic acid in the presence of hydrazine. • ♦ ♦ 14 87770 For the preparation of 1- [3-mercapto- (2S) -methylpropionyl] pyrrolidine (2S) -carboxylate with the formula (I li 3 (Juon IIS - CH2- Gil - CO - li- (1 (3) or a pharmaceutically acceptable salt thereof, preferably in addition to the omega-haloacylproline of formula III CH (2) I 3 COOH X - Clip-CII - CO - HS lii (S) •: color X for a halogen atom, a thiourea i and a solution, colors for which the isothuronium is formed with the formula x: (S) ™ 0H ^ C- S - CH0 - CH - CO - Hf II w <r 2 (3) l> of hydrolysis, which can be carried out by reaction with omega-haloacylprolines of formula III and thioureas and in which: organic dipolar aprotic solvents, followed by the addition of 15,87770 dimethylformamide, Ν, Ν-dimethylacetate hydrolysers of the isothiouronium formulation with Formula II or halogenated compounds in the form of a mixture in the hydrazine.