CH673279A5 - - Google Patents

Description

DESCRIPTION

(s)

(I)

or the pharmaceutically acceptable salts thereof, from an omega-haloacylproline of the formula

The invention relates to a new process for the production of 1- [3-mercapto- (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid of the formula ch,

i 3

x-ch2-ch-c0-n cs)

(s)

-cooh on)

CH.

15 I

hs-ch2-ch-c0-n-

Cs) '

CS)

cooh in which X represents a halogen atom, characterized in that the omega-haloacylproline of the formula III or a salt thereof is reacted with thiourea in an organic dipolar aprotic solvent, the isothiuronium compound of the formula obtained

H2N \ 3 "

>> c-s-ch2-ch-co-n

UH CS)

cooh

(II)

or hydrolysing an acid addition salt formed with hydrogen halide and, if desired, converting the product of the formula I into a salt or releasing it from a salt.

2. The method according to claim 1, characterized in that the isothiuronium compound of the formula II obtained or an acid addition salt formed with hydrogen halide thereof is isolated and then hydrolyzed.

3. The method according to claim 1 or 2, 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 acid addition salt obtained with hydrogen halide formed the isothiuronium compound of the formula II - if appropriate after isolation - hydrolyzed and, if desired, the product of the formula I converted into a salt or released from a salt.

4. Process according to claim 1 or 2, characterized in that the omega-haloacylproline of the formula III or a salt thereof is reacted with thiourea in an organic dipolar aprotic solvent, the isothiuronium compound of the formula II isolated, then hydrolyzed and, if desired, the product of the formula I converted into a salt or released from a salt.

5. The method according to claim 1, 2, 3 or 4, characterized in that N, N-dimethylformamide, N, N-dimethyl-acetamide or dimethyl sulfoxide is used as a dipolar aprotic solvent.

6. The method according to claim 1, 2, 3 or 4, characterized in that one carries out the reaction with the thiourea at 20 to 80 ° C, advantageously at 50 to 70 ° C.

7. The method according to claim 1, 2, 3 or 4, characterized in that the isothiuronium compound is hydrolyzed in the presence of hydrazine.

20th

or the pharmaceutically acceptable salts thereof.

The compound of formula I is known under the name captopril and has valuable hypotensive effects.

25 According to UK Pat. No. 1,576,161, the halogen atom of an omega-haloacylproline can be converted into a marcapto group using various reactants. The reaction takes place with the anion RS ~ where R is a hydrogen atom, a Q_4 alkyl group, a phenyl (C [4 Al-30 kyl) group, a triphenyl (Ci 2 alkyl) group or a group of the formula Rj -C - means in which R] for a C ^

O

Alkyl group or a phenyl group.

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

40 The simplest case in which R represents a hydrogen atom has not been taught in UK Patent No. 1,576,161.

If R represents a tert-butyl group, a benzyl group or a trityl group, the reactant used would be tert-butyl-mercaptan, benzyl mercaptan or trityl-45 mercaptan. The reactants listed are dangerous, carcinogenic or toxic compounds.

To carry out the substitution of the halogen atom, the carboxyl group of the proline must be provisionally provided with a protective group. Furthermore, the yield is unacceptably low. K. Hofmann and co-workers describe an analogous method with benzyl mercaptan [J. At the. Chem. Soc., 71, 1253 (1949)]: a 4-chloro-butyl derivative is reacted with the sodium salt of benzyl mercaptan, and from the S-benzyl-4- obtained with a yield of 66% of theory mercapto-butyl derivative becomes the protective group - ie the benzyl group - removed with sodium in ethanol. The overall yield is only 34% of theory.

60 Even more unfavorable results can be expected when using tert-butyl mercaptan and trityl mercaptan, because the spatial disability is significantly higher with the two compounds. The protective groups of this type are generally introduced into the molecules in reverse order: the mercaptover compound already formed is reacted with isobutylene or thionyl chloride [T.W. Greene, Protective Groups in Organic Synthesis, p. 193, 1981].

3rd

673 279

If R stands for a group of the formula R | -C -,

O

the captopril are extremely uneconomical. According to an example of UK Pat. No. 1,576,161, the analogous 1- (2-mercapto-acetyl) -proline is prepared using thiobenzoic acid. The yield calculated on the proline is only 15% of theory.

The case where R represents a hydrogen atom was described in UK Patent No. 2,065,643: N- [3-halogeno- (2S) -methyl-propionyl] - (S) -proline is reacted with an aqueous solution of sodium hydrosulfide . The reaction requires long-term heating, and the corresponding disulfide is also formed in an amount of 5 mol%. This by-product is then to be reduced in a special stage in the presence of an acid with zinc. The yield of the reduction is 71% of theory. If the sodium hydrosulfide is dissolved in N, N-dimethylformamide, the yield decreases to 65% of theory. The best result is apparently obtained by using an aqueous solution of ammonium hydrosulfide, but the reaction product and the by-products formed can only be isolated chromatographically. In this way too, a mixture of 92% captopril, 6% corresponding disulfide and 0.5% corresponding symmetrical sulfide is obtained. The formation of the last contamination is irreversible, i.e. under no circumstances can it be converted into captopril. Furthermore, the sulfide and captopril have an almost similar solubility, so they simply cannot be separated. The above are supported by an article by M. Shiwazaki and co-workers [Chem. Pharm. Bull., 30, 3129 (1982)]. So the latter method is not suitable for the production of captopril on an industrial scale.

According to US Pat. No. 4,332,725, the halogen atom is converted into the mercapto group by means of sodium thiosulfate. In this case, a so-called Buntesche salt is formed, which is heated with concentrated hydrochloric acid and thus converted into captopril. The yield is 70% of theory.

According to DE-OS No. 3 526 023, N- [3-halogeno- (2S) -methyl-propionyl] - (S) -proline is reacted with thiourea in water, an alcohol or an aqueous alkanol at 60 to 100 ° C. . A compound of the formula ch-, r e \

h9hk i j c00h z ": c-s-ch9-ch-co-n (

h? n (s) iv x ~

Formula III or a salt thereof in an organic di-polar aprotic solvent with thiourea, the resulting isothiuronium compound of the formula

5 PH

H2Nn j 3

^ c-s-ch2-ch-c0-n nh cs)

it)

10th

cooh

II

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 was practically impossible to rework this known method.

It has been found that the compound of the formula I is derived from an omega-haloacylproline of the formula ch-

x-ch2-ch-co-n

(s)

c00h

III

wherein X stands for a halogen atom, can be produced economically if the omega-halo-acylproline or an acid addition salt formed with hydrogen halide thereof - optionally after isolation - is hydrolyzed and, if desired, the product of the formula I is converted into a salt or from releases a salt.

The free carboxyl group of the compound of formula I can be converted into a salt with an inorganic or organic base. If a salt of the compound of formula 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.

25 The reaction of the compound of formula III or a salt thereof with thiourea takes place only in an organic dipolar aprotic solvent such as N, N-dimethyl-formamide, N, N-dimethyl-acetamide or dimethyl sulfoxide. In general, the reaction is carried out at a temperature of 20 to 80 ° C, advantageously from 50 to 70 ° C under atmospheric pressure. As usual, the reaction is complete after 15 to 25 hours. If an acid binder, e.g. an organic base is present in the reaction mixture, the compound 35 of formula II is obtained in the 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 is isolated before the next reaction stage - the hydrolysis. In general, the acid addition salt of the compound of formula II formed with the hydrogen halide remains in the solution, as a result of which it is generally hydrolyzed without isolation.

The isothiuronium compound of the formula II or the acid addition salt thereof is advantageously hydrolyzed in the presence of a base such as hydrazine at a temperature of from 0 to 30 ° C., advantageously from 10 to 15 ° C. under atmospheric pressure. The product of formula I is obtained from the reaction mixture in a manner known per se, e.g. isolated by Ex-50 traction and evaporation.

According to the invention, the isothiuronium compound of the formula II is prepared in an almost theoretical yield and converted into captopril by hydrolysis. Even if the end product is recrystallized, an overall 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 an impurity, which is why the iodometrically determined purity of captopril is 99.5%.

60 The invention is explained in more detail with reference to the following examples, but is not restricted to these examples.

Preparation of the starting compound: 1- [3-bromo- (2S) -methylpropionyl] -pyrrolidine (2S) -carboxylic acid-65 re-monohydrate

3.34 g (0.02 mole) of 3-bromo-2-methylpropionic acid and 4.60 g (0.02 mole) of (S) -proline-benzyl ester hydrochloride are dissolved in 50 ml of anhydrous dichloromethane and the

673 279 4

holding solution, the mixture of 1.9 g of triethylamine is adjusted to 1 with 20% hydrochloric acid solution with cooling and 5 ml of anhydrous dichloromethane and then 3.92 g with ice water, and the solution is mixed with

(0.019 moles) N, N'-dicyclo-20 ml dichloromethane, dissolved in 20 ml dichloromethane, extracted four times, dried over anhydrous hexyl-carbodiimide at 0 ° C. with stirring and cooling, filtered and filtered with reduced. The reaction mixture is evaporated at 5 tem pressure for a further 2 hours. The remaining oil will run out

0 ° C, and then recrystallized for a further 12 hours at room temperature trichlorethylene.

door stirred. The reaction mixture is filtered, giving 1.64 g of the title compound, which at 104

Filtrate with 20 ml 9% hydrochloric acid solution, 20 ml water, melts up to 106 ° C. The yield is 81% of theory. 5% sodium hydrocarbonate solution and finally [a] d = —129.5 ° (c = 2; ethanol)

Extracted 20 ml of water. The organic phase is over 10

anhydrous magnesium sulfate dried and mixed. Example 3

6.40 g (95% of theory) l- [3-bromo-2-methylpropionyl] pyr- l- [3-mercapto- (2S) methylpropionyl] pyrrolidine (2S) -

rolidin (2S) -carboxylic acid benzyl esters are obtained in the form of carboxylic acid light yellow oil. 5.28 g (0.02 moles) of l- [3-bromo- (2S) -methylpropionyl] pyr-

Thin layer chromatography (silica gel, 3 parts benzene, 15 rolidin (2S) -carboxylic acid and 1.67 g (0.022 mole) thiourea-

1 part glacial acetic acid): Rf = 0.44 and 0.48, which are a diastereoid dissolved in 15 ml N, N-dimethyl-formamide, and correspond to a mer ratio of 1: 1. _ The solution obtained is kept at 60 ° C. for 24 hours.

The oil obtained is dissolved in 60 ml of ethyl acetate and stirred. The solvent is evaporated under reduced pressure of the solution, 0.6 g of 10% palladium / carbon catalyzed, the residue added in 30 ml of distilled water. The suspension is dissolved at room temperature and the solution obtained is hydrogenated with 6.00 g of 50% hydrazine solution and under atmospheric pressure. When the solution was treated with ice water under cooling and a long-range connection was stirred under cooling for a further hour by thin layer chromatography. The reaction gas can no longer be detected, the catalyst is mixed, 50 ml of 5% sulfuric acid solution are filtered in, washed with ethyl acetate, the organic solution is added, the precipitate which has separated out is filtered off, evaporated off with medium and the residue is evaporated Water crystallized- 25 water and then washed with dichloromethane. The watered. This gives 2.00 g of the title compound, 10 g of sodium chloride are added to the 69% phase, and this melts to 72 ° C. The yield is 42.5% of theory. The mixture is treated with 30 ml of dichloromethane four times extra- [a] d = - 88.1 ° (c = 1; ethanol). The combined organic solutions are dried over anhydrous magnesium sulfate, filtered and evaporated under Example 1 under reduced pressure. The remaining oil l- [3-mercapto- (2S) -methylpropionyl] pyrrolidine (2S) - is recrystallized from 20 ml of trichlorethylene.

carboxylic acid This gives 3.33 g of the title compound, which at 104

10.56 g (0.0374 moles) of l- [3-bromo- (2S) -methylpropionyl] - melts to 106 ° C. The yield is 82% of theory. pyrrohdin- (2S) -carboxylic acid and 3.04 g (0.040 mole) thio- [a] & = —129.5 ° (c = 2; ethanol)

Urea are dissolved in 30 ml of N, N-dimethyl-acetamide under 35 Example 4

Dissolved nitrogen, and the reaction mixture is at 60 ° C A. l - [(2S) -methyl-3-isothiouroniumpropionyl] pyrroli-

stirred under nitrogen for 15 to 20 hours. The Lödin- (2S) -carboxylat solvent is evaporated under reduced pressure 5.64 g (0.02 mole) l- [3-bromo- (2S) -methylpropionyl] -pyr-

and the residue dissolved in 50 ml of distilled water. The rolidin (2S) -carboxylic acid monohydrate are dissolved in 50 ml of di-obtained solution, 6.00 g (0.12 moles) of hydrazine-40-chloromethane, and the resulting solution is washed with 5 g of water under cooling with ice water and under Nitrogen-anhydrous magnesium sulfate is stirred for one hour, add, and the reaction mixture is stirred for 30 minutes. The drying agent is filtered, washed with 10 ml of dichloromethane with ice water and a further 30 minutes with than, the organic solutions are combined at room temperature touched. The reaction mixture and evaporated under reduced pressure. The back 100 ml of 5% sulfuric acid solution is added, and the 45 stand is precipitated in 15 ml of anhydrous N, N-dimethylacetamide, filtered, with water and then with, with 1.52 g (0.02 mole ) washed anhydrous thiourea be-dichloromethane. The filtrate is treated with 30 ml of di- and stirred under nitrogen for 24 hours. Sel-chloromethane extracted four times, the combined organic during the reaction, the flask, which contains the reaction solutions are washed twice with 20 ml of water, mixed, is kept in an oil bath at 70 ° C. Then and the organic phase is each with 15 ml of dichloromethane, the mixture is cooled with ice water and extracted twice with 150 ml. The organic phases are diluted in acetonitrile. The resulting mixture is digested, dried over anhydrous magnesium sulfate, filtered 2.8 ml (0.02 mole) of triethylamine in 20 ml of acetonitrile and evaporated under reduced pressure. 7.54 g (99% stirring within 30 to 40 minutes added dropwise. The Reak theory) oil remains, the mixture from 25 ml of trichlorethylene is stirred for a further 2 hours, which is never recrystallized. 55 impact filtered, suspended in 20 ml acetonitrile, filtered,

6.10 g of the title product are thus obtained, which are suspended at 104 to again in 20 ml of acetonitrile, filtered and dried at-106 ° C. in a dry state. The yield is 80% of theory. net. 4.2 g of the title compound are thus obtained, which melts at 187 [a] g = —129.5 ° (c = 2; ethanol) to 189 ° C. The yield is 81% of theory.

[a] d = -107 to 111 ° C (e = 1; acetic acid).

Example 2 60 Thin Layer Chromatography:

l- [3-Mercapto- (2S) -methylpropionyl] pyrrolidine (2S) - (6 parts of a mixture of pyridine, water and carboxylic acid glacial acetic acid in a ratio of 20: 11: 6.4 parts of ethyl acetate-

2.64 g (0.01 mole) of l- [3-bromo- (2S) -methylpropionyl] pyrate) Rf = 0.41. (A mixture of butanol, glacial acetic acid and rolidin (2S) -carboxylic acid and 0.76 g (0.01 mole) of thiourea-water in a ratio of 7: 1: 3) Rf = 0.2.

Substance is dissolved in 10 ml of dimethyl sulfoxide and the solution containing 65 B. l- [3-mercapto- (2S) -methylpropionyl] pyrrolidine (2S) is carboxylic acid at 60 to 70 ° C for 24 hours stirred, then with 30 ml of 10% sodium hydroxide solution, 2 ml (0.02 mole) of 50% hydrazine are treated with stirring and stirred for a further hour. The pH and 2.59 g (0.01

5

673 279

Mole) 1 - [(2S) -methyl-3-isothiuroniumpropionyl] pyrrolidine (2S) -carboxylic acid ester in 25 ml of water was added dropwise under nitrogen. The reaction mixture is stirred for a further 30 minutes with cooling, then the cooling bath is removed and the mixture is stirred for a further 30 minutes. The reaction mixture is cooled again to a temperature below 10 ° C, treated with the 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. The organic solutions are combined, washed with 15 ml 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 of oily residue is recrystallized from 10 ml of trichlorethylene, the crystals are washed with n-hexane and dried.

This gives 1.62 g of the title compound which melts at 103 10 to 104 ° C. The yield is 80% of theory, [a] d - -129 to 130 ° (c = 2; ethanol).

C.

Claims (2)

673 279 2nd PATENT CLAIMS 1. Process for the preparation of l- [3-mercapto- (2S) -methylpropionyl] pyrrolidine (2S) -carboxylic acid of the formula ch- hs-ch2-ch-co-n (s) cooh 8. The method according to claim 1, 2, 3 or 4, characterized in that the isothiuronium compound is hydrolyzed at 0 to 30 ° C, advantageously at 10 to 15 ° C.