HU203322B - Process for producing n-[2(s)-methyl-3-isothiorhonium-propionyl]-(s)-prolinate - Google Patents

Abstract

The present invention relates to a novel process for the preparation of the isothuronium base of formula (I) from the isothiuronium salt of formula (Ia) wherein X is halogen, preferably bromine, in an inert organic solvent. According to the present invention, the isothiuronium salt of formula (III) is reacted with at least a stoichiometric amount of an oxirane of formula (H) wherein R is hydrogen, C1-C4 alkyl or phenyl. h2nx c-s h2n ch3! CH2-Ch-C0-N (S) Θ cooL0 / r-ch-ch2 (I) (Π) HAc © (III) Scope of the description: 3 pages, Figure 1 EN 203 322 A -1-

Description

The present invention relates to a novel process for the preparation of N- [2 (S) -methyl-3-isothiuronium propionyl] (S) -prolinate of formula (I).

The compound of formula (I) is an important intermediate for the preparation of 1- (3-mercapto-2 (S) -methyl-propionyl) -2 (S) -pyrrolidine-carboxylic acid (captopril). is disclosed in German Federal Publication.

It is also known from U.S. Patent No. 35,260,023. German Patent Publication according to which 1- (3-halo-2 (S) -methyl-propionyl) -2 (S) -pyrrolidine carboxylic acid in aqueous, alcoholic or aqueous alcoholic medium with thiourea at 60-100 ° C. describes the preparation of captopril without isolation of the intermediate isothiuronium salt, but the results are not reproducible, nor can captopril be isolated from the reaction mixture in this manner.

No. 37 21 430. Whereas the process known from the German Patent Publication allows the use of dipolar aprotic solvents to prepare the isothiuronium salt of formula (ΙΠ) from 1- (3-halo-2 (S) -methylpropionyl) -2 (S) pyrrolidinecarboxylic acid with thiourea, wherein X represents a halogen atom, preferably a bromine atom. According to the known process above, the preparation of captopril from the isothiuronium salt of formula (ΙΠ) is then solved in two ways. In one embodiment, the dipolar aprotic solvent present is removed by distillation in vacuo and the residue is hydrolyzed under very mild conditions to yield the desired product directly in about 80% yield without isolation of the isothiouronium base. However, it is a disadvantage of scale-up that the presence of dipolar aprotic solvents (such as dimethylacetamide) is difficult to remove completely on a commercial scale, and solvent residues impede captopril production in the final step. In another embodiment of the above known process, the resulting isothiuronium salt of Formula (ΠΙ) is first separated with an organic base to isolate the isothiuronium base of Formula (I), e.g. This solution undoubtedly has the industrial advantage of eliminating the relatively high boiling point dipolar aprotic solvent present in the thiuronium salt, which may be particularly difficult to scale up, but the disadvantage of this solution is that , the isothiuronium base cannot be completely purified in this way. This may reduce the yield of the final product at larger batch sizes.

The isothiuronium base of formula (I) liberates the liberated isothiuronium moiety with the proline carboxyl group present.

It has now been found that the isothiuronium base of formula (I) can be prepared from the isothiuronium salt of formula (ΙΠ) in an inert organic solvent, substantially free of impurities and in an inert organic solvent, if the thiuronium salt of formula (ΠΙ) is hydrogen, (C1-C4) alkyl or phenyl.

The oxirane of formula (II) is preferably used in at least stoichiometric amounts.

Oxiranes are cheap, bulk starting materials, with propylene oxide being particularly preferred. The base release is carried out at room temperature by the addition of an inert organic solvent, preferably acetonitrile, from which the isothiouronium base of formula (I) can be well filtered and also triturated in the presence of dipolar aprotic solvent, preferably by filtration in an inert organic solvent.

The isothiuronium base of formula (I) obtained by the process of the present invention is not contaminated with the hydrogen halide of an organic base, since no oxide salt formation is obtained, thereby obtaining a highly pure isothiuronium base of formula (I) in almost quantitative yield.

A further advantage of the process according to the invention is that the isothiuronium base of formula (I) thus obtained can be obtained in a very good yield (85-90%) even after enlargement, which is at least 99.5% pure by HPLC analysis and not contains impurity 3-mercapto-2-methylpropionic acid.

The invention is illustrated in detail by the following examples:

Example 1 1- [2 (S) -methyl-3-isothiuronium propionyl] - (S) prolinate

1- (3-Bromo-2 (S) -propionyl) - (S) -proline monohydrate (112.8 g, 0.4 mol) was dried over MgSO4 (50 g) in dichloromethane (1000 mL). The desiccant was filtered off, washed with dichloromethane and the solvent was evaporated. The residue is dissolved in 300 ml of Ν, Ν-dimethylacetamide (the residual dichloromethane is evaporated) and then 30.4 g (0.4 mol) of thiourea are added under inert atmosphere (e.g. under nitrogen) for 12 hours at 60 ° C. stirred. After cooling to room temperature, propylene oxide (46.4 g, 0.8 mol) in anhydrous acetonitrile (300 mL) was added. A white crystalline product precipitates from the reaction mixture, which is stirred for several hours, filtered, washed with acetonitrile and dried. The title product weighing 101.5 g (98%), mp 202-203 ° C (decomposition point), optical rotation ^[alpha] n d: -111 ° (c = 1, acetic acid).

Example 2 1- [2 (S) -methyl-3-isothiuronium propionyl] - (S) prolinate

In the same manner as in Example 1, the salt is liberated with a solution of 40 ml of ethylene oxide in 300 ml of anhydrous acetonitrile at -10 ° C. The reaction mixture was then allowed to warm to room temperature and after stirring for several hours, the crystalline title product was filtered. Yield 98.4 g (95%), the physical constant is the same as in Example 1.

-2EN 203322 A

Example 3

Preparation of cptopril

25.9 g (0.1 mol) of 1- [2 (S) -methyl-3-isothiuronium propionyl] - (S) -prolylate prepared according to Examples 1 or 2 are dissolved in 250 ml of ice water under nitrogen. and 20 ml of 50% hydrazine hydrate are added at 10 ° C. After stirring for half an hour at 10 ° C, it was acidified with 0 ml of 18% hydrochloric acid and cooled to 0 ° C. To the aqueous solution was added sodium chloride (100 g) and extracted with dichloromethane (3 x 200 mL). The combined organic phases are washed with 150 ml of water and the aqueous phase is repeatedly extracted with 50 ml of dichloromethane. The combined dichloromethane phases were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. The residue was crystallized with ethyl acetate (25 mL). Stir at 0 ° C for 5 hours, filter, wash with n-hexane. 17.25 g (85%) of captopril, mp 103-104 ° C, optical rotation [ce] ² d: -129.5 '(c = 2, ethanol). HPLC purity 99.7%.

Example 4 1- [2 (S) -methyl-3-isothiuronium propionyl] - (S) proline

Dissolve 11.28 g (40 mmol) of N- [3-bromo-2 (S) -methylpropionyl] - (S) -proline monohydrate in 30 ml of N, N-dimethylacetamide, add 3.04 g (40 mmol). thiourea and stirred in an inert atmosphere for 12 hours at 60 ° C. After cooling to room temperature, a solution of 4.64 g (80 mmol) of propylene oxide in 30 mL of acetonitrile is added dropwise to the reaction mixture. The precipitated crystalline product was cooled with ice water, after stirring for 5 hours, filtered, washed with acetonitrile and dried.

9.63 g (93%) of the title compound were obtained having the same physical constants as in Example 1.

Claims (2)

A process for preparing the isothiuronium base of formula (I) from the isothiuronium salt of formula (III) wherein X is a halogen atom, preferably a bromine atom, in an inert organic solvent, characterized in that the isothiuronium salt of formula (ox) wherein R is hydrogen, at least a stoichiometric amount of a C 1 -C 4 alkyl group or a phenyl group. Process according to claim 1, characterized in that the oxirane of the formula (II) is propylene oxide.