HU196959B - Process for producing merkapto-acyl-proline derivatives - Google Patents

Description

The present invention relates to a novel process for a known mercapto

for the preparation of acyl - proline derivatives.

More particularly, the invention relates to 1- [3-mercapto (2S) -methyl-propionyl] -pyrrolidine (2S) of formula I

- relates to a new process for the production of carboxylic acid.

The compound of formula I, internationally known as captopril, has an antihypertensive effect based on inhibition of the angiotensin converting enzyme.

According to Hungarian Patent Application No. 181,965, the halogen atoms of a haloacyl-proline-type compound can be exchanged for several mercapto groups. The exchange is carried out with an ion of formula (IV) in which R is hydrogen, (C1-C4) -alkyl, alkyl (C1-C4) -alkyl, alkyl (C1-C2) -phenylalkyl or a (C1-C2) -phenylalkyl. V may be represented by the formula wherein R 1 is C 1-4 alkyl or phenyl.

Only those pathways starting from the above compounds are suitable for the preparation of captopril, in which the sulfur substituent can be removed from the compound formed in the halogen substitution reaction, i.e. it is a protecting group. Thus, only the cases where R is hydrogen or where R is a protecting group, that is to say, only one of the C 1-4 alkyl groups where R is a tert-butyl group, the alkyl part being C 1-4 phenyl-alkyl, need be investigated. - only in the case where R is benzyl, in the alkyl part of the triphenylalkyl group having 1 to 2 carbon atoms only when R is trityl and finally in the case where R is a group of formula V .

Hungarian Patent No. 181,965 does not teach any simplicity when R is hydrogen.

Cases where R is tert-butyl, benzyl or trityl may be considered together. These would use tert-butyl mercaptan, benzyl mercaptan or trityl mercaptan, which are very dangerous, carcinogenic, toxic substances. A temporary protection of the proline carboxyl group would be required and, ultimately, the reactions would not be carried out satisfactorily. For example, in the case of benzyl mercaptan, K. Hofmann et al., J. Am. Chem. Soc., 71, 1253 (1949) describes a close analogy. They react with the sodium salt of benzylmercaptan to yield the 4-chlorobutyl derivative to give (S) in 66% yield.

benzyl - 4 - mercapto - butyl, which is deprotected with nascent hydrogen, which has been extensively prepared in ethanol with the aid of metal sodium. Thus, total production is only 34%. Even more results are not expected for the sterically shaded tertiary butyl mercaptan and trityl mercaptan. These protecting groups are also incorporated in nein, but in the reverse order: the existing mercapto compound is reacted with isobutylene or thionyl chloride. [T. W. Greene, Protective Groups in Organic Synthesis, 193 p. (1981).]

According to the above-mentioned patent, the target compound can be prepared only in very poor yields when R is a group of formula (V). Starting from proline, analogue 1 (.2-mercaptoacetyl) proline was obtained in only 15% yield from proline using thiobenzoic acid.

British Patent 2,065,643 discloses the case where R is hydrogen. The halogen in 1- [3-halo - (2S) -methyl-propionyl] -pyrrolidine - (2S) -carboxylic acid is reacted with an aqueous solution of sodium hydrogen sulfide. After prolonged heating, the product is formed, but also 5 mol% of the disulfide is formed, which is why in a separate step, in the presence of an acid, the disulfide is reduced to captopril. This gives the product in 71% yield.

If a solution of sodium hydrogen sulfide in dimethylformamide is used, the above yield is reduced to 65%. An aqueous solution of ammonium bisulfide appears to achieve the best results, but separation of the individual components was achieved only by column chromatography. Thus, a mixture of 6% disulfide and 0.5% symmetric sulfide was obtained with 92% product. The latter impurity, even though it is irreversibly formed against the disulfide, does not produce captopril, but solubility is so similar to captopril that it is hardly possible to separate it by preparative means. The foregoing is corroborated by M. Shimazaki et al., Chem. Pharm. Bull. 30, 3129 (1982). Therefore, this process variant is not suitable for large-scale industrial applications.

Hungarian Patent No. 184,082 discloses a process for the conversion of a halogen atom to a mercapto group with sodium thiosulfate. The first to be formed is the so-called Bunte salt which, after heating with concentrated hydrochloric acid, gives captopril in 70% yield.

No. 35,226,023. According to German Patent Application, 1- [3-halo - (2S) -methyl-propionyl] -pyrrolidine - (2S) -carboxylic acid is reacted with thiourea in aqueous, alkanolic or aqueous alkanolic medium at 60-100 ° C. The compound of formula (Π), wherein X is halogen, is hydrolyzed in the reaction mixture without isolation with an alkali metal hydroxide or carbonate.

Reproducing the latter known procedure, we could not isolate the pure product; the crude product contained about 15% captopril with high levels of thiourea.

It is an object of the present invention to provide a process for the preparation of captopril which can be used to obtain high purity material in good yield using inexpensive, simple reagents. *

It has now been found that the above object is achieved by reacting an omega-haloacyl-proline of formula (III) wherein X is haloatomine with a thiourea in a solvent and hydrolyzing the resulting isothiuronium salt of formula (II) wherein X is as defined above. by reacting a compound of formula (III) with a thiourea in an organic dipolar aprotic solvent, preferably N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide, and forming the isothiuronium salt of formula (II) or the corresponding free ba-23

196,959 zys, optionally after isolation, are hydrolyzed in the presence of hydrazine.

The preparation of the starting compound of formula (III) is illustrated in Example 4.

In formulas II and III, X preferably represents a bromine atom.

The reaction of the compound of formula III with thiourea is only an organic dipolar aprotic solvent ^! in N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide. Generally, the reaction is carried out at 20-80 ° C, preferably 50-70 ° C, at atmospheric pressure. The reaction time is usually 15 to 25 hours. When an acid acceptor such as an organic base is added to the reaction mixture, the free base corresponding to the isothiuronium salt of formula II is obtained in the form of a solid. In the absence of an acid acceptor, the isothiouro- is of formula (II). niium salt is formed.

The product formed by the reaction of the thiourea with the compound of formula (III) is optionally isolated before the next reaction step, hydrolysis. Since the isothiuronium salt of formula II remains in solution after formation, it is usually hydrolyzed without isolation.

The hydrolysis of the isothiuronium salt of formula (II) or the corresponding free base is carried out in the presence of hydrazine at a temperature of 0 to 30 ° C, preferably 10 to 15 ° C, at atmospheric pressure. The compound of formula (I) formed by hydrolysis is isolated from the reaction mixture in a manner known per se, for example by extraction and evaporation.

Both reaction steps of the process of the present invention can be carried out in near quantitative yields, thus including a single crystallization purification step to achieve a total yield above 80%.

A further advantage is that the process according to the invention does not produce disulfide or symmetric sulfide contamination. The captopril produced has a purity of at least 99.5% (measured by iodometric titration).

The invention is further illustrated by the following non-limiting Examples.

Example 1

- [3 - Mercapto - (2S) - methyl - propionyl] - pyrrolidine - (2S) - carboxylic acid (captopril). '

10.56 g (0.0374 mol) of 1- [3-bromo-2 (S) -methylpropionyl] pyrrolidine (2S) -carboxylic acid and 3.04 g (0.040 mol) of thiourea are dissolved in 30 ml of N, N- dinylacetamide and stirred at 60 ° C under nitrogen for 15-20 hours. The solvent was evaporated under reduced pressure at an external temperature of 60 ° C. and stirred for 30 minutes at room temperature. 100 ml of 5% sulfuric acid are added and the white precipitate is filtered off, washed with water and then with dichloromethane. The filtrate was extracted with dichloromethane (4 x 30 mL). The combined dichloromethane phases were washed with water (2 x 20 mL) and the aqueous layer was extracted with dichloromethane (2 x 15 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The remaining oil (7.54 g, 99%) was recrystallized from trichloroethylene (25 mL).

Yield: 6.10 g (80%) of the title compound.

M.p .: 106'C 104 from [α] ο ⁵ = - 129.5 ° (c = 2, ethanol)

Example 2

- [3 - Mercapto - (2S) - methyl - propionyl] - pyrrolidine - (2S) - carboxylic acid (captopril)

Dissolve 26.4 g (0.1 mol) of 1- [3-bromo (2S) -methylpropionyl] pyrrolidine (2S) -carboxylic acid and 7.6 g (0.1 mol) of thiourea in 100 ml of dimethylsulfoxide. . After stirring at 60-70 ° C for 24 hours, the solvent was evaporated under reduced pressure, the residue was dissolved in 150 ml of distilled water and 16 g of hydrazine hydrar was added under ice-water cooling under nitrogen. The mixture was stirred at room temperature for 30 minutes, adjusted to pH 1 with 20% hydrochloric acid, cooled in ice-water, extracted with dichloromethane (4 x 200 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. and the residual oil is crystallized from trichlorethylene.

Yield: 16.4 g (81%) of the title compound.

M.p .: 104-106'C [a] £ ⁵ = - 129.5 ° (c = 2, ethanol)

Example 3

- [3 - Mercapto - 2 (S) - methyl - propionyl] - pyrrolidine - (2S) - carboxylic acid (captopril)

5.28 g (0.020 mol) of 1- [3-bromo-2 (S) -methylpropionyl] - (S) -proline and 1.67 g (0.022 mol) of thiourea are dissolved in 15 ml of dimethylformamide and stirred at 60 ° C. 24 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in distilled water (30 ml) and 50% hydrazine solution (6.00 g) was added under ice-water cooling, followed by stirring under ice-water cooling for 1 hour. 50 ml of a 5% sulfuric acid solution are then added and the precipitate is filtered off, washed with water and then with methylene chloride. Sodium chloride (10 g) was added to the aqueous phase and extracted with dichloromethane (4 x 30 mL). The combined dichloromethane layers were dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residual oil was recrystallized from trichlorethylene (20 mL).

Yield: 3.33 g (82%) of the title compound.

M.p .: 104-106'C [Section ⁵ = -129.5 ° (c = 2, ethanol)

Example 4

I - [3 - Bromo - 2 (S) - methylpropionyl] pyrrolidine (2S) - carboxylic acid monohydrate (Starting material A).

196,959

3.34 g (0.02 mol) of 3-bromo-2-methylpropionic acid and 4.60 g (0.02 mol) of (S) -proline benzyl ester hydrochloride are dissolved in 50 ml of anhydrous dichloromethane and then 0 '. A solution of 1.9 g of triethylamine in 5 ml of anhydrous dichloromethane was added under cooling at C and mechanical stirring, followed by a solution of 3.92 g (0.019 mol) of dicyclohexylcarbodiimide in 20 ml of dichloromethane at 0 ° C. The reaction mixture was kept at 0'C for an additional two hours and then stirred at room temperature for 12 hours. The reaction mixture is filtered and the filtrate is extracted with 20 ml of 9% hydrochloric acid, 20 ml of water, 5% sodium bicarbonate solution and finally 20 ml of water. The organic layers were dried over magnesium sulfate and evaporated. The product (title compound ester) is a light yellow oil, 6.40 g (95%), [Rf; 0.44 and 0.48, which corresponds to a 1: 1 mixture of diastereomers (running mixture: benzene glacial acetic acid = 3: 1)]. The above oil was dissolved in ethyl acetate (60 mL) and 10% palladium on carbon (0.6 g) was added. It is hydrogenated at atmospheric pressure until the starting material is reacted according to vrk. The catalyst is filtered off, washed with ethyl acetate, then the solvent is evaporated off and the residue is recrystallized from water.

Yield: 2.00 g (42.5%) of the title compound.

M.p. 69-72'C [α] D ³ = ~ 88.1 '(c = 1; ethanol)

Example 5

A. 1 - [(2S) - Methyl-3-isothiuronium-1-oxo-propyl]

- proline

1- [3-Bromo-2 (S) -methylpropionyl] proline monohydrate (5.64 g, 20 mmol) was dissolved in dichloromethane (50 mL), stirred with glacial magnesium sulfate (5 g) for 1 h. The desiccant was filtered, washed with dichloromethane (10 mL), and the solvent was evaporated in vacuo from a 40 ° C water bath. The residue was dissolved in 15 ml of anhydrous N, N-dimethylacetamide, 1.52 g (20 mmol) of thiourea were added and stirred under a stream of nitrogen in a 70 ° C oil bath for 24 hours. Cool with ice-water, dilute with acetonitrile (150 mL) and add dropwise a solution of triethylamine (2.8 mL, 20 mmol) in acetonitrile (20 mL) over 30-40 minutes. After stirring for 2 hours, the precipitate was filtered off, suspended in 2 x 20 ml of acetonitrile, filtered and dried. 3.8-4.2 g (73-81%) of the title compound are obtained, m.p. 187-189'C.

[αβ = ⁵ - 107 to 11Γ (c = 1; acetic acid)

Rf: 0.41 [(pyridine: water: glacial acetic acid - 20: 11: 6): ethyl acetate = 6: 4]

0.2 (butanol: glacial acetic acid: water = 7: I: 3)

Β. 1- [3-Mercapto (2S) -methyl-propionyl] -pyrrolidine (2S) -carboxylic acid (captopril)

2.59 g (0.01 mol) of N - [2 (S) - methyl - 3 - isothiuronium

1-Oxo-propyl] -prolinate is stirred with 25 ml of water under a stream of nitrogen under ice-cooling and 2 ml of a 50% (0.02 mol) solution of hydrazine are added dropwise. Stir for 30 minutes under ice-cooling and then stop cooling for an additional 30 minutes. It was re-cooled with ice-water 4 below + 10 ° C and 4 ml of 18% aqueous hydrochloric acid solution was added dropwise. After stirring for 30 min, 6-10 g of sodium chloride are added and extracted with dichloromethane (3 x 20 mL). The combined organic phases are washed with 15 ml of water and the water is shaken with 5 ml of dichloromethane. The dichloromethane phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated in vacuo from a 35 ° C water bath. The residual oil (1.9-2.03 g) was crystallized with 10 ml of trichloroethylene. After cooling for 5-8 hours, the precipitated product is filtered off, washed with n-hexane.

1.46-1.62 g (72-80%) of the title product are obtained, m.p. 103-104'C.

[αβ = ⁵ - 129 to 130 (C = 2, ethanol)

Comparative Example (Reproduction of Example 5 of German Patent Publication No. 35 26 023)

A mixture of 0.81 g (0.01 mol) of thiourea, 1.41 g (0.005 mol) of 1- [3-bromo (2S) -methylpropionyl] pyrrolidine (2S) -carboxylic acid and 15 ml of ethanol was refluxed for 3 hours. under refrigeration. After cooling to room temperature, a solution of sodium hydroxide (0.39 g, 0.0098 mol) in distilled water (5 ml) was added and refluxed for an additional hour. The ethanol was evaporated under reduced pressure, the residue was dissolved in 10 ml of water and the resulting homogenous aqueous solution was acidified to pH = 1 with 2N hydrochloric acid. The homogeneous solution was extracted with ethyl acetate (3 x 20 mL), and the combined organic solutions were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 0.84 g of an oily residue is obtained which is dissolved in 5 ml of ethyl acetate and the product is crystallized from the solution. However, this was not achieved by changing the crystallization temperature. Hexane was then added to the solution, but no crystalline product was obtained. Crystallization could not be achieved even by systematically changing the ratio of ethyl acetate to hexane.

TLC analysis of 0.84 g of an oily residue (pyridine: glacial acetic acid: water: ethyl acetate = 16: 5: 9: 70; developed with 1% acetic acid in 2,6-dichloro-benzoquinone-4-chlorimide) gave:

thiourea (about 50%) captopril (about 15%) was also observed for two substances of unknown composition at R _r = 0.09 and 0.29, respectively. Their amount was about 15-15%.

Claims (2)

Claims A process for the preparation of 1- [3-mercapto (2S) methylpropionyl] pyrrolidine (2S) -carboxylic acid of formula (I) from an omega-halo acyl proline of formula (III) wherein X is halogen in a solvent with thiourea and forming the isothiuronium salt of formula II wherein X is 4196 959 .7. characterized in that the reaction of the compound of formula III with thiourea is carried out in an organic dipolar aprotic solvent, preferably N, N-dimethylformamide, N, N-dimethylacetamide or dimethylsulfoxide, and hydrolyzing the resulting isothiuronium salt of formula II or the corresponding free base, optionally after isolation, in the presence of hydrazine. (Priority: June 26, 1987) 2. A process for preparing 1- [3-mercapto (2S) methylpropionyl] pyrrolidine (2S) -carboxylic acid of formula (I) from an omega-halo acyl-proline of formula (III) in which X is a halogen atom in a solvent. reaction with thiourea and hydrolysis of the resulting isothiuronium salt of formula II, wherein X is as defined above, characterized in that the reaction of the compound of formula III with thiourea in an organic dipolar aprotic solvent, preferably N, N-dimethylformamide , N, N - dimethyl in acetamide or dimethyl sulfoxide and hydrolyzing the resulting isothiuronium salt of formula (11), if desired after isolation, in the presence of hydrazine.