JPS6327475A - Manufacture of mercaptoacylproline - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The invention relates to a novel process for the preparation of 1-(3-mercapto-(2S)-methylpropionyl)-pyrrolidine(2S)-carboxylic acid of formula l: or its pharmaceutically acceptable salts. .

The compound of formula I, known by its international name captopril, is described in British Patent No. 1,57 for its valuable antihypertensive activity.
According to the specification of No. 6,161, the halogen atom of haloacylproline can be converted into a mercapto group using various reagents. The reaction is carried out using the anion R-8C formula, where R is hydrogen, C
1-4 alkyl group, phenyl (C1-4 alkyl), triphenyl-(C1-2 alkyl) or formula R1-C-(
In the formula, R1 represents a C1-4 alkyl group or a phenyl group. ). ].

Of the various R-8 anions, only a few are suitable for the production of captopril. Here, the substituent containing the sulfur atom of the compound formed during the substitution reaction of the nitrogen atom can be removed. That is, it is the same as a protecting group. The meaning of R below falls within this range. namely, hydrogen, tertiary butyl, benzyl, triphenylmethyl (trityl), and R1-M-, where R is as defined above.

No teaching is given for the simplest case when R represents hydrogen.

When R represents tert-butyl, benzyl or trityl, the reagent used is tert-butyl mercaptan, benzyl mercaptan or trityl mercaptan, all of which are dangerous, carcinogenic and toxic compounds. be. In order to accomplish the substitution of the halogen atom, the carboxyl group of proline must be temporarily preserved. Moreover, the yields of such reactions are unacceptably low. For example, K. Hofmann
) describe a case very similar to that of benzyl mercaptan [Journal of America 7-
Chemiforce A/-7 Saetei (J, Am, Chem, S
oc, Vol. 71, p. 1253 (1949)]. That is, the S-benzyl-4-mercaptobutyl derivative was obtained in a yield of 66% by reacting the 4-chlorobutyl derivative with benzyl mercaptan sodium salt. protecting group,
It is removed by the nascent hydrogen generated by the sodium in the ethanol. Therefore, the total yield is 34%.

Since both tertiary butyl mercaptan and trityl mercaptan have strong steric hindrance, only bad results can be expected with these. Generally, such protecting groups are introduced into molecules in the reverse manner. That is, the mercapto compound present is reacted with inbutylene or thionyl chloride [
T double knee green ('r, W, G
Protective Groups in Organic Synthesis (ProtectiveG) by Mr.
roups in Organic 5ynthesi
s), page 193.

1981].

If R stands for a radical of the formula R-C-, cabdobril can only be prepared in very low yields. British Patent No. 1,57
According to the embodiment of No. 6,161, similar ]-(
2-Mercaptoacetyl) proline has been prepared using thiobenzoic acid in a low yield of 15% calculated on proline.

GB 2,065,643 describes the case where R stands for hydrogen. That is, N-
(3-halo(2S)-methylpropionyl) -(S
) - reacting proline with an aqueous solution of sodium hydrogen sulfide. Reaction products are formed upon prolonged heating. However, the corresponding disulfide is also generated with 5 molti. This by-product must be reduced with zinc during the separation step in the presence of acid. The yield is 71 inches. When sodium hydrogen sulfide is dissolved in N,N-dimethylformamide, the above yield is reduced to 65%. The best results can be obtained with aqueous solution of φ-metal and ammonium hydrogen sulfide. However, the reaction products and by-products present can only be separated by column chromatography. This also yields a mixture of 92th captopril, 6% disulfide, and 0.5th symmetrical sulfide. The latter contaminating by-products are irreversibly formed. In other words, it cannot be converted to captopril. Furthermore, the solubility of this symmetrical sulfide is similar to that of captopril and therefore cannot be separated by simple preparation methods. The above facts are based on M Shimazaki CM, Shimaza
It has been confirmed by the literature of Mr. Ki) et al. [Chem, Pharm, Bull]
Volume 30, No. 3, page 29 (1982)]. The latter method is therefore not suitable for industrial scale production.

According to US Pat. No. 4,332,725, halogen atoms are converted to mercapto groups using sodium thiosulfate. In this case, the so-called Punte salt is first formed, which is heated with concentrated hydrochloric acid to give captopril with a yield of 70%.

In published German patent application no. 3526023, N-(3-halo(2S)-methylpropionyl)
-(S)-proline is reacted with thiourea in water, alkanol or an aqueous alkanol solution at 60 to 100°C to obtain the compound 2): (wherein, X represents a halogen atom). This compound is hydrolyzed without separation with an alkali metal hydroxide or alkali metal carbonate in the reaction mixture.

However, in practice it has not been possible to reproduce this latter known method.

It has been found that compounds of formula I can be prepared from omega-haloacylprolines of formula Il: [A'] where X represents a halogen atom. Omegano-lowacylproline of formula 1 or a salt thereof is dissolved in a dipolar non-protic organic solvent (organ
nic dipolar aprotic 5olv-
ent) with thiourea to obtain an isothiuronium compound of formula II: or its hydrohalide. After separating it as the case may be,
Hydrolysis and, if desired, the product of formula I is rearranged into or derived from a salt.

Free carboxyl groups of compounds of formula I can be converted into salts with organic or organic bases. In the method of the invention, the formula l
If a salt of the compound is obtained, the free carboxylic acid can be derived in a manner known per se.

21u, X represents a halogen atom, preferably
Represents a bromine atom.

The reaction between the compound (2) or its salt and thiourea is N,N-
It proceeds only in dipolar aprotic organic solvents such as dimethylformamide, N, N-u methylacetamide or dimethylsulfoxide. Usually, under atmospheric pressure, 20-80℃,
Preferably, the reaction is carried out at 50-70°C. Usually the reaction time is 15 to 25 hours. acid binding agents such as organic bases
When using , compound 2〇 can also be obtained as a solid.

In the absence of an acid binder, the corresponding hydrohalide addition salt is formed. If desired, the compound of formula II is separated off before the next reaction step, ie hydrolysis. in principle,
The hydrohalide of the compound of formula II leaks and is therefore generally hydrolyzed without separation.

The isothiuronium compound or hydrohalide addition salt thereof is hydrolyzed under atmospheric pressure, preferably in the presence of a base such as hydrazine, at 0-30°C, suitably 0-15°C. The product of formula l can be prepared in a manner known per se,
Separation from the reaction mixture, for example by extraction or evaporation.

The isothiuronium compound of formula II is obtained almost quantitatively and hydrolyzed almost quantitatively to captopril. Even if the latter product (captopril) is recrystallized, the annual yield is over 80%.

The resulting captopril is not contaminated with either the corresponding disulfide or the symmetrical sulfide and is therefore at least 99.5
% purity (determined by iodometric titration).

The method of the invention is further illustrated by the following non-limiting examples.

Starting compounds: Preparation of ]-(]3-promo2S)-methyl-propionyl)-pyrrolidine-(28)-carboxylic acid monohydrate 3, 34 g (0.02 mol) of 3-meromo-2-methylpropionic acid and 4 .609 (0.02 mol) of benzylpyrrolidine-(2S)-carboxylate hydrochloride,
It was dissolved in anhydrous methylene chloride having a resistance of 50%.

1.99% of triethylamine dissolved in 5 ml of anhydrous methylene was added to the stirred mixture at 0°C under cooling.
and then 20 m/m of methylene chloride was added.
．． 92 g (0.019 mol) of N,N/-dicyclohexyl-carbodiimide were added at the same temperature. The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for a further 12 hours. Filtered mixture? 20d(7) 9% hydrochloric acid, 20
Extraction was performed with td(7) water, 20d aqueous sodium bicarbonate solution, and then 20d water. The organic solution was dried over ignited magnesium sulphate and evaporated. 6.40g (
95%) of indyl 1-(3-7' lomo-2-methylpropionyl)-pyrrolidine-(28)-carboxylate was obtained as a pale yellow oil.

Tfl. c. (Silica gel, benzene/glacial acetic acid 3:
]): 2 spots) * Rf-0.4 4 and 0.481
;1 Compatible with this diastereomani.

The oil was dissolved in 60 mJ of ethyl acetate and to the resulting solution was added 0.6 g of 10% palladium/carbon catalyst. The reaction mixture was hydrogenated under atmospheric pressure until no ester was present as determined by TLC. The catalyst was removed by filtration, washed with rrPTz ethyl, the organic solvent was evaporated, and the residue was recrystallized from water. .

There were thus obtained 2.0 0 9 (42.5%) of the title compound. Melting point: 69-72°C (α), = -88.1' (C = 1: xll/-l) Example 1 1-(3-mercapto-(2S)-methylpropionyl)-pyrrolidine-(28)- Carboxylic acid 10, 56 juice (
0.0374 mol) of 1-(3-zlomo- (2S)-
Methylpropionyl)-pyrrolidine-uS)-carvone W and 3.049 (0.040 mol) of thiourea were dissolved in 30 M of N,N-dimethylacetamide and the reaction mixture was heated at 60 °C under nitrogen. Stirred for 15-20 hours. The organic solvent was removed under reduced pressure and the residue was dissolved in 50 ml of distilled water. 6.001) (0.12 mol) of hydrazine hydrate was added under nitrogen while cooling the flask with ice water. The reaction mixture was stirred for 30 minutes under cooling and then for an additional 30 minutes at room temperature. ]Of) 5% of m/
Add sulfuric acid and filter the white precipitate, washing with water and then methylene chloride. Solution F was extracted with 4 x 30 d of methylene chloride, 44 g of the extracts were combined, washed with 2 x 20 d of water, and the aqueous phase was extracted with 2 x 15 d of methylene chloride. The organic phases were combined, dried over ignited magnesium sulphate, filtered and evaporated under reduced pressure. 7.549 (99
%) of the residual oil was crystallized from 25 m/ml of trichlorethylene. In this way, 6.10g (80%)
The title compound was obtained. Melting point 104-106°C.

[α)25=-129,5° (C intestine 2. Ethanol)
Example 2 l-(3-mercapto-(2S)-methylpropionyl)-pyrrolidine-(28)-carboxylic acid 2.649 (
0,010 mol) of 1-(3-bromo(2S)-methylpropionyl)-pyrrolidine-(2S)-carboxylic acid and 0.769 (0,010 mol) of thiourea in 10
- dissolved in dimethyl sulfoxide. solution, 24
Stir at 60-70 °C for an hour, then 10% of 30 d
Add aqueous sodium hydroxide solution and stir the mixture for another 1 hour.
Stirred. The mixture was acidified under cooling with 20% hydrochloric acid until pHHI3 was reached and then extracted with 4×20 yd of methylene chloride. The extracted organic solutions were combined, dried over ignited magnesium sulphate and evaporated under reduced pressure. The residual oil was crystallized from trichlorethylene.

1.64 g (81%) of the title compound was obtained. Melting point = 10
4-106°C, [α]25=-129,5° (C=2; ethanol) Example 3 l-(3-mercapto-(2S)-methylpropionyl)-pyrrolidine-(2S)-carboxylic acid5. 28Lj(
0,02 mol) of 1-(3-promo(2S)-methylpropionyl)-pyrrolidine-(2S)-carboxylic acid and 1.679 (0,022 mol) of thiourea in 15-
〇Dissolved in N,N-dimethylformamide, mixture f:
The mixture was stirred at 60°C for 24 hours.

The solvent was distilled off under reduced pressure, and the residue was dissolved in 301 distilled water. 6.09 of 50% hydrazine was added to the solution cooled with ice water, and the reaction mixture W was stirred for 1 hour while cooling with ice water. Then, 50% pentathiosulfuric acid was added, and the precipitate was filtered and washed with water and methylene chloride. 101i) of sodium chloride was added to the aqueous phase and the aqueous phase was extracted with 4×30 d of methylene chloride. The organic solutions were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The residual oil was crystallized from 20 d of trichlorethylene. 3.331 (82%) marked metal objects were obtained. Melting point = 104-106°C [α]25=-129,5'(C=2; ethanol) Example 4 A, 1-((28)-Methyl-3-isothiuroniumpropionyl)-pyrrolidine-(2S) 5.649 (0.02 mol) of 1-(3-bromo-(2)
S)-Methylpropionyl)-pyrrolidine-(,2S)
-Carboxylic acid monohydrate) t50i1D Dissolved in methylene chloride, and the resulting solution was stirred for 1 hour with 5 g of ignited magnesium chloride sulfate.

The drying agent was filtered, washed with 10 rttl of methylene chloride, and the organic solutions were combined and evaporated under reduced pressure. 15m of leftover
1 of anhydrous N,N-dimethylacetamide, 1.5
29 (0.02 mol) of thiourea and the flask containing the reaction mixture? Stirred under nitrogen for 24 hours while kept on a 70°C oil bath. The mixture was cooled with ice water and diluted with 150 ml of acetonitrile. The resulting mixture was added with 2.8d(0,
02 mol) of triethylamine while stirring.
I taught him for 40 minutes. The reaction mixture was stirred for a further 2 hours, the precipitate formed was filtered, suspended in 20 d of acetonitrile, filtered, resuspended in 20 tl of acetonitrile, filtered and dried. 4.29 (81%) of the title compound was obtained. Melting point: 187-189℃ [α] =-
107--111'(C-1; acetic acid) Tlc, (6 parts of a 20:11:6 mixture of pyridine, water, glacial acetic acid, 4 parts of ethyl acetate): Rf=o, 41; (butanol, glacial acetic acid, 7:1:3 mixture of water): Rj-0,2 B, 1-(3-mercapto-(2S)-methylpropionyl)-pyrrolidine-(28)-carboxylic acid 2 liters (0
,02 mol) of 50 thihydrazine was dissolved in 25 rnl of water under nitrogen and cooling with ice water.
mol) of 1-((28)-methyl-3-isothiuroniumpropionyl)-20 lysine-(2S)-carboxylate. The mixture was stirred for an additional 30 minutes under cooling, then the cooling bath was removed and the mixture was stirred for an additional 30 minutes.
Stirring was continued for a minute.

The reaction mixture was again cooled to below 0°C and treated with two portions of concentrated hydrochloric acid and two portions of water. The mixture was stirred for 30 minutes, then 6-109 sodium chloride was added and the product was
Extracted with 20xJ of methylene monide. The organic solutions were combined, washed with 15 st of water, and the aqueous phase was extracted with t-5 mJ of methylene chloride. The M phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residual oil of 2.039% was crystallized from 10st trichlorethylene. The product was washed with n-hexane and dried. 1.62
9 (80%) of the title compound t- was obtained. Melting point: ]o3~1
04℃

Claims (8)

[Claims] (1) Formula III: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ From the omega-halo-acylproline of III (in the formula, X represents a halogen) Formula I: ▲Mathematical formula,
There are chemical formulas, tables, etc. ▼ A method for producing 1-{3-mercapto-(2S)-methylpropionyl}pyrrolidine-(2S)-carboxylic acid of formula III, omega-halo-acylproline or its salt of formula III. and,
By reacting with thiourea in a dipolar aprotic organic solvent, the formula
II ▲Mathematical formulas, chemical formulas, tables, etc.▼ Obtain the isothiuronium compound of II or its hydrohalide, optionally hydrolyzed after separation and, if desired, convert the product of formula I into a salt or derive it from a salt. The manufacturing method. (2) Reacting an omega-halo-acylproline of formula III or a salt thereof with thiourea in a dipolar aprotic organic solvent to obtain the corresponding hydrohalide of an isothiuronium compound of formula II, optionally after separation. , hydrolysis and, if desired, converting the product of formula I into or deriving from a salt. (3) Omega-halo-acylproline of formula III or its salt is reacted with thiourea in a dipolar aprotic organic solvent to obtain an isothiuronium compound of formula II, which is separated and then hydrolyzed. , and, if desired, converting the product of formula I into or deriving from a salt. (4) The method according to any one of claims 1 to 3, wherein the dipolar aprotic solvent is N,N-dimethylformamide, N,N-dimethyl-acetamide, or dimethylsulfoxide. (5) The method according to any one of claims 1 to 3, wherein the reaction with thiourea is carried out at 20 to 80°C, preferably 50 to 70°C. (6) The method according to any one of claims 1 to 3, wherein the reaction with thiourea is carried out in the presence of an acid binding agent. (7) The method according to any one of claims 1 to 3, wherein the isothiuronium compound is hydrolyzed in the presence of hydrazine. (8) Claim 1 in which the isothiuronium compound is hydrolyzed at 0 to 30°C, preferably 10 to 15°C.
The method according to any one of Items 3 and 6.