NL8303983A - Captopril prepn. by cyclisation by dehydration - of n-2(s)-3-hydroxy 2-methyl-propionyl S-thio:proline and reaction of prod with an aq. or alcoholic base - Google Patents

Abstract

Captopril (I) (1-((25) 3-mercapto-2-methyl propionyl) L-proline) is prepd. by (A) cyclisation by dehydration of N-2(S)-3-hydroxy 2-methylpropionyl S-thioproline (II) in the presence of triphenylphosphine or triethylphosphite and an ester of azidocarboxylic acid HOOC-N=N-COOH to form (4S.9aS)-hexa- hydro 4-methyl 1H.5H-pyrrolo-(2.1-c) (1.4)thiazepine 1.5-dione (III), and (B) reacting the (III) with an aq. or alcoholic base to form the (I). The intermediates N-(2(S)-3-hydroxy 2-methylpropionyl) S-proline (IV) and N-2(S)-3-hydroxy 2-methylpropionyl S-thioproline (II) are claimed as new.

Description

♦ · ί € Ρ & c -

Short designation: Process for the preparation of captopril and new intermediates.

The invention relates to a process for preparing captopril by reacting a compound of the formula (1) of the formula sheet with an aqueous or alcoholic base.

Such a method is known from the Netherlands Patent Application 8202153 laid open to public inspection. This provides a stereospecific method for preparing the known antihypertensive agent captopril or 1 - [(2S) -3-mercapto 2-methylpropionyl] L-proline .

The drawback of this method is that the compound of formula (1) i.e. (4S.9aS) -hexahydro 4-methyl 1H.5H-pyrrolo- [2.1-c] - [1.4] -thia-10 zepine 1.5 -dione, which in turn must be prepared by hydrogenation of the corresponding 4-methylene derivative, which must in turn be obtained by first reacting N-tert.butoxycarbony1 S-proline using ethyl chlorofonate followed by NaSH in the corresponding thio derivative and reacting it with α-bromomethacrylic acid to form α- (N-tert-butoxycarbonyl S-prolyl) thiomethacrylic acid, which is then converted to a- (S-thioprolyl) methacrylic acid hydrobromide with HBr in acetic acid, which is then cyclized to the 4-methylene derivative with the aid of dicyclohexylcarbodiiraide and 4-dimethylamino pyridine. An alternative to this method is to first prepare the corresponding 4-methylidene oxazepine derivative and convert this compound to the corresponding thiazepine derivative, but this is practically equally complicated.

It has now been found that the compound of formula (1) can be prepared by subjecting a compound of formula (2) to a cyclizing dehydration in the presence of triphenylphosphine or triethylphosphite and an ester of azidocarboxylic acid (HOOC -N = N-COOH). Since the thioproline derivative of formula (2) can be easily obtained from the corresponding proline derivative, which in turn is easy to prepare, a simple synthesis for captopril thus becomes available.

The invention therefore relates to a process of the type described in the preamble, which is characterized in that the compound (11 is prepared by cyclic dehydration of a compound of the formula (21 in the presence of triphenylphosphine or triethylphosphite and an ester of azidocarboxylic acid.

As background information on the prior art for the preparation of thioesters and thiolactones, the following may be used. It was already known that thioesters and thiolactones could be prepared by δ 3 0 3 9 8 3 • 4 Λ f '-1-1ΙΙ-—, - ,,, - - - 1 - η I - ».-. -. 2 - Acylation of thiols (see Synthesis, 1981, 549; Tetrahedron 'Letters 1979, [4319 and Houben-Weyl, Vbl. IX, pp. 753-755) or by alkylation of thio acids (see, for example, Houben -Weyl, Vol IX, pp. 749-750; J. Org.

.Chem. 43, 1283 (1978); and Tetrahedron Letters 1976, 3409). In the first method, low yields and a high degree of by-product formation were obtained due to the inherently low reactivity of thiols (which are very weak bases) to the reactive carboxylic acid derivatives. According to this method, compound (1) was only able to yield; 10-15% are formed using dicyclohexyl or diisopropylcarbodiimide as a condensing agent in the presence of dimethylamino-pyridine (U.S. Patent 4v 192,945; J. Heterocycles: Chem. 17, | ; V.Jl647 (1980)). The second method requires the presence of good exit groups, and is still cumbersome, because activation of the.! · First. . Hydroxyl function is required by conversion to bromide or tosylate. Mixtures Products and low yields are often observed due to the rigorous conditions used in presentable cases (see, for example, Chem. Lett. 1977, 437).

! In addition, there is a third method, namely the addition of; thio acids asm an activated double bond (see, e.g., J. C. S.

20 [Chem * Cómmun. 1981, 307). It is an intramolecular variant of this: v .... -.

ï. reaction, which is discussed in the above discussed Dutch patent application 8202153.

| ··; [the. preparation of. compound (1) is used and which to a large extent. 1 · * · / · L *. ·. '....' * *. 1 stereo selective.

.T ... · '·. · ·. . j j; ^^ Tj ·· 'The present method is a new approach to preparation! 25 ftan compound (1), using an enantiodifferent conversion of the pro-S methyl group from the cheap and easy; "[Available isbutyric acid to the hydroxymethyl group. This microbial turnover- i ί. ; ·. . \ r - - _ .. · - ···· '.. »• ting (a description of this can be found, for example, in Biotech · * Bioeng. j! 1 * • 13, 203 (1971)) gives in high yields and good optical purity it; ! 30 S-2-methyl 3-hydroxypropionic acid of the formula (3). S-Proline is now simply acylated with the chloride of this acid to yield the new intermediate N- [2 (S) -3-hydroxy-2-methylpropionyl] S-proline. This intermediate is then converted to the analogous N-2 (S1-3-hydroxy-1 * 2-methylpropionyl S-thioproline), also a new compound, and this compound is then subjected to the dehydrating ring closure. combination of triphenylphosphine and azidocarboxylic acid ester, which reagents may form a complex: f.

to shape. In Synthesis 1981, 1 you will find an overview article about the usability of this reagent, while its application for the intermolecular "ΊκΓϊΊΓΒΊΠ" .....

OMO ^ uC * - 3 - ï.

thioacylation of secondary alcohols and of alcohols of the benzyl series and aliphatic series is described in Tetrahedron Letters 22, 3119 (1981). The dehydrating ring closure can be performed in various inert solvents, such as toluene, benzene, dichloromethane, dioxane, tetrahydrofuran or the dimethyl ether of diethylene glycol and the reaction can. : are performed at temperatures from -20 ° C to approximately 5Q ° C.

The following non-limiting examples further illustrate the invention.

EXAMPLE I

10 | N- [2 (S) -3-hydroxy 2-methylpropionyl] S-proline

5.75 g (50.0 mmol) of S-proline were dissolved in 50 ml of 1N sodium hydroxide solution. Men! . cooled the solution to 0 ° C. and added, with stirring, 50 ml of * 1N sodium hydroxide solution and 6.1 g (50.0 mmol) of 2 (S) -methyl 3-hydroxypropionic acid chlorida; to. This. acid chloride was prepared from 2 (S) -methyl 3-hydroxypropionic acid; .Which? 15 'was in turn obtained by microbial hydroxylation of isdbutyric acid according to the article of C.T. Goodhue and J.R. Schaeffer, Biotech. Bioeng.

13, 203 (1971). After stirring for 1 hour at room temperature, the pH was adjusted to 1? the solution was saturated with sodium chloride and extracted three times with 100 ml of ethyl acetate each time. The combined organic extracts were dried and evaporated to dryness. The crude product (IR: 3360 (wide),

, 2980 (wide), 1730, 1650, 1590, 1180, 910 cm @ 1) were prepared according to Example II

. · (-: used further. ...

• EXAMPLE II

; N-2 (S) -3-hydroxy 2-methylpropionyl-s-thioproline.

8.04 g (40.0 mmol) of the N-2- (S) -3-hydroxy-2-methylpropionyl S-proline prepared according to Example I were dissolved and 4.04 g (40.0 mmol) of tri- ·,. ethylamine in 100 ml anhydrous THF and added dropwise at 0 ° C.

| . ♦ solution of 4.34 g (40.0 mmol ·) of ethyl chloroformate in 40 ml of THF. After stirring at 0 ° C for 2 hours, the precipitate was filtered off (5.5 g triethylamine-30 hydrochloride) and the filtrate was added to a suspension of 2.5 g = (45.0 mmol) anhydrous NaHS in 30 ml THF . After stirring for an additional 2 hours at room temperature, a methanolic solution of hydrochloric acid was added and the pH adjusted to 1. The solvent was evaporated and the residual oil slurried in 100 ml of water and extracted three times with 100 ml of dichloro-35 methane each time. The dried organic extracts were evaporated and the resulting 10.0 g (92%) residual oil were used without further purification as described below in Example III. A sample was purified on a silica gel column using ethyl acetate ethanol; : (6: 4) as an eluent. The pure product, a heavy yellow oil, withstood ~ wyr98 ~ 3 ..... ~ ......- W4C22Ï.C · *> v - 4 - numerous attempts at crystallization. IR: 3300-3450 (broad), 2980, 2880, 1690, 1645, 1430, 1020 cm -1. NMR (CDCl 3): 1.9 (s, 3H); 2.0 (broad s, 6H); 2, 4 (wide m, 2H); 2.7 (m, 1H); 3.7 (wide t, 2H); 4.7 (wide m, 1H).

EXAMPLE III

5 (4S, 9aS) -Hexahydro 4-methyl 1H.5H-pyrrolo- [2.1-c] [1.4] -thiazepine-1,5-dione

In a solution of 5.25 g (20.0 mmol) of triphenylphosphine in 60 ml of THF

4.1 g (20.0 mmol) of diisopropylazidocarboxylate were added with intensive stirring and ice cooling. After stirring for 1 hour, a solution of 4.34 g (20.0 mmol) of the N-2 (S) -3-hydroxy 2-methylpropionyl 5-thioproline in 30 ml of THF prepared in Example 2 was added dropwise and stirring was continued for 1 hour at room temperature. The clear solution was washed with twice 50 ml of water and evaporated to dryness and the crude product was purified on a column of silica gel using dichloromethane as eluent. 3.42 g (86%) of pure product were thus obtained, which after crystallization

20 ° C

lization from ethyl acetate had a melting point of 104-106 ° C. [α] D = -112 ° (c = 1.0 in MeOH).

EXAMPLE IV

N- (2S) -3-mercapto 2-methylpropionyl S-proline 20 19.9 g (0.1 mol) (4S, 9aS) .- hexahydro 4-methyl 1H.5H-pyrrolo [2.1-c] were dissolved [1.4] -thiazepine 1,5-dione in 500 ml 10% ammonia in methanol and stir the solution at 30 ° C for 45 minutes. The solvent was then evaporated, the crude product dissolved 200 ml of water and purified on a column with ion exchanger Dowex-50. After evaporation of the 25 fractions which reacted positively to iodine platinum reagent, 2.16 g were obtained (quantitative yield) crude product in the form of a glassy solid. After crystallization from ethyl acetate-hexane, the product melted at 103-105 ° C; []] = = -132 ° (c = 1.0 in 96% EtOH).

EXAMPLE V

30 (4S.9aS) -Hexahydro 4-methyl · 1B.5H-pyrrolo [2.1-c] [1.4] -thlazepine 1.5-dione &

The above compound was prepared as described in Example III, but using dioxane as a solvent and diethylazidocarboxylate in combination with the triphenylphosphine; the reaction was first run at -5 ° C to 0 ° C for 2 hours and then at room temperature for another 6 hours. After further processing as described in Example III, pure product was obtained in a yield of 71%, mp 103-105 ° C.

EXAMPLE VI

1 (4S.9aS) -Hexahydro 4-methyl 1H.5H-pyrrolo- [2.1-c] [1.4] -thlazepine 1.5- 40 dione 8303983 * 7 - 5 -

The above compound was prepared as described in Example III, but using triethyl phosphite as the electrophilic compound together with diisopropylazidocarboxylate. The reaction was run overnight at 0 ° C and the product after further processing as described in Example 3 was isolated and crystallized from chloroform. One

20 ° C

thus obtained large prisms with melting point 105-106 ° C; [α] D = -116 ° (c = 2.0 in MeOH).

* 8303983

Claims (7)

1. Process for preparing captopril by reacting a compound of the formula (1) with an aqueous or alcoholic base, characterized in that the compound (1) is prepared by cyclic dehydration of a compound of the formula ( 2) in the presence of triphenylphosphine or triethylphosphite and an ester of azidocarboxylic acid. 2. Process according to claim 1 #, characterized in that the reaction is carried out in tetrahydrofuran. 3. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature between -20 ° C and room temperature. 4. Process according to claims 1-3, characterized in that the vJ *. The reaction is carried out by slowly adding a solution of compound J: (2) to a pre-formed solution of the triphenylphosphine or triethylphosphite complex with an ester of azidocarboxylic acid. 15 ; 5. Process according to claims 1 to 4, characterized in that the compound of formula (2) is prepared by reacting N- [2 (S) -3-hydroxy ": 2-methylpropionyl] S-proline with ethyl chloroformate, followed by reaction with Na 2 S or NaHS. 6 * N- [2 (S) -3-hydroxy-2-methylpropionyl] S-proline. 20 N-2 (S) -3-hydroxy 2-methylpropionyl S-thioproline. i i I. -. * i i I '8303983