HU214579B - New process for producing lysinoprile - Google Patents

Abstract

FIELD OF THE INVENTION The present invention relates to a novel process for producing lysine prodrug and dihydrate of formula (I) in the form of a prodrug. Lysine or dihydrate is an active ingredient in antihypertensive drugs. ŕ

Description

The present invention relates to a novel process for the preparation of lisinopril of formula I and its dihydrate.

Lysinopril, together with other compounds that inhibit the action of the angiotensin converting enzyme, was first described in EP 12401. In each of the methods described herein, the product was obtained as a diastereomeric mixture from which the desired S, S, S diastereomer was isolated by chromatography.

Subsequent processes attempted to achieve improved diastereomeric selectivity. Thus, European Patent 168769 discloses the reaction of ethyl 4-phenyl-2-oxobutyrate with N ⁶ - (trifluoroacetyl) -L-lysyl-L-proline to form a compound of formula Π in which N ² - (1S) ), the diastereomer predominates over the N ² (1R) diastereomer, but separation was achieved only in 51% yield.

According to Hungarian Patent Application No. 207837, the N ² - (IS) and N ² (1 R) diastereomers were separated in an early step and were obtained in good yield to form S, S configuration IV. However, this compound was subsequently reacted with prolinetyl ester according to Hungarian Patent Application No. 207736, which caused problems on industrial scale.

Surprisingly, it has now been found that the new S, S, S configuration of the compound of Formula IV and V obtained by the reaction of the compounds of Formula IV and V can be quantitatively hydrogenated to the compound of Formula II and thus obtained convertible into lisinopril.

Accordingly, the present invention provides a process for the preparation of lisinopril of formula I and its dihydrate comprising hydrogenating the novel compound of formula III or a salt thereof in the presence of a catalyst and hydrolyzing the resulting compound of formula II, optionally without isolation.

In a preferred embodiment of the process of the invention, the catalyst is palladium on carbon in the hydrogenation.

Alternatively, the compound of formula II obtained by hydrogenation may be isolated by evaporation, if desired, and converted into a salt. On an industrial scale, the reaction is conveniently carried out by hydrolysis without isolation of the compound of formula (II), for example with tetramethylammonium hydroxide, followed by precipitation of the desired lysinopril dihydrate by adjusting the pH.

The starting compound of the formula III (named N ² - (1S) - [1- (ethoxycarbonyl) -3-phenylpropyl] -N ⁶ - (trifluoroacetyl) - (L) -lysyl- (L ) -proline-benzyl ester) is a novel compound (see Hungarian Patent Application No. 770/95). The compound can be prepared by reaction of compounds of formulas IV and V by known peptide chemistry methods (e.g., M. Bodanszky, Principles of Peptide Synthesis, Springer Verlag, Berlin, 1984). This compound of formula III can be substantially converted to the compound of formula II by catalytic hydrogenation. Subsequently, hydrolysis of the compound of formula II yields the lisinopril of formula I or its dihydrate.

The most important advantage of the process according to the invention is that lisinopril can be obtained via a simple, well-defined novel intermediate, in a very good industrial scale.

A further advantage of the process is that the intermediates are obtained in the desired diastereoisomeric form (S, S, Sizomers), so that no further separation, cumbersome separation techniques are required.

The process of the invention is highly reproducible and suitable for large-scale production.

The invention is illustrated by the following examples:

Example 1

Preparation of lisinopril dihydrate (compound of formula 1)

14.71 g (20 mmol) of the maleate salt of the compound of Formula III, which has the chemical name N ² - (1S) - [1- (ethoxycarbonyl) -3-phenylpropyl] -N ⁶ - (trifluoroacetyl) - (L) -Lysyl- (L) -proline-benzyl ester maleate (see Hungarian Patent Application No. 7 70/95) - Dissolve in 100 ml of dichloromethane and add 80 ml of 5% by weight aqueous potassium. extracted with carbonate solution, dried over anhydrous magnesium sulfate and the solvent evaporated. The residue was dissolved in 100 ml of ethanol and hydrogenated in the presence of 1 g of 10% palladium on carbon. After uptake of one molar equivalent of hydrogen, the catalyst is filtered off, the ethanolic solution being ca. The reaction mixture was evaporated to half volume, cooled to 0 ° C, and a 25% (w / w) aqueous solution of tetramethylammonium hydroxide (23.4 mL, 66 mmol) was added. After stirring for 8 hours at 20-25 ° C, 50 ml of ethanol are added and the pH is adjusted to 6.5 with 50% trifluoroacetic acid. The product crystallizes out of solution and is filtered after cooling to 0 ° C. The crystals were washed with 85% ethanol-water.

Product: 7.85 g (89%) of lisinopril dihydrate, mp 169-172 ° C, [a] ² D ⁵ = -41.2 ° (0.25 M zinc acetate).

Example 2

Preparation of lisinopril dihydrate by isolation of the compound of formula II

The maleate salt of compound III (14.71 g, 20 mmol) (see Example 1) was dissolved in dichloromethane (100 mL) and extracted with 80% aqueous potassium carbonate (80 mL) and dried over MgSO4. then the solvent was evaporated. The residue was dissolved in 100 ml of ethanol and hydrogenated in the presence of 1 g of 10% palladium on carbon. After uptake of one equivalent of hydrogen (about 15 per reaction time), the catalyst is filtered off and the filtrate is evaporated. 10.5 g (approximately 100%) of compound II are obtained as a colorless oil. Name of compound:

N ² - (1S) - [1- (ethoxycarbonyl) -3-phenylpropyl] -N ⁶ - (trifluoroacetyl) - (L) - lysyl- (L) -proline which was purified without and converted to lysinopril dihydrate with a pH adjustment of trifluoroacetic acid as described in Example 1.

The dibenzene L-tartrate salt of the compound of formula II can be isolated as a salt by dissolving 2.1 g (4 mmol) of the base in 10 mL of diethyl ether and adding 1.5 g (4 mmol) of dibenzolyl (L). ) tartaric acid.

HU 214 579 Β

The salt crystallized out of the solution with n-hexane, which was filtered and washed with n-hexane.

The dibenzoyl L-tartrate salt of compound II has a melting point of 95-97 [deg.] C., [[alpha]]] = -64.5 [deg.] (C-1, methanol).

Claims (1)

A process for the preparation of lisinopril (I) and its dihydrate, which comprises hydrogenating the compound (III) or a salt thereof in the presence of a catalyst and hydrolyzing the resulting compound (II), optionally without isolation, in a manner known per se.