HU190732B - Process for preparing n-/1(s)-substituted-propyl/-(s)-alanyl-(s)-proline-derivatives - Google Patents

Abstract

The present invention relates to a process for the catalytic hydrogenation of a compound of formula (I), wherein R1 is an ethoxycarbonyl group of the formula S, S, S, wherein R1 is a protecting group as defined in formula I and a peptide bond R; and optionally deprotecting the R group in a manner known per se. R 'CH3 -1-

Description

(54) PROCEDURE

FOR THE MANUFACTURE OF N- [1 (S)-SUBSTITUTED-PROFILE] - (S) -ALANYL- (S) -PROLINE DERIVATIVES (57)

The present invention relates to a compound of formula I in the S, S, S configuration wherein R ^{1 is an} ethoxycarbonyl group, by reacting a compound of the formula Π wherein R ^{1 has} the meaning given by formula and R is a peptide bond protecting group. hydrogenated catalytically and optionally deprotecting R in a manner known per se.

R 'CH ₃

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The present invention relates to a novel process for the preparation of a compound of formula I (enalapril) wherein R * is ethoxycarbonyl.

Enalapril of formula I, together with other compounds having a similar structure, is disclosed in European Patent No. 12,401 for inhibiting the action of an angiotensin converting enzyme. The compound was prepared by condensation of L-alanine-Lproline with ethyl 2-oxo-4-phenylbutyric acid followed by reduction of the adduct containing an unsaturated bond and separation of diastereomers in a total yield of 26 to 53%.

In our experiments, we have found that a steel compound can be prepared in better yields by first reacting an alanyl-proline ester (in which the esterifying group is a peptide-bond protecting group) with ethyl 3-benzoyl acrylate and the diastereomer of S, S, separated from the few R, S, S diastereomers. The salt thus obtained liberates the base to give the new oxo compounds of the formula R, in which R ¹ is a protecting group as defined in formula I and compatible with R peptide bond, which can be catalytically hydrogenated and if the protecting group cannot be cleaved by reduction, by acid treatment after hydrogenation - converted to enalapril. The overall yield of this solution is 77-78%, which is significantly better than the known process. The preparation of the novel compounds of formula Π is illustrated by way of example.

The present invention therefore relates to a process for the preparation of a compound of formula I of formula S, S, wherein R ^{1 is} ethoxycarbonyl, by catalytically reacting a compound of formula Π wherein R * is a protecting group of formula I and R hydrogenation and optionally deprotection of the protecting group R in a manner known per se.

The process of the present invention is based on the novel compounds of formula II which are catalytically hydrogenated. The catalyst used is a platinum metal or metal oxide such as palladium or platinum, but Raney nickel may also be used. Palladium is applied in a form applied to a carrier (charcoal, calcium carbonate, barium sulfate, etc.).

The reaction is carried out in an inert organic solvent, e.g. alkanols, aliphatic or aromatic hydrocarbons, in the presence of an ether, an ester, at atmospheric pressure. During the initial stage of the reduction, the reaction temperature is maintained between 20 and 30 ° C. In the subsequent phase of the reduction, the temperature is max. It can be raised to 60 ° C.

When a protecting group compatible with the R peptide bond in the parent compound of formula II is benzyl, it is cleaved by catalytic reduction. If the protecting group in question is tert-butyl or the like, it is cleaved in a manner known per se, in particular with trifluoroacetic acid or hydrochloric acid dioxane.

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

Example 1

N- [l (S) -ethoxycarbonyl-3-phenylpropyl] - (S) -alanyl- (S) -proline maleate

0.39 g (0.89 mmol) of N- [1 (S) -ethoxycarbonyl-3'-phenyl-3-oxopropyl] - (S) -alanyl- (S) -proline tert-butyl ester are dissolved in 40 ml of ethanol and Hydrogenated in the presence of 1 g of palladium on charcoal. After uptake of the theoretically necessary hydrogen, the catalyst is filtered off and washed with ethanol. The solvent was evaporated and the residue (0.38 g, practically quantitative) was dissolved in 5 ml of trifluoroacetic acid and stirred for 1 hour at room temperature. The trifluoroacetic acid was evaporated and the residue was dissolved in dichloromethane (25 ml) and extracted with water (10 ml), water (10 ml) containing 3% pyridine, and then again with water (10 ml). The dichloromethane phase was dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated from the filtrate. The residual oil (0.32 g, 97%) was dissolved in acetonitrile and a salt was prepared with maleic acid (0.1 g, 0.89 mmol). The precipitated crystals are filtered off and washed with ether. Yield: 0.4 g (92%) of the title compound.

M.p. 147-148 ° C.

[α] D = -42.1 ° (c = 2, methanol)

Elemental analysis for C24H32N2O9 (M = 492.53):

CHN calcd% 58.53; 6.55; 5.68;

Found: 58.79; 6.64; 5.61.

The new starting material was prepared as follows:

(S) -alanyl- (S) -proline-tert-butyl ester (4.84 g, 20 mmol) was dissolved in dry benzene (40 mL) and ethyl 3-benzoyl acrylate (4.08 g, 20 mmol) was added with stirring at room temperature. . After stirring for one hour at room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (20 mL) and maleic acid (2.32 g, 20 mmol) was added. After one hour, the precipitated crystals were filtered off and washed with diethyl ether. 7.2 g of the primary product and partial concentration of the mother liquor yield an additional 2.3 g of the secondary product.

Total yield: 84.5% N- [1 (S) -ethoxycarbonyl-3-phenyl-3-oxypropyl] - (S) -alanyl (S) -proline tert-butyl ester maleate.

103-106 ° C.

Elemental Analysis: Calculated for CHN: 59.77; 6.80; 4.98;

Found: 60.01; 6.74; 5.00.

Example 2

N-f (S) -ethoxycarbonyl-3-phenylpropyl] - (S) -alanyl- (S) -proline maleate

4.46 g (10 mmol) of N- [1 (S) -ethoxycarbonyl-3-phenyl-3-oxo-propyl] - (S) -alanyl (S) -proline tert-butyl ester are dissolved in 40 ml of ethyl acetate and Hydrogenate (0.5 g, 10% palladium on charcoal) at room temperature for 2 hours and then at 50 ° C for 4 hours. After uptake of the theoretically necessary hydrogen, the catalyst is filtered off and the ethyl acetate solution is worked up as described in Example 1. Yield: 91% of the title compound having the same physical constants as in Example 1.

The reaction can be carried out in the same yield starting from N- [1 (S) -ethoxycarbonyl-3-phenyl-3-oxopropyl] - (S) -alanyl (S) -proline-benzyl ester. In this case, however, the trifluoroacetic acid treatment is omitted.

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PATENT CLAIMS

Claims (3)

A process for the preparation of a compound of formula I in the S, S, S configuration where R 'is an ethoxycarbonyl group, characterized in that a compound of the formula Π - wherein R ^{1 has} the meaning given in formula R and R is a peptide bond hydrogenated catalytically and optionally deprotecting R in a manner known per se. Process according to claim 1, characterized in that the catalytic hydrogenation is carried out in the presence of palladium on carbon in an inert organic solvent. The process according to claim 1, wherein the catalytic hydrogenation is carried out at a temperature of from 20 to 30 ° C during the initial stage of reduction. 1 drawing Published by the National Office of Inventions Responsible for publishing: Zoltán Himer Head of Department Published by Technical Publisher 87.1305 / 3 HPO Printing House, Budapest -31 - » 190 732 NGO ₄ : C 07 K 5/08 CO ZZ o · SHE' ΊΧ