CS266584B2 - Method of 1-/n-(1-ethoxy carbonyl-3-oxo-3-phenylpropyl)-l-alanyl/-l-proline's benzyl esther production - Google Patents

Abstract

The benzyl ester of 1-(N-(1-ethoxycarbonyl 3-oxo 3-phenyl propyl) L-alanyl) L-proline is made by condensn. of the benzyl ester of L-proline with a cpd. of formula (I), in which W is a reactive ester gp. in equimolar amts. Reaction is in an inert organic solvent e.g. chloroform, acetone, tetrahydrofuran or mixts. of these, at -10 deg. C up to reflux twmp. The prod. is sepd. and purified by conventional methods.

Description

The present invention relates to a process for the preparation of 1- [N- (1-ethoxycarbonyl-3) -benzyl ester. -oxo-3-phenylpropyl) -L-alanyl] -L-proline by reacting the L-proline benzyl ester with a compound of formula (I) wherein W is a halogen atom, the -O COORJ group in which .—. θ γ ^Η 3 θ

R1 denotes straight-chain or branched C1-C8-CH2H-C1-C8-alkyl or ^2- C1-C4-alkyl; * bicyclohexylisourea, x denotes asymmetric CO ₂ Ethical carbon atom, in the form of the L-stereoisomer, in a molar ratio of 1: 1 in an organic solvent at a temperature of 0 to 40 ° C. The compounds obtained are intermediates for the manufacture of pharmaceuticals.

CS 266 584 B2

CS 266 584 B2

The present invention relates to a process for the preparation of 1- [n- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl) -L-alanyl] -L-proline benzyl ester, which is an intermediate for obtaining compounds with interesting therapeutic properties.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of 1- [N- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl) -L-alanyl] -L-proline benzyl ester, comprising reacting an L-prolinebenzyl ester with a compound of formula (I). a compound of formula I

CHo 0

.. II ³ I

C-CHn-CH-NH-C-

CO ₂ Et where a halogen atom, a -O COOR 4 group, in a branched or branched chain of 1 to 8 urea atoms, denotes an asymmetric carbon atom in which R 1 represents a linear carbon alkyl or bicyclohexylisoL-stereoisomer in a 1: 1 molar ratio in an organic solvent at 0 to 40 ° C.

Furthermore, W may be a residue of isourea or dicyclohexylurea, in a suitable solvent as in the reaction medium, thereby forming an amide bond.

The course of the chemical reaction in the process according to the invention can be illustrated by the following reaction scheme:

The ratio of reactants used is preferably 1: 1, which means that the components are used in a stoichiometric amount.

The reaction medium may be an organic solvent such as acetone, chloroform, tetrahydrofuran, ethyl ether or the like or a mixture thereof.

CS 266 584 B2

The process of the invention is carried out at a temperature of -10 ° C to the reflux temperature of the reaction solvent, preferably at a temperature of 0 to 40 ° C.

After completion of the reaction, the desired product is isolated by conventional means and, if desired, diastereoisomers may be isolated by column chromatography, fractional crystallization or the like.

The invention will be illustrated by the following examples:

Example 1

A mixture of 20.5 g (0.1 mol) of L-proline benzyl ester and 34.8 g (0.1 mol) of N- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl) -L-alanilic acid hydrochloride (general formula) (In which W represents a chlorine atom) was stirred at room temperature for 12 hours in 200 ml of chloroform. After completion of the reaction, the chloroform solution was washed twice with 40 ml of 10% aqueous sodium carbonate solution, then dried and evaporated to dryness. The resulting oily liquid was washed with 2 x 20 mL of hexane-ether to give 38 g of 1 - [- N- (1-ethoxycarbonyl-3-oxo-3- (phenylpropyl) -L-alanil-JL-proline) benzyl ester in practically pure form. in 80% yield as a viscous oil.

The infrared spectrum has the following intense and characteristic bands (cm ^-1 ). 3 300-3 200, 3 000-2 900, 1 720, 1680-1 640, 1 400, 1 300, 1 260, 1 170, 1 000, 975, 730 and 690.

1 H-NMR (d 6 -DMSO) ppm, δ): 1.3 absorption of complex (6H, 2 absorption of complex (4ц), 3.2 triplet (2H), 3.55 absorption of complex (3H), 4.2 absorption complex (4H), 5.1 singlet (2H), 7.2 singlet (5H, 7.4 singlet (5H)).

Example 2

To a solution of 10.25 g (0.05 mol) of L-proline benzyl ester in 150 ml of anhydrous acetone cooled to 0 ° C was slowly added a solution of 18.25 g (0.05 mol) of the compound of formula I (W = О C00). Et) Which was obtained from an acid in which W is OH and ethyl chloroformate] in 60 ml of anhydrous acetate. The solution was allowed to stand for one hour under these conditions and then 1M sodium hydroxide solution was added until pH 12-13 and after the addition was complete the reaction mixture was stirred at room temperature for one hour. The reaction mixture was poured into 300 ml of cold water. The mixture was separated, dissolved in chloroform, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give 14.4 g of 1- [n- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl) benzyl ester in 60% yield. 1-L-alanil-L-proline in the form of a viscous oily liquid having the same properties as the final product obtained by the method of Example 1.

Example 3

To a solution of 10.25 g (0.05 mol) of L-proline benzyl ester in 100 ml of anhydrous tetrahydrofuran cooled to 0 ° C is slowly added a freshly prepared solution of 25 g (0.0 mol) of the compound of formula I in which W is dicyclohexylisourea [a solution is obtained by reacting a compound of formula I in which W is OH and bicyclohexylcarbodiimidyl in 100 ml of anhydrous tetrahydrofuran. The mixture was stirred at 0 ° C for 2 hours and then at room temperature for 3 hours. A 10% potassium carbonate solution of pH 10-12 and 200 ml of toluene are then added. The precipitated dicyclohexylisourea is filtered off and the organic phase is washed, dried over anhydrous sodium sulphate, filtered and evaporated to dryness in vacuo to give 15.3 g of the title compound as a viscous oil having the same properties as the product of Example 1.

Yield 63%.

CS 266 584 B2

OBJECT OF THE INVENTION

Claims (2)

A process for the preparation of 1- [N- (1-ethoxycarbonyl-3-oxo-3-phenylpropyl) -L-alanyl] -L-proline benzyl ester, comprising reacting L-proline benzyl ester with a compound of formula I where CO ₂ Et (I) represents a halogen atom, the group -COOR 6 in which it represents a straight or branched chain alkyl of 1 to 8 carbon atoms or bicyclohexylisourea denotes an asymmetric carbon atom, in the form of an L-stereoisomer, in a molar ratio of 1 1 in an organic solvent at 0 to 40 ° C. 2. The process of claim 1 wherein the reaction solvent is selected from chlorinated hydrocarbons such as chloroform, ketones such as acetone, ethers such as diethyl ether, cyclic ethers such as tetrahydrofuran, or a mixture thereof. Severography, n. P., MOST