CS271971B1 - Preparation of 4-phenyl-4-piperidinecarboxylic acid ethyl ether hydrochloride - Google Patents

Abstract

The solution relates to a method for preparing 4-phenyl-4-piperidinecarboxylic acid ethyl ether hydrochloride by catalytic hydrogenation of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether hydrochloride in order to eliminate the use of an expensive palladium catalyst. The idea is that N-debenzylation is carried out by pressure hydrogenation under Raney nickel catalysis in polar organic solvents. The prepared compound is an intermediate in the direct pharmaceutical production of the analgesic pistidine.

Description

1 CS 271 971 B1

The invention relates to a process for the preparation of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride from 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride by catalytic hydrogenation N-debenzylation using Raney nickel as catalyst. 4-Phenyl-4-piperidinecarboxylic acid ethyl ester is an intermediate in the industrial pharmaceutical production of the pethidine analgesic.

4-Phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride is prepared by pressure-free catalytic hydrogenation of N-debenzylation of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride, using a palladium catalyst at 50-60 ° C and hydrogen overpressure. 20 kPa for 40 hours (Eisleb 0, U.S. Pat. No. 2,167,351; U.S. Pat. No. 2,486,792). The disadvantage of this process is the high price of palladium and the long reaction time.

The above drawbacks are avoided by the preparation of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride by catalytic hydrogenation of N-debenzylene with 1-benzyl-4-phenyl-4-piperidinecarboxylic acid hydrochloride according to the invention, wherein N is Debenzylene is subjected to pressurized hydrogenation at a pressure of 0.2 to 5 MPa, with catalysis of 2 to 20% by weight. Raney nickel, based on the starting material weight, in polar organic solvents such as ethyl alcohol, methylene chloride or mixtures thereof with water, at a temperature of 70-150 ° C. The reaction takes place virtually quantitatively without any by-products and takes 1.5 hours at a temperature of 90 ° C and a pressure of 2 MPa. In the following, the process of the invention is illustrated by the examples without being limited thereto. Example 1

20 g (0.055 mol) of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride, 75 ml of ethyl alcohol, 25 ml of distilled water and 1 g of Raney-nickel (5% w / w) are added to a 250 ml stirrer autoclave. weight of starting material). The autoclave is closed, rinsed twice with nitrogen and three times with hydrogen, and the autoclave contents are heated to 90 ° C with stirring. At this temperature, it is hydrogenated at 1.5 MPa for 2 hours with vigorous stirring. Then the autoclave is cooled to 20 ° C, the hydrogen is discharged, the autoclave is purged twice with nitrogen. The Raney-nickel is filtered off, the filtrate is concentrated by means of a vacuum evaporator. 14.7 g (98%) of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride are obtained.

The content (HPLO) is 98% by weight. Example 2

20 g (0.055 mol) of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride, 130 ml of ethyl alcohol and 4 g of Raney-nickel (20% by weight of the starting material) are added to a 250 ml stirrer autoclave. ). The autoclave is sealed, purged twice with nitrogen and three times with hydrogen, and the autoclave contents are heated to 70 ° C with stirring. this temperature is hydrogenated with hydrogen at 0.2 MPa for 10 hours with vigorous stirring. Then the autoclave is cooled to 20 ° C, the hydrogen is discharged, the autoclave is purged twice with nitrogen. Raney-nickel is filtered off, the filtrate is concentrated in a vacuum evaporator. 14.85 g (99%) of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride are obtained. Content (HPLC) is 96.9% by weight. Example 3

The procedure is as in Example 2e, except that methanol is used in place of ethyl alcohol, 0.4 g of Raney nickel (2% by weight of starting material) is used and hydrogenated at 5 MPa for 1.5 hours and at 150 ° C. 14.75 g (98.4%) of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride are obtained.

HPLC (97.5) content.

Claims (1)

Process for the preparation of 4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride by catalytic hydrogenation N-debenzylation of 1-benzyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester hydrochloride, characterized in that the N-debenzylation is carried out by pressure hydrogenation at a pressure of 0.2 to 5 MPa, catalyzed by 2 to 20 wt. Raney nickel, based on the weight of the starting material, in polar organic solvents such as e.g. ethyl alcohol, methyl alcohol or mixtures thereof with water, at a temperature of 70 to 150 ° C.