CS270532B1 - A method of preparing l-matyl-4-phenyl-4-piparidinecarboxylic acid ethyl ether A method of preparing l-matyl-4-phenyl-4-piparidinecarboxylic acid ethyl ether - Google Patents

Abstract

Solution aa relates to the method of preparation of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester by N-methylation of 4-phenyl-4-piperidinecarboxylate ethyl ester with formaldehyde and formic acid in polar organic solvents. 1-Methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether hydrochloride is produced in the pharmaceutical industry and used in therapeutic practice as an analgesic (psthidine).

Description

The present invention relates to a process for the preparation of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether from 4-phenyl-4-piperidinecarboxylic acid ethyl ether by N-methylation and formaldehyde and formic acid. 1-Methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether hydrochloride is manufactured in the pharmaceutical industry and is used in therapeutic practice as an analgesic (pethidine).

1-Methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether was prepared from 4-phenyl-4-piperidinecarboxylic acid ethyl ether hydrochloride and formaldehyde by reductive methylation under pressurized catalytic hydrogenation on a palladium catalyst at 50-60 ° C and water overpressure. 20 kPa for 40 hours (Eieleb O .: U.S. Patent 2,167,351). The disadvantages of this process are the high cost of palladium and the long reaction time. The salt of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ester is prepared by N-methylation of 4-phenyl-4-piperidinecarboxylic acid ethyl ether with methyl iodide (Brit, patent 592 016). The disadvantage of this procedure is also the relatively high cost of methyl iodide and its toxicity.

These disadvantages are overcome by the process for the preparation of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether by N-methylation of 4-phenyl-4-piperidinecarboxylic acid ethyl ether according to the invention, which consists in converting N-methylaea ea with formaldehyde and formic acid in polar organic solvents such as e.g. methyl alcohol, ethyl alcohol or a mixture thereof with water, at a temperature of 60 ° C to the boiling point of the solvent used.

The reaction proceeds practically quantitatively without by-products and takes 4 hours in ethyl alcohol at the boiling point of the solvent.

In SalŠ, the process according to the invention is illustrated by way of examples, without being limited thereto.

Example 1

233 g (0.1 mol) of 4-phenyl-4-piperidinecarboxylic acid ethyl ether and 120 ml of ethanol are introduced into a 250 ml flask equipped with a stirred condenser.

14.5 ml (0.1 mol) of 37% formaldehyde and 9 ml (0.2 mol) of 85% formic acid are added. The reaction mixture was heated to reflux with stirring and stirred at reflux for 4 hours. Carbon dioxide escapes during the reaction. The reaction mixture is cooled to 20-30 ° C and 20% aqueous sodium hydroxide solution is added to pH-9.

Ethanol is then distilled off. 120 ml of petrol and 50 ml of deethylated water are added. The organic layer was slurried and washed with 50 mL of distilling water. Gasoline was distilled off to give 24 g (97%) of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether.

The content (HPLC) is 97% by weight.

Example 2

23.3 g (0.1 mol) of 4-phenyl-4-piperidinecarboxylic acid ethyl ether, 100 ml of ethyl alcohol and 20 ml of water are introduced into a 250 ml flask equipped with a stirrer and a reflux condenser.

14.5 ml (0.1 mol) of 37% formaldehyde and 9 ml (0.2 mol) of 85% formic acid are added. The reaction mixture was heated to reflux with stirring and stirred at reflux for 4.5 hours. After the reaction, carbon dioxide escapes. Then, ethyl alcohol was distilled off from the reaction mixture, and 25 ml of 50% aqueous sodium hydroxide solution was added to the distillation residue. After brief stirring and stirring, the organic layer is separated and washed with 20 ml of water. The crude product thus obtained is distilled under vacuum (160 to 165 ° C at a pressure of 0.4 to 0.6 kPa).

21.7 g (87.7%) of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether are obtained.

Ohaeh (HPL6) is 09.8% by weight.

CS 270 532 Bl

Example 3

The procedure is as in Example 1, except that methyl alcohol is used as the solvent instead of ethyl alcohol.

23.8 g (96%) of 1-methyl-4-phenyl-4-piperidinecarboxylic acid ethyl ether are obtained.

The content (HPLC) is 97% by weight.

Claims (1)

OBJECT OF THE INVENTION A method of synthesis of ethyl l-methyl-4-phenyl-4-piperidinecarboxylate N-methylation etyleeteru acid can 4-phenyl-4-piperidinecarboxylate, characterized in that N-methyl ^J Tylac e and performs a formsldehydom and formic acid in a polar organic solvent for the as e.g. . methyl alcohol, ethyl alcohol or a mixture thereof with water, at a temperature of 60 ° C to the temperature of the solvent used.