CS263293B1 - Method of purification of 1-amino-2,6-dimethylpiperidine-prepared reduction of 1-nitroao-2, e-dimethylpiperidine - Google Patents

Abstract

l-amino-cis-2,6-dimethylpiperidine is a key intermediate in the production of the diuretic Clopamide (4-chloro-N-(cis-2,6-dimethylpiperidino)-3-sulfamoylbenzamide). The solution relates to the purification of crude l-amino-2,6- -dimethylpiperidine after reduction of 1-nitroso- . -2,6-dimethylpiperidine contaminated with 2,6-dimethylpiperidine. By treating an equivalent of sodium hydrogen sulfate monohydrate or anhydrous (based on the amount of 2,6-dimethylpiperidine present) with an anhydrous solution of the crude mixture after reduction in diethyl ether, an adduct with 2,6- -dimethylpiperidine is formed, which is removed. The method is very suitable for industrial use due to its high yields, product quality and ease of implementation.

Description

The invention relates to 1-amino-cis-2,6-dimethylpiperidine which is one of the key components of the preparation of 4-chloro-N- (cis-2,6-dimethylpiperidino) -3-sulfamoylbenzamide. This substance is used under the generic name Clopamide in pharmacy as a diuretic and is also produced in Czechoslovakia.

Several methods for preparing 1-amino-2,6-dimethylpiperidine have been described in the literature, each by reducing the corresponding 1-nitroso derivative. Basic data on the preparation of the substance are described by the following authors.

C. G. Overberger et al. in J. Org. Chem. 22, 858 (1957) describes the preparation of 1-amino-2,6-dimethylpiperidine by reduction with sodium dithionite (Na 2 SO 4).

C. G. Overberger et al. in J. Am. Chem. Soc. 77, 4 100, (1957) carry out the preparation of 1-amino-2,6-dimethylpiperidine by reduction with lithium aluminum hydride in ether.

E. Jucker and A. Lindenmann prepare 1-amino-2,6-dimethylpiperidine by reduction with zinc dust in dilute acetic acid, see Helv. Chim. Acta 45 (7) 2,316 (1962).

M. London and M. Borovička in MS. AO 253 620 performs the preparation of 1-amino-2,6-dimethylpiperidine also by reduction with zinc in dilute acetic acid and the same authors in Czechoslovakia. AO 253 243 prepare 1-amino-2,6-dimethylpiperidine by reduction with synhydride in toluene.

P. Taufmann, M. London and M. Borovička in MS. AO 263 292 perform the same reduction with sulfuric acid and zinc.

The isolated product of all of these reactions is purified, if indicated, by rectification, but the parameters of the rectification columns for that particular rectification are not listed.

By means of GC-chromatography, it was found that in the crude product after reduction, in addition to the desired 1-amino-cis-2,6-di-ethylpiperidine, 2,6-dimethylpiperidine is present in the crude product. raw product rectification key role. Technological mastery of this operation would require foreign exchange investment in the purchase of efficient operational rectification columns, despite their high energy consumption and the need for qualified operation and maintenance.

M. London in MS. AO 253 898 describes the purification of crude 1-amino-2,6-dimethylpiperidine contaminated with 2,6-dimethylpiperidine on the basis of differences in the dissociation constants of these substances. This honey is very effective and removes undesirable 2,6-dimethylpiperidine to a sufficient degree. The reaction is carried out in an aqueous medium by substances of an acidic nature. The disadvantage of this process is the relatively low yields of 1-amino-2,6-dimethylpiperidine, and the fact that the trans-isomer of this compound is increased in the aqueous medium in which the reaction is carried out, which is to a greater extent for further synthesis. undesirable.

These disadvantages are solved by the process according to the invention, wherein the crude 1-amino-2,6-dimethylpiperidine is dissolved in a triple amount of diethyl ether, sodium bisulfate monohydrate or anhydrous finely divided in an amount equivalent to 2,6-dimethylpiperidine present is added and the reaction is carried out well. at 0 to 36 ° C for 0.5 to 5 hours depending on the size of the batch. The solid undesired adduct of sodium hydrogensulfate with 2,6-dimethylpiperidine is then filtered off, and after concentration of diethyl ether, the desired 1-amino-2,6-dimethylpiperidine of very good quality and excellent yield is obtained.

This method of separating 1-amino-2,6-dimethylpiperidine is particularly suitable for operational purposes due to its high yields, product quality and simple design. It can be made in any quantity and does not require any investment or investment in equipment.

Example «

To a mixture (50.0 g) containing 4.63 t of 2,6-dimethylpiperidine and 91.26% of 1-amino-2,6-dimethyl piperidine dissolved in diethyl ether (150.0 mL) was added with stirring at 36 ° C sodium bisulfite monohydrate (2.17 g) and stir for 1 hour. The suspension is filtered and the filtrate is concentrated in vacuo. The product according to GC-chromatography contains 0.65% undesirable 2,6-dimethylpiperidine and 96.32% 1-amino-cis-2,6-dimethylpiperidine. Yield: 45 g.

Claims (1)

A process for the purification of crude 1-amino-2,6-dimethylpiperidine prepared by reducing 1-nitroao-2,6-dimethylpiperidine by treating a solution of crude 1-amino-2,6-dimethylpiperidine with an equivalent of sodium hydrogen sulfate or monohydrate, characterized in that The reaction is carried out in an anhydrous medium preferably in diethyl ether at temperatures of 0 to 36 ° C for 0.5 to 5 hours.