CS253796B1 - Process for preparing 1-amino-cis-2,6-dimethyl-piperidine - Google Patents

Abstract

l-nitroso-cis-2,6-dimethylpiperidine is a basic intermediate in the preparation of 1-amino- -cis-2,6-dimethylpiperidine, which is used to prepare the diuretic Clopamide. The solution relates to a method for producing l-amino-cis-2,6- -dimethylpiperidine by nitrosating cis-2,6-dimethylpiperidine and subsequent reduction of the resulting l-nitroso-cis-2,6-dimethylpiperidine. The essence of the solution lies in adding an equivalent of urea and acetic acid to the reaction mixture after nitrosation, heating the mixture to 60 to 100 °C for 2 to 5 hours, cooling the product, shaking it into an organic solvent and carrying out the reduction.

Description

The present invention provides a process for the preparation of 1-amino-cis-2,6-dimethylpiperidine which is an important intermediate step in the synthesis of the diuretic Clopamide.

All previously published data on 1-amino-cis-2,6-dimethylpiperidine synthesis work with 1-nitroso-cis-2,6-dimethylpiperidine, which was isolated by distillation (E. Jucker, A. Lindenmann Helv. Chim. Acta 45 ( 7) 2,316 (1962) CG Overberger et al., J. Am Chem Soc.

100 (1955)), which is then reduced in the next step either by lithium aluminum hydride or by reduction with zinc in acetic acid or by other suitable methods.

The processes cited have such technological disadvantages that they cannot be used in production at all. The main drawback of these syntheses is the method of isolation and further processing of 1-nitroso-cis-2,6-dimethylpiperidine, which belongs to the group of potent carcinogens, and any manipulation of this substance, especially on an industrial scale, is very dangerous from the point of view of work safety. Another drawback of the published processes is that they do not solve the problem of nitrite removal in the aqueous phase after nitrosation, which is extremely ecologically important.

Both of these serious shortcomings in the literature refer to the process according to the invention which, after nitrosation in an aqueous mineral acid medium, is carried out with an excess of alkali nitrite and urea is added to the reaction mixture and the reaction mixture is heated to 60-100 ° C. Now glacial acetic acid is slowly added dropwise over 2 to 5 hours in the same molar amount as the urea, whereby a reaction is carried out in which the unreacted alkaline nitrite present is broken down and removed completely from the reaction mixture. The reaction mixture is then heated at 60-100 ° C for a further four hours, cooled to room temperature, diluted with water and an inert organic solvent, preferably toluene, is added. The reaction product is taken up in an organic solvent and thus separated from the aqueous phase, which is removed after further shaking with the solvent. The organic phase was combined with the first crop and some water was added in the reactor and all organic solvent was distilled from the mixture while stirring, leaving 1-nitroso-cis-2,6-dimethylpiperidine suspended in water in the reactor and subsequent reduction. is carried out in water, or the reduction is carried out directly in this organic solvent.

The process according to the invention thus starts from cis-2,6-dimethylpiperidine via 1-nitroso-cis-2,6-dimethylpiperidine by reduction under conditions which allow the reaction mixture to be worked up after nitrosation of cis-2,6-dimethylpiperidine without -nitroso-cis-2,6-dimethylpiperidine isolated. There was thus obtained 1-amino-cis-2,6-dimethylpiperidine in high yield and good quality. The process according to the invention is productive, simple, fast and saves raw materials. At the same time, it solves socially significant problems from the ecological point of view.

The following examples illustrate the process of the invention, but do not limit the generality of the process.

Example 1

Cis-2,6-dimethylpiperidine (169.8 g) was diluted with water (108 mL) and 50% sulfuric acid (114 mL) was added. A solution of sodium nitrite (442.5 g) in water (630 mL) was added dropwise at 0 to +3 ° C with stirring. After all the sodium nitrite solution was added, urea (261 g) was added dropwise and after heating to 90-100 ° C acetic acid (261 ml) was added dropwise. After stirring at 90-100 ° C for 3 hours, the reaction mixture is cooled to 20-30 ° C and ether (450 mL) is added. After stirring briefly, the aqueous phase was separated and removed by shaking with ether (450 mL). The ethereal shake was added to the reaction vessel to the first ether extract, washed with water (1500 mL), and 1,380 mL of water was added again. The ether is now distilled off from the mixture, leaving a slurry of 1-nitroso-2,6-dimethylpiperidine in water to cool. At 0 to +3 ° C, reduction is now carried out with zinc powder (490.5 g) and 50% acetic acid solution (2160 ml) to yield 151 g of 1-amino-cis-2,6-dimethylpiperidine, 78.9 % theory.

Example 2

Cis-2,6-dimethylpiperidine (169.8 g) was diluted with water (108 mL) and 50% sulfuric acid (114 mL) was added. A solution of sodium nitrite (442.5 g) in water (630 mL) was added dropwise with stirring at 0 to +3 ° C. After all the sodium nitrite solution was added, urea (261 g) was added dropwise and after heating to 90-100 ° C acetic acid (261 ml) was added dropwise. After stirring for 3 hours at 90-100 ° C, the reaction mixture was cooled to 20-30 ° C and toluene (450 mL) was added. After stirring briefly, the aqueous phase was separated and discarded after shaking with toluene (450 mL). The toluene shake was added to the reaction vessel to the first toluene extract, washed with water (1500 mL) and dried by azeotropic distillation. Reduction with a 70% solution of bis- (2-methoxyethoxy) sodium aluminum hydride is now carried out to give 181 g of 1-amino-cis-2,6-dimethylpiperidine, 94% of theory.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of 1-amino-cis-2,6-dimethylpiperidine by nitrosation of cis-2,6-dimethylpiperidine to 1-nitroso-cis-2,6-dimethylpiperidine and subsequent reduction to 1-amino-cis-2,6 -dimethyl-piperidine, characterized in that urea-acetic acid equivalent is added to the reaction mixture after the nitrosation of cis-2,6-dimethylpiperidine containing unreacted alkali nitrites and the mixture is heated at 60-100 ° C for 2 to 5 hours? After cooling to room temperature, shake 1-nitroso-cis-2,6-dimethylpiperidine into an organic solvent, preferably ether or toluene, and reduce. 2. The process of claim 1 wherein water is added to the organic phase containing 1-nitroso-cis-2,6-dimethylpiperidine, the organic solvent is distilled off, and 1-nitroso-cis-2,6-dimethylpiperidine is reduced.