CS263294B1 - Method of 1-amino-cis-2,l-dimethyl piperidine cleaning - Google Patents

Abstract

1-amino-cis-2,6-dimethylpiperidine is a key intermediate in the production of diuretics Clopamide (4-chloro-N- (cis-2,6-dimethylpiperidino) -3-sulfamoylbenzamide). Solution relates to the purification of crude 1-amino-cis-2,6- -dimethylpiperidine obtained by reduction 1-nitroso-cis-2,6-dimethylpiperidine, depleted of cis-2,6-dimethylpiperidine. The raw material is heated in the scraped 0.1 to 1 mm thick film 40 to 110 ° C under non-condensable pressure gases of 0.013 to 5.332 kPa for 5 to 30 s, steam condenses on cooler at temperature of -15 to 5 ° C. The method uses the benefits of heat-sensitive distillation film evaporator when it is reduced to a minimum risk of increasing the undesired 1-amino- trans-2,6-dimethylpiperidine which is thermodynamically more stable from both isomers. The method seems to be the only operational one possible way to obtain pure 1-amino- -cis-2,6-dimethylpiperidine.

Description

The invention relates to a process for the purification of 1-amino-cis-2,6-dimethylpiperidine which is one of the key components of the preparation of 4-chloro-N- (cis-2,6-dimethylpiperidine) -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-cis-2,6-dimethylpiperidine are described in the literature. Basic data on the preparation of this compound are described by the following authors: C. G. Oberberger et al. in J. Org. Chem. 22, 858 (1957), C. G. Overgerber et al. in J. Am. Chem. Soc. 77, 4 100 (1957), E. Jucker and A. Lindenmann in Helv. Chim, Acta 45 (7), 2 316 (1962), M. London and M. Borovicka in MS.

AO 253 620 and in MS. AO 253 243, P. Taufmann, M. London and M. Borovicka in MS. AO 263 292

Further, a method for separating 1-amino-cis-2,6-dimethylpiperidine from cis-2,6-dimethylpiperidine impurity (M. London in AO 253 898) is described in the literature.

The isolated product, i.e. crude 1-amino-2,6-dimethylpiperidine, always contains a number of impurities, besides the desired 1-amino-cis-2,6-dimethylpiperidine it is also a thermodynamically more stable trans derivative, as well as a cis and trans 2 reduction product, 6-dimethylpiperidine, 1-nitroso-cis-2,6-dimethylpiperidine and a small percentage of other impurities.

In the literature, 1-amino-cis-2,6-dimethylpiperidine is always purified, if at all, by rectification, but the parameters of the rectification columns or other details regarding product quality and yield are not given. In practice, it has been verified that the crude product, prepared by the reaction of any one of the aforementioned authors, after distillation or rectification yields a substance containing such high levels of 1-amino-trans-2,6-dimethylpiperidine that it is unusable for further synthesis. This is the case even if partially pre-purified 1-amino-cis-2,6-di-ethylpiperidine is used according to the method disclosed in U.S. Pat. AO 253,898 (M. London). This undesirable process has been found to occur as a result of long-term thermal loading during rectification or distillation, and is therefore highly thermolabile. therefore, ordinary distillation can only be used for small scale purification on a laboratory scale.

All these disadvantages are solved by the process according to the invention, which consists in the fact that the substance is subjected to distillation on a film evaporator. AO 253 898 enriched 1-amino-cis-2,6-dimethylpiperidine heats in a wiped film 0.1 to 1 mm thick to a temperature of 40 to 110 ° C at a pressure of non-condensable gases of 0.013 to 5.332 kPa for 5 to 30 s. condensate in an amount of 90 to 95% of the feed to the evaporator cooler at a temperature of -15 to 5 ° C.

The process for purifying crude 1-amino-cis-2,6-dimethylpiperidine of the invention has a number of advantages. It is the only process in the literature to obtain 1-amino-cis-2,6-dimethylpiperidine at very high quality (97-99.5% by GLC) without increasing the content of the undesired trans isomer by more than 0.2 to 0.3% according to GLC. The crude, intense yellow-red color with turbidity is thus purified to a colorless to slightly yellow product. At the same time, this purification method can be applied without any special requirements in the art as the only known effective method of final purification of 1-amino-cis-2,6-dimethylpiperidine.

Example

Crude 1-amino-cis-2,6-dimethylpiperidine yellowish red, containing 96.41 8 1-amino-cis-2,6-dimethylpiperidine, 0.86 8 1-amino-trans-2,6-dimethylpiperidine, 0.11 8 cis-2,6-dimethylpiperidine, 1.32 8 l-nitroso-cis-2,6-dimethylpiperidine and 1.30 8 other impurities according to GLC analysis were wiped in a film evaporator (type F-100 by Ergon Kromeriz) with a thickness of 0.8 mm at a mean residence time of 12 s heated to 95 ° C at a pressure of 4.666 kPa. At a cooler temperature of 0 ° C, a pale yellow clear distillate was obtained in an amount of 95.91 δ from the feed. The distillation residue was about 3.23% of the feed. The pure product after distillation showed 97.40% of 1-amino-cis-2,6-dimethylpiperidine, 1.06% of 1-aminotrans-2,6-dimethylpiperidine, 0.10% of cis-2,6-dimethylpiperidine, 0.46 µl of 1-nitroso-cis-2,6-dimethylpiperidine and 0.98% of other impurities. The product thus obtained is perfectly suitable for further synthesis. >

Claims (1)

object of the invention Process for the purification of 1-amino-cis-2,6-dimethylpiperidine prepared by reduction of 1-nitroso-cis-2,6-dimethylpiperidine, deprived of cis-2,6-dimethylpiperidine, characterized in that the raw material is heated in a 0-film-wiped film , 1 to 1 mm film evaporators at a temperature of 40 to 110 ° C at a non-condensable gas pressure of 0.013 to 5.332 kPa for 5 to 30 s and the vapors formed condense at 90 to 95% of the evaporator cooler feed temperature of -15 to 5 ° C .