CS253620B1 - Process for preparing 1-amino-cis-2,6-dimethylpiperidine - Google Patents

Abstract

The preparation of l-amino-cis-2, 6-dimethylpiperidine is described by reducing 1 mole of 1-nitroso-cis-2,6-dimethylpiperidine with 5 moles of zinc powder by the action of 12 moles of 50% acetic acid at a temperature of -3 to +3 °C for 2 hours with subsequent reaction at a temperature of +20 to +30 °C for 1 to 2 hours in a high yield suitable for industrial use. The substance is an intermediate for the production of the diuretic Clopamide.

Description

1-Amino-cis-2,6-dimethylpiperidine is one of the key components in the preparation of 4-chloro-N- (cis-2,6-dimethylpiperidino) -3-sulfamoylbenzamide. This substance is used as a diuretic under the generic name Clopamide in pharmacy. Several methods for preparing 1-amino-cis-2,6-dimethylpiperidine from the corresponding 1-nitroso derivative are described in the literature. Basic data on the preparation of the substance are described by the following authors.

C. G. Verberger et al., J. Org. 22,858 (1957) describe the preparation of 1-amino-cis-2,6-dimethylpiperidine by reduction of sodium dithionite (NagSgO 4) with 1-nitroso-cis-2,6-dimethylpiperidine and consider this method to be laboratory feasible.

C. G. Verberger et al., J. Am. Chem. 77, 4100, (1955) describe the preparation of 1-amino-cis-2,6-dimethylpiperidine also by reducing the nitroso derivative, but this time using lithium aluminum hydride in ether. For safety reasons, this methodology, as described by these authors, can only be used on a laboratory scale.

Technically most acceptable seems to be the method of Swiss authors E.Jucker and A. Lindenmann, Helv.Chim.Acta 45 (7) 2316 (1962), which describes the preparation of 1-amino-cis-2,6-dimethylpiperidine from 1-nitroso-cis -2,6-dimethylpiperidine by reduction with zinc dust and acetic acid in aqueous medium. According to these authors, ros 1 mole of nitroso derivative suspended in water is added 7 moles of zinc dust and 1.85 moles of a 50% aqueous acetic acid solution are added dropwise over 45 minutes at 0 to + 3 ° C. Stirring is continued for 4 hours at room temperature and then for 15 minutes at 100 ° C. The mixture is filtered while hot, made alkaline with solid potassium hydroxide and the product is taken up in ether and isolated by conventional methodology. Yield or quality of the product is not stated by the authors.

This procedure was found to be impractical for several reasons. The main reason is that when authors cite2

In the temperature and time regime of 253,620, 1-amino-cis-2,6-dimethylpiperidine is reduced to about cis-2,6-dimethylpiperidine by approx. 90%, which was proved by GC-chromatography as well as preparatively. For this reason, the yield of the desired product is very low (up to 10%). Another major drawback of this process is the precipitation of solid zinc hydroxide during the stirring phase at normal temperature, which is caused by the hydrolysis of zinc acetate during the reduction, leading to total solidification of the reaction mixture.

The disadvantages of the cited process are solved by the process according to the invention which consists in adding only 5 moles of zinc powder to 1 mole of 1-nitroso-cis-2,6-dimethylpiperidine suspended in water and dropping it at -3 to + 3 ° C. 12 moles of 50% acetic acid. Further, the reaction mixture was stirred at this temperature for a total of 2 hours, including the time from the addition of acetic acid. Thereafter, the temperature was raised to +20 ° C to +30 ° C and stirred for a further 1-2 hours, after which time the reaction mixture was worked up by conventional methods as exemplified. This gives crude 1-amino-cis-2,6-dimethylpiperidine in a yield of 85% which, after analysis by GC chromatography, contains 80 to 85% of the desired 1-amino-cis-2,6-dimethylpiperidine.

The process according to the invention is particularly suitable from the technological point of view, since it is possible to prepare 1-amino-2,6-dimethylpiperidine on any scale and in a relatively constant quality.

The following exemplary embodiment illustrates but does not limit the method of the invention.

Example 1-nitroso-cis-2,6-dimethylpiperidine (213 g) was suspended in 1380 ml of water and zinc dust (490.5 g) was added. The temperature of the reaction mixture is adjusted to -3 to + 3 ° C and 50% acetic acid solution (2160 ml) is added dropwise with stirring at this temperature, while the time is measured. The reaction mixture was stirred at -3 to + 3 ° C for 2 hours, then the internal temperature of the reaction was adjusted to 20 to 30 ° C and stirred for an additional 1.5 hours, then the reaction mixture was filtered, basified with solid potassium hydroxide and the product was shaken into ether (3x300 mL). After drying with anhydrous potassium carbonate (30 g), the ether was evaporated to dryness. Remaining yellowish oil (163 g, ie, about 85% th ·)

- 3 253 620 contains 84% of 1-amino-cis-2,6-dimethylpiperidine according to GC-chromatography and distilled at 65 to 80 ° C at 6,665 kPa ·

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of 1-amino-cis-2,6-dimethylpiperidine by reduction of 1-nitroso-cis-2,6-dimethylpiperidine with zinc in aqueous acetic acid (characterized in that 1 mol of starting 1-nitrosocis-2,6-dimethylpiperidine is reduced) in a protic environment, 5 moles of zinc powder was treated with 12 moles of 50% acetic acid at -3 to + 3 ° C for 2 hours, after which the reaction mixture was reacted for 1 to 2 hours at temperatures of + 20 to + 30 ° C.