CS263292B1 - Process for preparing raw 1-amino-cis-2,6-dimethylpiperidine - Google Patents

Abstract

The preparation of crude 1-amino- -cis-2,6-dintethylpiperidine by reduction 1-nitroso-cis-2,6-dimethylpiperidine zinc powder by the action of dilute acid sulfuric acid at 0 to 5 ° C. After adding all sulfuric acid to the reaction alkaline the mixture with aqueous ammonia and the product was extracted with ether. It is prepared as follows a product containing 85 to 93% of the desired product 1-amino-cis-2,6-dimethylpiperidine. The method is advantageous for operating conditions. The substance is an intermediate for the production of a diuretic Clopamid.

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 nitroso derivative are described in the literature. Basic data on the preparation of the substance are described by the following authors.

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

C. G. Overberger et al., J. Am. Chem. Soc. 77, 4100 (1955), describe the reduction of a nitroso derivative with lithium aluminum hydride in an ether medium. For safety reasons, this methodology can only be used on a laboratory scale.

Swiss authors E. Jucker and A. Lindemann, Helv. Chim. Acta 45 (7), 2 316 (1962), describe the preparation of 1-amino-cis-2,6-dimethylpiperidine by reduction with zinc dust and acetic acid in an aqueous medium. According to these authors, Κ 1 mole of nitroso derivative suspended in water was added 7 mol of zinc and 1.85 mol of a 50% aqueous acetic acid solution were added dropwise over 45 minutes at 0 to 3 ° C. After stirring for 4 h at room temperature, the mixture was filtered hot, basified with solid potassium hydroxide, extracted with ether and isolated. Yield and product quality are not given. This procedure was found to be impractical for several reasons. The main reason is that in the authors mentioned time and temperature regime hydrogenolytic cleavage of the bond between nitrogen and the product of the reaction is predominantly cis-2,6-dimethylpiperidine, which was proved by GC-ohromatography as well as preparatively. Thus, the yield of the desired product is very low, 10-20%.

The production of 1-amino-cis-2,6-dimethylpiperidine is further solved by the uat. AO 253 620 wherein the desired compound is prepared by reducing the nitroso derivative with zinc dust in aqueous acetic acid. The reaction is carried out by adding 5 mol of zinc to 1 mole of 1-nitroso-cis-2,6-dimethylpiperidine suspended in water and dropping 12 mol of 50% acetic acid at a temperature of -3 to 3 ° C. The reaction mixture was stirred at this temperature for 2 h and at 20-30 ° C for 2 h. After the usual isolation, a product is obtained which contains 75 to 80% of the desired 1-amino-cis-2,6-dimethylpiperidine. This process is reproducible and feasible on a technological scale, but has some significant drawbacks. The temperature and time parameters due to the exothermic reaction cannot be maintained in the larger scale reduction. The final product contains undesirable cis-2,6-dimethylpiperidine (15-20%) and 1-amino-trans-2,6-dimethyl piperidine (2-4%). Both of these compounds complicate further processing, the tris isomer cannot be removed from the product by known methods. Another drawback is the difficult extraction of the product after alkalization, which is carried out from a mixture of poorly soluble zinc salts in water. For use on a commercial scale, another major drawback is the possibility of a small feedstock feedstock due to the large volume of the reaction mixture.

The disadvantages of these methods are solved by the process according to the invention which consists in adding to the mol of 1-nitroso-cis-2,6-dimethylpiperidine dissolved in ether water and 4.2 mol of zinc at a reaction mixture temperature of 0 to 5 ° C. 2.8 mol of sulfuric acid diluted with water (1: 2 by volume) was added dropwise. After all the acid has been added, the solution is basified at 0-5 ° C with aqueous ammonia solution to form a clear solution, which is extracted with ether and worked up in the usual manner as exemplified. A GLC product containing 85 to 93% of the desired 1-amino-cis-2,6-dimethylpiperidine, 0.1 to 2% of unreacted 1-nitroso-cis-2,6-dimethylpiperidine, 0.1 to 0, 5% of 1-amino-trans-2,6-dimethylpiperidine and a small amount of unidentifiable impurities. These by-products can be removed by purification methods used in organic chemistry.

The method of preparation according to the invention is reproducible on an industrial scale, is relatively easy from a technological point of view, it is not demanding in terms of raw materials or energy.

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

Example

In a 6 L sulfonation flask equipped with a stirrer, dropping funnel, thermometer, and reflux condenser, 477.3 g (3.36 mol) of 1-nitroso-cis-2,6-dimethylpiperidine were dissolved in 1200 mL of ether. To the solution was added 600 mL of water and cooled to 0 ° C. Furthermore, 922 g (14.10 mol) of zinc dust were controlled. 940 g of 98% sulfuric acid diluted with 1,900 ml of water were carefully added with stirring. The addition was conducted at 0-5 ° C for 5 h. A 25% aqueous ammonia solution was then added dropwise at this temperature. A total of 3 L of ammonia was added. The resulting clear solution was extracted four times with 500 mL of ether. The combined ether extracts were dried over anhydrous potassium carbonate (200 g) for 20 h. After filtration, the ether was evaporated, the residue was a yellowish oil, weighing 356 g, representing a yield of 82.7%.

This crude product contained 91.26% 1-amino-cis-2,6-dimethylpiperidine as determined by GLC, 4.63% cis-2,6-dimethylpiperidine, 0.42% 1-amino-trans-2,6-dimethylpiperidine, 0.11% of 1-nitroso-cis-2,6-dimethylpiperidine, the remainder of the solvent and a small amount of unidentifiable impurities.

Claims (1)

Process for the preparation of crude 1-amino-cis-2,6-dimethylpiperidine by reduction of 1-nitroso-cis-2,6-dimethylpiperidine by zinc, characterized in that water and 4.2 mol of zinc powder are added to 1 mol of the starting material in ether. Then, a solution of 2.8 mol of sulfuric acid diluted with water (1: 2 by volume) is added dropwise at 0-5 ° C, then the mixture is basified at this temperature with an excess of aqueous ammonia to pH 9-10 and the product isolated.