Method of preparing 1-amino-2, 6-dimethylpiperidine

Details Method of preparing 1-amino-2, 6-dimethylpiperidine Method of preparing 1-amino-2, 6-dimethylpiperidine

1994-05-17

1996-05-07

Ivy, C. Warren

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D21198

Patent

active

055148069

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a process for the preparation of 1-amino-2,6-dimethylpiperidine.
1-Amino-cis-2,6-dimethylpiperidine is a key intermediate product in the synthesis of the loop saluretic clopamide (4-chloro-N-(cis-2,6-dimethylpiperidino-sulfamoylbenzamide) and the cardiovascular agent pirsidomine (3-(cis-2,6-dimethylpiperidino)-N-(4-methoxybenzoyl)-sydnonimine).
All the known preparation processes for 1-amino-2,6-dimethylpiperidine are based on reduction of 1-nitro-so-2,6-dimethylpiperidine. All show an incomplete conversion and above all ecological deficiencies.
Furthermore, the production of large amounts of waste salts in the reduction with sodium dithionite (C.G. Overberger, J.G. Lombardino and R.G. Hiskey, J. Org. Chem. 22 (1957) 858) is a disadvantage.
The use of zinc in dilute acetic acid as the reducing agent (E. Jucker and A. Lindamann, Helv. Chim. Acta, 45 (1962) 2316-2325, in particular 2323) leads to a considerable heavy metal pollution of the resulting waste water.
Reduction with complex hydrides, such as lithium aluminum hydride in ether (C.G. Overberger, L.C. Palmer, S.S. Marks and N.R. Byrd, J. Am. Cham. Soc. 77 (1955) 4100) or bis(2-methoxyethoxy)-sodium aluminum hydride in toluene (M. Londyn and M. Borovicka, Czechoslovakian Patent 253243, applied for on 21.01.1986) cannot be carried out on a larger scale for safety reasons. A process is known from U.S. Pat. No. 2,979,505 for the preparation of substituted hydrazines, such as, for example, N-aminopiperidine, in which the corresponding nitrosamines are hydrogenated in the presence of a palladium catalyst which contains a certain amount of a soluble iron salt. The hydrogenation of heterocyclic nitrosamines, such as, for example, of nitrosopiperidine, by this process is carried out in aqueous or ethanolic solution.
According to Hungarian Patent 15614, the preparation of 1-amino-cis-2,6-dimethylpiperidine by this process is unsatisfactory both in respect of the yield (65%) and in respect of the selectivity (60 to 70%). According to the process of Hungarian Patent 15614, 1-amino-cis-2,6-dimethylpiperidine is therefore prepared by nitrosation of cis-2,6-dimethylpiperidine and hydrogenation of the resulting nitroso compound in aqueous ammoniacal solution in the presence of a palladium catalyst partly poisoned with an Fe(II) salt, the two reactions being carried out in the absence of chloride ions. This process shows considerable problems both in the reaction and in the working-up of the reaction mixture obtained. Thus, for example, the use of ammonia requires additional process technology measures to avoid corrosion and emission. Furthermore, the amount of ammonia used is high (100 to 150 g of ammonia per kg of product). The incomplete conversion, which causes the product to contain still unreacted 1-nitroso-2,6-dimethylpiperidine, is, as in the other processes, a disadvantage. In the process of Hungarian Patent 15614, it is still at least 3%. Nevertheless, the main difficulty is the large amount of water in the reaction mixture, which is caused by the process and makes isolation of the product very much more difficult.
During subsequent rectification, the product and by-product (cis-2,6-dimethylpiperidine) pass over together with water (as a rule at 85.degree. to 95.degree. C./atmospheric pressure), so that there is the prospect of isolation of the product only if extremely expensive columns are employed. Only multi-stage extractor processes remain as alternatives for isolation of the product. The organic solvents used here require increased safety measures and treatment of the waste water and waste air. To remove the relatively strongly basic by-product 2,6-dimethylpiperidine the addition of a corresponding amount of acid substances is necessary, which means that the waste water is polluted even more (M. Londyn, Czechoslovakian Patent 253898).
The object of the present invention was therefore to provide a process for the preparation of 1-amino-2,6-dimethylpiperidine by reduction of 1-nitroso-2,6-dimethylpiperidine which does not have th

REFERENCES:
patent: 2979505 (1961-04-01), Tuemmler et al.

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