Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-05-17
1996-04-23
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D71198
Patent
active
055104894
DESCRIPTION:
BRIEF SUMMARY
This is the U.S. National Stage application of PCT/EP92/02594 filed Nov. 12, 1992.
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-nitroso-2,6-dimethylpiperidine. All these have an incomplete conversion and, above all, have ecological deficiencies.
Furthermore, the production of large amounts of waste salts in the reduction with sodium dithionite (C. G. Overberger, J. G. Lombardinc and R. G. Hiskey, J. Org. Chem. 22 (1957) 858) is a disadvantage.
The use of zinc in dilute acetic acid as a reducing agent (E. Jucker and A. Lindemann, Helv. Chim. Acta, 45 (1962) 2316-2325, in particular 2323) leads to considerable heavy metal pollution of the waste water formed.
The reduction with complex hydrides, such as lithium aluminum hydride in ether (C. G. Overberger, L. C. Palmer, B. S. Marks and N. R. Byrd, J. Am. Chem. 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 USP 2 979 505 for the preparation of substituted hydrazincs, such as, for example, N-aminopiperidine, in which the corresponding nitroso amines are hydrogenated in the presence of a palladium catalyst which contains a certain amount of a soluble iron salt. According to the Hungarian Patent Specification 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 Specification 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 poisoned with an Fe(II) salt, the two reactions being carried out in the absence of chloride ions. This process has 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. The amount of ammonia used furthermore is high (100 to 150 g of ammonia per 1 kg of product). Nevertheless, the main problem here, as also in the case of the other processes, is the incomplete conversion, which causes the product to contain still unreacted 1-nitroso-2,6-dimethylpiperidine. In the process of Hungarian Patent Specification 15614, this amount is still at least 3%.
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 the disadvantages of the processes which have been disclosed to date and by which, in particular, a complete conversion is achieved.
The invention thus relates to a process for the preparation of 1-amino-2,6-dimethylpiperidine by catalytic hydrogenation of 1-nitroso-2,6-dimethylpiperidine using a palladium catalyst partly poisoned with iron ions. The process according to the invention is characterized in that it is carried out in an aqueous solvent in the presence of a surfactant or mixture of surfactants.
Aqueous solvents which can be used are mixtures of water with water-miscible organic solvents, such as, for example, alcohols, glycols, glycol ethers and the like. Water is preferably used as the aqueous solvent.
Surfactants are classified into anionic, nonionic, cationic and amphoteric types, of which the anionic and nonionic types are particularly preferred in the process according to th
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Bauer Wolfgang
Kujath Eckard
Rybczynski Wolfgang
Schrod Manfred
Cassella Aktiengesellschaft
Covington Raymond
Ivy C. Warren
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