Process for the preparation of enantiomerically enriched 3-aminopiperidine
The present invention relates to a process for the preparation of enantiomerically enriched 3-aminopiperidine, and in particular of its R-enantiomer (R)-3-aminopiperidine. The invention also relates to an enantiomerically enriched intermediate of said process and to specific acid-addition salts of 3-aminopiperidine (hereinafter also APIP) that are useful for obtaining a single enantiomer of APIP, and to crystalline (R)-3-aminopiperidine-dihydrochloride-monohydrate and crystalline (S)-3-aminopiperidine-di-hydrochloride-monohydrate.
1. A process for preparing 3-aminopiperidine, which process comprises the following steps:
a) providing piperidine-3-carboxylic acid hydrazide, and
b) transforming piperidine-3-carboxylic acid hydrazide into piperidine-3-carbonyl azide by reacting piperidine-3-carboxylic acid hydrazide with a nitrite in the presence of an acid, and
c) reacting piperidine-3-carbonyl azide in the presence of water and an acid, at a temperature in the range of 50 to 150° C., whereby piperidine-3-carbonyl azide is converted into 3-aminopiperidine, where steps b) and c) are performed without isolation of piperidine-3-carbonyl azide, and
where in step c) the reaction mixture obtained after the completion of the conversion in step b) is added to a solvent which contains water and which has a temperature in the range of 50 to 150° C.
2. The process of claim 1 , where step a) comprises reacting a C 1 -C 4 -alkylester or benzylester of piperidine-3-carboxylic acid with hydrazine.
3. The process of claim 2 , wherein the C 1 -C 4 -alkylester of piperidine-3-carboxylic acid is ethyl ester of piperidine-3-carboxylic acid.
4. The process of claim 1 , where piperidine-3-carboxylic acid hydrazide is provided in a non-racemic mixture of its enantiomers, where the mixture is enantiomerically enriched with regard to one of its enantiomers.
5. The process of claim 4 , where a C 1 -C 4 -alkylester of piperidine-3-carboxylic acid, which is enantiomerically enriched with regard to one of its enantiomers, is reacted with hydrazine to provide the piperidine-3-carboxylic acid hydrazide.
6. The process of claim 5 , wherein the C 1 -C 4 -alkylester of piperidine-3-carboxylic acid is ethyl ester of piperidine-3-carboxylic acid.
7. The process of claim 5 , where step a) comprises subjecting a racemic C 1 -C 4 -alkylester of piperidine-3-carboxylic acid, to enantiomeric enrichment with regard to the R-enantiomer by fractional crystallization of an acid addition salt of the C 1 -C 4 -alkylester of piperidine-3-carboxylic acid with a chiral acid.
8. The process of claim 7 , wherein the C 1 -C 4 -alkylester of piperidine-3-carboxylic acid is ethyl ester of piperidine-3-carboxylic acid.
9. The process of claim 7 , where the chiral acid is tartaric acid or mandelic acid.
10. The process of claim 9 , wherein the chiral acid is L-tartaric acid or D-mandelic acid.
11. The process of claim 1 , where step b) comprises reacting piperidine-3-carboxylic acid hydrazide with an organic nitrite, in the presence of an acid.
12. The process of claim 1 , where 3-aminopiperidine is isolated from step c) as its dihydrochloride or dihydrochloride mono-hydrate.
13. The process of claim 1 , where the transformation in step b) is carried out in a solvent selected from water, polar organic solvents and mixtures thereof to provide a solution or dispersion of piperidine-3-carbonyl azide.
14. The process of claim 1 , where the reaction mixture obtained after the completion of the conversion in step b) is introduced directly to the conversion in step c).
15. The process of claim 1 , wherein the water-containing solvent is water, or mixtures of water with polar organic solvents.