Process for the preparation of enantiomerically enriched 3-aminopiperidine
The present invention relates to a process for the preparation of enantiomerically enriched 3-aminopiperidine, as 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-monohydrateand crystalline (S)-3-aminopiperidine-dihydrochloride-monohydrate.
1. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its R-enantiomer, the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution, suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine, where the chiral carboxylic acid A is a compound of the formula A,
wherein k is 0, 1, 2, 3, 4 or 5, R is C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy or halogen, and X is S(O) 2 , C(O) or NHC(O), where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.
2. The process according to claim 1 , wherein the carboxylic acid A is selected from (S)- 2 -phenylsulfonylamino-propionic acid, (S)- 2 -( 4 -methylphenyl)sulfonylamino-propionic acid, (S)-2-(4-chlorophenyl)sulfonylamino-propionic acid, (R)-2-(3-phenylureido)-propionic acid and (R)-2-(3-(4-chlorophenyl)ureido)-propionic acid.
3. The process of claim 1 , wherein the mixture of the enantiomers of 3-aminopiperidine is a racemic mixture of the enantiomers of 3-aminopiperidine.
4. The process of claim 1 , wherein k is 0, 1, 2 or 3.
5. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its S-enantiomer, the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution, suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine, where the chiral carboxylic acid A is the compound of the formula A,
wherein k is 0, 1, 2, 3, 4 or 5, R is C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy or halogen, and X is S(O) 2 , C(O) or NHC(O), where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.
6. The process according to claim 5 , wherein the carboxylic acid A is selected from (R)-2-phenyl sulfonylamino-propionic acid, (R)-2-(4-methylphenyl)sulfonylamino-propionic acid, (R)-2-(4-chlorophenyl)sulfonylamino-propionic acid, (S)-2-(3-phenylureido)-propionic acid and (S)-2-(3-(4-chlorophenyl)ureido)-propionic acid.
7. The process of claim 5 , wherein the mixture of the enantiomers of 3-aminopiperidine is a racemic mixture of the enantiomers of 3-aminopiperidine.
8. The process of claim 5 , wherein k is 0, 1, 2 or 3.
9. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its R-enantiomer, the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution, suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine, where the chiral carboxylic acid A is the compound of the formula A,
wherein k is 0, 1, 2, 3, 4 or 5, R is CN, NO 2 , C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy or halogen, or two adjacent variables R may together represent an optionally substituted butadien-1,4-diyl, and X is S(O) 2 or NHC(O), where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.
10. The process of claim 9 , wherein the mixture of the enantiomers of 3-aminopiperidine is a racemic mixture of the enantiomers of 3-aminopiperidine.
11. A process for enantiomeric enrichment of 3-aminopiperidine with regard to its S-enantiomer, the process comprising the fractional crystallization of 3-aminopiperidine in the form of its acid-addition salt with a chiral carboxylic acid A from a solution, suspension or emulsion containing a mixture of the enantiomers of 3-aminopiperidine, where the chiral carboxylic acid A is the compound of the formula A,
wherein k is 0, 1, 2, 3, 4 or 5, R is CN, NO 2 , C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy or halogen, or two adjacent variables R may together represent an optionally substituted butadien-1,4-diyl, and X is S(O) 2 or NHC(O), where the chiral carboxylic acid A has an enantiomeric excess with regard to one of its enantiomers.
12. The process of claim 11 , wherein the mixture of the enantiomers of 3-aminopiperidine is a racemic mixture of the enantiomers of 3-aminopiperidine.
13. The acid-addition salt of 3-aminopiperidine with the chiral carboxylic acid A,
and the hydrates thereof,
wherein k is 0, 1, 2, 3, 4 or 5, R is C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy or halogen, and X is S(O) 2 , C(O) or NHC(O).
14. The acid-addition salt of claim 13 , which has an enantiomeric excess with regard to one of the enantiomers of 3-aminopiperidine of at least 70%.
15. The acid-addition salt of claim 13 , wherein k is 0, 1, 2 or 3.
16. The acid-addition salt of 3-aminopiperidine with the chiral carboxylic acid A,
and the hydrates thereof,
wherein k is 0, 1, 2, 3, 4 or 5, R is CN, NO 2 , C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy or halogen, or two adjacent variables R may together represent an optionally substituted butadien-1,4-diyl, and X is S(O) 2 or NHC(O).
17. The acid-addition salt of claim 16 , which has an enantiomeric excess with regard to one of the enantiomers of 3-aminopiperidine of at least 70%.