Process for the preparation of optically active chiral amines
The present invention relates to the production of optically pure secondary amines, which can be used as intermediate products in a synthesis of for instance pharmaceutical products.
1. A process for the preparation of an optically active chiral amine and pyruvate as alpha-ketone by-product comprising:
a) providing an amino acceptor and alanine as an amino donor;
b) reacting the amino acceptor and the amino donor with a (R)- or (S)-selective transaminase;
c) obtaining the desired optically active chiral amine and pyruvate as alpha-ketone by-product; and
d) removing pyruvate from the reaction mixture with a decarboxylase to shift the equilibrium to the product side, wherein the optically active chiral amine is selected from the group consisting of cephalosporine, heterocyclic boronic acids, L-dihydroxyphenylalanine (L-Dopa), α-methyldopa, D-phenylglycine, β-hydroxyphenylglycine, phenylalanine, alanine, 3-aminopiperidine, alkyl-3-amino-butanoates, 3-aminopyrrolidine (3-AP), 3-pyridyl-1-ethylamine (3-PEA), N-1-boc-3-aminopyrrolidine (B3AP), 3-aminobutyric acid ethyl ester (3-ABEE), 3-aminopentanoic acid methyl ester (3-APME), α-methyl-4-(3-pyridyl)-butanamine, glutamate, phosphinothricine, β-aminobutyrate, sec-butylamine, methoxyisopropylamine, and 1-N-boc-3-aminopiperidine.
2. The process according to claim 1 , wherein the decarboxylase is a pyruvate decarboxylase (PDC).
3. The process according to claim 1 , wherein the transaminase is from Vibrio fluvialis, Alcaligenes denitrificans, Klebsiella pneumoniae or Bacillus thuringiensis.
4. The process according to claim 1 , wherein the process is carried out in a reaction mixture having a pH from 6.0 to 7.0.
5. The process according to claim 1 , wherein the process is carried out in a reaction mixture having a pH from 6.0 to 6.9.
6. The process according to claim 1 , wherein the amino acceptor is B3OP.
7. The process according to claim 2 , wherein the acetaldehyde formed by the action of the PDC is removed.
8. The process according to claim 7 , where the acetaldehyde is removed by reaction with at least one enzyme.
9. The process according to claim 8 , wherein the enzyme is an alcohol dehydrogenase.
10. The process according to claim 7 , wherein the acetaldehyde is removed by feeding gaseous nitrogen into the reaction mixture.
11. The process according to claim 7 , wherein the acetaldehyde is removed by applying a reduced pressure to the reaction mixture.
12. The process according to claim 7 , wherein the acetaldehyde is removed by chemical methods.
13. A process for the preparation of an optically active chiral 3-AP or an optically active chiral B3AP comprising:
a) providing 3-OP or B3OP as an amino acceptor and providing an amino donor;
b) reacting the amino acceptor and the amino donor with a (R)- or (S)-selective transaminase; and
c) obtaining the optically active chiral 3-AP or the optically active chiral B3AP and an alpha-ketone by-product.
14. The process according to claim 1 , further comprising carrying out the process in a reaction mixture having a pH from approximately 5.0 to 9.5.
15. The process according to claim 1 , further comprising carrying out the process for a reaction time of 40 to 70 minutes.
16. The process according to claim 1 , further comprising carrying out the process in a temperature range from 10° to 65° C.
17. The process according to claim 1 , wherein the reaction is carried out in the presence of at least one pyruvate decarboxylase and at least one alcohol dehydrogenase.
18. The process according to claim 1 , wherein the reaction is carried out in the presence of at least one pyruvate decarboxylase, at least one alcohol dehydrogenase and additionally in the presence of gaseous nitrogen (N 2 ).
19. The process according to claim 1 , wherein the optically active chiral amine is an optically active chiral 3-AP or an optically active chiral B3AP.