Process for the preparation of optically active chiral amines

Patent metadata

Field	Value
Publication number	US-9551018-B2
Application number	US-201514740646-A
Country	US
Kind code	B2
Filing date	Jun 16, 2015
Priority date	Feb 13, 2006
Publication date	Jan 24, 2017
Grant date	Jan 24, 2017

Abstract

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.

First claim

What is claimed is:

1. A process for the preparation of a compound selected from a group consisting of 3-aminopyrrolidone derivatives, chephalosporine, derivatives of cephalosporine, heterocyclic boronic acids, L-dihydroxphenylalanine (L-Dopa), α-methyldopa, D-phenylglycine, β-hydroxyphenylglycine, phosphinothricine, pyrimido derivatives and pyrrolidone derivatives, the process comprising:
a) providing an amino acceptor and an amino donor,
b) reacting the amino acceptor and the amino donor with a transaminase,
c) obtaining a desired optically active chiral amine and a ketone by-product, and
d) converting the optically active chiral amine to the compound, and
wherein the amino acceptor is selected from a group consisting of phenylpyruvic acid, a salt thereof, pyruvic acid, a salt thereof, 2-ketoglutarate, 3-oxobutyrate, 2-butanone, 3-oxopyrrolidine, 3-pyridylmethylketone, 3-oxobutyric acid ethyl ester, 3-oxopentanoic acid methyl ester, N-1-boc-3-oxopiperidinone, N-1-boc-3-oxopyrrolidine, 3-oxo-piperidine, alkyl-3-oxo-butonoates, methoxy-acetone and 1-oxotetralone.

2. The process according to claim 1 , wherein the transaminase is a (R)- or (S)-selective transaminase.

3. The process according to claim 1 , wherein the amino donor is selected from the group consisting of amines or amino acids, in particular from β-alanine, alanine, α-methylbenzylamine (α-MBA), glutamate, phenylalanine and γ-aminobutyrate, glycin, 3-aminobutyrate, isopropylamine, 2-aminobutane and a salt, for instance a chloride, of any one thereof.

4. The process according to claim 1 , wherein the obtained amines are amines, in particular mono- or bicyclic amines, in particular amines of 5 to 6-membered cyclic or S-, O-, or N-substituted heterocyclic hydrocarbons or aromatic amines, in particular alkyl- or alkoxy-substituted aromatic amines.

5. The process according to claim 1 , wherein the obtained amines are selected from the group consisting of phenylalanine, alanine, 3-am inopiperidine, 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-methylbenzylamine (α-MBA), 1-aminotetraline, α-methyl-4-(3-pyridyl)-butanamine, glutamate, β-aminobutyrate, sec-butylamine, methoxyisopropylamine, derivatives of 3-aminopyrrolidine, 1-N-boc-3-aminopiperidin, cephalosporine and derivatives of cephalosporine.

6. The process according to claim 1 , wherein the transaminase is from Vibrio fluvialis, Alcaligenes denitrificans, Klebsiella pneumoniae or Bacillus thuringiensis.

7. The process according to claim 1 , wherein the ketone by-product obtained in step c is pyruvate.

8. The process according to claim 1 , wherein the ketone by-product obtained in step c) is in a further process step e) removed from by reaction with at least one enzyme.

9. The process according to claim 8 , wherein the enzyme used in step e) is a decarboxylase.

10. The process according to claim 8 , wherein the at least one enzyme used in step e) is a synthase.

11. The process according to claim 8 , wherein the enzyme used in step e) is a dehydrogenase.

12. The process according to claim 8 , wherein the enzyme is a pyruvate decarboxylase (PDC).

13. The process according to claim 8 , wherein the enzyme is a lactate dehydrogenase (LDH).

14. The process according to claim 8 , wherein the enzyme is an acetolactate synthase.

15. The process according to claim 12 , wherein acetaldehyde formed by the action of the PDC is removed.

16. The process according to claim 15 , where acetaldehyde is removed by reaction with at least one enzyme.

17. The process according to claim 16 , wherein the enzyme is an alcohol dehydrogenase.

18. The process according to claim 15 , wherein the acetaldehyde is removed by feeding gaseous nitrogen into the reaction mixture.

19. The process according to claim 15 , wherein the acetaldehyde is removed by applying a reduced pressure to the reaction mixture.

20. The process according to claim 15 , wherein the acetaldehyde is removed by chemical methods.

21. The process according to claim 1 , further comprising removing the optically active chiral amine obtained in step c).

22. The process according to claim 1 , wherein the process is carried out in a reaction mixture having a pH from 5.0 to 9.5, preferably 6.0 to 7.0, preferably 6.0 to 6.9.

23. The process according to claim 1 , wherein the process is carried out for a reaction time of 40 to 70 minutes.

24. A process for the preparation of a compound selected from 3-aminopyrrolidone derivatives, the process comprising:
a) providing an amino acceptor and an amino donor,
b) reacting the amino acceptor and the amino donor with a transaminase,
c) obtaining a desired optically active chiral amine and a ketone by-product, and
d) converting the optically active chiral amine to the compound, and
wherein the amino acceptor is N-1-boc-3-oxopyrrolidine.

25. The process according to claim 1 , wherein the amino donor is alanine.

26. The process according to claim 12 , wherein the acetaldehyde formed by the reaction of the PDC is removed by feeding gaseous nitrogen (N 2 ) into the reaction mixture.

27. The process according to claim 12 , wherein the reaction is carried out in the presence of at least one pyruvate decarboxylase and at least one alcohol dehydrogenase.

28. The process according to claim 12 , 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 ).

Assignees

• Lonza Ag

Inventors

• Robins Karen
• Scheuer Uwe
• Hohne Matthias

Classifications

• C12P13/02

  Amides, e.g. chloramphenicol {or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes (peptides C12P21/00 or C07K)} · CPC title

• C12Y206/01018

  Beta-alanine-pyruvate transaminase (2.6.1.18) · CPC title

• C12N9/1096 Primary

  transferring nitrogenous groups (2.6) · CPC title

• C12P13/001

  Amines; Imines · CPC title

• C12P13/22

  Tryptophan; Tyrosine; Phenylalanine; 3,4-Dihydroxyphenylalanine · CPC title