Process for the preparation of optically active amines

Details Process for the preparation of optically active amines Process for the preparation of optically active amines

1998-06-01

2002-05-14

Saucier, Sandra (Department: 1651)

Chemistry: molecular biology and microbiology

Process of utilizing an enzyme or micro-organism to destroy...

Resolution of optical isomers or purification of organic...

Reexamination Certificate

active

06387692

ABSTRACT:

The present invention relates to a novel process for preparing known, optically active amines which can be employed as intermediates for preparing pharmaceuticals and crop protection agents. Moreover, the invention relates to novel optically active acylated amines.
It is already known from DE-A 4 332 738 that optically active, primary and secondary amines can be prepared by initially enantioselectively acylating racemic amine in the presence of a hydrolase using an ester which has an electron-rich heteroatom in the acid moiety in the vicinity of the carbonyl carbon atom, then separating the resulting mixture of optically active (S)-amine and optically active acylated (R)-amine (=amide), thereby affording the (S)-amine, and obtaining the other enantiomer, if desired, from the acylated (R)amine by amide cleavage. Suitable hydrolases are lipases from Pseudomonas, for example Amano P, or from Pseudomonas spec. DSM 8246. The degree of optical purity of the enantiomers that are obtained is very high. However, this process has the disadvantages that relatively long reaction times are required for the enzymatic acylation and that the reaction is carried out in highly dilute solution. Only after relatively long reaction times is the remaining (S)-enantiomer obtained in sufficiently high optical yield. For practical purposes, the space-time yields that can be achieved are therefore inadequate. It is a further disadvantage that relatively high amounts of enzyme are required with respect to the substrate. Besides, the enzyme has very high activity, so that purification, concentration and work-up requires considerable effort.
Furthermore, Chimica 48, 570 (1994) discloses that racemic amines will react enantioselectively with ethyl acetate in the presence of lipase from
Candida antarctica
to give mixtures of (S)-amine and acetylated (R)-amine (=amide) from which (S)-amine and acetylated (R)-amine can be isolated, it being possible to set free the acetylated (R)-amine by subsequent amide cleavage. Disadvantages of this method are that once more relatively long reaction times are required and that furthermore the yields are not always satisfactory. In addition, the ratio of enzyme to substrate is again so disadvantageous that an economical utilization of the process is scarcely possible.
It has now been found that optically active amines of the formula
in which
R represents aryl which is optionally mono- to trisubstituted by identical or different substituents, but where the positions of the aryl group which are adjacent to the linking point do not carry any substituents, or
 represents optionally benzo-fused heteroaryl which is optionally mono- to trisubstituted by identical or different substituents, but where the positions of the heteroaryl group which are adjacent to the linking point do not carry any substituents, or
 represents alkyl having 1 to 7 carbon atoms, halogenoalkyl having 1 to 7 carbon atoms and 1 to 5 halogen atoms or alkoxyalkyl having 1 to 7 carbon atoms in the alkyl moiety and 1 to 3 carbon atoms in the alkoxy moiety, and
m represents the numbers 0, 1, 2 or 3,
are obtained by
a) reacting, in a first step, racemic amines of the formula
in which
R and m are each as defined above,
with esters of the formula
 in which
R
1
represents alkyl having 1 to 10 carbon atoms or represents halogenoalkyl having 1 to 6 carbon atoms and 1 to 5 halogen atoms,
R
2
represents hydrogen, alkyl having 1 to 10 carbon atoms, halogenoalkyl having 1 to 6 carbon atoms and 1 to 5 halogen atoms or represents phenyl which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, amino, hydroxyl, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, phenyl and phenoxy,
X represents oxygen, sulphur or an -NR
3
- group in which
R
3
represents alkyl having 1 to 4 carbon atoms, and
n represents the numbers 0, 1, 2 or 3,
 in the presence of lipase from Candida antarctica and, if appropriate, in the presence of a diluent,
b) separating, in a second step, the resulting mixture of (S)-amine of the formula
in which
R and m are each as defined above,
and acylated (R)-amine of the formula
 in which
R, R
2
, X, m and n are each as defined above, and
c) if appropriate, setting free, in a third step, the (R)-amine of the formula
in which
R and m are each as defined above,
from the acylated (R)-amine of the formula (III) by treatment with acid or base, if appropriate in the presence of a diluent.
(R)-amines are understood to mean those optically active compounds of the formula (I) which exhibit the (R) configuration at the asymmetrically substituted carbon atom. Correspondingly, (S)-amines are understood to mean those optically active compounds of the formula (I) which exhibit the (S) configuration at the chiral centre. In the formulae, the asymmetrically substituted carbon atom is in each case indicated by (*).
It is extremely surprising that optically active amines of the formula (I*) can be prepared in high yield and very good optical purity by the process according to the invention. From the known prior art, it could not be foreseen that the specific use of lipase from Candida antarctica effects a high enantioselectivity and a faster reaction in the reaction between amine and ester than the enzyme systems used hitherto in similar processes.
The process according to the invention enjoys a number of advantages. Thus, it makes possible the preparation of a large number of optically active amines in high yield and excellent optical purity. It is also favourable that the reaction can be carried out at relatively high substrate concentration and that the reaction times are short. It is therefore possible to achieve space-time yields which are satisfactory even for practical purposes. It is a further advantage that the biocatalyst required is available in relatively large amounts and that it is stable even at elevated temperatures. In terms of the amount of enzyme relative to the substrate, the biocatalyst is employed in a relatively low amount and low enzyme activity. Finally, no difficulties are involved in carrying out the reaction and isolating the desired substances, namely either the (S)- or the (R)-amines.
If racemic 1-(4-chlorophenyl)-ethylamine is reacted with methyl methoxyacetate in the presence of lipase from Candida antarctica, the resulting components are separated and the (R)-enantiomer of N-[1-(4-chlorophenyl)ethyl]-methoxyacetamide is treated with hydrochloric acid, the course of the process according to the invention can be illustrated by the equation that follows.
The formula (I) provides a general definition of the racemic amines required as starting materials for carrying out the process according to the invention.
R preferably represents optionally substituted phenyl of the formula
in which
 R
4
, R
5
and R
6
independently of one another each represent hydrogen, halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, halogenoalkyl having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, halogenoalkoxy having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, cyano, dialkylamino having 1 to 4 carbon atoms in each alkyl group, nitro, phenyl, phenoxy or benzyl, or
R represents naphthyl which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, halogenoalkyl having 1 to 4 carbon and 1 to 5 identical or different halogen atoms, alkoxy having 1 to 4 carbon atoms and halogenoalkoxy having 1 to 4 carbon atoms and 1 to 5 identical or different halogen atoms, but where the positions ortho to the carbon atom through which the naphthyl radical is bonded are unsubstituted, or
R represents optionally benzo-fused heteroaryl having 5 or 6 ring members and 1 to 3 heteroatoms, such as nitrogen, oxygen and/or sulphur, in the heterocycle, where these radicals may be mono- to trisubstituted b

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