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
1998-11-20
2001-02-13
Barts, Samuel (Department: 1621)
Chemistry: molecular biology and microbiology
Process of utilizing an enzyme or micro-organism to destroy...
Resolution of optical isomers or purification of organic...
C435S128000
Reexamination Certificate
active
06187582
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
Process for preparing optically active amines 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.
BACKGROUND OF THE INVENTION
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. Moreover, a relatively expensive acylation component is necessary.
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.
DETAILED DESCRIPTION OF THE INVENTION
It has now been found that optically active amines of the formula
in which
R represents alkyl having 1 to 10 carbon atoms, halogenoalkyl having 1 to 10 carbon atoms and I to 5 halogen atoms, alkoxyalkyl having 1 to 10 carbon atoms in the alkyl moiety and 1 to 3 carbon atoms in the alkoxy moiety or alkenyl having 2 to 10 carbon atoms, or represents a radical of the formula
—(CH
2
)
m
—R
2
, in which
R
2
represents aryl or aryloxy 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
R
2
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, and
m represents the numbers 0, 1, 2 or 3, and
R
1
represents hydrogen or alkyl, are obtained by
a) reacting, in a first step, racemic amines of the formula
in which
R and R
1
are each as defined above, with esters of the formula
in which
R
3
represents hydrogen, alkyl having 1 to 12 carbon atoms, alkenyl having 2 to 12 carbon atoms, alkinyl having 2 to 12 carbon atoms, halogenoalkyl having I to 10 carbon atoms and 1 to 5 fluorine and/or chlorine atoms, or represents a radical of the formula —CH
2
—C═N or —(CH
2
)
n
—R
5
, in which
R
5
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 and n represents the numbers 0, 1, 2 or 3, or
R
3
represents a radical of the formula —CH
2
—COOR
6
, in which R
6
represents alkyl having 1 to 4 carbon atoms, and
R
4
represents alkyl having 1 to 10 carbon atoms, or represents halogenoalkyl having 1 to 6 carbon atoms and 1 to 5 halogen atoms,
where, however, R
3
does not represent methyl when R
4
represents ethyl, in the presence of hydrolases, 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 R
1
are each as defined above, and acylated (R)-amine of the formula
in which
R, R
1
and R
3
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 R
1
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 an enantioselective amine synthesis is possible even with those esters which do not have an electron-rich heteroatom in the acid moiety in the vicinity of the carbonyl carbon atom. Furthermore, it could not be expected that better results can be obtained by the process according to the invention than by the corresponding reaction using ethyl acetate as acylation component.
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. Furthermore, the acylation components are reasonably priced and readily accessible materials. 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 butyl n-acetate in the presence of lipase from Candida antarctica, the resulting components are separated and the (R)-enantiomer of N-[1-(4-chlorophenyl)-ethylacetamide 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 straight-chain or branched alkyl having 1 to 7 carbon atoms, halogenoalkyl having 1 to 5 carbon atoms and 1 to 5 fluorine and/or chlorine atoms, alkoxyalkyl having 1 to 5 carbon atoms in the alkyl moiety and 1 to 3 carbon atoms in the alkoxy moiety, alkenyl having 2 to 8 carbon atoms, or represents a radical of the formula
—(CH
2
)
m
—R
2
, in which
R
2
preferably represents optionally substituted phenyl of th
Barts Samuel
Bayer Aktiengesellschaft
Gil Joseph C.
LandOfFree
Process for producing optically active amines does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for producing optically active amines, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for producing optically active amines will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2601016