Process for preparing optically active amines

Details Process for preparing optically active amines Process for preparing optically active amines

1997-08-25

1999-03-23

Dees, Jose' G.

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving luciferase

564302, 564303, 564304, 564463, 435 27, 435 22, C10Q 134, C07C20900, C07C21100, C07B 5700

Patent

active

058857877

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a novel process for preparing (R)-amines by the enzymic hydrolysis of N-acylamine racemates.
It has already become known to prepare optically active N-p-aminophenyl-acetylamino derivatives by the enzymic cleavage of the corresponding racemates using benzylpenicillin acylase as biocatalyst (cf. J. Org. Chem. 44 2222 2225 (1979). However, a disadvantage of this process is that the optical yields are very low in some cases. In addition, the (S)-enantiomer of the starting racemate is preferentially hydrolysed in this method. Thus, for example, the (R)-enantiomer of N-p-amino-1-phenylacetyl-1-phenethylamine and the free (S)-amine are formed from the corresponding racemate. A further disadvantage is that the biocatalyst reacts in a very substrate-specific manner and only those compounds which contain a phenylacetyl group can be employed.
It is furthermore known that (S)-amines and (R)-enantiomers can be prepared from N-acylated 1-methyl-1-phenyl-alkylamines by means of converting racemates of N-acyl-1-methyl-1-phenyl-alkylamines using particular biocatalysts (cf. EP-A 0 399 589). This process suffers from the disadvantage that the corresponding (R)-amines can only be obtained if the (R)-enantiomers of the N-acyl-1-methyl-1-phenyl-alkylamines are deacylated in an additional reaction step.
It has now been found that (R)-amines of the formula ##STR3## in which R.sup.1 represents optionally substituted alkyl, cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, where, however, R.sup.1 and R.sup.2 are not identical, and ##STR4## in which R.sup.1, R.sup.2 and n have the abovementioned meanings, and substituted alkyl or optionally substituted alkoxy, where the carbon chain in those radicals which contain more than one carbon atom can be interrupted by heteroatoms or heteroatom groups, or substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl, N-acyl-amines of the formula (II), in the presence of water and optionally in the presence of an organic diluent, at a pH of between 3.0 and 10.0 and at temperatures of between 0.degree. C. and 80.degree. C.
(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. In the formula (I), the asymmetrically substituted carbon atom is indicated by (*)
It is extremely surprising that (R)-amines can be prepared. by the process according to the invention, since the state of the art has hitherto only disclosed that (S)-amines can be obtained from racemates of N-acylamines using biocatalysts.
The process according to the invention enjoys a number of advantages. Thus, it enables (R)-amines of the formula (I) to be prepared in extremely high optical purity. It is also advantageous that the N-acylamines which are required as starting compounds are readily accessible and that the acyl radical can be varied over a wide range. Finally, no difficulties are involved, either, in implementing the reaction and isolating the desired substances.
In the present case, unless otherwise defined, alkyl represents saturated aliphatic hydrocarbon radicals which can be straight-chain or branched.
In the present case, unless otherwise defined, cycloalkyl represents saturated carbocyclic radicals which optionally form a bicyclic or polycyclic ring system with other fused or bridged rings.
In the present case, unless otherwise defined, cycloalkenyl represents unsaturated carbocyclic radicals which optionally form a bicyclic or polycylic ring system with other fused or bridged rings.
In the present case, unless otherwise defined, aryl represents aromatic, monocyclic, bicyclic or polycyclic hydrocarbon radicals such as, for example, phenyl, naphthyl, anthranyl or phenanthryl, preferably phenyl or naphthyl, in particular phenyl.
In the present case, unless otherwise defined, heterocyclyl represents saturated or unsaturated cyclic radicals in which at least one ring member is

REFERENCES:
Rossi, J. Org. Chem., vol. 44, No. 13, 1979, "Approach to the Use of Benzylpenicillinacylase for configurational Coorelations of Amino Compounds . . . " 2222-2225.
Ogawa, Bioorganic & Medicinal Chemistry, vol. 2, No. 2, pp. 429-432, 1994, Enzymatic Asymmetric Synthesis of .alpha.-Methyl Arylalkylalcohols by Arylalkyl Acylamidases.
Margolin, A.L., Synthesis of Optically Pure Mechanism-Based Inhibitors of .gamma.-Aminobutyric Acid Aminotransferase (GABA-T) via Enzyme-Catalyzed Resolution, Tetrahedron Lett., 34, 1239-42, 1993.

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