Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Patent
1998-11-10
2000-03-21
Barts, Samuel
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
564307, C07B 5700
Patent
active
060404795
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The present invention concerns an improved process for the resolution of racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone (ketamine).
Pharmacological investigations show clear qualitative and quantitative differences between the R- and S-ketamine enantiomers. Not only preclinically but also in a clinical study, S-ketamine always behaves better than the antipode or the racemate. From these points of view, the exclusive therapeutic use of the enantiomer is to be preferred, as to the resolution of the racemate. Therefore, in the following, the S-enantomer is always meant which as salt is present in the S-(+)-configuration and as pure base in the S-(-)-configuration.
From German published specification DE-A-2 062 620 is known a process for the resolution of racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone in which racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone is reacted with the use of an enantiomeric form of tartaric acid in a solvent mixture of water and acetone, the tartaric acid salt formed is isolated by filtration and subsequent double recrystallisation with acetonitrile, whereupon one isomer is liberated from the tartaric acid salt by reaction with alkali. However, the process suffers from poor yields, the use of toxic solvents, impure products and the necessity of having to carry out many process steps.
Therefore, it was the task of the present invention to provide an improved process for the resolution of racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone in which the above difficulties do not occur.
Consequently, the subject of the present invention is a process for the resolution of racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone of the formula: ##STR1## wherein * signifies an asymmetrical carbon atom, which comprises the following steps:
1) reaction of racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone with an enantiomeric form of tartaric acid,
2) isolation of the formed tartaric acid salt of 2-(o-chlorophenyl)-2-methylaminocyclohexanone and
3) reaction of the isolated tartaric acid salt of 2-(o-chlorophenyl)-2-methylaminocyclohexanone with alkali, whereby an isomer of 2-(o-chlorophenyl)-2-methylaminocyclohexanone can be isolated, alcohol and/or ketone, ether or ester. ##STR2##
In the scope of the process according to the present invention, racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone is reacted in a first step with an enantiorneric form of tartaric acid with the formation of a tartaric acid salt of 2-(o-chlorophenyl)-2-methylaminocyclohexanone. As solvent in this reaction, there are used water or a mixture of water and an organic solvent selected from the group consisting of straight-chained or branched C.sub.1 -C.sub.6 -alcohols and/or ketones, esters or ethers, preferably isopropanol and/or acetone. Water or a mixture of water and isopropanol or a mixture of water or acetone is preferably used. In the case of using a mixture of water and isopropanol, the ratio of water:isopropanol is preferably 1.5:1. In the case of using a mixture of water and acetone, the ratio of water:acetone is preferably 1:0.33-5.0 and especially 1:3. Other organic solvents which can also be considered include, for example, methanol, ethanol, n-propanol, butanol, t-butanol, pentanol, hexanol, methyl ethyl ketone, dimethyl ketone, propyl methyl ketone and/or ethyl acetate.
In a second step, the formed tartaric acid salt of 2-(o-chlorophenyl)-2-methylaminocyclohexanone is isolated, this preferably taking place by filtration. In the case of using a mixture of water and acetone in a ratio of 1:10-20, the tartaric acid salt formed is, preferably after an isolation for the further enrichment of an enriched tartrate of an isomer of 2-(o-chlorophenyl)-2-methylaminocyclohexanone from the solvent mixture used in step, recrystallised from water and acetone. In the case of the use of water or of a mixture of water and isopropanol or of a mixture of water and acetone in a ratio of 1:0.33-5.0 as solvent, a recrystallisation of the isolated tartaric acid salt of 2-(o-chlorophenyl)-2-me
Gangkofner Stefan
Grunenwald Jean-Marie
Steiner Klaus
Anderson Elizabeth M.
Barts Samuel
Cu Chemie Uetikon GmbH
Goedecke Aktiengesellschaft
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