Process for separating carbinols

Details Process for separating carbinols Process for separating carbinols

1997-08-05

1998-12-15

Ramsuer, Robert W.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D23112

Patent

active

058499318

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/EP96/05596 filed Dec. 4, 1996.
The present invention relates to a new process for separating a carbinol of formula 1 into its enantiomers, as well as the racemization of one of the latter, by performing a sequential process with the object of obtaining the desired enantiomer in high yield. The stereoisomers of 1 are the key compounds for the synthesis of the enantiomers of the compound of formula 2 ##STR1## formula 2, is a compound with analgesic properties, currently in the clinical study phase, described in European Patent EP 289 380. Both Hueso, J. Berrocal, B. Gutierrez, A. J. Farre and J. Frigola, Bioorganic & Medicinal Chemistry Letters, 1993, 3, 269-272!, and the outcome of this has been that the dextrorotatory enantiomer is the more active.
The enantiomers (+)-2 and (-)-2 are obtained, respectively, by alkylation of (+)-1 and (-)-1. The stereoisomer (+)-1 has been obtained in a very low yield from ethyl (R)-mandelate, which has determined in this way the absolute configuration (R)-(+)-1. The enantiomers of 1 have also been obtained by complex processes of separation by column chromatography or of fractional crystallizations of the diastereoisomeric esters formed by reacting 1 with (+)-O-acetylmandelic acid. The yields were 22% for the enantiomer (-)-1 and 25% for the enantiomer (+)-1.
In addition, the use of biocatalysts applied to the separation of racemic synthesis", edited by Stefano Servi, Kluwer Academic Publishers, London, 1992. b) "Enzymes in synthetic organic chemistry" edited by C. H. Wong and G. M. Whitesides, Elsevier Science, Oxford 1994. c) "Biotransformations in Organic Chemistry", edited by K. Faber, Lange and Springer, 1995!.
There are many different classes of enzymes used for the separation of stereoisomers, including hydrolases (especially lipases, proteases and esterases), liases and oxidoreductases. Hydrolases are among the most attractive enzymes to be used in the separations, since they are commercially available at low cost and some of them show a reasonable tolerance to organic solvents.
The use of organic solvents in enzyme-catalyzed reactions has various advantages: a) most organic substrates are more soluble in organic solvents than in water; b) recovery of the reaction products is facilitated to an exceptional extent; c) the enzymes are readily collected to be reused; d) in some cases, the enantioselectivity is high. In spite of the advantages of using enzymes in organic solvents, there are also, however, some disadvantages; a) the search for a suitable solvent; b) the low speed of reaction; c) the decrease in the optical purity of the see: a) A. M. Klibanov, Trends Biochem. Sci., 1989, 14, 141. b) C. S. Chen, C. J. Sih, Angew. Chem. Int. Ed. Engl., 1989, 28, 695!. The conclusive finding that some enzymes can act in organic solvents has been one of the main causes of the spectacular increase, during the last decade, in the use of biotransformations for the preparation of products Collins, G. N. Sheldrake, S. Crosby, "Chirality in Industry", Wiley, London, 1992. b) S. C. Stinson, Chem. & Eng. News, 1994, 38. c) A. L. Margolin, Enzyme Microb. Technol. 1993, 15, 266!.
The subject of the present invention consists in providing a commercially usable process for obtaining the dextrorotatory stereoisomer (R)-(+)-1, which process could also be usable for obtaining the levorotatory stereoisomer (S)-(-)-1.
The process to which the present invention relates is based on biocatalysis, using a biocatalyst to perform selectively a transesterification between the racemic alcohol 1 and an ester of formula 3, in which R.sub.1 represents a methyl or ethyl radical and R.sub.2 represents a vinyl or isopropenyl radical. By means of an enzyme which permits the appropriate stereo-selectivity, it is possible to obtain a reaction mixture which contains the unreacted enantiomer of 1 at the same time as the ester of formula 4, in which R.sub.1 represents a methyl or ethyl radical, formed from the other enantiomer of 1. ##STR2##
The separation and recovery of the un

REFERENCES:
patent: 4963492 (1990-10-01), Keller et al.
Chemical Abstracts, vol. 119, No. 7, Aug. 16, 1993, Abstract No. 72535b, Hueso-Rodriguez, J.A., et al., "Preparation of the enantiomers of the analgesic E-3710", 2 pages.

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