Resolution of immixtures of stereoisomeric alcohols

• US 5,714,642 A
• Filed: 09/05/1995
• Issued: 02/03/1998
• Est. Priority Date: 09/05/1994
• Status: Expired due to Fees

• Current Assignee: Rhone-Poulenc Chimie
• Original Assignee: Rhone-Poulenc Chimie
• Inventors: Didion, Christophe, Petre, Dominique
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US08/523,469
• Time in Patent Office: 882 Days
• Field of Search: 568/810, 568/834, 568/817, 568/829
• US Class Current: 568/810
• CPC Class Codes: C07C 33/20 monocyclic
• CPC Class Codes: C07C 35/12 Menthol
• CPC Class Codes: C07C 35/28 the condensed ring system containing seven carbon atoms
• CPC Class Codes: C07C 67/56 by solid-liquid treatment; by chemisorption
• CPC Class Codes: C11B 9/0015 containing oxygen as the only heteroatom
• CPC Class Codes: C11B 9/0019 carbocylic acids; Salts or esters thereof
• CPC Class Codes: C12P 41/004 by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
• CPC Class Codes: C12P 7/02 containing a hydroxy group

Abstract

Immixture of stereoisomeric alcohols is resolved by selectively enzymatically acylating one of the stereoisomers thereof, in the presence of a catalytically effective amount of a hydrolase, for example a lipase, esterase or acylase, in a biphasic hydroorganic reaction medium, and thence separating the alcohol stereoisomer from the ester stereoisomer thus formed.

Claims

1. A process for the resolution of immixture of stereoisomeric alcohols, comprising selectively enzymatically acylating one of the stereoisomers thereof, in the presence of a hydrolase, in a biphasic hydroorganic reaction medium, and thence separating the alcohol stereoisomer from the ester stereoisomer thus formed.

2. The process as defined by claim 1, said immixture of stereoisomeric alcohols comprising a mixture of enantiomers or positional stereoisomers.

3. The process as defined by claim 2, said immixture of stereoisomeric alcohols comprising a mixture of enantiomers of an alcohol having the formula (I):

space="preserve" listing-type="equation">R--OH (I)

in which R is a hydrocarbon radical having at least 4 carbon atoms comprising a monovalent, substituted or unsubstituted, linear or branched, saturated or unsaturated, acyclic aliphatic radical, or a monocyclic or polycyclic, saturated or unsaturated, carbocyclic or heterocyclic radical, with the proviso that the hydroxy group either may or may not be borne by the asymmetric carbon atom.

4. The process as defined by claim 3, wherein formula (I), R is the residue of a linear or branched, saturated or unsaturated aliphatic chiral alcohol which may be substituted by a cyclic ring member, or of a saturated or unsaturated, monocyclic carbocyclic or heterocyclic chiral alcohol, or of a polycyclic, carbocyclic or heterocyclic chiral alcohol containing at least two saturated and/or unsaturated carbocycles.

5. The process as defined by claim 3, wherein formula (I), R is a linear or branched, saturated or unsaturated, acyclic aliphatic radical.

6. The process as defined by claim 3, wherein formula (I), R is a linear or branched alkyl, alkenyl, alkadienyl or alkynyl radical having from 4 to 40 carbon atoms.

7. The process as defined by claim 3, wherein formula (I), the hydrocarbon chain or backbone of the radical R is interrupted by a heteroatom, or by one of the following groups:

##STR11## and/or bear one of the substituents --OH, --COOR₁, --CHO, --NO₂, --X or CF₃, wherein R₁ is hydrogen or a linear or branched alkyl radical having from 1 to 4 carbon atoms.

8. The process as defined by claim 3, wherein formula (I), R is a linear or branched, saturated or unsaturated, acyclic aliphatic radical optionally substituted by a cyclic substituent bonded thereto by a simple valence bond or via one of the following groups:

##STR12## wherein R₁ is hydrogen or a linear or branched alkyl radical having from 1 to 4 carbon atoms.

9. The process as defined by claim 3, wherein formula (I), R is a saturated or unsaturated monocyclic carbocyclic or heterocyclic radical having from 3 to 8 ring atoms.

10. The process as defined by claim 3, wherein formula (I), R is polycyclic and carbocyclic.

11. The process as defined by claim 3, wherein formula (I), R is polycyclic and heterocyclic.

12. The process as defined by claim 2, said immixture of stereoisomeric alcohols comprising a mixture of stereoisomers of 2-phenyl-1-propanol, 1-phenylethanol, menthol or nortricyclanol.

13. The process as defined by claim 2, said immixture of stereoisomeric alcohols comprising a mixture of positional stereoisomers.

14. The process as defined by claim 13, said immixture of stereoisomeric alcohols comprising a mixture of the stereoisomers of cyclohexanol.

15. The process as defined by claim 2, said immixture of stereoisomeric alcohols comprising a mixture of stereoisomers of 4-tert-butylcyclohexanol, 4-isobornylcyclohexanol or 4-isocamphylcyclohexanol.

16. The process as defined by claim 1, comprising acylating with an ester of an organic acid, or with an organic acid anhydride.

17. The process as defined by claim 16, comprising acylating with an acylation agent having the formula (II):

##STR13## wherein n is a number equal to 1, 2 or 3;

R₁ is a lower alkyl radical; and

if n=1, R₂ is a lower alkyl or alkenyl radical or a --CO--R₃ radical, in which R₃, which may be identical to or different from R₁, has the same definition as R₁, or if n=2, R₂ is a lower alkylene or alkenylene radical, or, if n=3, R₂ is a lower triyl alkyl radical.

18. The process as defined by claim 17, said acylation agent comprising an organic acid ester of formula (II), wherein R₂ is a methyl or vinyl radical, a halogenomethyl radical, a mono-, di- or trihalogenomethyl radical, a methylsulfate radical, or an ethylsulfate radical, when n=1;

a diethylene radical, when n=2;

or a propan-1,2,3-triyl radical, when n=3.

19. The process as defined by claim 17, said acylation agent comprising an organic acid anhydride of formula (II), wherein R₁ and R₃ are identical and are each an alkyl radical having from 1 to 3 carbon atoms.

20. The process as defined by claim 17, said acylation agent comprising triacetin, vinyl acetate or acetic anhydride.

21. The process as defined by claim 1, said hydrolase comprising a lipase, esterase or acylase.

22. The process as defined by claim 21, said hydrolase comprising a carboxylesterase, a triacylglycerol lipase or a triacylglycerol acylase.

23. The process as defined by claim 21, said hydrolase comprising a lipase from an organ of a higher mammal.

24. The process as defined by claim 21, said hydrolase comprising a lipase from the microorganisms Geotricum candidum, Penicillium cyclopium, Penicillium rogueforti, Candida cylindracea, Rhizopus delemar, Rhizopus niveus, Mucor javanicus, Pseudomonas fluorescences, or Pseudomonas species.

25. The process as defined by claim 21, said hydrolase comprising an esterase from pig or horse liver.

26. The process as defined by claim 21, said hydrolase comprising an acylase from a microorganism of the genus Aspergillus.

27. The process as defined by claim 1, the pH of the aqueous phase of said reaction medium being compatible with the activity of the enzyme.

28. The process as defined by claim 1, the organic phase of said reaction medium comprising a water-immiscible organic solvent.

29. The process as defined by claim 28, said organic solvent comprising an aliphatic or aromatic hydrocarbon, an aliphatic or aromatic halogenated hydrocarbon, or an aliphatic, cycloaliphatic or aromatic ether/oxide.

30. The process as defined by claim 28, the ratio by volume between the aqueous phase and the organic phase ranging from 0.1 to 10.

31. The process as defined by claim 28, the amount of enzyme employed ranging from 1% to 10% by weight of the mixture of stereoisomeric alcohols.