Resolution of alpha-(phenoxy)phenylacetic acid derivatives
AssigneeMetabolex, Inc.
InventorEdward Daugs
Life of this patent
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Abstract
The present invention provides a method for producing an enantiomerically enriched α-(phenoxy)phenylacetic acid compound of the formula: from its enantiomeric mixture, where R1 is alkyl or haloalkyl and X is halide.
Claims23
A method for producing an enantiomerically enriched α-(phenoxy)phenylacetic acid compound of the formula:
- wherein
- R1 is alkyl or haloalkyl, and
- X is halide;
- from an enantiomeric mixture of the α-(phenoxy)phenylacetic acid compound comprising a first and a second enantiomers, said method comprising:
- (a) producing a solution comprising a solid enantiomerically enriched acid-base salt of the first enantiomer by contacting the enantiomeric mixture of the α-(phenoxy)phenylacetic acid compound with less than 0.5 molar equivalents of an enantiomerically enriched chiral amine compound under conditions sufficient to produce the ratio of the amount of free first enantiomer to the amount of the free second enantiomer in the solution is about 1 to 3;
- and
- (b) separating the solid acid-base salt of the first enantiomer from the solution at a temperature where the concentration of an acid-base salt of the second enantiomer of the α-(phenoxy)phenylacetic acid compound is near or below its saturation point.
A method for enantiomerically enriching (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid from an enantiomeric mixture of 4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid, said method comprising:
- (a) producing a solution comprising an enantiomerically enriched acid-base salt of (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid by contacting the enantiomeric mixture of 4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid with less than 0.5 molar equivalent of an enantiomerically enriched (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol in about 4 grams of an alcoholic solvent per gram of (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenyl acetic acid;
- (b) separating the enantiomerically enriched acid-base salt from the solution which is enriched with (+)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid;
- and
- (c) removing (1R,2R)-2-amino-1-(4-nitrophenyl)-1,3-propanediol from the acid-base salt to produce enantiomerically enriched (−)-4-chloro-α-(3-trifluoromethylphenoxy)phenylacetic acid.
An acid-base salt derived from a α-(phenoxy)phenylacetic acid compound of the formula:
- and a chiral amine compound of the formula:
- wherein
- R1 is alkyl or haloalkyl;
- X is halide;
- each of R2 and R3 is independently hydrogen or alkyl;
- or R2 and R3 together with atoms to which they are attached to form a heterocyclic ring moiety;
- R4 is hydrogen or alkyl;
- each of R5 and R6 is independently hydrogen or alkyl, or one of R5 or R6 is an amine protecting group;
- and
- Ar is aryl.
An enantiomerically enriched (−)-4-chloro-α-(3-trifluoromethyl-phenoxy)phenylacetic acid having an enantiomeric excess of at least about 95%.
A process for enantioselectively producing a α-(phenoxy)phenylacetate compound of the formula:
- said method comprising:
- (a) producing a racemic mixture of a α-(phenoxy)phenylacetic acid of the formula:
- (b) resolving the racemic mixture of the α-(phenoxy)phenylacetic acid using less than 0.5 molar equivalent of an enantiomerically enriched chiral amine compound to produce an enantiomerically enriched α-(phenoxy)phenylacetic acid;
- (c) producing an enantiomerically enriched activated α-(phenoxy)phenyl-acetic acid by contacting the enantiomerically enriched α-(phenoxy)phenylacetic acid with a carboxylic acid activating reagent;
- and
- (d) contacting the enantiomerically enriched activated α-(phenoxy)phenyl-acetic acid with a compound of the formula (R5—O)wM to produce the α-(phenoxy)phenyl-acetate compound, wherein
- R1 is alkyl or haloalkyl;
- X is halide;
- R7 is heteroalkyl;
- M is hydrogen or a metal;
- and
- the subscript w is the oxidation state of M.
Dependencies are inferred from the claim text.