# US 7,465,842 B2 · Enantioselective biotransformation for preparation of protein tyrosine kinase inhibitor intermediates

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- Number: US 7,465,842 B2
- Document ID: US7465842B2
- Status: Granted
- Kind: B2
- Application number: 11/213,025
- Filed: 2005-08-26
- Published: 2006-03-02
- Granted: 2008-12-16
- Earliest claimed: 2004-08-26
- Assignees: Agouron Pharmaceuticals, Inc.
- Inventors: Pei-Pei Kung; Carlos Martinez; Junhua Tao
- Web page: https://patentgrep.com/patent/US7465842B2

## CPC

- C12P 41/004: {by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction}
- C07C 33/46: containing only six-membered aromatic rings as cyclic parts
- C12P 7/22: aromatic
- C07B 2200/07: Optical isomers
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The invention relates to biocatalytic methods for preparing enantiomerically pure stereoisomers of 1-(2,6-dichloro-3-fluorophenyl)ethanol. Disclosed are methods of preparation of the desired (S)-enantiomer, which methods are based on a combination of enzymatic resolution, chemical esterification and chemical hydrolysis with inversion of 1-(2,6-dichloro-3-fluorophenyl)ethyl esters or stereoselective bio-reduction of 2,6-dichloro-3-fluoro-acetophenone with a biocatalyst such as an enzyme or a microorganism. The chiral (S)-enantiomer can be used in the synthesis of certain enantiomerically enriched, ether linked 2-aminopyridine compounds that potently inhibit auto-phosphorylation of human heptocyte growth factor receptor.

## Claims

### Claim 1

(1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol in an enantiomerically pure form.

### Claim 2

(1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol having an enantiomeric purity equal to at least 80%.

### Claim 3 (depends on 2)

(1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol as defined in claim 2 having an enantiomeric purity equal to at least 95%.

### Claim 4 (depends on 2)

(1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol as defined in claim 2 having an enantiomeric purity equal to at least 97%.

### Claim 5

A composition comprising (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol substantially free from its corresponding R-enantiomer.

### Claim 6

A composition comprising (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol that is at least 80% free of (1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol.

### Claim 7 (depends on 6)

The composition as defined in claim 6 comprising (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol that is at least 95% free of(1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol.

### Claim 8 (depends on 6)

The composition as defined in claim 6 comprising (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol that is at least 97% free of(1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol.

### Claim 9 (depends on 1)

A method for preparing the product of claim 1, (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol, comprising the steps of:
contacting of a mixture of enantiomeric 1-(2,6-dichloro-3-fluorophenyl)ethanol esters of formula (I):
wherein R is hydrogen, C1-C20-alkyl, C3-C8-cycloalkyl, C6-C14-aryl, C7-C15-arylalkyl, C1-C20-alkoxy, C1-C20-alkylamino, wherein said hydrocarbon radicals can optionally be monosubstituted or polysubstituted with hydroxyl, formyl, oxy, C1-C6-alkoxy, carboxy, mercapto, sulpho, amino, C1-C6-alkylamino or nitro or halogen,
with an enzyme selected from the group consisting of Amano D (R. delemar lipase), Amano AY (C. rugosa lipase), Amano F (R. oryzae lipase) and pig liver esterase in an aqueous solution, an organic solvent, or a mixture of organic and aqueous solvents wherein only (R)-enantiomer is selectively hydrolyzed to give a mixture of (1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol and a (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester;
converting the mixture of (1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester to (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol; and
recovering (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the converting step comprises:
a) reacting (1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol in the mixture of (1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester with an organic sulfonyl halide in an aprotic solvent to form a mixture of an organic sulfonic acid ester of (1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester;
b) further reacting the organic sulfonic acid ester of (1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol in the mixture of the organic sulfonic acid ester of (1R)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester with an alkali metal salt of an aliphatic carboxylic acid in an aprotic solvent to form a mixture of an aliphatic carboxylic acid ester of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester; and
c) transforming the mixture of the aliphatic carboxylic acid ester of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester into (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the transforming step c) comprises:
solvolyzing the mixture of the aliphatic carboxylic acid ester of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester in an alcoholic or aqueous solvent in the presence of a basic substance to form (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol.

### Claim 12 (depends on 11)

The method according to claim 11, wherein in the transforming step c) the mixture of the aliphatic carboxylic acid ester of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol ester is solvolyzed in methanol in the presence of sodium methoxide to form (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol.

### Claim 13 (depends on 12)

The method according to claim 12, wherein:
R is methyl;
in the reacting step a) the organic sulfonyl halide is methanesulfonyl chloride, the aprotic solvent is pyridine;
in the reacting step b) the alkali metal salt of aliphatic carboxylic acids is potassium acetate, the aprotic solvent is dimethylformamide.

### Claim 14 (depends on 13)

The method according to claim 13, wherein the enzyme is used in an amount of 0.1 to 100 parts by weight based on 100 parts by weight of the mixture of enantiomeric 1-(2,6-dichloro-3-fluorophenyl)ethanol esters.

### Claim 15 (depends on 9)

The method according to claim 9, wherein the contacting step of the mixture of enantiomeric 1-(2,6-dichloro-3-fluorophenyl)ethanol esters with the biocatalyst is carried out in an aqueous solution at 0 to 60° C. with maintenance of pH at 4 to 12.

### Claim 16 (depends on 13)

The method according to claim 13, wherein the biocatalyst is pig liver esterase.