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PREPARATION OF (3R)-3-AMINO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYRIC ACID ETHYL ESTER AND METHYL ESTER

IP.com Disclosure Number: IPCOM000201788D
Publication Date: 2010-Nov-23
Document File: 2 page(s) / 80K

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PREPARATION OF (3R)-3-AMINO-4-(2,4,5-TRIFLUOROPHENYL)-BUTYRIC ACID ETHYL ESTER AND METHYL ESTER

3(R)-amino-1-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazin-7-yl)- 4-(2,4,5-trifluorophenyl)butan-1-one phosphate, is a glucagon-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor.

Provided is a process for preparing intermediates of 3(R)-amino-1-(3-(trifluoromethyl)- 5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)pyrazin-7-yl)-4-(2,4,5-trifluorophenyl)butan-1- one phosphate:

3-Oxo-4-(2,4,5-trifluorophenyl)-butyric acid, ethyl ester and 3-Oxo-4-(2,4,5- trifluorophenyl)-butyric acid, methyl ester were converted to (3R)-3-Amino-4-(2,4,5- trifluorophenyl)-butyric acid ethyl ester and (3R)-3-Amino-4-(2,4,5-trifluorophenyl)- butyric acid methyl ester respectively by using developed transaminase enzyme.

The reaction conditions were:
Total volume: 100 μl
50 mM potassium phosphate buffer, pH 7.4
1 mM pyridoxal-phosphate (PLP)
5 mM each substrate (from a 10% stock solution in methanol)
500 mM isopropylamine
enzyme as whole cells from 100 μl culture
Incubate at 30°C with shaking for several hours (usually overnight).


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Mutant

(3R)-3-Amino-4-(2,4,5- trifluorophenyl)-butyric acid ethyl ester

(3R)-3-Amino-4-(2,4,5- trifluorophenyl)-butyric acid ethyl ester

% conversion after 3.5h

%conversion after 22h

%ee (R) % conversion after 3.5h

%conversion after 22h

%ee (R)

1 77.9 100.0 -95.1 70.3 99.0 -90.2

2 88.3 99.0 -98.1...