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Process for the preparation of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate and intermediates thereof.

IP.com Disclosure Number: IPCOM000199496D
Publication Date: 2010-Sep-07
Document File: 4 page(s) / 76K

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Process for the preparation of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)- 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate and intermediates thereof.

5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-4,5,6,7-tetrahydrothieno[3,2-
c]pyridin-2-yl acetate ('PRS') of the following formula:

N

O

O

O

S

F

is a novel platelet inhibitor from a member of the thienopyridine class of ADP (Adenosine diphosphate) receptor inhibitors. These inhibitors reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors.

    Hereinafter, are described a new processes for the preparation of 1- cyclopropyl-2-(2-fluorophenyl)ethanone of Formula V and 2-halo-1-cyclopropyl-2- (2-fluorophenyl)ethanone of Formula II, intermediates of PRS and a one pot process for the preparation of PRS using this intermediate.

The processes can be described in the following schemes:

O

Sc

h

eme I

O

O

OH

O

N

F

F

HNMe(OMe).HCl

F

Thionyl Chloride

MgBr

IX X

V

Scheme II

O

O

X

F

F

V II

X= halogen, for ex, chlorine, bromine etc.....

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Scheme-III

S

O N

S

O

O

O

O

S

X N

N

O

O

F

    The process for the preparation of 1-cyclopropyl-2-(2-fluorophenyl) ethanone of Formula V, comprises:
a) combining 2-fluorophenyl acetic acid of Formula IX, N,O-dimethyl hydroxylamine, a solvent, and a chlorination reagent to obtain 2-(2-fluorophenyl)-N- methoxy-N-methylacetamide of Formula X.
b) combining the obtained Formula X with a solvent and cyclopropyl magnesium bromide.

Preferably, the chlorination reagent is selected from the group consisting of: thionyl chloride, oxalyl chloride, and pivaloyl chloride. Most preferably, the chlorination reagent is oxalyl chloride or thionyl chloride.

Preferably, the solvent in step a) is selected from the group of: C1-C8 halogenated hydrocarbon, C1-C4 nitrile and C3-C8 ketone. More preferably, the solvent is selected from the group consisting of: methylene chloride, ethylene chloride, chlorobenzene, chloroform, carbon tetrachloride, acetonitrile, acetone, methyl ethyl ketone, and methylisobutyl ketone. Most preferably, the solvent is methylene chloride. Preferably the reaction mixture in step a) is maintained, optionally while stirring, at a temperature of about 30°C to about 80°C. Most preferably, at a temperature of about 40°C to about 60°C. Preferably, the reaction is maintained, optionally while stirring, for about 1 hour to about 10 hours. Most preferably for about 2 hours to about 6 hours.

The resulting Formula X may be recovered by conventional techniques, for example, extracting the reaction mixture with methylene chloride and washing the organic layer with water followed by evaporation of the solvent to obtain an oily product.

Preferably, the solvent in step b) is C3-C8 ether. More preferably, the solvent is selected from the group consisting of: diethyl ether, diisopropyl ether, methyl t-butyl ether and tetrahydrofuran. Most preferably, the solvent is diethyl ether.

Preferably the reaction mixture in step b) is mainta...