Preparation of prasugrel hydrochloride
AssigneeDr. Reddy's Laboratories, Inc.
InventorsRaghupathi Reddy Anumula, Goverdhan Gilla, Sampath Aalla, Dattatray Shamrao Metil, Srinivas Kurella, Kavitha Charagondla
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Abstract
The present application relates to process for the preparation of prasugrel, its pharmaceutically acceptable salts, and its intermediates.
Claims28
1-14. (canceled)
A process comprising:
- a) reacting 5,6,7,7a-tetrahydro-thieno[3,2-c]pyridin-2(4H)-one or a salt thereof with 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone in the presence of an inorganic base and in a solvent to produce 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one;
- b) acetylating in situ the obtained 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one in step a), into prasugrel by treating with an acetylating agent in the presence of an organic base;
- and
- c) optionally converting the prasugrel of step b), into prasugrel hydrochloride in the presence of a source of hydrogen chloride in an organic solvent.
A process for preparing prasugrel or a pharmaceutically acceptable salt thereof, having less than about 0.1% of 5-[(1RS)-2-cyclopropyl-1-(3-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate or any enantiomer of 5-[(1RS)-2-cyclopropyl-1-(3-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate comprising:
- a) purifying 2-fluoro phenyl acetic acid so the concentration of 3-fluoro phenyl acetic acid is less than about 0.1%;
- and
- b) preparing the prasugrel or a pharmaceutically acceptable salt from the 2-fluoro phenyl acetic acid obtained from step a).
A process for preparing prasugrel or a pharmaceutically acceptable salt thereof, having less than about 0.1% of the desfluoro impurity, the 3-fluoro impurity, the 4-fluoro impurity, or any enantiomer of an impurity comprising:
- a) purifying 2-fluoro phenyl acetic acid so the concentration of 3-fluoro phenyl acetic acid, 4-fluoro phenyl acetic acid, 2-phenyl acetic acid is less than about 0.1%;
- and
- b) preparing the prasugrel or its pharmaceutically acceptable salt involving the use of 2-fluoro phenyl acetic acid obtained from step a).
A process comprising:
- a) preparing a solution of prasugrel in a solvent;
- b) adding a solution of hydrogen chloride dissolved in a solvent to the solution of step a);
- c) optionally, adding a seed crystal of prasugrel hydrochloride to the reaction mass prepared in step b);
- d) isolating the precipitated prasugrel hydrochloride;
- and
- e) optionally, purifying prasugrel hydrochloride to obtain a more purified prasugrel hydrochloride.
A process comprising:
- a) measuring the level of 3-fluoro phenyl acetic acid in one or more batches of 2-fluoro phenyl acetic acid;
- b) selecting a batch having less than about 0.1% of 3-fluoro phenyl acetic acid;
- and
- c) synthesizing prasugrel or a salt thereof, having less than 0.1% of 5-[(1RS)-2-cyclopropyl-1-(3-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate from the batch of step b).
A process comprising:
- a) purifying 2-fluorophenyl acetic acid so that the concentration of 3-fluoro phenyl acetic acid is less than about 0.1%;
- b) reacting the pure 2-fluorophenyl acetic acid obtained in step a), with ethyl cyclopropanecarboxylate to provide 1-cyclopropyl-2-(2-fluorophenyl)ethanone;
- and
- c) brominating, with a suitable brominating agent, the 1-cyclopropyl-2-(2-fluorophenyl)ethanone obtained in step b), to provide 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone, having less than about 0.1% of 2-bromo-1-cyclopropyl-2-(3-fluorophenyl)ethanone.
A process comprising:
- a) reacting 2-fluoro phenyl acetic acid with an amine to produce an ammonium salt;
- and
- b) converting the ammonium salt obtained in step a), into 2-fluoro phenyl acetic acid that contains less than 0.1% of 2-phenyl acetic acid, 2-(3-fluorophenyl)acetic acid, or 2-(4-fluorophenyl)acetic acid.
Dependencies are inferred from the claim text.