Ranbaxy Laboratories, Inc.

S M Kumar

Yatendra Kumar

Rajesh Kumar Thaper

Jag Mohan Khanna

Satyananda Misra

A novel process of lactonizaton in the preparation of statins (e.g., the HMG--CoA reductase inhibitors lovastatin and simvastatin) employs very mild reaction conditions. The improved process comprises dissolving the open ring hydroxy acid form of the statins in an organic solvent by heating at a temperature, which ranges from ambient to reflux of the solvent, under anhydrous conditions to produce a solution, treating the solution with a mild catalyst at a temperature from about ambient to 50.degree. C., and adding water to the solution to cause the statins in lactone form to crystalize from the reaction mixture. The mild catalyst used in the reaction is a salt of an organic base with an organic or inorganic acid, such as pyridine hydrobromide, pyridine hydrochloride, or pyridinium, p-toluene sulfonate. The organic solvent comprises a lower alkanol, a non-alcoholic polar solvent, or a mixture of the two.

Process of lactonization in the preparation of statins

An improved process of lactonization in the preparation of statins (e.g., the HMG--CoA reductase inhibitors lovastatin and simvastatin) employs very mild reaction conditions. The improved process comprises treating the open ring hydroxy acid form of the statins with an excess of acetic acid and in the absence of a strong acid catalyst under mild heating conditions (e.g., ambient to 55.degree. C.), and adding an anti-solvent to the reaction mixture, thereby causing the statins in lactone form to crystalize from the reaction mixture. The acetic acid serves as both a solvent and a catalyst for the lactonization reaction.

A process for preparing simvastatin from lovastatin or mevinolinic acid in salt form comprises treating either starting material with cyclopropyl or butyl amine, the pyranone ring thereby being opened when lovastatin is the starting material, adding a methyl group to the 2-methylbutyrate side chain, and thereafter closing the open pyranone ring to produce simvastatin. The process is performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring. In a preferred embodiment, the starting material is treated with cyclopropyl amine which produces simvastatin via the novel intermediate lovastatin cyclopropyl amide.

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New Delhi, India

S M Kumar