Process for preparing amorphous rosuvastatin calcium free of impurities

Abstract

A pure amorphous form of rosuvastatin calcium having purity of more than 99.5%, preferably a purity of more than 99.8%, more preferably a purity of more than 99.9% as determined by HPLC area percentage, and free from any traces of alkali metal impurities is disclosed. A process of preparing said pure amorphous form of rosuvastatin calcium is disclosed, which comprises hydrolysis of C1-C5 alkyl esters of rosuvastatin, preferably terf-butyl ester of rosuvastatin, with an organic nitrogen base, e.g. guanidines, amidines, amines and quaternary ammonium hydroxides, in the presence of water, optionally containing aprotic solvent, following the conversion of thus obtained rosuvastain salt with a source of calcium to desired rosuvastatin calcium, which is then isolated. An alternative process is disclosed, which comprises the conversion of numerous novel ammonium salts of rosuvastatin, preferably tert-octylammonium salt of rosuvastatin, with the source of calcium to desired commercial rosuvastatin calcium. Rosuvastatin calcium is HMG CoA reductase, useful in the treatment of hyperlipidemia, hypercholesterolemia and atherosclerosis.

Description

technical field [0001] The present invention relates to a method for preparing amorphous rosuvastatin calcium substantially free of alkali metal impurities via rosuvastatin ammonium salt as an intermediate compound. Background technique [0002] Rosuvastatin is (+)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl) administered as calcium salt in therapy Amino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-heptenoic acid is the generic name of a commercial drug, and represented by Formula 1 below, said compound is 3-hydroxy-3- The inhibitor of methylglutaryl-coenzyme A reductase (HMG CoA reductase) can be used for treating hyperlipidemia, hypercholesterolemia and atherosclerosis. The synthesis of rosuvastatin and rosuvastatin calcium was first described in EP-B-521471 patent; in the last two steps of the whole synthesis, it is obtained as follows: in a polar solvent such as ethanol, in the presence of a base such as hydrogen In the presence of sodium oxide, hydrolysis ...

AI Technical Summary

Problems solved by technology

In fact, the preparation of rosuvastatin sodium salt, which may be an intermediate in the preparation of rosuvastatin calcium salt, may not be reproducible both in terms of yield and physical state, depending on reaction conditions and solvent evaporation , while the latter is difficult to control

International application WO 2005 / 23778 attempts to avoid said problem by extracting impurities from an aqueous solution of rosuvastatin sodium salt into a water-immiscible solvent without isolating rosuvastatin sodium salt, but by using C 1 -C 4 Alcohol as a reaction medium still presents the danger of transformation into specific impurities

That is, β-hydroxyacids are known to dehydrate in alcoholic alkaline solutions, possibly resulting in specific by-products after re-alkoxylation (see Scheme 1, where R and R 1 Independence means C 1 -C 5 Alkyl), O-alkyl derivatives of rosuvastatin, such as O-ethyl rosuvastatin

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