Diastereomeric purification of rosuvastatin
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsValerie Niddam-Hildesheim, Natalia Shenkar, Kobi Chen, Anna Balanov
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Abstract
The invention relates to diastereomerically pure rosuvastatin and processes for preparing diastereomerically pure rosuvastatin and its intermediates.
Claims73
A rosuvastatin intermediate of the following structure:
- wherein R1 is a C1-C4 alkyl group, having diastereomeric impurities of less than about 0.37%, as measured by area percentage HPLC.
A process for preparing a rosuvastatin intermediate diol ester having the structure
- wherein R1 is a carboxy protecting group, comprising:
- a) combining MeO-9-BBN with an organic solvent and a source of hydride ions;
- b) adding to said combination a solution of a rosuvastatin keto-ester in an organic solvent, wherein the rosuvastatin keto-ester has the following formula:
- wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and R1 is a carboxy protecting group, to obtain a reaction mixture;
- c) maintaining the reaction mixture to obtain the diol ester.
A one pot process for preparing rosuvastatin or a pharmaceutically acceptable salt thereof comprising:
- a) combining MeO-9-BBN with an organic solvent and a source of hydride ions;
- b) adding to said combination a solution of a rosuvastatin intermediate keto-ester in an organic solvent, wherein the rosuvastatin intermediate keto-ester has the following formula:
- wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and R1 is a carboxy protecting group, to obtain a reaction mixture;
- c) maintaining the reaction mixture to reduce the intermediate;
- and
- d) converting the reduced intermediate to rosuvastatin or a pharmaceutically acceptable salt thereof.
A process for preparing an intermediate diol ester having the structure
- wherein R1 is a carboxy protecting group comprising the steps of:
- a) combining Diethylmethoxy borane (DEMB) with an organic solvent and a source of hydride ions;
- b) adding to said combination a solution of a rosuvastatin keto-ester in an organic solvent, wherein the rosuvastatin keto-ester has the following formula:
- wherein X is hydrogen or forms a double bond to provide a ketone, with the proviso that at least one X forms a double bond, and R1 is a carboxy protecting group, to obtain a reaction mixture, wherein the total amount of the solvent from the keto ester-solution and the solvent that is combined with the DEMB is about 30 to about 80 volumes (ml per gram of keto ester) in the reaction mixture;
- and
- c) maintaining the reaction mixture.
The process of 21, wherein the source of hydride ions is present in an amount of about 2.7 equivalents (per gram of keto ester).
The process of 23, wherein the reaction mixture is maintained for about 0.5-3 hours.
A process for increasing the diastereomeric purity of rosuvastatin diol-ester of the formula:
- comprising crystallizing the diol-ester from a solvent selected from the group consisting of:
- C1-C4 alcohols, C3-C8 esters, C3-C8 ketones, C3-C8 ethers, C6 to C10 aromatic hydrocarbons, PGME (propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof.
A process for increasing the diastereomeric purity of rosuvastatin diol-ester of the formula:
- comprising slurrying the diol-ester in a solvent selected from the group consisting of:
- C1-C4 alcohols, C3-C8 esters, C3-C8 ketones, C3-C8 ethers, C6 to C10 aromatic hydrocarbons, PGME (propylene glycol monomethyl ether), water, acetonitrile, and mixtures thereof.
A process for preparing a pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof, wherein the process comprises converting t-butyl rosuvastatin ester having less than about 0.3% diastereomeric impurities, as measured by area percentage HPLC, to rosuvastatin or a pharmaceutically acceptable salt thereof, and combining the rosuvastatin with a pharmaceutically acceptable excipient.
A pharmaceutical composition comprising rosuvastatin or a pharmaceutically acceptable salt thereof prepared by converting t-butyl rosuvastatin ester having less than about 0.3% diastereomeric impurities, as measured by area percentage HPLC, to rosuvastatin or a pharmaceutically acceptable salt thereof, and combining the rosuvastatin with a pharmaceutically acceptable excipient.
Dependencies are inferred from the claim text.