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US 7,612,203 B2Granted
Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof
AssigneeTeva Pharmaceutical Industries Ltd.
InventorsValerie Niddam-Hildesheim, Anna Balanov, Natalia Shenkar
Life of this patent
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Abstract
The present invention provides rosuvastatin and intermediates thereof having a low level of alkylether impurity and processes for the preparation thereof.
Claims24
A process of preparing the compound of formula I having the structure:
- comprising the steps of:
- a) combining a compound of formula IV:
- wherein R is a carboxyl protecting group, with a C1-C5 alcohol to obtain a solution;
- b) cooling the solution at a temperature of about −10° C. to about 30° C.;
- c) combining the solution of step b) with a solution of methanesulfonic acid in a C1-C5 alcohol:water mixture having a ratio of about 6 to about 30 (v/v) to obtain a reaction mixture;
- and
- d) heating the reaction mixture at a maximum temperature of about 35° C. to obtain the compound of Formula I.
4 more elements
A process of preparing a compound of formula II-ether having the structure:
- comprising converting the compound of formula I-ether
- wherein R is a carboxyl protecting group that is not methyl ester and R1 is a C1-C8 linear or branched alkyl, into the compound of Formula II-ether.
A process of obtaining a compound of formula II having the structure:
- wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl;
- having about 0.02% to about 1.5% area by HPLC of a compound of formula II-ether having the structure:
- wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl;
- said process comprising:
- a) combining the compound of formula II
- with an organic solvent selected from the group consisting of aromatic hydrocarbons, C1-C5 alcohols, esters, ketones, ethers, C5-C8 linear or branched hydrocarbons, nitrites, mixtures thereof, and mixtures of any of these with water, to obtain a reaction mixture;
- b) heating the reaction mixture at a temperature of about 25° C. to about 110° C. to obtain a solution;
- c) cooling the solution to a temperature of about −10° C. to about 20° C. to obtain a precipitate;
- and
- d) recovering the compound of Formula II.
7 more elements
A process for preparing rosuvastatin and salts thereof having about 0.02% to about 0.2% area by HPLC of Rosu-alkylether of the structure:
- wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, said process comprising
- a) combining a compound of formula II:
- wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl, with an organic solvent selected from the group consisting of aromatic hydrocarbons, C1-C5 alcohols, esters, ketones, ethers, C5-C8 linear or branched hydrocarbons, nitrites, mixtures thereof, and mixtures of any of these with water, to obtain a reaction mixture;
- b) heating the reaction mixture at a temperature of about 25° C. to about 110° C. to obtain a solution;
- c) cooling the solution to a temperature of about −10°0 C. to about 20° C. to obtain a precipitate;
- and
- d) recovering the compound of Formula II;
- and
- e) converting the recovered compound into rosuvastatin or a salt thereof.
6 more elements
A process of preparing the compound of formula III-ether having the structure:
- wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation;
- said process comprising converting the compound of formula II-ether
- wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl, into the compound of formula III-ether.
A process for preparing Rosuvastatin or salts thereof having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether having the structure:
- wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, said process comprising the steps of:
- a) obtaining one or more samples of one or more batches of the compound of formula I
- wherein R is a carboxyl protecting group that is not methyl ester;
- b) measuring the level of the compound of formula I-ether:
- wherein R is a carboxyl protecting group that is not methyl ester and R1 is a C1-C8 linear or branched alkyl in each of the samples;
- c) selecting a batch from step a) having a level of the compound of formula I-ether, in an amount of about 0.02% to about 0.2% area by HPLC, based on the measurement of the samples from the batches;
- and
- d) preparing Rosuvastatin having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether using the selected batch.
5 more elements
A process for preparing Rosuvastatin having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether having the structure:
- wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, said process comprising the steps of:
- a) obtaining one or more samples of one or more batches of the compound of formula II
- wherein R is a carboxyl protecting group;
- b) measuring the level in each of the samples of the compound of formula II-ether having the structure:
- wherein R is a carboxyl protecting group, and R1 is a C1-C8 linear or branched alkyl;
- c) selecting a batch from step a) having a level of the compound of formula II-ether of about 0.02% to about 0.2% area by HPLC, based on the measurement of the samples from the batches;
- and
- d) preparing Rosuvastatin having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether using the selected batch.
5 more elements
A process for preparing a pharmaceutical formulation comprising Rosuvastatin having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether having the structure:
- wherein R1 is a C1-C8 linear or branched alkyl, and M is H or a metal cation, said process comprising the steps of:
- a) obtaining one or more samples of one or more batches of Rosuvastatin;
- b) measuring the level of the compound of formula III-ether in each of the samples;
- c) selecting a batch of Rosuvastatin having a level of the compound of formula III-ether of about 0.02% to about 0.2% area by HPLC, based on the measurement of the samples from the batches;
- d) preparing Rosuvastatm having about 0.02% to about 0.2% area by HPLC of the compound of formula III-ether using the selected batch;
- and
- e) preparing a formulation comprising the Rosuvastatin prepared in step d).
4 more elements
Dependencies are inferred from the claim text.