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PROCESS FOR PREPARATION OF ROSUVASTATIN

IP.com Disclosure Number: IPCOM000223895D
Publication Date: 2012-Dec-05
Document File: 9 page(s) / 116K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure provides a process for the preparation of rosuvastatin and pharmaceutically acceptable salts thereof, employing the intermediate compounds represented by Formulae IV and V. Formula IV Formula V

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PROCESS FOR PREPARATION OF ROSUVASTATIN

Abstract

The present disclosure provides a process for the preparation of rosuvastatin and pharmaceutically acceptable salts thereof, employing the intermediate compounds represented by Formulae IV and V.

       

Formula IV                                                    Formula V

Rosuvastatin calcium, chemically known as bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt, is an HMG-CoA reductase inhibitor which effectively lowers LDL cholesterol and triglyceride levels.

The present disclosure provides a process for the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof comprising the steps of:

a)            condensing N-[4-(4-fluorophenyl)-6-isopropyl-5-({[5-(pyridin-4-yl)-1,3-thiazol-2-

yl]sulfonyl}methyl)pyrimidin-2-yl]-N-methylmethanesulfonamide (Formula V)

Formula V

with tert-butyl (4R,6S)-6-formaldehyde-2,2-dimethyl-1,3-dioxane-4-acetate (Formula VI)

Formula VI

to obtain tert-butyl [(4R,6S)-6-{(E)-2-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-isopropylpyrimidin-5-yl]ethenyl}-2,2-dimethyl-1,3-dioxan-4-yl]acetate (Formula VII); and

Formula VII

b)      converting the compound of Formula VII of step (a) into rosuvastatin or a  pharmaceutically acceptable salts thereof.

The present disclosure also provides a process for the preparation of rosuvastatin or pharmaceutically acceptable salt thereof comprising the steps of:

a)      converting N-[4-(4-fluorophenyl)-6-isopropyl-5-({[5-(pyridin-4-yl)-1,3-thiazol-2-yl]sulfanyl}methyl)pyrimidin-2-yl]-N-methylmethanesulfonamide (Formula IV)

Formula IV

to N-[4-(4-fluorophenyl)-6-isopropyl-5-({[5-(pyridin-4-yl)-1,3-thiazol-2-yl]sulfonyl}methyl)pyrimidin-2-yl]-N-methylmethanesulfonamide (Formula V); and

b)         converting the compound of Formula V of step (a) to rosuvastatin or a pharmaceutically acceptable salt thereof.

The compound of Formula IV can be prepared by reacting a mixture of N-[4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide (Formula II) and diphenylchlorophosphate with 5-(pyridin-4-yl)-1,3-thiazole-2-thiol (Formula III) in presence of a base and a solvent.

                                

Formula II                                                     Formula III

As used herein, the term “pharmaceutically acceptable salt” refers to alkali metals (e.g., lithium, sodium, potassium or cesium), alkaline earth metals (e.g., beryllium, magnesium or calcium), ammonium, or amine salts.  The pharmaceutically acceptable salt can be crystalline, semi crystalline or amorphous in nature.

As used herein, the term “amine salt” refers to a salt of a primary amine (e.g., methyl amine, ethyl amine, n-propyl amine or n-butyl amine), a secondary ami...