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PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF ATORVASTATIN

IP.com Disclosure Number: IPCOM000225989D
Publication Date: 2013-Mar-19
Document File: 9 page(s) / 76K

Publishing Venue

The IP.com Prior Art Database

Abstract

The present disclosure provides a process for the preparation of (4R-cis)-1,1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrol-1-yl] ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate, an intermediate used for the preparation of atorvastatin.

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PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF ATORVASTATIN

Abstract

The present disclosure provides a process for the preparation of (4R-cis)-1,1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrol-1-yl] ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate, an intermediate used for the preparation of atorvastatin.

Atorvastatin calcium chemically is the calcium salt of [R-(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid (Formula I).

Formula I

It is an inhibitor of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) and is used as a hypolipidemic and hypocholesterolemic agent.

The present disclosure provides a process for preparing (4R-cis)-1,1-dimethylethyl-6-{2-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrol-1-yl] ethyl}-2,2-dimethyl-1,3-dioxane-4-acetate of Formula II;

Formula II

wherein the process comprises treating a compound of Formula III

Formula III

with a compound of Formula IV

Formula IV

in the presence of an amidine base and an organic acid in a solvent.  A compound of Formula III and a compound of Formula IV may be prepared by any method provided in the prior art, for example, as described in U.S. Patent No. 5,003,080 or U.S. Patent No. 7,994,343.  The amidine base may be, for example, 1,8-diazabicycloundec-7-ene or 1,5-diazabicyclo(4.3.0)non-5-ene.  The organic acid may be, for example, pivalic acid, formic acid, acetic acid, or isobutyric acid.  The solvent may be, for example, cyclohexane, toluene, hexane, heptane, ethyl acetate, methyl isobutyl ketone, or mixtures thereof.  The amidine base may be used in the range of about 0.2 to about 1 mole equivalent with respect to the compound of Formula III.  The compound of Formula IV may be used in the range of about 1 to about 1.1 mole equivalents with respect to the compound of Formula III.  The organic acid may be used in the range of about 0.2 to about 1 mole equivalent with respect to the compound of Formula III.  The organic acid may be added to a mixture containing the compound of Formula III, the compound of Formula IV and an amidine base in the solvent.  The mixture may be heated to about 40°C to about 60°C prior to the addition of the organic acid.  The resulting mixture may be stirred under reflux for about 16 hours to about 36 hours with concomitant removal of water.  The compound of Formula II may be isolated from the mixture by methods including layer separation, concentration, distillation, decantation, filtration, evaporation, centrifugation, or combinations thereof, and may be further dried.  The compound of Formula II obtained according to the present disclosure has HPLC purity of 99.5% or more.

The content of the impurity of Formula Va is not more than 0.1% in the compound of Formula II obtained according to the present disclosure.

Formula Va

The content of the impurity of...