Method for preparing atorvastatin calcium using new intermediates and resulting atorvastatin

NOVELTY – The atorvastatin calcium preparation method involves reacting methyl 4-methyl-3-oxopentanoate with excess aniline in presence of a catalyst to give 4-methyl-3-oxo-N-phenylpentanamide. 4-Methyl-3-oxo-N-phenylpentanamide is condensed with benzoic aldehyde in presence of catalyst to give 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide. 2-Benzylidene-4-methyl-3-oxo-N-phenylpentanamide is reacted with 4-fluorobenzaldehyde in presence of a catalyst and a base to obtain 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide. USE – Method for preparing atorvastatin calcium. DETAILED DESCRIPTION – The atorvastatin calcium preparation method involves reacting methyl 4-methyl-3-oxopentanoate with excess aniline in presence of a catalyst to give 4-methyl-3-oxo-N-phenylpentanamide. 4-Methyl-3-oxo-N-phenylpentanamide is condensed with benzoic aldehyde in presence of catalyst to give 2-benzylidene-4-methyl-3-oxo-N-phenylpentanamide. 2-Benzylidene-4-methyl-3-oxo-N-phenylpentanamide is reacted with 4-fluorobenzaldehyde in presence of a catalyst and a base to obtain 2-(2-(4-fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide. 2-(2-(4-Fluorophenyl)-2-oxo-1-phenylethyl)-4-methyl-3-oxo-N-phenylpentanamide is treated with 3-amino-1-propanol in presence of a catalyst to obtain (5-(4-fluorophenyl)-1-(3-hydroxypropyl))-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide. (5-(4-Fluorophenyl)-1-(3-hydroxypropyl))-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide is oxidized in presence of oxalyl chloride, dimethyl sulfoxide and triethylamine to obtain 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide. (L)-malic acid is esterified with methanol in presence of a catalyst to provide (S)-dimethyl malate. (S)-Dimethyl malate is reduced by using borane-methyl sulfide complex and sodium borohydride in regioselective manner to give a diol ester. Diol ester is employed directly in a reaction cattle for catalyzation with 2,2-dimethoxypropane in presence of a catalyst to provide (S)-methyl 2-(2,2-dimethyl-1,3-dioxolan-4-yl) compound. (S)-Methyl 2-(2,2-dimethyl-1,3-dioxolan-4-yl) compound is reacted with methylmagnesium chloride to provide (S)-1-(2,2-dimethyl-1,3-dioxolan-4-yl)propan-2-one. (S)-1-(2,2-Dimethyl-1,3-dioxolan-4-yl)propan-2-one is treated with chlorodicyclohexylborane, where the reaction medium is cooled, and then 5-(4-fluorophenyl)-2-isopropyl-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is added into the cooled medium to give 1-((R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxy-5-oxo-hexyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide. 1-((R)-6-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-hydroxy-5-oxo-hexyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide is reduced in presence of methoxydiethylborane and sodium borohydride to provide 1-((3R,5R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,5-dihydroxyethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-dipheny-1H-pyrrole-3-carboxamide. 1-((3R,5R)-6-((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3,5-dihydroxyethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-dipheny-1H-pyrrole-3-carboxamide is hydrolyzed in presence of acid to obtain 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-((3R,7S)-3,5,7,8-tetrahydroxyoctyl)-1H-pyrrole-3-carboxamide. The cleavage of 5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1-((3R,7S)-3,5,7,8-tetrahydroxyoctyl)-1H-pyrrole-3-carboxamide is performed with sodium periodate to give 1-(2-((2R,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide. 1-(2-((2R,4R)-4,6-Dihydroxytetrahydro-2H-pyran-2-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide is oxidized selectively in presence of manganese dioxide to obtain 5-(4-fluorophenyl)-1-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide. 5-(4-Fluorophenyl)-1-(2-((2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl)ethyl)-2-isopropyl-N,4-diphenyl-1H-pyrrole-3-carboxamide is treated with sodium hydroxide, potassium hydroxide or lithium hydroxide, preferably sodium hydroxide to obtain a salt. The obtained salt is treated with calcium acetate to obtain atorvastatin calcium. An INDEPENDENT CLAIM is included for a method for preparing statin.

Main Application Field

B03 (Other heterocyclics.)

INVENTORS:

DIAS LUIZ CARLOS
VIEIRA ADRIANO SIQUEIRA
BARREIRO ELIEZER JESUS DE LACERDA

470_ATORVASTATINA

Patent number: WO2012145808-A1;BR201101952-A2

PATENT STATUS:

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