Process for preparation of 4-fluoro-α-[2methyl-l-oxopropyl]-γ-oxo—N—β-diphenylbenzene butane amide

摘要

A process for preparation of 4-fluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butane amide also known as a diketone intermediate of atorvastatin, completely devoid of impurities 3,4-difluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-n-β-diphenylbenzene butane amide; methyl, 2{-2[-(4-fluorophenyl)-2-oxo-1-phenylethyl)]}-4-methyl-3-oxo pentanoate; 1,4-bis(4-fluorophenyl)-2,3-diphenylbutane-1,4-dione, 1-(4-fluorophenyl)-2-phenyl ethanone; 1-(4-fluorophenyl)-2-phenyl ethanone and containing about 0.05% or less of 2-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butane amide. In that process the said diketone intermediate of formula 1 is obtained by maintaining temperature −25° C. to 50° C. during Friedel-Crafts acylation, in situ halogenation of formula II in presence of a solvent and nucleophilic substitution from a compound of formula III with formula IV in presence of a base.

主权项

1. A process for controlling impurities during preparation of a compound of formula (I) the processing comprising: performing a Friedel-Crafts condensation of fluorobenzene with phenylacetyl chloride at a reaction temperature ranging from about—10° C. to 0° C. to afford a compound of Formula II; performing a halogenation of said formula II in at least one inert solvent to afford a compound of formula III wherein X is halogen; and performing a nucleophilic substitution of said formula III in a base in a solvent having a compound of formula IV to afford the compound of formula I; wherein said impurities consist of α-[-methyl-1-oxopropyl]-γ-oxo-N-β-diphenylbenzene butan amide, 3,4-difluoro-α-[2-methyl-1-oxopropyl]-γ-oxo-n-β-diphenylbenzene butane amide, 1,4-bis(4-fluorophenyl)-2,3-diphenylbutane-1,4-dione, 2{-2[-(4-fluorophenyl)-2-oxo-1-phenylethyl)]}-4-methyl-3-oxo pentanoate and 1-(4-fluorophenyl)-2-phenyl ethanone.