Process for the preparation of atorvastatin and intermediates

Details Process for the preparation of atorvastatin and intermediates Process for the preparation of atorvastatin and intermediates

2006-07-17

2008-09-30

Shiao, Rei-tsang (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S537000

Reexamination Certificate

active

07429613

ABSTRACT:
A process is provided for preparing (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, R-substituted ester 9 comprising:(a) reacting the aldehyde 1 with the enolate form of (S)-2-hydroxy-1,2,2-triphenylethyl acetate substituent in a chelating co-solvent;(b) hydrolysis of (R,S)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid, (S)-2-hydroxy-1,2,2-triphenylethyl ester (2aand 2b) using a base, preferably an alkali metal base, preferably in a solvent to form the carboxylic acid 7;(c) treating the acid 7 with a chiral base to form a salt and purifying the salt to obtain enantiomerically enriched (R)-7 chiral base salt;(d) alkylation of the (R)-7 chiral base salt or the free base derived from (R)-7, forming (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, R-substituted ester 9 and atorvastatin calcium 6,wherein R is a C1 to C6 alkyl, C6 to C9 aryl or C7 to C10 aralkyl.

REFERENCES:
patent: 4681893 (1987-07-01), Roth
patent: 5003080 (1991-03-01), Butler et al.
patent: 5273995 (1993-12-01), Roth
patent: 5298627 (1994-03-01), Butler et al.
Roth, B.D., et al., “Inhibitors of Cholesterol Biosynthesis. 3. Tetrahydro-4-hydroxy-6-[2-(1H-pyrrol-1-yl)ethyl]-2H-pyran-2-one Inhibitors of HMG-CoA Reductase. 2. Effects of Introducing Substituents at Positions Three and Four of the Pyrrole Nucleus”,J. Med. Chem., (1991), 34, 357-366.

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