Atorvastatin, an HMG-COA reductase inhibitor and effective lipid-regulating agent. Part II. Synthesis of side-chain-labeled [14C]atorvastatin

Abstract

[14C]Atorvastatin was synthesized in a ten-step sequence with an overall yield of 5.7%. The label was introduced as sodium [1-14C]acetate, which was converted via the acid chloride to the (S)-2-hydroxy-1,2,2-triphenylethyl ester 4. Chiral condensation of 4 with aldehyde 5 gave the chiral ester intermediate 6 with a yield of about 70%. Following transesterification of 6 to a methyl ester and condensation with tert-butyl lithioacetate to give (R)-β-ketoester 8, a second chiral center was generated by reduction of the hydroxyketone 3, giving the (R,R)-dihydroxy ester 9, which was then converted via the acid to the lactone 11. The desired pure diastereomer 11, obtained from the mother liquor during crystallization, was then converted to the corresponding calcium salt (2:1) 13 (atorvastatin). Copyright © 1999 John Wiley & Sons, Ltd.