A New and Efficient Synthesis of the HMG‐CoA Reductase Inhibitor Pitavastatin

Abstract

Abstract A new synthetic method for the preparation of pitavastatin is described. The approach circumvents various synthetic problems associated with the buildup of the 3,5‐dihydroxy‐C 7 acid side chain of HMG‐CoA reductase inhibitors (statins). The use of the C 6 ‐amide derivative 5 instead of ester derivatives in the coupling reaction with carboxaldehyde 8 ( Scheme 3 ) prevents undesired side reactions, such as eliminations and retro ‐aldol reactions. The method provides synthetic statins, such as pitavastatin, in >99% ee and exceptionally high overall yield. The enantiomerically pure starting material, (3 S )‐3‐{[( tert ‐butyl)dimethylsilyl]oxy}‐5‐oxo‐5‐{[(1 S )‐1‐phenylethyl]amino}pentanoic acid ( 3c ), is prepared by an improved procedure from 3‐{[( tert ‐butyl)dimethylsilyl]oxy}glutaric anhydride ( 1 ) and (1 S )‐1‐phenylethylamine ( 2c ; Scheme 1 ).