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A New and Efficient Synthesis of the HMG‐CoA Reductase Inhibitor Pitavastatin
Author(s) -
Acemoglu Murat,
Brodbeck Andre,
Garcia Angel,
Grimler Dominique,
Hassel Marc,
Riss Bernhard,
Schreiber Robert
Publication year - 2007
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200790106
Subject(s) - pitavastatin , chemistry , amide , hmg coa reductase , reductase , yield (engineering) , side chain , derivative (finance) , combinatorial chemistry , stereochemistry , organic chemistry , statin , enzyme , biochemistry , materials science , economics , financial economics , metallurgy , polymer
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 ).