Synthesis 2012; 44(11): 1700-1710
DOI: 10.1055/s-0031-1290916
paper
© Georg Thieme Verlag Stuttgart · New York

The Use of a Lactonized Statin Side-Chain Precursor in a Concise and Efficient Assembly of Pitavastatin

Jan Fabris
a   Cadonic Consultancy Services, LL.C., Cesta na postajo 74, 1351 Brezovica pri Ljubljani, Slovenia
b   Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27, 1234 Mengeš, Slovenia
,
Zdenko Časar*
b   Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27, 1234 Mengeš, Slovenia
c   Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia, Fax: +386(1)7237382   Email: zdenko.casar@sandoz.com
,
Ivana Gazić Smilović
b   Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27, 1234 Mengeš, Slovenia
› Author Affiliations
Further Information

Publication History

Received: 16 February 2012

Accepted after revision: 09 March 2012

Publication Date:
26 April 2012 (online)


Abstract

A concise and simple synthetic route to pitavastatin is described. The approach involves a highly stereoselective Wittig olefination reaction between a lactonized statin side-chain precursor and the triphenylphosphonium bromide salt of the corresponding quinoline heterocyclic core. The necessary O-tert-butyl(dimethyl)silyl-protected pitavastatin lactone was obtained in 75% yield and high purity by simple crystallization from aqueous methanol. Subsequent deprotection, hydrolysis, and cation exchange in a one-pot operation provided pitavastatin calcium in 93% yield.

Supporting Information