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Synfacts 2010(6): 0619-0619  
DOI: 10.1055/s-0029-1219846
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of BMS-644950

Contributor(s):Philip Kocienski
L. A. Hobson*, Jr. et al. R. L. Parsons *
Bristol-Myers Squibb Company, New Brunswick, USA
Development of a Scaleable Process for the Synthesis of a Next-Generation Statin
Org. Process Res. Dev.  2010,  14:  441-458  
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Publication History

Publication Date:
20 May 2010 (online)

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Key words

BMS-644950 - HMG-CoA reductase inhibitors - statins - Biginelli reaction - pyrimidines - Julia-Kocienski olefination

Significance

BMS-644950 is a development candidate for the treatment of hypercholestero­lemia. The route depicted delivered >70 kg of the API in 35% overall yield. The synthesis is ­noteworthy for the large-scale TEMPO oxidation (H → I, 83 mol scale) and Julia-Kocienski olefination (A + B → C, 78 mol scale).

Comment

The Julia-Kocienski olefination was performed by adding LiHMDS to a mixture of the aldehyde I and the sulfone J in THF at -70 ˚C (Barbier conditions). In this way the E-alkene product was obtained with high stereoselectivity (E/Z up to 200:1). Note the use of dimethyl carbonate and DABCO for the N-alkylation of G.

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