SYNTHESIS OF SYNVINOLIN - EXTREMELY HIGH CONVERSION ALKYLATION OF AN ESTER ENOLATE

被引:36
作者
ASKIN, D
VERHOEVEN, TR
LIU, TMH
SHINKAI, I
机构
[1] Department of Process Research, Merck, Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065
关键词
D O I
10.1021/jo00016a023
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
A efficient process for the commercial preparation of the therapeutically important cholesterol lowering drug synvinolin (2: simvastatin, ZOCOR) from mevinolin (1: lovastatin, MEVACOR) is reported. The synthesis relies upon deactivation of the delta-lactone carbonyl toward enolization via conversion to the bis[(tert-butyldimethylsilyl)oxy] butylamide 7. An extremely high conversion (99.7%) ester enolate alkylation of 7 affords 8 and 9. Subsequent desilylation and intramolecularly assisted basic amide hydrolysis in the presence of the dimethylbutyrate ester moiety yields 12, which is lactonized to 2. The overall yield from 1 to 2 is 86%.
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页码:4929 / 4932
页数:4
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