Practical asymmetric synthesis of efavirenz (DMP 266), an HIV-1 reverse transcriptase inhibitor

被引:207
作者
Pierce, ME [1 ]
Parsons, RL
Radesca, LA
Lo, YS
Silverman, S
Moore, JR
Islam, Q
Choudhury, A
Fortunak, JMD
Nguyen, D
Luo, C
Morgan, SJ
Davis, WP
Confalone, PN
Chen, CY
Tillyer, RD
Frey, L
Tan, LS
Xu, F
Zhao, DL
Thompson, AS
Corley, EG
Grabowski, EJJ
Reamer, R
Reider, PJ
机构
[1] Dupont Merck Pharmaceut Co, Chem Proc R&D Dept, Proc Res Facil, Deepwater, NJ 08023 USA
[2] Merck & Co Inc, Merck Sharp & Dohme Res Labs, Dept Proc Res, Rahway, NJ 07065 USA
关键词
D O I
10.1021/jo981170l
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
A highly enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz (1) is described. The synthesis proceeds in 62% overall yield in seven steps from 4-chloroaniline (6) to give efavirenz (1) in excellent chemical and optical purity. A novel, enantioselective addition of Li-cyclopropyl acetylide (4a) top-methoxybenzyl-protected ketoaniline 3a mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a) establishes the stereogenic center in the target with a remarkable level of stereocontrol.
引用
收藏
页码:8536 / 8543
页数:8
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