The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor

被引：35

作者：

Bien, Jeffrey ^{[1
]}

Davulcu, Akin ^{[1
]}

DelMonte, Albert J. ^{[1
]}

Fraunhoffer, Kenneth J. ^{[1
]}

Gao, Zhinong ^{[1
]}

Hang, Chao ^{[1
]}

Hsiao, Yi ^{[1
]}

Hu, Wenhao ^{[1
]}

Katipally, Kishta ^{[1
]}

Littke, Adam ^{[1
]}

Pedro, Aghogho ^{[1
]}

Qiu, Yuping ^{[1
]}

Sandoval, Maria ^{[1
]}

Schild, Richard ^{[1
]}

Soltani, Michelle ^{[1
]}

Tedesco, Anthony ^{[1
]}

Vanyo, Dale ^{[1
]}

Vemishetti, Purushotham ^{[1
]}

Waltermire, Robert E. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Chem & Synthet Dev, One Squibb Dr,POB 191, New Brunswick, NJ 08903 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2018年 / 22卷 / 10期

关键词：

asymmetric; cyclopropanation; direct arylation; palladium; rhodium; catalysis; HEPATITIS-C VIRUS; REDUCTIVE ALKYLATION; INDOLES; DISCOVERY; RECEPTOR;

D O I：

10.1021/acs.oprd.8b00214

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

The process development and kilogram-scale synthesis of beclabuvir (BMS-791325, 1) is described. The convergent synthesis features the use of asymmetric catalysis to generate a chiral cyclopropane fragment and coupling with an indole fragment via an alkylation. Subsequent palladium-catalyzed intramolecular direct arylation efficiently builds the central seven-membered ring. The target was prepared in 12 linear steps with five isolations in an overall yield of 8%.

引用

页码：1393 / 1408

页数：16

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