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

共 50 条

[1] Highly Diastereoselective Synthesis of a HCV NS5B Nucleoside Polymerase Inhibitor
Zhong, Yong-Li
Cleator, Ed
Liu, Zhijian
Yin, Jianguo
Morris, William J.
Alam, Mahbub
Bishop, Brian
Dumas, Aaron M.
Edwards, John
Goodyear, Adrian
Mullens, Peter
Song, Zhiguo Jake
Shevlin, Michael
Thaisrivongs, David A.
Li, Hongming
Sherer, Edward C.
Cohen, Ryan D.
Yin, Jingjun
Tan, Lushi
Yasuda, Nobuyoshi
Limanto, John
Davies, Antony
Campos, Kevin R.
JOURNAL OF ORGANIC CHEMISTRY, 2019, 84 (08): : 4780 - 4795
[2] Discovery of an irreversible HCV NS5B polymerase inhibitor
Zeng, Qingbei
Nair, Anilkumar G.
Rosenblum, Stuart B.
Huang, Hsueh-Cheng
Lesburg, Charles A.
Jiang, Yueheng
Selyutin, Oleg
Chan, Tin-Yau
Bennett, Frank
Chen, Kevin X.
Venkatraman, Srikanth
Sannigrahi, Mousumi
Velazquez, Francisco
Duca, Jose S.
Gavalas, Stephen
Huang, Yuhua
Pu, Haiyan
Wang, Li
Pinto, Patrick
Vibulbhan, Bancha
Agrawal, Sony
Ferrari, Eric
Jiang, Chuan-kui
Li, Cheng
Hesk, David
Gesell, Jennifer
Sorota, Steve
Shih, Neng-Yang
Njoroge, F. George
Kozlowski, Joseph A.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (24) : 6585 - 6587
[3] Diastereoselective synthesis of a purine phosphoramidate prodrug inhibitor of HCV NS5B polymerase
Zhang, Hai-Ren
Reddy, P. Ganapati
Ross, Bruce S.
Rachakonda, Suguna
Sofia, Michael J.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2011, 242
[4] HCV NS5B polymerase inhibitors
Watkins, William J.
Ray, Adrian S.
Chong, Lee S.
CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT, 2010, 13 (04) : 441 - 465
[5] HCV NS5B Polymerase Inhibitors
Burton, James R., Jr.
Everson, Gregory T.
CLINICS IN LIVER DISEASE, 2009, 13 (03) : 453 - +
[6] Quinolones as HCV NS5B polymerase inhibitors
Kumar, Dange V.
Rai, Roopa
Brameld, Ken A.
Somoza, John R.
Rajagopalan, Ravi
Janc, James W.
Xia, Yu M.
Ton, Tony L.
Shaghafi, Michael B.
Hu, Huiyong
Lehoux, Isabelle
To, Nhat
Young, Wendy B.
Green, Michael J.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (01) : 82 - 87
[7] Efficient and stereoselective synthesis of PSI-6130: Potent inhibitor of HCV NS5B polymerase
Wang, Peiyuan
Chun, Byoung-Kwon
Rachakonda, Suguna
Du, Jinfa
Khan, Noshena
Shi, Junxing
Stec, Wojciech J.
Cleary, Darryl
Ross, Bruce S.
Sofia, Michael J.
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2009, 238
[8] A randomized, placebo-controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1
Tatum, H.
Thuluvath, P. J.
Lawitz, E.
Martorell, C.
DeMicco, M.
Cohen, S.
Rustgi, V.
Ravendhran, N.
Ghalib, R.
Hanson, J.
Zamparo, J.
Zhao, J.
Cooney, E.
Treitel, M.
Hughes, E.
JOURNAL OF VIRAL HEPATITIS, 2015, 22 (08) : 658 - 664
[9] In Silico Studies of Crystal Structure of HCV NS5B Polymerase and Inhibitor Complex
Tiwari, Gargi
Pandey, Vishnudatt
Tiwari, Rakesh Kumar
Ojha, Rajendra Prasad
MATERIALS TODAY-PROCEEDINGS, 2018, 5 (07) : 15431 - 15438
[10] Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B Polymerase: Phenylboronate as a Transient Protecting Group
Mayes, Benjamin A.
Arumugasamy, Jeevanandam
Baloglu, Erkan
Bauer, David
Becker, Alan
Chaudhuri, Narayan
Latham, G. Mark
Li, Jie
Mathieu, Steve
McGarry, F. Patrick
Rosinovsky, Elodie
Stewart, Alistair
Trochet, Christophe
Wang, Jingyang
Moussa, Adel
ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2014, 18 (06) : 717 - 724

← 1 2 3 4 5 →