Synthesis and Process Optimization of Boceprevir: A Protease Inhibitor Drug

被引：15

作者：

Bhalerao, Dinesh S. ^{[1
]}

Arkala, Anil Kumar Reddy ^{[1
]}

Madhavi, Y. V. ^{[1
]}

Nagaraju, M. ^{[1
]}

Gade, Srinivas Reddy ^{[1
]}

Kumar, U. K. Syam ^{[1
]}

Bandichhor, Rakeshwar ^{[1
]}

Dahanukar, Vilas H. ^{[1
]}

机构：

[1] Dr Reddys Labs Ltd, IPD, R&D, Qutubullapur 500073, Andhra Pradesh, India

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2015年 / 19卷 / 11期

关键词：

HEPATITIS-C; UREAS; INTERFERON-ALPHA-2B; CARBONYLATION; COMBINATION; DISCOVERY; RIBAVIRIN; AGENT;

D O I：

10.1021/op500065t

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

Efforts toward the synthesis and process optimization of boceprevir 1 are described. Boceprevir synthesis was optimized by telescoping the first three steps and last two steps of the five-step process. Optimization of oxidation, which is one of the critical steps in the total synthesis, is discussed: A control strategy for the three impurities is described. A novel process for the synthesis of fragment A (2) has been developed, which is the key starting material for the synthesis of boceprevir.

引用

页码：1559 / 1567

页数：9

共 29 条

[1] Toward the Back-Up of Boceprevir (SCH 503034): Discovery of New Extended P4-Capped Ketoamide Inhibitors of Hepatitis C Virus NS3 Serine Protease with Improved Potency and Pharmacokinetic Profiles [J].

Bogen, Stephane L. ;

Pan, Weidong ;

Ruan, Sumei ;

Nair, Latha G. ;

Arasappan, Ashok ;

Bennett, Frank ;

Chen, Kevin X. ;

Jao, Edwin ;

Venkatraman, Srikanth ;

Vibulbhan, Bancha ;

Liu, Rong ;

Cheng, Kuo-Chi ;

Guo, Zhuyan ;

Tong, Xiao ;

Saksena, Anil K. ;

Girijavallabhan, Viyyoor ;

Njoroge, F. George .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (12) :3679-3688

[2] A novel synthesis of isocyanates and ureas via β-elimination of haloform [J].

Braverman, S ;

Cherkinsky, M ;

Kedrova, L ;

Reiselman, A .

TETRAHEDRON LETTERS, 1999, 40 (16) :3235-3238

[3] Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C [J].

Davis, GL ;

Esteban-Mur, R ;

Rustgi, V ;

Hoefs, J ;

Gordon, SC ;

Trepo, C ;

Shiffman, ML ;

Zeuzem, S ;

Craxi, A ;

Ling, MH ;

Albrecht, J .

NEW ENGLAND JOURNAL OF MEDICINE, 1998, 339 (21) :1493-1499

[4]

Dener J. M., 2009, [No title captured], Patent No. [WO200939361 A2, 200939361]

[5] Transition metal-catalyzed oxidative carbonylation of amines to ureas [J].

Diaz, Delmy J. ;

Darko, Ampofo K. ;

McElwee-White, Lisa .

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2007, 2007 (27) :4453-4465

[6] Characterization of Human Liver Enzymes Involved in the Biotransformation of Boceprevir, a Hepatitis C Virus Protease Inhibitor [J].

Ghosal, Anima ;

Yuan, Yuan ;

Tong, Wei ;

Su, Ai-Duen ;

Gu, Chunyan ;

Chowdhury, Swapan K. ;

Kishnani, Narendra S. ;

Alton, Kevin B. .

DRUG METABOLISM AND DISPOSITION, 2011, 39 (03) :510-521

[7] Nitroxide TEMPO: A genotoxic and oxidative stress inducer in cultured cells [J].

Guo, Xiaoqing ;

Mittelstaedt, Roberta A. ;

Guo, Lei ;

Shaddock, Joseph G. ;

Heflich, Robert H. ;

Bigger, Anita H. ;

Moore, Martha M. ;

Mei, Nan .

TOXICOLOGY IN VITRO, 2013, 27 (05) :1496-1502

[8] Synthesis of carbamates and ureas using Zr(IV)-catalyzed exchange processes [J].

Han, Chong ;

Porco, John A., Jr. .

ORGANIC LETTERS, 2007, 9 (08) :1517-1520

[9] Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis [J].

Heathcote, EJ ;

Shiffman, ML ;

Cooksley, WGE ;

Dusheiko, GM ;

Lee, SS ;

Balart, L ;

Reindollar, R ;

Reddy, RK ;

Wright, TL ;

Lin, A ;

Hoffman, J ;

De Pamphilis, J .

NEW ENGLAND JOURNAL OF MEDICINE, 2000, 343 (23) :1673-1680

[10]

Hiroaki K., 2010, [No title captured], Patent No. [EP2221294 A1, 2221294]

← 1 2 3 →