Development of a Scaleable Process for the Synthesis of a Next-Generation Statin

被引：18

作者：

Hobson, Lindsay A. ^{[1
]}

Akiti, Otute ^{[1
]}

Deshmukh, Subodh S. ^{[1
]}

Harper, Shannon ^{[1
]}

Katipally, Kishta ^{[1
]}

Lai, Chiajen. J. ^{[1
]}

Livingston, Robert C. ^{[1
]}

Lo, Ehrlic ^{[1
]}

Miller, Michael M. ^{[1
]}

Ramakrishnan, Srividya ^{[1
]}

Shen, Lifen ^{[1
]}

Spink, Jan ^{[1
]}

Tummala, Srinivas ^{[1
]}

Wei, Chenkou ^{[1
]}

Yamamoto, Kana ^{[1
]}

Young, John ^{[1
]}

Parsons, Rodney L., Jr. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Dept Chem Proc Res & Dev, New Brunswick, NJ 08903 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2010年 / 14卷 / 02期

关键词：

OLEFINATION; OXIDATION; ALCOHOLS;

D O I：

10.1021/op100010n

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

This manuscript details life process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,4-aminotriazole fragment. A key feature of the synthesis is the use and optimization of a modified Julia-Kocienski olefination reaction. Specifically, we report an unprecedented dependence of the product olefin geometry on reaction temperature, where an E:Z ratio as high as 200:1 can be obtained. Initial insights into the mechanistic rationale for this observation are also provided. Finally, a purity upgrade sequence via an intermediate crystalline form is highlighted is a method of controlling the final API quality.

引用

页码：441 / 458

页数：18

共 31 条

[1] (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(methyl(1-methyl-1H-1,2,4-triazo1-5-yl)amino)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid (BMS-644950):: A rationally designed orally efficacious 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor with reduced myotoxicity potential [J].

Ahmad, Saleem ;

Madsen, Cort S. ;

Stein, Philip D. ;

Janovitz, Evan ;

Huang, Christine ;

Ngu, Khehyong ;

Bisaha, Sharon ;

Kennedy, Lawrence J. ;

Chen, Bang-Chi ;

Zhao, Rulin ;

Sitkoff, Doree ;

Monshizadegan, Hossain ;

Yin, Xiaohong ;

Ryan, Carol S. ;

Zhang, Rongan ;

Giancarli, Mary ;

Bird, Eileen ;

Chang, Ming ;

Chen, Xing ;

Setters, Robert ;

Search, Debra ;

Zhuang, Shaobin ;

Nguyen-Tran, Van ;

Cuff, Carolyn A. ;

Harrity, Thomas ;

Darienzo, Celia J. ;

Li, Tong ;

Reeves, Richard A. ;

Blanar, Michael A. ;

Barrish, Joel C. ;

Zahler, Robert ;

Robl, Jeffrey A. .

JOURNAL OF MEDICINAL CHEMISTRY, 2008, 51 (09) :2722-2733

[2]

ANELLI PL, 1987, J ORG CHEM, V52, P2559

[3]

[Anonymous], COMMUNICATION

[4]

[Anonymous], COMMUNICATION

[5] A DIRECT SYNTHESIS OF OLEFINS BY REACTION OF CARBONYL-COMPOUNDS WITH LITHIO DERIVATIVES OF 2-[ALKYL-SULFONYL OR (2'-ALKENYL)-SULFONYL OR BENZYL-SULFONYL]-BENZOTHIAZOLES [J].

BAUDIN, JB ;

HAREAU, G ;

JULIA, SA ;

RUEL, O .

TETRAHEDRON LETTERS, 1991, 32 (09) :1175-1178

[6]

Biginelli P., 1893, GAZZ CHIM ITAL, V23, P360

[7] The modified Julia olefination:: alkene synthesis via the condensation of metallated heteroarylalkylsulfones with carbonyl compounds [J].

Blakemore, PR .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 2002, (23) :2563-2585

[8]

Blakemore PR, 1998, SYNLETT, P26

[9]

Brodfuehrer P. R., 2002, PCT Patent Appl., Patent No. [WO 2002098854, 2002098854, WO 2,002,098,854]

[10]

Cannizzaro S., 1853, Liebigs Annalen, V88, P129, DOI [10.1002/jlac.18530880114, DOI 10.1002/JLAC.18530880114]

← 1 2 3 4 →