A Scalable Route for the Regio- and Enantioselective Preparation of a Tetrazole Prodrug: Application to the Multi-Gram-Scale Synthesis of a PCSK9 Inhibitor

被引：15

作者：

Akin, Anne ^{[2
]}

Barrila, Mark T. ^{[2
]}

Brandt, Thomas A. ^{[2
]}

Dechert-Schmitt, Anne-Marie R. ^{[1
]}

Dube, Pascal ^{[3
]}

Ford, David D. ^{[3
]}

Kamlet, Adam S. ^{[1
]}

Limberakis, Chris ^{[1
]}

Pearsall, Andrew ^{[3
]}

Piotrowski, David W. ^{[1
]}

Quinn, Brian ^{[3
]}

Rothstein, Sarah ^{[3
]}

Salan, Jerry ^{[3
]}

Wei, Liuqing ^{[1
]}

Xiao, Jun ^{[1
]}

机构：

[1] Pfizer Inc, Med Design, Eastern Point Rd, Groton, CT 06340 USA

[2] Pfizer Inc, Chem Res & Dev, Eastern Point Rd, Groton, CT 06340 USA

[3] Nalas Engn Serv Inc, 85 Westbrook Rd, Centerbrook, CT 06409 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2017年 / 21卷 / 12期

关键词：

HYDRAZOIC ACID; REDUCING LIPIDS; SAFETY; NITRILES; EFFICACY; AZIDES;

D O I：

10.1021/acs.oprd.7b00304

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

The synthesis of multigram quantities of small molecule PCSK9 inhibitor (R,S)-3 is described. The route features a safe, multikilogram method to prepare 5-(4-iodo-1-methyl-1H-pyrazol-5-yl)-2H-tetrazole (10). A three-component dynamic kinetic resolution between tetrazole 10, acetaldehyde, and isobutyric anhydride was catalyzed by a chiral DMAP catalyst to afford enantiomerically enriched hemiaminal ester (S)-12 on multikilogram scale. Magnesiation, transmetalation, and Negishi coupling provided access to Boc-intermediate (R,S)-13, which was deprotected to provide (R,S)-3 in multigram quantities.

引用

页码：1990 / 2000

页数：11

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