Overcoming the Challenges of Making a Single Enantiomer N-1 Substituted Tetrazole Prodrug Using a Tin-Mediated Alkylation and Enzymatic Resolution

被引：6

作者：

Akin, Anne ^{[1
]}

Barilla, Mark T. ^{[1
]}

Brandt, Thomas A. ^{[1
]}

Brennan, John ^{[1
]}

Henegar, Kevin E. ^{[1
]}

Hoagland, Steve ^{[1
]}

Kumar, Rajesh ^{[1
]}

Magano, Javier ^{[1
]}

McInturff, Emma L. ^{[1
]}

Nematalla, Asaad ^{[1
]}

Piotrowski, David W. ^{[2
]}

Van Haitsma, Jared ^{[3
]}

Wei, Liuqing ^{[2
]}

Xiao, Jun ^{[2
]}

Yu, Shu ^{[1
]}

机构：

[1] Pfizer Worldwide Res & Dev, Chem Res & Dev, Eastern Point Rd, Groton, CT 06340 USA

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

[3] Pfizer Worldwide Res & Dev, Res Analyt, Eastern Point Rd, Groton, CT 06340 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2019年 / 23卷 / 06期

关键词：

PCSK9; inhibitor; N-1 tetrazole alkylation; enzymatic resolution; tin-mediated alkylation; Suzuki coupling; REDUCING LIPIDS; NITROGEN BONDS; INHIBITORS; EFFICACY; SAFETY;

D O I：

10.1021/acs.oprd.9b00104

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

The synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor 3 is described. This complex structure contains a tetrazole modified by a chiral hemiaminal carbonate prodrug. A regioselective tin-mediated alkylation was utilized to access the N-1 alkylated tetrazole isomer, and a highly selective enzymatic hydrolysis efficiently provided the desired prodrug enantiomer. A Suzuki-Miyaura coupling was employed for the final fragment union, which was challenging due to base sensitivity of the prodrug. This route was enabled and used to manufacture multikilogram quantities of API 3 in an efficient manner.

引用

页码：1167 / 1177

页数：11

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