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

共 23 条

[1]

[Anonymous], 1998, TB 700 2 DEP DEFENSE, P5

[2]

[Anonymous], REC TRANSP DANG GOOD

[3] Organic azides:: An exploding diversity of a unique class of compounds [J].

Bräse, S ;

Gil, C ;

Knepper, K ;

Zimmermann, V .

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2005, 44 (33) :5188-5240

[4] Efficient, protection-free Suzuki-Miyaura synthesis of ortho-biphenyltetrazoles [J].

Cousaert, N ;

Toto, P ;

Willand, N ;

Deprez, B .

TETRAHEDRON LETTERS, 2005, 46 (38) :6529-6532

[5] Preparation of 5-substituted 1H-tetrazoles from nitriles in water [J].

Demko, ZP ;

Sharpless, KB .

JOURNAL OF ORGANIC CHEMISTRY, 2001, 66 (24) :7945-7950

[6] Suzuki-Miyaura Cross-Coupling of Unprotected, Nitrogen-Rich Heterocycles: Substrate Scope and Mechanistic Investigation [J].

Duefert, M. Alexander ;

Billingsley, Kelvin L. ;

Buchwald, Stephen L. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2013, 135 (34) :12877-12885

[7] Development of a Practical Synthesis of Stearoyl-CoA Desaturase (SCD1) Inhibitor MK-8245 [J].

Girardin, Melina ;

Dolman, Sarah J. ;

Lauzon, Sophie ;

Ouellet, Stephane G. ;

Hughes, Greg ;

Fernandez, Paul ;

Zhou, George ;

O'Shea, Paul D. .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2011, 15 (05) :1073-1080

[8] Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor [J].

Gutmann, Bernhard ;

Obermayer, David ;

Roduit, Jean-Paul ;

Roberge, Dominique M. ;

Kappe, C. Oliver .

JOURNAL OF FLOW CHEMISTRY, 2012, 2 (01) :8-19

[9] Boronic Acids and Derivatives-Probing the Structure-Activity Relationships for Mutagenicity [J].

Hansen, Marvin M. ;

Jolly, Robert A. ;

Linder, Ryan J. .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2015, 19 (11) :1507-1516

[10] Why is tetrazole formation by addition of azide to organic nitriles catalyzed by zinc(II) salts? [J].

Himo, F ;

Demko, ZP ;

Noodleman, L ;

Sharpless, KB .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2003, 125 (33) :9983-9987

← 1 2 3 →