Continuous Process Improvement in the Manufacture of Carfilzomib, Part 2: An Improved Process for Synthesis of the Epoxyketone Warhead

被引：21

作者：

Beaver, Matthew G. ^{[1
]}

Shi, Xianqing ^{[2
]}

Riedel, Jan ^{[1
]}

Patel, Parth ^{[1
]}

Zeng, Alicia ^{[1
]}

Corbett, Michael T. ^{[2
]}

Robinson, Jo Anna ^{[1
]}

Parsons, Andrew T. ^{[1
]}

Cui, Sheng ^{[1
]}

Baucom, Kyle ^{[2
]}

Lovette, Michael A. ^{[2
]}

Icten, Elcin ^{[1
]}

Brown, Derek B. ^{[2
]}

Allian, Ayman ^{[2
]}

Flick, Tawnya G. ^{[2
]}

Chen, Wendy ^{[2
]}

Yang, Ning ^{[1
]}

Walker, Shawn D. ^{[1
]}

机构：

[1] Amgen Inc, Proc Dev, Cambridge, MA 02142 USA

[2] Amgen Inc, Proc Dev, Thousand Oaks, CA 91320 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2020年 / 24卷 / 04期

关键词：

asymmetric epoxidation; continuous manufacturing; carfilzomib; CATALYTIC ASYMMETRIC EPOXIDATION; ENANTIOSELECTIVE EPOXIDATION; REAGENTS; SCALE;

D O I：

10.1021/acs.oprd.0c00052

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

The development and kilogram-scale demonstration of an improved process for the synthesis of the epoxyketone warhead of carfilzomib is described. Critical to the success of this process was: (1) development of a scalable asymmetric epoxidation protocol; (2) identification of a crystalline intermediate with improved physical properties for isolation; (3) discovery and optimization of epimerization conditions to set the target stereochemistry; and (4) introduction of a seeded-bed coaddition crystallization to facilitate isolation of the final low-melting target. The results of kilogram-scale demonstration runs are shared, including details of a continuous process for the safe execution of an exothermic Barbier-type Grignard process.

引用

页码：490 / 499

页数：10

共 26 条

[1]

Beaver M., 2018, Patent No. 2018027021

[2] Asymmetric Epoxidation of α-Substituted Acroleins Catalyzed by Diphenylprolinol Silyl Ether [J].