Synlett 2013; 24(3): 333-337
DOI: 10.1055/s-0032-1318026
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© Georg Thieme Verlag Stuttgart · New York

Commercial Manufacture of Halaven®: Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones

Brian C. Austad
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Trevor L. Calkins
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Charles E. Chase
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Francis G. Fang*
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Thomas E. Horstmann
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Yongbo Hu
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Bryan M. Lewis
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Xiang Niu
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Thomas A. Noland
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
John D. Orr
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Matthew J. Schnaderbeck
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Huiming Zhang
a  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Inc., 4 Corporate Drive, Andover, MA 01810-2441, USA   Fax: +1(978)6889886   Email: Frank_Fang@eri.eisai.com
,
Naoki Asakawa
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Naoki Asai
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Hiroyuki Chiba
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Takashi Hasebe
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Yorihisa Hoshino
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Hiroyuki Ishizuka
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Takashi Kajima
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Akio Kayano
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Yuki Komatsu
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Manabu Kubota
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Hirofumi Kuroda
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Mamoru Miyazawa
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Katsuya Tagami
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
,
Tomohiro Watanabe
b  Pharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
› Author Affiliations
Further Information

Publication History

Received: 13 November 2012

Accepted after revision: 18 December 2012

Publication Date:
10 January 2013 (online)


Abstract

The evolution of the synthesis of Halaven® (E7389, INN eribulin mesylate) from a medicinal chemistry process to the execution of the final process on pilot scale is described. The completion of the synthesis of Halaven® from C1–C13 ester and C14–C35 sulfone alcohol involves a series of chemo-, regio-, and stereoselective transformations. Furthermore, a high-dilution macrocyclization presented a number of challenges for industrial-scale manufacture (throughput, processing time, and side reactions). This paper describes studies at Eisai leading to an understanding, optimization, and control of the chemistry that realized the reproducible commercial production of Halaven®.

Supporting Information

Primary Data

 
  • References and Notes


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    • Ion-exchange-resin-based protocol is reported for effective construction of Halaven®/halichondrin C8–C14 polycyclic ring system:
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