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. Austada, Trevor L. Calkinsa, Charles E. Chasea, Francis G. Fang*a, Thomas E. Horstmanna, Yongbo Hua, Bryan M. Lewisa, Xiang Niua, Thomas A. Nolanda, John D. Orra, Matthew J. Schnaderbecka, Huiming Zhanga, Naoki Asakawab, Naoki Asaib, Hiroyuki Chibab, Takashi Hasebeb, Yorihisa Hoshinob, Hiroyuki Ishizukab, Takashi Kajimab, Akio Kayanob, Yuki Komatsub, Manabu Kubotab, Hirofumi Kurodab, Mamoru Miyazawab, Katsuya Tagamib, Tomohiro Watanabeb
  • aPharmaceutical 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
  • bPharmaceutical Science & Technology, Eisai Product Creation Systems, Eisai Co., Ltd., 22 Sunayama, Kamisu-Shi, Ibaraki 314-0255, Japan
Further Information

Publication History

Received: 13 November 2012

Accepted after revision: 18 December 2012

Publication Date:
10 January 2013 (eFirst)

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®.

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