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Application of Continuous Flow for DIBAL-H Reduction and n-BuLi Mediated Coupling Reaction in the Synthesis of Eribulin Mesylate

By Fukuyama, Takashi; Chiba, Hiroyuki; Kuroda, Hirofumi; Takigawa, Teiji; Kayano, Akio; Tagami, Katsuya

Published on CMKC

Abstract

Here we examined the use of continuous flow conditions for the final assembly of eribulin mesylate aimed to avoid cryogenic condition. The diisobutylaluminum hydride reduction of ester 2 to aldehyde 3 and n-butyllithium-mediated coupling of aldehyde 3 and sulfone fragment 4 to produce sulfone-diol 5 were investigated. Under optimized continuous flow conditions, both reactions could be run at temperatures higher than those used under batch conditions. For the diisobutylaluminum hydride reduction of ester 2 to aldehyde 3, under optimized continuous flow conditions at −50 °C, aldehyde 3 was afforded with better HPLC area ratio than it was under batch conditions at −70 °C. Furthermore, continuous operation for 87 min afforded the same quality of 3 as was produced with a short-time operation (yield, 96.5%). For the n-butyllithium-mediated coupling of 3 and 4, under optimized continuous flow conditions at 10 °C, 5 was afforded with a better conversion rate than it was under batch conditions at −70 °C.

Journal

Organic Process Research & Development. Volume 20, 2016, 503-509

DOI

10.1021/acs.oprd.5b00353

Type of publication

Peer-reviewed journal

Affiliations

  • Eisai Co. Ltd.

Article Classification

Research article

Classification Areas

  • API

Tags