Application of Continuous Flow for DIBAL-H Reduction and n-BuLi Mediated Coupling Reaction in the Synthesis of Eribulin Mesylate
| Autor: | Hirofumi Kuroda, Teiji Takigawa, Hiroyuki Chiba, Katsuya Tagami, Takashi Fukuyama, Akio Kayano |
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| Rok vydání: | 2015 |
| Předmět: |
chemistry.chemical_classification
Eribulin Mesylate 010405 organic chemistry Continuous operation Organic Chemistry 010402 general chemistry 01 natural sciences Aldehyde High-performance liquid chromatography Coupling reaction 0104 chemical sciences Sulfone Reduction (complexity) chemistry.chemical_compound chemistry Yield (chemistry) Organic chemistry Physical and Theoretical Chemistry Nuclear chemistry |
| Zdroj: | Organic Process Research & Development. 20:503-509 |
| ISSN: | 1520-586X 1083-6160 |
| DOI: | 10.1021/acs.oprd.5b00353 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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