Process Development and GMP Production of a Potent NAE Inhibitor Pevonedistat

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• 作者：Ian Armitage ; Eric L. Elliott ; Frederick Hicks ; Marianne Langston ; Ashley McCarron ; Quentin J. McCubbin ; Erin O鈥橞rien ; Matt Stirling ; Lei Zhu
• 刊名：Organic Process Research & Development
• 出版年：2015
• 出版时间：September 18, 2015
• 年：2015
• 卷：19
• 期：9
• 页码：1299-1307
• 全文大小：517K
• ISSN：1520-586X

文摘

A practical synthesis of a novel NEDD8-activating enzyme (NAE) inhibitor pevonedistat (MLN4924) is described. Key steps include an enantioselective synthesis of an amino-diol cyclopentane intermediate containing three chiral centers and a novel, regioselective sulfamoylation using N-(tert-butoxycarbonyl)-N-[(triethylenediammonium)sulfonyl]azanide. The linear process, involving six solid isolations, has been carried out in multiple cGMP productions on 15鈥?0 kg scale to produce pevonedistat in 98% (a/a) chemical purity and 25% overall yield.