Process Development and GMP Production of a Potent NAE Inhibitor Pevonedistat

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-butoxycarb...

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Bibliographic Details
Published in:Organic process research & development 2015-09, Vol.19 (9), p.1299-1307
Main Authors: Armitage, Ian, Elliott, Eric L, Hicks, Frederick, Langston, Marianne, McCarron, Ashley, McCubbin, Quentin J, O’Brien, Erin, Stirling, Matt, Zhu, Lei
Format: Article
Language:English
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Summary: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 15–30 kg scale to produce pevonedistat in 98% (a/a) chemical purity and 25% overall yield.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.5b00209