Investigating Scale-Up and Further Applications of DABAL-Me3 Promoted Amide Synthesis

Methods for the batch scale up of DABAL-Me3 promoted direct ester to amide synthesis have been demonstrated at 10–100 g scales using a tert-amide model compound. Procedures for 20 g scale couplings in standard laboratory glassware and up to 0.1 kg in industry-standard jacketed glass reactors in near...

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Bibliographic Details
Published in:	Organic process research & development
Main Authors:	Lee, Darren S, Amara, Zacharias, Poliakoff, Martyn, Harman, Thomas, Reid, Gary, Rhodes, Barrie, Brough, Steve, McInally, Thomas, Woodward, Simon
Format:	Journal Article
Language:	English
Published:	American Chemical Society 17-07-2015
Online Access:	Get full text
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Summary:	Methods for the batch scale up of DABAL-Me3 promoted direct ester to amide synthesis have been demonstrated at 10–100 g scales using a tert-amide model compound. Procedures for 20 g scale couplings in standard laboratory glassware and up to 0.1 kg in industry-standard jacketed glass reactors in near quantitative yields are given. A derivative of the anticancer agent Imatinib (Gleevec) has been synthesized on a 26 g scale (98% yield, >98% purity) establishing DABAL-Me3 as a potential alternative for the synthesis of amides in API scale preparations. Continuous flow methodology provides a method for larger scales (productivities of >50 g h–1). In addition, nitriles were coupled to primary amines and hydrazines with DABAL-Me3, resulting in the clean formation of free amidines (16 examples) and amidrazones.
ISSN:	1083-6160 1520-586X
DOI:	10.1021/acs.oprd.5b00101