1. Process Development and Scale-Up of a Benzoxazepine-Containing Kinase Inhibitor
- Author
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Anders Lohse, Neil G. Andersen, Sriram Naganathan, Denise L. Andersen, Stephen Lau, and Mads Detlef Sørensen
- Subjects
chemistry.chemical_compound ,chemistry ,Kinase ,Process development ,Stereochemistry ,Yield (chemistry) ,Organic Chemistry ,Oxazepine ,Physical and Theoretical Chemistry ,Discovery and development of mTOR inhibitors ,Benzoic acid - Abstract
The benzoxazepine core is present in several kinase inhibitors, including the mTOR inhibitor 1. The process development for a scalable synthesis of 7-bromobenzoxazepine and the telescoped synthesis of 1 are reported. Compound 1 consists of three chemically rich, distinct fragments: the tetrahydrobenzo[f][1,4]oxazepine core, the aminopyridyl fragment, and the substituted (methylsulfonyl)benzoyl fragment. Routes were developed for the preparation of 3-fluoro-2-methyl-4-(methylsulfonyl)benzoic acid (17) and tert-butyl 7-bromo-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (2). The processes for the two compounds were scaled up, and over 15 kg of each starting material was prepared in overall yields of 42% and 58%, respectively. A telescoped sequence beginning with compound 2 afforded 7.5 kg of the elaborated intermediate 5-(2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-2-amine dihydrochloride (6) in 63% yield. Subsequent coupling with benzoic acid 17 gave 7.6 kg of the target compound 1 in 84% yield. The pref...
- Published
- 2015