Process Development and Scale-Up of a Benzoxazepine-Containing Kinase Inhibitor

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 preferred hydrochloride salt was eventually prepared. The overall yield for the synthesis of inhibitor 1 was 21% over eight isolated synthetic steps, and the final salt was obtained with 99.7% HPLC purity.