- Manufacture of the PI3K β-Sparing Inhibitor Taselisib. Part 1: Early-Stage Development Routes to the Bromobenzoxazepine Core
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Two convergent regioselective routes for the synthesis of the tetracyclic imidazobenzoxazepine triazole 1, a key intermediate toward the synthesis of taselisib, are described. In the first-generation route, a chemoselective Negishi cross-coupling reaction was developed between iodoimidazole 3 and triazole 7, which enabled the delivery of initial kilogram quantities of 1. Because of the inefficiencies in the preparation of the imidazole 3, a second-generation route via a highly regioselective imidazole ring formation between α-chloroketone 11 and aryl amidine 12 was developed. The resulting imidazole 14 provided the handle to efficiently install the seven-membered benzoxazepine ring system in one pot with two-step N-alkylation and SNAr tandem reactions.
- Remarchuk, Travis,Angelaud, Rémy,Askin, David,Kumar, Archana,Thompson, Andrew S.,Cheng, Hua,Reichwein, John F.,Chen, Yanping,St-Jean, Frédéric
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p. 775 - 782
(2019/05/24)
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- PROCESS FOR MAKING BENZOXAZEPIN COMPOUNDS
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Processes are described for the preparation of PI3K inhibitor, GDC-0032, Formula (I), having the structure: Formula (I) (GDC-0032), and intermediates useful for the preparation of (I).
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Page/Page column 9; 24
(2014/09/29)
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