Manufacture of the PI3K β‑Sparing Inhibitor Taselisib. Part 1: Early-Stage Development Routes to the Bromobenzoxazepine Core

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 tr...

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Veröffentlicht in:	Organic process research & development 2019-05, Vol.23 (5), p.775-782
Hauptverfasser:	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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container_title	Organic process research & development
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creator	Remarchuk, Travis Angelaud, Rémy Askin, David Kumar, Archana Thompson, Andrew S Cheng, Hua Reichwein, John F Chen, Yanping St-Jean, Frédéric
description	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.
doi_str_mv	10.1021/acs.oprd.9b00049
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title	Manufacture of the PI3K β‑Sparing Inhibitor Taselisib. Part 1: Early-Stage Development Routes to the Bromobenzoxazepine Core
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