Synthesis of (S)-3-amino-benzo[b][1,4]oxazepin-4-one via Mitsunobu and SNAr reaction for a first-in-class RIP1 kinase inhibitor GSK2982772 in clinical trials

Two new synthetic routes were developed to prepare the RIP1 kinase inhibitor clinical candidate GSK2982772 involving a key (S)-3-amino-benzob]1,4]oxazepin-4-one intermediate prepared via Mitsunobu and S_NAr cyclization reactions. Both routes are practical and cost effective compared to the initial medicinal chemistry route and are also applicable to kilogram scale-up to support on-going clinical studies.