The Development of a Robust Process for a CRF1 Receptor Antagonist

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• 作者：Se虂vrine Broxer ; Monica A. Fitzgerald ; Chris Sfouggatakis ; Jessica L. Defreese ; Evan Barlow ; Gerald L. Powers ; Michael Peddicord ; Bao-Ning Su ; Yue Tai-Yuen ; Charles Pathirana ; James P. Sherbine
• 刊名：Organic Process Research & Development
• 出版年：2011
• 出版时间：March 18, 2011
• 年：2011
• 卷：15
• 期：2
• 页码：343-352
• 全文大小：1069K
• 年卷期：v.15,no.2(March 18, 2011)
• ISSN：1520-586X

文摘

A scalable and robust process was developed for the preparation of pexacerfont (2), a pyrazolotriazine corticotropin-releasing factor receptor 1 antagonist (CRF₁). The formation of the core hydroxypyrazolotriazine moiety was achieved through two consecutive cyclizations of a semicarbazide, employing reaction conditions that are significantly milder than those reported in the literature. Further conversion to the key chloropyrazolotriazine intermediate was accomplished through a novel catalytic process using phosphorous oxychloride as the chlorinating agent. The active pharmaceutical ingredient 2 was obtained in >99.5% purity with a 68% overall yield for the six synthetic steps.