Synthesis of 4-Substituted Phthalazin-1(2H)-ones from 2-Acylbenzoic Acids: Controlling Hydrazine in a Pharmaceutical Intermediate through PAT-Guided Process Development

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• 作者：Steven M. Mennen ; Melody L. Mak-Jurkauskas ; Matthew M. Bio ; L. Steven Hollis ; Kelly A. Nadeau ; Andrew M. Clausen ; Karl B. Hansen
• 刊名：Organic Process Research & Development
• 出版年：2015
• 出版时间：July 17, 2015
• 年：2015
• 卷：19
• 期：7
• 页码：884-891
• 全文大小：480K
• ISSN：1520-586X

文摘

A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.