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Gefapixant Citrate (MK-7264) Sulfonamide Step Speciation Study: Investigation into Precipitation–Dissolution Events during Addition of Chlorosulfonic Acid
Organic Process Research & Development ( IF 3.4 ) Pub Date : 2023-02-08 , DOI: 10.1021/acs.oprd.2c00313 Nelo R. Rivera, Ryan D. Cohen, Si-Wei Zhang, Zachary E. X. Dance, Holst M. Halsey, Siqing Song, Xiaodong Bu, Mikhail Reibarkh, Hong Ren, Alfred Y. Lee, Darryl Chang, Sachin Lohani
Organic Process Research & Development ( IF 3.4 ) Pub Date : 2023-02-08 , DOI: 10.1021/acs.oprd.2c00313 Nelo R. Rivera, Ryan D. Cohen, Si-Wei Zhang, Zachary E. X. Dance, Holst M. Halsey, Siqing Song, Xiaodong Bu, Mikhail Reibarkh, Hong Ren, Alfred Y. Lee, Darryl Chang, Sachin Lohani
Sulfonamidation is the pre-penultimate step in the commercial synthesis of gefapixant citrate. Several stress studies were performed during process characterization of this step to ensure process robustness and to mitigate potential upset scenarios. One parameter explored was the slow addition of chlorosulfonic acid (CSA) to form the sulfonic acid intermediate. During the extended addition, an unexpected series of precipitation–dissolution events were observed. To better understand these events and accommodate a CSA tank switch during the reaction, a detailed investigation using a variety of analytical techniques was performed, which revealed the formation of various protonated species of both the diaminopyrimidine starting material and sulfonic acid intermediate with stark differences in their solubility properties. This behavior explained the changes in solubility observed in the reaction system during CSA addition. This detailed speciation study supported the CSA addition procedure that was ultimately adopted for commercial process to ensure operation robustness.
中文翻译:
Gefapixant 柠檬酸盐 (MK-7264) 磺胺类步骤形态研究:氯磺酸添加过程中沉淀-溶解事件的研究
磺酰胺化是吉法匹克柠檬酸盐商业合成中的前倒数第二个步骤。在此步骤的过程表征过程中进行了多项压力研究,以确保过程稳健性并减轻潜在的干扰情况。探索的一个参数是缓慢添加氯磺酸 (CSA) 以形成磺酸中间体。在延长添加过程中,观察到一系列意想不到的沉淀-溶解事件。为了更好地了解这些事件并在反应期间适应 CSA 罐开关,使用各种分析技术进行了详细调查,结果揭示了二氨基嘧啶原料和磺酸中间体的各种质子化物质的形成,它们的质子化程度存在明显差异溶解特性。这种行为解释了在添加 CSA 期间在反应系统中观察到的溶解度变化。这项详细的形态研究支持 CSA 添加程序,该程序最终被商业过程采用,以确保操作稳健性。
更新日期:2023-02-08
中文翻译:
Gefapixant 柠檬酸盐 (MK-7264) 磺胺类步骤形态研究:氯磺酸添加过程中沉淀-溶解事件的研究
磺酰胺化是吉法匹克柠檬酸盐商业合成中的前倒数第二个步骤。在此步骤的过程表征过程中进行了多项压力研究,以确保过程稳健性并减轻潜在的干扰情况。探索的一个参数是缓慢添加氯磺酸 (CSA) 以形成磺酸中间体。在延长添加过程中,观察到一系列意想不到的沉淀-溶解事件。为了更好地了解这些事件并在反应期间适应 CSA 罐开关,使用各种分析技术进行了详细调查,结果揭示了二氨基嘧啶原料和磺酸中间体的各种质子化物质的形成,它们的质子化程度存在明显差异溶解特性。这种行为解释了在添加 CSA 期间在反应系统中观察到的溶解度变化。这项详细的形态研究支持 CSA 添加程序,该程序最终被商业过程采用,以确保操作稳健性。