A scalable two-pot sulfonamidation through the process has been developed for the synthesis of gefapixant citrate, a P2X3 receptor antagonist that is under investigation for the treatment of refractory and unexplained chronic cough. Direct conversion of the diaryl ether precursor to a sulfonyl chloride intermediate using chlorosulfonic acid, followed by treatment with aqueous ammonia hydroxide, provided the desired sulfonamide in high yield. A pH-swing crystallization allowed for the formation of a transient acetonitrile solvate that enables the rejection of two impurities. After drying, the desired anhydrous free base form was isolated in high yield and purity.

中文翻译：

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开发柠檬酸Gefapixant（MK-7264）的绿色和可持续制造工艺。第5部分：通过直接氯磺酰化工艺完成API游离碱

已经开发出通过该方法的可扩展的两锅磺酰胺化方法，用于合成柠檬酸吉法匹沙汀，一种正在研究中的P2X3受体拮抗剂，用于治疗顽固性和无法解释的慢性咳嗽。使用氯磺酸将二芳基醚前体直接转化为磺酰氯中间体，然后用氢氧化氨水溶液处理，以高收率提供了所需的磺酰胺。pH波动结晶允许形成瞬态乙腈溶剂化物，该溶剂化物能够排除两种杂质。干燥后，以高产率和纯度分离出所需的无水游离碱形式。