Development of the Commercial Manufacturing Process for Xanomeline Tartrate, an Active Pharmaceutical Ingredient in KarXT

IF 3.3 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development Pub Date : 2026-10-16 Epub Date: 2026-07-16 DOI:10.1021/acs.oprd.6c00185

Joseph Ryan, Aida Ajaz, Rajender Vemula, Christopher R. H. Hale, Giorgio Attardo, MVRCH Murthy, Yolanda Gasanz, Vijaya B. Gondi

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Abstract

Development of the commercial manufacturing strategy and process employed for xanomeline tartrate (KTX-001), a key active pharmaceutical ingredient (API) in KarXT, is described. The development process involved identifying efficient processes for key bond-forming steps, including the conversion of regulatory starting material nicotinaldehyde (1) to stage 1 regulatory intermediate chlorothiadiazole 2, nucleophilic aromatic displacement of the chlorine atom within 2 with 1-hexanol followed by methylation to generate stage 2 regulatory intermediate pyridinium 4, and selective partial reduction of the pyridine ring to produce the API freebase, which after tartrate salt formation gave access to stage 3 regulatory intermediate crude xanomeline tartrate (crude KTX-001). A recrystallization process was developed to provide the drug substance xanomeline tartrate (KTX-001) in an overall yield of 35% from nicotinaldehyde (1) with HPLC purity of >99.0% on scales of 500+ kilograms per batch, suitable for reliable supply of this commercial drug substance.

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KarXT活性药物成分酒石酸Xanomeline商业化生产工艺的开发

描述了KarXT的关键活性药物成分（API）酒石酸异诺米林（KTX-001）的商业生产策略和工艺的发展。开发过程包括确定关键键形成步骤的有效过程，包括将调节起始材料烟醛(1)转化为第1阶段调节中间体氯噻二唑2，用1-己醇将2中的氯原子亲核芳香置换，然后甲基化生成第2阶段调节中间体吡啶4，以及选择性部分还原吡啶环以产生原料药自由碱。在酒石酸盐形成后，获得第3阶段调节中间体粗酒石酸黄嘌呤（粗KTX-001）。开发了一种重结晶工艺，以烟碱醛(1)为原料，总收率为35%，高效液相色谱纯度为> - 99.0%，每批500公斤以上，适合于该商业原料药的可靠供应。

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来源期刊

Organic Process Research & Development 化学-应用化学

CiteScore

6.90

自引率

14.70%

发文量

251

审稿时长

2 months

期刊介绍： The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.