{"title":"Development of Scalable Processes for the Preparation of 4-(chloromethyl)-1-cyclohexyl-2-(trifluoromethyl)benzene: A Key Intermediate for Siponimod","authors":"Biyue Lin, Shuming Wu, Qingbo Xiao, Jingping Kou, Ji’an Hu, Zhu Zhu, Xinglin Zhou, Jiang Weng* and Zhongqing Wang*, ","doi":"10.1021/acs.oprd.3c00170","DOIUrl":null,"url":null,"abstract":"<p >This paper presents the development of two generations of routes for the synthesis of the key intermediate <b>8-Cl</b> of siponimod. The first generation focuses on a cyanation reaction followed by alkaline hydrolysis to introduce the benzoic acid group, replacing the hazardous nucleophilic carboxylation mediated by <i>n</i>-BuLi in the reported manufacturing route. Furthermore, the use of LiAlH<sub>4</sub> for the carboxylic acid reduction is substituted with a milder acid anhydride reduction enabled by NaBH<sub>4</sub>. Overall, the first-generation route demonstrates an 11.6% increase in yield over 8 steps, effectively addressing concerns related to scale-up effects and safety-critical operations. In the second generation, a two-step synthesis involving nickel-catalyzed Kumada–Corriu coupling and Blanc chloromethylation is devised to produce benzyl chloride <b>8-Cl</b>, starting from the readily available and cost-effective material 1-halo-2-(trifluoromethyl)benzene <b>9</b>. The second-generation route is successfully demonstrated at large scales ranging from hundreds to kilo grams, resulting in a remarkable 32.5% yield increase and approximately 65% reduction in process mass intensity for the synthesis of intermediate <b>8-Cl</b>.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"27 8","pages":"1474–1484"},"PeriodicalIF":3.1000,"publicationDate":"2023-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.3c00170","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
This paper presents the development of two generations of routes for the synthesis of the key intermediate 8-Cl of siponimod. The first generation focuses on a cyanation reaction followed by alkaline hydrolysis to introduce the benzoic acid group, replacing the hazardous nucleophilic carboxylation mediated by n-BuLi in the reported manufacturing route. Furthermore, the use of LiAlH4 for the carboxylic acid reduction is substituted with a milder acid anhydride reduction enabled by NaBH4. Overall, the first-generation route demonstrates an 11.6% increase in yield over 8 steps, effectively addressing concerns related to scale-up effects and safety-critical operations. In the second generation, a two-step synthesis involving nickel-catalyzed Kumada–Corriu coupling and Blanc chloromethylation is devised to produce benzyl chloride 8-Cl, starting from the readily available and cost-effective material 1-halo-2-(trifluoromethyl)benzene 9. The second-generation route is successfully demonstrated at large scales ranging from hundreds to kilo grams, resulting in a remarkable 32.5% yield increase and approximately 65% reduction in process mass intensity for the synthesis of intermediate 8-Cl.
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.
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