Development of Scalable Processes for the Preparation of 4-(chloromethyl)-1-cyclohexyl-2-(trifluoromethyl)benzene: A Key Intermediate for Siponimod

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.