An improved synthetic process for ATX inhibitor Cudetaxestat (PAT-409)

Abstract

A highly efficient protocol for the preparation of autotaxin (ATX) inhibitor Cudetaxestat (PAT-409) was developed. The procedure began with the creative application of Sandmeyer isonitroso acetanilide isatin synthesis method without the introduction of Grignard reagent for the construction of 6-chloro-7-fluoro-1H-indole (3), considerably improving yield through “one-pot” water involved multicomponent cyclization. Subsequently, the catalytic base was altered from K₃PO₄ to Cs₂CO₃ to undergo Ullmann coupling, leading to an appreciable 80% yield of 6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indole (5). After phenylthiolate displacement of the in situ formed 3-chloroindole, the key intermediate ethyl 3-((6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate (7) was chlorinated using N-chlorosuccinimide (NCS) in one batch to get ethyl 3-((2,6-dichloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate (8) in elevated yield (65%), which creatively avoided cumbersome operation steps and was favor for multi-gram synthesis. In the ultimate saponification reaction, LiOH was replaced with highly economical NaOH to accomplish a surprisingly high yield (85.2%). Above all, this promising synthetic process could favourably afford Cudetaxestat in 7.05% overall yield and 99.24% purity.