A synthetic process of momelotinib was optimized.The starting material 4-fluronitrobenzene underwent nucleophilic substitution and reduction to give 4-morpholinylaniline(3).The key intermediate 4-(2-hydroxypyrimidin-4-yl)benzoic acid(6)was synthesized from methyl 4-acetylbenzoate by condensation,nucleophilic substitution,intra-molecular cyclization and hydrolysis reactions.Then,intermediate6 underwent chlorination,nucleophilic substitution to give N-cyanomethyl-4-(2-chloropyrimidin-4-yl)benzamide(8).Intermediate 8 was coupled with intermediate 3 to give momelotinib.The structure of momelotinib was confirmed by MS and NMR spectra.The total yield was 42.9％(from methyl 4-acetylbenzoate)with the purity of 99.58％.The improved process have the advantages of reduced cost,milder reaction conditions and convenient reaction operation,and is suitable for large-scale preparation.
momelotinib4-(2-hydroxypyrimidin-4-yl)benzoic acidsynthetic process
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