Sulfone Displacement Approach for Large-Scale Synthesis of 4-Chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine

Route evaluation, process development, and large-scale manufacturing of 4-chloro- N -(1-methyl-1 H -pyrazol-4-yl)pyrimidin-2-amine ( 1 ) are described. The improved route consists of two linear chemical steps: oxidation of 4-chloro-2-(methylthio)pyrimidine ( 11 ) to 4-chloro-2-(methylsulfonyl)pyrimidine ( 7 ) and displacement of the sulfonyl with N -(1-methyl-1 H -pyrazol-4-yl)formamide ( 10 ) under basic conditions followed by in situ hydrolysis of the N -formyl intermediate to deliver compound 1 . N -(1-Methyl-1 H -pyrazol-4-yl)formamide ( 10 ) was readily prepared from 1-methyl-1 H -pyrazol-4-amine ( 4 ) via reaction with formic acid. The route allows for large-scale production of 4-chloro- N -(1-methyl-1 H -pyrazol-4-yl)pyrimidin-2-amine ( 1 ). Density functional theory (DFT) calculations were carried out to better understand the observed reactivity and selectivity.