反应详情

For the synthesis of the pyrazole derivative, first, as illustrated in Reaction Scheme 7, methyl 3-methoxy-5-methylbenzoate of Formula 2a is allowed to undergo a nucleophilic attack at its carboxylic carbon by the activated methylene group of 4-methyl-2-(methylthio)-pyrimidine, represented by Formula 10, at room temperature (e.g., 20° C.-30° C.) in the presence of lithium hexamethyldisilazide (LHMDS) in tetrahydrofuran to afford 1-(3-methoxy-5-methylphenyl)-2-(2-methylsulfanylpyrimidin-4-yl)ethanone. The compound of Formula 11 is converted into a pyrazole derivative through a two step successive process. In this regard, the compound of Formula 11 is heated with N,N-dimethylformamide dimethylacetal, successively followed by cyclization with hydrazine hydrate into 3-(3-methoxy-5-methylphenyl)-4-(2-methylthiopyrimidine-4-yl]-1H-pyrazol, represented by Formula 12. Thereafter, the compound of Formula 12 is converted into a cyano compound of Formula 13 by heating with iodoacetonitrile in DMF, subsequently by the oxidation of the sulfide with meta-chloroperbenzoic acid to a sulfone, [4-(2-methanesulfonylpyrimidin-4-yl)-3-(3-methoxy-5-methylphenyl)pyrazol-1-yl]acetonitrile, represented by Formula 14. The sulfone compound of Formula 14 is then subjected to nucleophilic substitution with 3-hydroxyazetidine hydrochloride, and then to demethylation with boron tribromide into [4-[2-(3-hydroxyazetindin-1-yl)-pyrimidin-4-yl]-3-(3-hydroxy-4-methylphenyl)-pyrazol-1-yl]acetonitrile, represented by Formula 16.

1. custom(e.g., 20° C.-30° C.)