Pyrazole → 2-(2-Chloropyridin-5-yl)-1-(3-methoxy-5-methylphenyl)ethanone

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Reaction Steps

For the synthesis of the pyrazole derivative, first, as illustrated in Reaction Scheme 10, 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 2-chloro-5-methylpyridine in the presence of lithium hexamethyldisilazide to afford 2-(2-chloropyridin-5-yl)-1-(3-methoxy-5-methylphenyl)ethanone, represented by Formula 28. The compound of Formula 28 is converted into a pyrazole derivative through two successive steps. In this regard, the ethanone compound of Formula 28 is heated with N,N-dimethylformamide dimethylacetal, successively followed by cyclization with hydrazine hydrate into 4-(2-chloropyridin-5-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol, represented by Formula 29. The reaction of the pyrazole compound of Formula 29 with iodoacetonitrile in the presence of potassium carbonate produces two regioisomers 4-(2-chloropyridin-5-yl)-3-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile, represented by Formula 30, and 4-(2-chloropyridin-5-yl)-5-(3-methoxy-5-methylphenyl)-1H-pyrazol-1-yl)acetonitrile, represented by Formula 31. In the presence of a palladium catalyst, the regioisomers of Formulas 31 and 32 are subjected to nucleophilic substitution with various arylboronic acids to synthesize various compounds represented by Formulas 32a-c and 33a-c. Finally, these compounds are demethylated with boron trifluoride dimethyl sulfide to synthesize target pyrazole derivatives of Formulas 34a-c and 35a-c.

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