4-Chloropyridine → 3-Phenyl-1H-pyrazolo[4,3-c]pyridine

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Reaction Steps

A 2 M aqueous solution of sodium hydroxide (20 mL, manufactured by Kanto Chemical Co., Inc.) was added to a solution of 4-chloropyridine hydrochloride (3.18 g) in tetrahydrofuran (20 mL, manufactured by Kanto Chemical Co., Inc.) to neutralize the solution, and then the mixture was extracted with ethyl acetate (3×50 mL), washed with brine mL), and dried (MgSO4). The solvent was then evaporated to give 4-chloropyridine. 4-Chloropyridine was added dropwise to a solution of lithium diisopropylamide (23% solution in tetrahydrofuran/ethylbenzene/heptane, 14.1 mL, manufactured by Sigma-Aldrich Corp.) in tetrahydrofuran (40 mL, manufactured by Kanto Chemical Co., Inc.) at −78° C., and the mixture was stirred for 30 minutes. Subsequently, N-methoxy-N-methylbenzamide (3.55 mL, manufactured by Sigma-Aldrich Corp.) was further added to the mixture at the same temperature, and while the temperature was gradually raised to room temperature, the mixture was stirred overnight. A saturated aqueous solution of ammonium chloride (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×50 mL), washed with brine (50 mL), and dried (MgSO4). The solvent was then evaporated, isopropanol (20 mL, manufactured by Kanto Chemical Co., Inc.) and hydrazine hydrate (5.0 mL, manufactured by Tokyo Chemical Industry Co., Ltd.) were added to the obtained residue, and the mixture was stirred for one hour at room temperature. A saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×30 mL), washed with brine (50 mL), and dried (MgSO4). The solvent was then evaporated, and a saturated aqueous solution of ammonium chloride (50 mL) was added to the reaction solution. The mixture was extracted with ethyl acetate (3×50 mL), washed with brine (50 mL), and dried (MgSO4), and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1), to give 4.1 g of the title compound. LC-MS: HPLC retention time 0.64 minutes, m/z (M+H) 232, condition C-1.

Provenance & Evidence