Hydrochloric Acid → 1-(3-Fluorophenyl)-5-carboxymethylpyrazole

Participants

Reaction Steps

To a stirring solution of ethyl vinyl ether (340 mL, 3.55 mol) in diethyl ether (200 mL), cooled in an ice bath, is added dropwise a solution of malonyl dichloride (69 mL, 0.71 mol) in ether (20 mL). Stirring is continued at 0° C. for 2 h, then a solution of triethylamine (196 mL) and ethanol (350 mL) in ether (210 mL) is added with cooling. More ether is added to further precipitate triethylamine hydrochloride, the mixture is then filtered, and the filtrate concentrated. The residue is taken up in ethanol (710 mL), then triethyl orthoformate (177 mL, 1.07 mol) and concentrated HCl (5 mL) is added. The mixture is stirred overnight then concentrated. To the residue is added ethanol (500 mL) and 3-Fluorophenylhydrazine hydrochloride (27.6 g, 0.17 mol). The mixture is heated at reflux for 2 h, then cooled and concentrated. Ethyl acetate is added, the mixture is washed with aqueous bicarbonate, then with water, dried (Na2SO4), concentrated, and the residue purified by silica gel chromatography. Ethanol (20 mL) and 1 N NaOH (100 mL) are added, and heated at reflux for 1 h. The mixture is cooled and washed with ethyl acetate. The aqueous layer is cooled and acidified, the solid collected by filtration, rinsed well with water and dried to give 1-(3-Fluorophenyl)-5-carboxymethylpyrazole as a gold solid. 1H NMR (CDCl3): δ 7.68 (d, J=1.8 Hz, 1H), 7.41-7.48 (m, 1H), 7.10-7.26 (m, 3H), 6.44 (d, J=2.1 Hz, 1H), 3.77 (8, 2H). LCMS: 221.2 (MH+), 219.2(MH−).

Provenance & Evidence