Hydrochloric Acid → [4-(6-Chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of (3,5-dimethyl-4-hydroxy-phenyl)-acetic acid methyl ester (6a) (12.5 g, 0.064 mol) in anhydrous dimethyl sulfoxide (256 mL) under argon at room temperature was treated with 3,6-dichloro-4-isopropyl pyridazine (7) (18.43 g, 0.096 mol) followed by anhydrous potassium carbonate (17.69 g, 0.12 mol) and copper (I) iodide (6.09 g, 0.032 mol). The reaction mixture was heated to 90° C. for 24 h. At this time, the reaction was cooled to room temperature and was poured onto a 1N aqueous hydrochloric acid solution (200 mL) and ice. The aqueous layer was diluted with water (100 mL) and extracted with ethyl acetate (2×500 mL). The aqueous layer was made basic (pH=8) by the addition of a 1N aqueous sodium hydroxide solution. The water layer was extracted again with ethyl acetate (1×500 mL). The combined organics were washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. The resulting residue was purified by column chromatography using silica gel eluted with 5-15% ethyl acetate in petroleum ether to afford [4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid methyl ester (8a) (15 g, 67%) and a minor amount of isomer as a white solid; EI(+)-HRMS m/z calcd for C18H21ClN2O3 (M+) 348.1241, found 348.1237. Molecular Weight=348.8327; Exact Mass=348.1241

Provenance & Evidence