Water → 1-(4-(Propan-2-yloxy)phenyl)ethan-1-one

Participants

Reaction Steps

Sodium hydride (1.32 g, 33 mmol, 60% suspension in mineral oil) was suspended in anhydrous DMF (20 mL). A solution of 4-hydroxy acetophenone (4.08 g, 30 mmol) in anhydrous DMF (20 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 30 min. A solution of 2-bromopropane (4.61 g, 37.5 mmol) in anhydrous DMF (10 mL) was added slowly. The reaction mixture was stirred at room temperature overnight. Water (100 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL). Dried over anhydrous Na2SO4. Removal of solvent gave 1-(4-isopropoxy phenyl)ethanone as a pale yellow solid (3.52 g, 66%). To a stirred solution of 2-methoxy-5-pyrrolidin-1-ylmethyl nicotinic acid methyl ester (0.5 g, 2.0 mmol) and 1-(4-isopropoxy phenyl)ethanone in anhydrous DMF (10 mL), sodium hydride (96 mg, 2.4 mmol, 60% suspension in mineral oil) was added in small portions under nitrogen. The reaction mixture was stirred overnight at room temperature. Reaction mixture was stirred at 80° C. for 1 hours. Water (30 mL) was added. The mixture was extracted with chloroform (150 mL). The organic layer was washed with water (30 mL) and brine (30 mL). Dried over anhydrous Na2SO4. Removal of solvent gave brown solid (0.66 g) which was used in next step without further purification. The above solid (0.626 g, 1.58 mmol) and pyridine hydrochloride (1.18 g, 15.8 mmol) were mixed together and stirred at 190° C. for 20 min. Cooled to room temperature. Water (10 mL) was added, neutralized to pH ˜9. The mixture was extracted with chloroform (2×100 mL). The organic layer was washed with brine (50 mL) and dried (Na2SO4). Removal of the solvent gave 2-(4-isopropoxy phenyl)-6-pyrrolidin-1-ylmethyl pyrano[2,3-b]pyridine-one (0.237 g, 41%) as yellow solid. To a solution of the above compound in anhydrous CH2Cl2 (10 mL) was added 1.0 M solution of hydrogen chloride in ether dropwise. The reaction mixture was stirred for 10 min. The solvent was removed under reduced pressure. The residue was washed with hexane and ether. Purified by triturating with 10% methanol in ether to give 2-(4-isopropoxyphenyl)-6-(pyrrolidin-1-ylmethyl)-4H-pyrano[2,3-b]pyridin-4-one hydrochloride (0.20 g, 83%) as yellow solid. MS (ES) m/z: 264 (M); MP 261-263° C.

Provenance & Evidence