Ethyl chloronicotinate → HCID 10654983, compound

Ethyl-2-chloronicotinate (11.1 g, 60 mmol) was dissolved in anhydrous methanol (60 mL). Sodium methoxide (18 mL, 25 wt % in methanol) was added slowly at room temperature under nitrogen. The reaction mixture was stirred under reflux for 15 h. The methanol was removed under vacuum. The residue was taken into ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous NH4Cl solution (1×100 mL) and brine (50 mL), and dried over anhydrous Na2SO4. Removal of solvent gave ethyl-2-methoxynicotinate (9.9 g, 91%) as yellow oil. To a solution of 3,5-dimethyl-4-hydroxyacetophenone (2.5 g, 15 mmol) in anhydrous DMF (75 mL) was added imidazole (3.3 g, 48 mmol) and tert-butyldimethylsilylchloride (2.7 g, 18 mmol). The reaction mixture was stirred at room temperature under nitrogen for 15 hours. Water (200 mL) was added. The mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (2×100 mL), brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave a colorless oil in quantitative yield (4.4 g). To a stirred solution of the 3,5-dimethyl-4-tert-butyldimethylsilyloxy acetophenone (1.6 g, 5.6 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl) amide (6.8 mL, 1.0 M solution in THF) at −40° C. over a period of 15 min. under nitrogen. The stirring continued at 40° C. for 15 min. A solution of ethyl-2-methoxynicotinate in anhydrous THF (15 mL) was added slowly. The stirring was continued at −40° C. for 10 min. Then allowed to warm to room temperature and stirred for another 15 h at room temperature. The reaction mixture was diluted with ethyl acetate (200 mL). A saturated aqueous NH4Cl solution (50 mL) was added. The organic layer was separated and dried over anhydrous Na2SO4. Removal of solvent gave the crude product (2.4 g), which was used in next step without purification. The above compound (2.31 g, 5.6 mmol) and pyridinium hydrochloride (6.5 g, 56 mmol) was mixed together and stirred at 190° C. for 3 hours. The mixture was cooled to room temperature and water (100 mL) was added. The solid was separated by filtration, washed with water and dried under vacuum. The crude product was purified by column chromatography (SilicaGel 230-400 mesh; 2% methanol in CH2Cl2 as eluent) to give the desired intermediate in (0.6 g, 40% yield from two steps) as an off-white solid. To a solution of the desired intermediate (0.86 g, 3.2 mmol) in anhydrous DMF (20 mL) was added sodium hydride (0.180 g, 4.49 mmol, 60% suspension in mineral oil) in small portions and stirred for 15 min. under nitrogen. A solution of 1-chloro-2-iodoethane (0.765 g, 4.02 mmol) in anhydrous DMF (5 mL) was added dropwise. The reaction mixture was stirred for 3 days (progress of the reaction mixture was monitored by TLC). Water (100 mL) was added. The mixture was extracted with THF and ethyl acetate (1:2, 150 mL). The organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. The crude material was purified by column chromatography (Silica Gel 230-400 mesh; 2-5% MeOH in CH2Cl2 as eluent) to give 2-[-(2-chloroethoxy)-3,5-dimethylphenyl]pyrano[2,3-b]pyridine-4-one (0.4g, 38%) of as a pale yellow solid. The above compound (0.19 g, 0.58 mmol) was dissolved in anhydrous DMSO (5 mL). Morpholine (0.25 g, 2.9 mmol) and triethylamine (0.29 g, 2.9 mmol) were added and the reaction mixture was stirred at 110° C. for 15 h. The reaction mixture was cooled to room temperature and water (20 mL) was added. A solid precipitated out and was isolated by filtration. It was washed with water and dried under vacuum. The crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 2-5% MeOH in CH2Cl2 as eluent) to give 2-[3,5-dimethyl-4-(2-morpholinyl-ethoxy)phenyl]pyrano[2,3-b]pyridine-4-one (0.11 g, 50%) as a pale yellow solid. To a solution of above compound (0.098 g, 0.26 mmol) in anhydrous CH2Cl2 (5 mL) was added hydrogen chloride (1 mL, 1.0 M solution in ether) dropwise. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed and the solid was triturated with 10% methanol in ether to give 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-4H-pyrano[2,3-b]pyridin-4-one (0.09 g 77%) as the hydrochloride; MS (ES) m/z: 381.03 (M+1); MP 276-278° C.

1. temperatureunder reflux for 15 h
2. customThe methanol was removed under vacuum
3. washThe organic layer was washed with a saturated aqueous NH4Cl solution (1×100 mL) and brine (50 mL)
4. dry with materialdried over anhydrous Na2SO4
5. customRemoval of solvent

ORD record

ord-015429fc28354c0ca5c7e91ee3d2381e

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08410109B2