Ethyl chloronicotinate → HCID 10654983, compound

Ethyl-2-chloronicotinate (11.14g, 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 hours. Methanol was removed under vacuum. The residue was dissolved in ethyl acetate (200 mL). The organic layer was washed with a saturated aqueous NH4Cl solution (1×100 mL) and brine (50 mL). Dried over anhydrous Na2SO4. Removal of solvent gave ethyl-2-methoxynicotinate as yellow oil (9.88 g, 91%). To a solution of 3,5-dimethyl-4-hydroxyacetophenone (2.46 g, 15 mmol) in anhydrous DMF (75 mL) was added imidazole (3.27 g, 48 mmol) and tert-butyldimethylsilylchloride (2.71 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) and brine (100 mL), and dried over anhydrous Na2SO4. Removal of solvent gave 3,5-demthyl-4-tert-butyldimethylsilyloxy acetophenone as a colorless oil in quantitative yield (4.4 g). To a stirred solution of 3,5-demthyl-4-tert-butyldimethylsilyloxy acetophenone (1.58 g, 5.6 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl) amide (6.8 mL, 1.0M solution in THF) at −40° C. over a period of 15 min. under nitrogen. Stirring was continued at −40° C. for 15 min. A solution of ethyl-2-ethoxynicotinate in anhydrous THF (15 mL) was added slowly. Stirring was continued at 40° C. for 10 min. The mixture was allowed to warm to room temperature. Stirring was continued 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 desired crude compound (2.4 g) which was used in next step without purification. The above compound (2.31 g, 5.6 mmol) and pyridinium hydrochloride (6.47 g, 56 mmol) was mixed together and stirred at 190° C. for 3 hours. The mixture was cooled to room temperature. Water (100 mL) was added. The solid was filtered off, 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 2-(4-hydroxy-3,5-dimethylphenyl)-4H-pyrano[2,3-b]pyridin-4-one (0.598 g, 40% yield over two steps); MS (ES) m/z: 268.91 (M+1), 267.88 (M); MP 295-297 C

1. temperatureunder reflux for 15 hours
2. customMethanol was removed under vacuum
3. dissolutionThe residue was dissolved in ethyl acetate (200 mL)
4. washThe organic layer was washed with a saturated aqueous NH4Cl solution (1×100 mL) and brine (50 mL)
5. dry with materialDried over anhydrous Na2SO4
6. customRemoval of solvent

ORD record

ord-cf8c9bd0502e419395015aa630a389e0

Source dataset

uspto-grants-2013_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08410109B2