| 71% |
at 20℃; for 1.5 - 16 h; Heating / reflux |
In a 500 ml_ dry round bottom flask with reflux condenser and magnetic stirrer was placed with 2-chloro-3-ethyl nicotinate (40.0 g, 215.5 mmol) in methanol (200 ml_). CH3ONa in methanol (25percent, 65 ml_, 301.7 mmol) was added slowly and the reaction mixture was refluxed for 16 hours. The reaction was cooled to room temperature, quenched by addition of a saturated aqueous NH4CI solution. The aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed well with water, brine, dried over Na2SO4 and concentrated to give 35 g of 2-methoxy-3-methyl nicotinate with 97percent yield. Sodium hydride (60percent in oil, 9.21 g, 230.3 mmol) was added to a dry 500 ml_ round bottom flask followed by 100 ml_ DMF. 4-Methoxyacetophenone (31.45 g, 209.44 mmol) in 50 ml_ dry DMF was added drop-wise at 00C over 30 min. The reaction mixture was stirred for 1 h at room temperature. 2-Methoxynicotinic acid methyl ester (35 g, 209.44 mmol) was dissolved in 50 ml_ dry DMF and added EPO <DP n="50"/>slowly, keeping the temperature at O0C. The mixture was stirred for 16 h at room temperature, then quenched by addition of a saturated aqueous NH4CI solution and diluted with water. The solid was filtered off, washed with water and dried to give 56.7 g diketo product in 95percent yield.; A solution of ethyl 2-chloronicotinitate (6.0 g, 0.0323 mol) in anhydrous methanol (10 ml_) at room temperature was added sodium methoxide (10 ml_, 25percent in methanol). The reaction mixture was stirred for half hour then heated to reflux for one hour. The mixture was poured into water and extracted with ethyl acetate and the organic layer was washed with water until neutral, dried over sodium sulfate, and concentrated to give methyl 2-methoxynicotinitate (5.2 g, 96.3percent).; In a 500 mL dry round bottom flask with reflux condenser and magnetic stirrer was placed with 2-chloro-3-ethyl nicotinate (40.0 g, 215.5 mmol) in methanol (200 mL), and sodium methoxide (65 mL, 301.7 mmol, 25percent in methanol) was added slowly and the reaction mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature and the reaction was quenched by addition of saturated aqueous NH4CI solution, followed by extraction with ethyl acetate. The combined organic layers were washed well with water, brine, dried over Na2SO4 and concentrated to give 2-methoxy-3-methyl nicotinate (35 g, 97percent). To a dry 500 mL round bottom flask was added NaH (9.21 g 230.3 mmol, 60percent in mineral oil) in DMF (100 mL). 4-Methoxyacetophenone (31.45 g, 209.44 mmol) in dry DMF (50 mL) was added dropwise at 00C over 30 min. The reaction mixture was stirred for 1 h at room temperature. Then 2-methoxynicotinic acid methyl ester (35 g, 209.44 mmol) dissolved in dry DMF (50 mL) was added slowly on cooling. The mixture was stirred for 16 h at room temperature. The reaction was quenched by addition of saturated NH4CI solution and diluted with water. The solid was filtered off, washed with water and dried to give the diketo product (56.7 g, 95 percent). Polyphosphoric acid (8.0 g) was heated at 900C and the diketo compound (1.0 g, 3.50 mmol) was added slowly and heated at 900C for 1 hour. The reaction mixture was cooled to room temperature and diluted with water. The solid was isolated by filtration, washed with water and dried to give 2- (4-methoxyphenyl)-4H-pyrano[2,3-b]pyridine-4-one (570 mg, 64percent). MS (ES) m/z: 254.89 (M+1), 253.90 (M); MP 269-2700C.; In a 250 mL dry round bottom flask with a reflux condenser and magnetic stirrer was placed with 2-chloro-3-ethyl nicotinate (12.0 g, 64.7 mmol) in dry methanol (200 mL), and CH3ONa (21 mL, 97.0 mmol, 25percent in methanol) were added slowly and the reaction mixture was refluxed for 16 hour. The reaction mixture was cooled to room temperature and quenched by addition of a saturated aqueous NH4CI solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give 2-methoxy-3-methyl nicotinate (10.0 g, 93percent). In a dry 500 mL round bottom flask NaH (549 mg, 13.7 mmol, 60percent in mineral oil) was added in DMF (10 mL). Acetophenone (1.5 g, 12.5 mmol) in dry DMF (10 mL) was added drop-wise at O0C in 30 min. The reaction mixture was stirred for 1 h at room temperature. 2- Methoxy-3-m ethyl nicotinate (2.08 g, 12.5 mmol) dissolved into dry DMF (10 mL) was added slowly on cooling. After addition the mixture was stirred for 16 h at EPO <DP n="71"/>room temperature. The reaction mixture was quenched by addition of a saturated aqueous NH4CI solution and diluted with water. The solid was filtered off, washed with water and dried to give the diketo product (2.94 g, 92percent). Poly phosphoric acid (15.0 g) was heated at 9O0C and the diketo compound (1.5 g, 3.50 mmol) was added slowly and heated at 9O0C for 1 hours. The reaction mixture was cooled to room temperature and diluted with water. The solid was separated by filtration, washed with water and dried to give pure 2-phenyl-4H-pyrano[2,3- b]pyridin-4-one (655 mg, 50percent); MS (ES) m/z: 224.94 (M+1 ), 223.95 (M); MP 103- 1050C; In a 250 ml_ dry round bottom flask with reflux condenser and magnetic stirrer was placed 2-chloro-3-ethyl nicotinate (12.0 g, 64.7 mmol) in dry methanol (200 ml_), and CH3ONa (21 ml_, 97.0 mmol, 25percent in methanol) were added slowly and the reaction mixture was refluxed for 16 hour. The reaction mixture was cooled to room temperature and quenched by addition of a saturated aqueous NH4CI solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give 2-methoxy-3-methyl nicotinate (10.0 g, 93percent). In a dry 250 ml_ round bottom flask NaH (1.68 g, 41.0 mmol, 60percent in mineral oil) was added in DMF (20 ml_). 4'-Methyl acetophenone (5 g, 37.3 mmol) in dry DMF (10 ml_) was added dropwise at O0C in 30 min. The reaction mixture was stirred for 1 h at room temperature. 2-Methoxy- 3-methyl nicotinate (6.23 g, 37.3 mmol) dissolved in dry DMF (10 ml_) was added slowly on cooling. After addition the mixture was stirred for 16 h at room temperature. The reaction mixture was quenched by addition of a saturated aqueous NH4CI solution and diluted with water. The solid was filtered off, washed with water and dried to give the diketo product (9.36 g, 92.5percent). Poly phosphoric acid (30.0 g) was heated at 9O0C and the diketo compound (4.36 g, 16.1 mmol) EPO <DP n="72"/>was added slowly and heated at 9O0C for 1 hours. The reaction mixture was cooled to room temperature and diluted with water. The solids was separated by filtration, washed with water and dried to give 2-p-tolyl-4H-pyrano[2,3-b]pyridin-4- one (3.38 g, 89percent). To a solution of 2-p-tolyl-4H-pyrano[2,3-b]pyridin-4-one (1.0 g, 4.2 mmol) in CCI4 (50 ml_), NBS (788 mg, 4.44 mmol) was added under nitrogen, and heated under reflux for 4 h in presence of 600 w light. The reaction mixture was cooled to room temperature and filtered. The solids were dried and washed with water to give the bromide compound (698 mg, 52percent). To a solution of the bromide compound (698 mg, 2.20 mmol) in DMF (20 ml_), potassium acetate (649 mg, 6.62 mmol) was added. The mixture was heated at 1000C for 1 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give the crude acetyl flavone (597 mg, 92percent). To a solution of acetyl flavone (597 mg, 2.0 mmol) in methanol (15 mL), K2CO3 (840 mg, 6.07 mmol) was added and stirred for 2 h at room temperature. The solvent was removed and the product was taken into water and neutralized by dilute HCl. The solid was isolated by filtration, washed with water and purified by chromatography using 5percent MeOH in dichloromethane to give 2-(4-(hydroxymethyl)phenyl)-4H- pyrano[2,3-b]pyridin-4-one (300 mg, 59percent); MS (ES) m/z: 254.89 (M+1 ), 253.88 (M); MP 218-2190C; In a 500 mL dry round bottom flask with reflux condenser and magnetic stirrer was placed 2-chloro-3-ethyl nicotinate (40.0 g, 215.5 mmol) in methanol (200 mL), and CH3ONa (65 mL, 301.7 mmol, 25percent in methanol) was added slowly and the reaction mixture was refluxed for 16 hour. The reaction mixture was cooled to room temperature, quenched by addition of saturated NH4CI solution and extracted by ethyl acetate. The combined organic layer was washed well with water, brine, dried over Na2SO4 and concentrated to give 2- methoxy-3-methyl nicotinate (35 g, 97percent yield). In a dry 500 mL round bottom flask sodium hydride (9.21 g, 230.3 mmol, 60percent) was added in DMF (100 mL). 4- EPO <DP n="77"/>Methoxyacetophenone (31.5 g, 209 mmol) in dry DMF (50 ml_) was added dropwise at O0C over 30 min. The reaction mixture was stirred for 1 h at room temperature. 2-Methoxynicotinic acid methyl ester (35 g, 209 mmol) dissolved in dry DMF (50 ml_) was added slowly on cooling. After addition the mixture was stirred for 16 h at room temperature. The reaction mixture was quenched by addition of a saturated aqueous NH4CI solution and diluted with water. The solids were filtered off, washed with water and dried to give the diketo product (56.7 g, 95 percent). The above diketo compound (56.7 g, 199 mmol) and pyridinium hydrochloride (345 g) were placed in a 1000 ml_ round bottom flask and the mixture was heated at 19O0C for 5 hours. The reaction mixture was cooled to room temperature and diluted with water. The solids were separated by filtration and purified by column chromatography using 5percent methanol in CH2CI2 to give 2- (4-Hydroxy-phenyl)-pyrano[2,3-b]pyridin-4-one (23.25 g, 48.8percent). 2-(4-Hydroxy- phenyl)-pyrano[2,3-b]pyridin-4-one (0.48 g, 2.0 mmol) was suspended in anhydrous THF (25 mL). Triphenyl phosphene (0.577 g, 2.2 mmol), N1N- dimethylaminoethanol (0.213 g, 2.4 mmol) and Λ/,Λ/-diisopropylethylamine (0.37 g, 3.0 mmol), were added. To the stirred solution was added diethylazodicarboxylate (0.383 g, 2.2 mmol). After the addition of DEAD, the reaction mixture became a clear solution. The reaction mixture was stirred at room temperature overnight. Additional triphenyl phosphene (0.288 g, 1.1 mmol), Λ/,/V-dimethylaminoethanol (0.107 g, 1.2 mmol)* Λ/,M-diisopropylethylamine (0.185 g, 1.5 mmol), and diethylazodicarboxylate (0.191 g, 1.1 mmol) were added and stirring was continued for 15 hours. The solvent was removed under vacuum. The crude material was purified by column chromatography (Silica Gel 230-400 mesh; 2-5percent methanol in CH2CI2 as eluent) to give 2-[4-(2-dimethylamino ethoxy) phenyl] pyrano[2,3-b]pyridine-4-one as white solid (0.445 g, 72percent). The above compound (0.2 g, 0.644 mmol) was dissolved in anhydrous Dichloromethane (10 mL). HCI in ether (3 mL, 1.0 M) was added dropwise. A yellow precipitate was formed. The reaction mixture was stirred at room temperature for 30 min. under nitrogen. The solvent was removed and the crude compound was triturated with ether to give 2- (4-(2-(dimethylamino)ethoxy)phenyl)-4H-pyrano[2,3-b]pyridin-4-one dihydrochloride (0.24 g, 97percent) as a pale yellow solid. MS (ES) m/z: 311.98 (M+1 ), 310.94 (M); MP 236-2380C; A mixture of quinoxaline-6-carboxylic acid (2 g, 11.49 mmol) and thionyl chloride (30 mL) was stirred at reflux for 2 hours. The reaction mixture was concentrated to dryness using a rotary evaporator to afford quinoxaline-6- EPO <DP n="101"/>carboxylic acid chloride (crude quantitative). A solution of the above acid chloride (11.49 mmol) in DCM (50 mL) and pyridine (20 mL) was mixed with N,O-dimethyl hydroxylamine HCI salt (2.24 g, 23 mmol) and stirred at room temperature for 12 hours. The reaction was quenched by adding aqueous HCI (50 mL, 1 N), extracted with DCM (3x100 mL), concentrated using a rotary evaporator. The residue was further purified by column (Siψ2, Hexanes/EtOAc = 1 :3) to yield quinoxaline-6-carboxylic acid methoxy-methyl-amide (2 g, 80percent). To a solution of the above Weinreb amide (2.0 g, 9.2 mmol) in THF (30 mL) at O0C was added methyl magnesium bromide (3.9 mL, 11.6 mmol). The reaction mixture was stirred at O0C for 2 hours and then 1 hour at room temperature, quenched by adding aqueous HCI (20 mL, 1 N), extracted with DCM (3x100 mL), concentrated using a rotary evaporator. The residue was further-purified by column (SiO2, Hexanes/EtOAc = 1 :3) to yield 6-acetylquinoxaline (1.17 g, 74percent). A solution of 2- chloronicotinic acid ethyl ester (5.0 g, 27 mmol) in MeOH (25 mL) was mixed with sodium methoxide (25.6 mL, 112.5 mmol) and stirred at reflux for 12 hours. The reaction was quenched by adding water (100 mL), extracted with DCM (3x100 mL), concentrated using a rotary evaporator to afford 2-methoxynicotinic acid methyl ester (3.2 g, 71percent). A solution of 6-acetylquinoxaline (0.62 g, 3.6 mmol), 2- methoxynicotinic acid methyl ester (0.64 g, 3.8 mmol), and sodium hydride (0.46 g, 11.4 mmol) in THF (100 mL) was stirred at room temperature for 16 hours. The reaction was quenched by adding water (100 mL) and AcOH (20 mL), extracted with dichloromethane (3x100 mL), and concentrated using a rotary evaporator. The residue was re-dissolved in DCM (5 mL) and MeOH (3 mL) and was diluted with Hexanes (50 mL). The solid was removed by filtration and the filtrate was concentrated to afford the diketo compound (0.7 g, 60percent). A solution of the above diketone (0.4 g, 1.3 mmol) in AcOH (50 mL) and sulfuric acid (cone, 15 drops) was stirred at reflux for 1 hour. Most of the solvent was removed using a rotary evaporator. The residue was re-dissolved in MeOH and neutralized with potassium carbonate to pH = 8. The solid residue was removed by filtration, washed with MeOH and DCM. The filtrate was extracted with CH2CI2 (3x100 mL) and concentrated using a rotary evaporator. The solid residue was purified by column (SiO2, Hexanes/EtOAc/MeOH = 2:2:1) to afford 2-(quinoxalin-6-yl)-4H- EPO <DP n="102"/>pyrano[2,3-b]pyridin-4-one (90 mg, 24percent); MS (ES) m/z: 276 (M+1 ); MP 272.3- 274.80C |
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