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In N,N-dimethyl-formamide; |
EXAMPLE 114A 1-bromo-4-fluoro-2-methoxybenzene A mixture of 2-bromo-5-fluorophenol (2 mL, 17.8 mmol)), sodium hydride (0.5 g, 20.8 mmol) and iodomethane (5 mL, 82 mmol) in DMF (20 mL) was heated to 60 C., stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. |
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In N,N-dimethyl-formamide; |
Example 114A 1-bromo-4-fluoro-2-methoxybenzene A mixture of 2-bromo-5-fluorophenol (2 mL, 17.8 mmol)), sodium hydride (0.5 g, 20.8 mmol) and iodomethane (5 mL, 82 mmol) in DMF (20 mL) was heated to 60 C., stirred for 16 hours, diluted with ethyl acetate (100 mL), washed sequentially with 1M HCl, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. |
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With potassium carbonate; In water; acetone; |
EXAMPLE 108 8-Fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 208, structure 41 of Scheme XI, where R1 =F, R2 =H) 2-Bromo-5-fluoroanisole (structure 36 of Scheme XI, where R1 =F, R2 =H) In a 250 mL r.b. flask, a solution of 2-bromo-5-fluorophenol (Lancaster: 7.0 mL, 64 mmol, 1.0 equivuiv) in acetone (140 mL) was treated with iodomethane (Aldrich: 4.8 mL, 77 mmol, 1.2 equivuiv), potassium carbonate (8 g), and water (1 mL). The reaction mixture was heated at reflux for 6 h, cooled to rt, clarified with H2 O (40 mL), and the bulk of the volatiles was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3*120 mL); the extracts were washed with brine (1*80 mL), combined, dried (K2 CO3), filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65 C., 0.7 Torr) afforded 13.22 g (quant) of 2-bromo-5-fluoroanisole as a colorless liquid. Data for 2-bromo5-fluoroanisole: 1 H NMR (400 MHz, CDCl3): 7.46 (dd, J=10.6, 8.7, 1H); 6.64 (dd, J=10.4, 2.8, 1H); 5.58 (dt, J=10.4, 2.4, 1H); 3.88 (s, 3H). |
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With potassium carbonate; In water; acetone; |
EXAMPLE 108 8-Fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 208, structure 41 of Scheme XI, where R1 =F, R2 =H) 2-Bromo-5-fluoroanisole (structure 36 of Scheme XI, where R1 =F, R2 =H) In a 250 mL r.b. flask, a solution of 2-bromo-5-fluorophenol (Lancaster: 7.0 mL, 64 mmol, 1.0 equivuiv) in acetone (140 mL) was treated with iodomethane (Aldrich: 4.8 mL, 77 mmol, 1.2 equivuiv), potassium carbonate (8 g), and water (1 mL). The reaction mixture was heated at reflux for 6 h, cooled to rt, clarified with H2 O (40 mL), and the bulk of the volatiles was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3*120 mL); the extracts were washed with brine (1*80 mL), combined, dried (K2 CO3), filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65 C., 0.7 Torr) afforded 13.22 g (quant) of 2-bromo-5-fluoroanisole as a colorless liquid. Data for 2-bromo-5-fluoroanisole: 1 H NMR (400 MHz, CDCl3): 7.46 (dd, J=10.6, 8.7, 1H); 6.64 (dd, J=10.4, 2.8, 1H); 5.58 (dt, J=10.4, 2.4, 1H); 3.88 (s, 3H). |
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With potassium carbonate; In water; acetone; |
EXAMPLE 108 8-Fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 208, structure 41 of Scheme XI, where R1 =F, R2 =H) 2-Bromo-5-fluoroanisole (structure 36 of Scheme XI, where R1 =F, R2 =H) In a 250 mL r.b. flask, a solution of 2-bromo-5-fluorophenol (Lancaster: 7.0 mL, 64 mmol, 1.0 equivuiv) in acetone (140 mL) was treated with iodomethane (Aldrich: 4.8 mL, 77 mmol, 1.2 equivuiv), potassium carbonate (8 g), and water (1 mL). The reaction mixture was heated at reflux for 6 h, cooled to rt, clarified with H2 O (40 mL), and the bulk of the volatiles was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3*120 mL); the extracts were washed with brine (1*80 mL), combined, dried (K2 CO3), filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65 C., 0.7 Torr) afforded 13.22 g (quant) of 2-bromo-5-fluoroanisole as a colorless liquid. Data for 2-bromo-5-fluoroanisole: 1 H NMR (400 MHz, CDCl3): 7.46 (dd, J=10.6, 8.7, 1 H); 6.64 (dd, J=10.4, 2.8, 1 H); 5.58 (dt, J=10.4, 2.4, 1 H); 3.88 (s, 3 H). |
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With potassium carbonate; In water; acetone; |
EXAMPLE 108 8-Fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 208, structure 41 of Scheme XI, where R1 =F, R2 =H) 2-Bromo-5-fluoroanisole (structure 36 of Scheme XI, where R1 =F, R2 =H) In a 250 mL r.b. flask, a solution of 2-bromo-5-fluorophenol (Lancaster: 7.0 mL, 64 mmol, 1.0 equivuiv) in acetone (140 mL) was treated with iodomethane (Aldrich: 4.8 mL, 77 mmol, 1.2 equivuiv), potassium carbonate (8 g), and water (1 mL). The reaction mixture was heated at reflux for 6 h, cooled to rt, clarified with H2 O (40 mL), and the bulk of the volatiles was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3*120 mL); the extracts were washed with brine (1*80 mL), combined, dried (K2 CO3), filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65 C., 0.7 Torr) afforded 13.22 g (quant) of 2-bromo-5-fluoroanisole as a colorless liquid. Data for 2-bromo-5-fluoroanisole: 1 H NMR (400 MHz, CDCl3): 7.46 (dd, J=10.6, 8.7, 1 H); 6.64 (dd, J=10.4, 2.8, 1 H); 5.58 (dt, J=10.4, 2.4, 1 H); 3.88 (s, 3 H). |
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With potassium carbonate; In water; acetone; |
EXAMPLE 108 8-Fluoro-1,2-dihydro-2,2,4-trimethyl-5-coumarino[3,4-f]quinoline (Compound 208, structure 41 of Scheme XI, where R1 =F, R2 =H) 2-Bromo-5-fluoroanisole (structure 36 of Scheme XI, where R1 =F, R2 =H) In a 250 mL r.b. flask, a solution of 2-bromo-5-fluoro. phenol (Lancaster: 7.0 mL, 64 mmol, 1.0 equivuiv) in acetone (140 mL) was treated with iodomethane (Aldrich: 4.8 mL, 77 mm01, 1.2 equivuiv), potassium carbonate (8 g), and water (1 mL). The reaction mixture was heated at reflux for 6 h, cooled to rt, clarified with H2 O (40 mL), and the bulk of the volatiles was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3*120 mL); the extracts were washed with brine (1*80 mL), combined, dried (K2 CO3), filtered, and concentrated to a clear oil. Bulb-to-bulb distillation (60-65 C., 0.7 Torr) afforded 13.22 g (quant) of 2-bromo-5-fluoroanisole as a colorless liquid. Data for 2-bromo-5-fluoroanisole: 1 H NMR (400 MHz, CDCl3): 7.46 (dd, J=10.6, 8.7, 1 H); 6.64 (dd, J=10.4, 2.8, 1 H); 5.58 (dt, J=10.4, 2.4, 1 H); 3.88 (s, 3 H). |
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With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 3h; |
Reference Example 29 (1) In 15 ml of N, N-dimethylformamide were dissolved 3.94 g of [2-BROMO-5-FLUOROPHENOL] and 1.62 ml of methyl iodide, slowly added thereto was 5.08 g of potassium carbonate under ice-cooling. The mixture was stirred at room temperature for 3 hours. After insoluble matters were removed by filtration, distilled water was added to the filtrate, and the mixture was extracted with diethyl ether and washed with saturated brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography- (hexane : ethyl acetate=19: [1-9] : 1), to give 4.10 g of [1-BROMO4-FLUORO-2-] methoxybenzene. MS (m/z): 204/206 [(M++L) O] (2) To 7 ml of tetrahydrofuran were added 486 mg of magnesium and trace of iodine, and dropped thereto was a solution of 4.10 g of the compound of the above [(1)] in 16 ml of tetrahydrofuran, to prepare Grignard reagent. To the solution, a solution of 1.96 g of 4-methoxypyridine in 7 ml of tetrahydrofuran was added dropwise under nitrogen atmosphere [AT-60C] or below. Subsequently, a solution of 3.75 g of benzyl chloroformate in 18 ml of tetrahydrofuran was added dropwise, and the mixture was stirred for 3 hours. The temperature of the mixture was raised to room temperature, and 40 ml of a 5% aqueous citric acid solution was added thereto. The mixture was extracted with ethyl acetate and washed with saturated brine. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=2: [1-1] : 2), to give 3.15 g of [1-BENZYLOXYCARBONYL-2- (4-FLUORO-2-METHOXYPHENYL)-4-OXO-] 3,4-dihydro-2H-pyridine. MS (m/z): 356 [[M++1]] (3) In a mixed solution of 79 ml of ethanol and 6 ml of tetrahydrofuran was dissolved 3.15 g of the compound of the above (2), and added thereto was 706 mg of sodium borohydride and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and distilled water was added to the residue. The mixture was extracted with chloroform, and the organic layer was dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: acetone=19: [1-9] : 1), to give 1.62 g of [1-BENZYLOXYCARBONYL-2- (4-FLUORO-2-] methoxyphenyl)-4-hydroxypiperidine. MS (m/z): 360 [[M++1]] (4) In 20 ml of toluene was dissolved 1.62 g of the compound of the above (3), added thereto was 876 mg of 1, [1'-] carbonyldiimidazole and the mixture was stirred at [60C] for an hour. Added thereto was 1.09 ml of ethanolamine, and the mixture was stirred at [60C] for 6 hours. To the reaction mixture was added distilled water and the mixture was extracted with chloroform. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (chloroform: acetone=4: [1-1] : 1), to give 1.81 g of [1-BENZYLOXYCARBONYL-2- (4-FLUORO-2-METHOXYPHENYL)-4- (2-] hydroxyethylaminocarbonyloxy) piperidine. MS (m/z): 447 [[M++L]] [(5)] In 20 ml of methanol was dissolved 1.81 g of the compound of the above (4), and added thereto was 90 mg of 10% palladium-carbon, and the mixture was stirred at room temperature for an hour under hydrogen atmosphere. After insoluble matters were removed by filtration, the filtrate was concentrated. To the residue was added diethyl ether and precipitates were collected by filtration, to give 1.30 g of [2- (4-FLUORO 2-METHOXYPHENYL)-4- (2-] hydroxyethylaminocarbonyloxy) piperidine as shown in Table 134 below. |
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With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 3h; |
A total of 10 g of 2-bromo-5-fluoro-phenol was dissolved in 105 ml of N,N-dimethylformamide, 10.9 g of potassium carbonate and 4.9 ml of iodomethane were added under ice-cooling, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extracting with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated, to give 9.75 g of the title compound as a yellow oil.1H-NMR ( 400 MHz, CDCl3 ) d 3.88 ( 3H, s ), 6.59 ( 1H, td, J = 8.4, 2.8 Hz ), 6.65 ( 1H, dd, J = 10.4, 2.8 Hz ), 7.47 ( 1H, dd, J = 8.4, 6.0 Hz ) |
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With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; |
To a mixture of 2-bromo-5-fluorophenol (10 g, 50.8 mmol) and iodomethane (11.2 g, 78.7 mmol) in dimethylformamide (100 mL) was added potassium carbonate (10.9 g, 79 mmol) and the mixture stirred at room temperature for 3 hrs. The mixture was diluted with water (100 mL) and extracted with ether (50 mL×3). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 11.3 g of 1-bromo-4-fluoro-2-methoxybenzene as an amber colored oil. |
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With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; |
1-Bromo-4-fluoro-2-methoxybenzene. To a mixture of 2-bromo-5-fluorophenol (10 g, 50.8 mmol) and iodomethane (11.2 g, 78.7 mmol) in dimethylformamide (100 mL) was added potassium carbonate (10.9 g, 79 mmol) and the mixture stirred at room temperature for 3 hrs. The mixture was diluted with water (100 mL) and extracted with ether (50 mL×3). The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 11.3 g of 1-bromo-4-fluoro-2-methoxybenzene as an amber colored oil. |
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With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; |
l-Bromo-4-fluoro-2-methoxybenzene. To a mixture of 2-bromo-5- fluorophenol (10 g, 50.8 mmol) and iodomethane (11.2 g, 78.7 mmol) in dimethylformamide (100 mL) was added potassium carbonate (10.9 g, 79 mmol) and the mixture stirred at room temperature for 3 hrs. The mixture was diluted with water (100 mL) and extracted with ether (50 mLx3). The combined extracts were washed <n="153"/>with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain 11.3 g of l-bromo-4-fluoro-2-methoxybenzene as an amber colored oil. |
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With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h; |
Step A: 1-bromo-4-fluoro-2-methoxybenzene: To a solution of2-bromo-5-fluorophenol (50 g,0.26 mol) in 300 mL ofDMF was added K2C03 (72.8 g, 0.520 mol) at one portion and Mel (44.6g, 0.310 mol) was added dropwise at 0 C. After the mixture was stirred at r.t. for 3 hours, thereaction was poured into IL of water and extracted with EtOAc (300 mL X 3). The combined organic layers were washed with water, brine, dried and concentrated to afford 1-bromo-4-fluoro-2-methoxybenzene. |
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With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;Cooling; |
Step A: 1-bromo-4-fluoro-2-methoxybenzene: A solution of 2-bromo-5-fluorophenol (15 g, 79mmol) in 125 mL of anhydrous DMF was added K2C03 (17.0 g, 138 mmol) and Mel (14.0 g,102 mmol) under cooling, then the reaction was stirred at room temperature for 3 hours. The mixture was poured to water, extracted with diethyl ether, washed with water and brine, dried over anhydrous Na2SO4 and concentrated to give 1 -bromo-4-fluoro-2-methoxybenzene. |
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With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h; |
To a solution of 2-bromo-5-fluorophenol (50 g, 0.26 mol) in 300 mLof DMF was added K2CO3 (72.8 g, 0.520 mol) at one portion and MeI (44.6 g, 0.310 mol) was added dropwise at0 C. After the mixture was stirred at r.t. for 3 hours, the reaction was poured into 1L of water and extracted withEtOAc (300 mL X 3). The combined organic layers were washed with water, brine, dried and concentrated to afford1-bromo-4-fluoro-2-methoxybenzene. |