methyl 4-(bromomethyl)-2-fluorobenzoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Use a method similar to the Example 428, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and methyl 4-bromomethyl-2-fluorobenzoate, to give the desired intermediate as a white solid.

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (7-Methyl-2-propyl-3H-benzoimidazol-5-yl)methanol (3 g, 15 mmol; prepared as described in Preparation 7) was dissolved in 20 mL of dry DMF. The solution was cooled to 0° C. and sodium hydride (598 mg, 15 mmol, 60 wt % in mineral oil) was added. The mixture was stirred for 30 minutes. 4-Bromomethyl-2-fluorobenzoic acid methyl ester (3.7 g, 15 mmol; prepared as described in Preparation 3) in 50 mL of DMF was added, and the mixture was warmed to room temperature and stirred for 10 minutes. The solution was partitioned between EtOAc (300 mL) and 150 mL 10% LiCl (aqueous). The organic layer was separated, dried over MgSO4 and concentrated. The concentrate was flash chromatographed to produce Intermediate (8a) as a clear oil (2.4 g). MS m/z: [M+H+] calcd for C21H23FN2O3, 371.7. found 371.0. the mixture was warmed to room temperature stirred for 10 minutes The solution was partitioned between EtOAc (300 mL) and 150 mL 10% LiCl (aqueous) The organic layer was separated dried over MgSO4 concentrated chromatographed

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (7-Methyl-2-propyl-3H-benzoimidazol-5-yl)methanol (3 g, 15 mmol; prepared as described in Preparation 7) was dissolved in 20 mL of dry DMF. The solution was cooled to 0° C. and sodium hydride (598 mg, 15 mmol, 60 wt % in mineral oil) was added. The mixture was stirred for 30 minutes. 4-Bromomethyl-2-fluorobenzoic acid methyl ester (3.7 g, 15 mmol; prepared as described in Preparation 3) in 50 mL of DMF was added, and the mixture was warmed to room temperature and stirred for 10 minutes. The solution was partitioned between EtOAc (300 mL) and 150 mL 10% LiCl (aqueous). The organic layer was separated, dried over MgSO4 and concentrated. The concentrate was flash chromatographed to produce Intermediate (8a) as a clear oil (2.4 g). MS m/z: [M+H+] calcd for C21H23FN2O3, 371.7. found 371.0. the mixture was warmed to room temperature stirred for 10 minutes The solution was partitioned between EtOAc (300 mL) and 150 mL 10% LiCl (aqueous) The organic layer was separated dried over MgSO4 concentrated chromatographed

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of [4-butyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol (1.02 g, 3.24 mmol) in anhydrous DMF (150 mL) add cesium carbonate (2.7 g, 8.10 mmol) and 4-bromomethyl-2-fluoro-benzoic acid methyl ester (0.8 g, 3.24 mmol). Stir the resulting mixture overnight then pour into a 1M aqueous solution of potassium hydrogenophosphate and extracted three times with diisopropyl ether. Wash the combined extracts with water, dry over MgSO4, filter and concentrate under vacuum. Purify the residue by flash chromatography on silica gel (eluting with a gradient of heptane/ethyl acetate) to give the title compound (0.3 g) as a yellow solid. extracted three times with diisopropyl ether Wash the combined extracts with water dry over MgSO4 filter concentrate under vacuum Purify the residue by flash chromatography on silica gel ( eluting with a gradient of heptane/ethyl acetate)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 2-fluoro-4-methyl-benzoic acid methyl ester (1.12 g, 6.66 mmol) in carbon tetrachloride (12 mL) add N-bromosuccinimide (1.18 g, 6.66 mmol) and benzoyl peroxide (10 mg). Heat the resulting mixture to 60° C. for 15 hours then concentrate under vacuum to half and filter. Concentrate the filtrate under vacuum and purify the resulting crude product by flash chromatography on silica gel (eluting with 5/1 heptane/ethyl acetate) to give the title compound (1.35 g) as a white solid. then concentrate under vacuum to half filter Concentrate the filtrate under vacuum purify the resulting crude product by flash chromatography on silica gel (eluting with 5/1 heptane/ethyl acetate)

反応条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 7.17 g of 6-nitroindan-5-ol was dissolved in 80.0 mL of DMF, and 10.9 g of methyl 4-(bromomethyl)-2-fluorobenzoate and 6.63 g of potassium carbonate were added thereto, followed by stirring at 50° C. overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1) to obtain 11.1 g of methyl 2-fluoro-4-{[(6-nitro-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzoate. To the reaction liquid followed by extraction with ethyl acetate the organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1 to 1:1)

反応条件: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Methyl 4-(bromomethyl)-2-fluorobenzoate (0.300 g; 1.21 mmol) was suspended in a mixture of water (1 mL) and 1,2-dimethoxyethane (3 mL) and 3-fluorophenylboronic acid (0.193 g; 1.34 mmol), tetrakis(triphenylphosphine)palladium(0) (0.071 g; 0.0061 mmol) and sodium carbonate (0.259 g; 2.43 mmol) were successively added. The resulting suspension was heated at 130° C. in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 1 to 12% of ethyl acetate in heptane) to give 0.164 g (52%) of methyl 2-fluoro-4-(3-fluorobenzyl)benzoate as an oily residue. were successively added washed with water The organic layer was concentrated under reduced pressure the residue was purified by flash chromatography on silica gel (eluent 1 to 12% of ethyl acetate in heptane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of methyl 2-fluoro-4-methylbenzoate (0.655 g; 3.89 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g; 4.67 mmol) and benzoyl peroxide (0.097 g; 0.390 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12% ethyl acetate in heptane) to give 0.676 g (70%) of methyl 4-(bromomethyl)-2-fluorobenzoate as a solid which was directly used in the next step. The mixture was refluxed for 18 hours the resulting suspension was concentrated under reduced pressure The residue was purified by flash chromatography on silica gel (eluent 1 to 12% ethyl acetate in heptane)

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of 2-fluoroaniline (0.12 mL, 1.2 mmol) and potassium carbonate (207 mg, 1.5 mL) in DMF (5 mL) was added methyl 4-(bromomethyl)-2-fluoro-benzoate (247 mg, 1 mmol). The mixture was heated to 60° C. for 18 hours. The solvent was removed in vacuo. The mixture was partitioned between DCM (15 mL) and water (15 mL), the layers were separated and the organic phase was passed through a hydrophobic fit. The solvent was removed in vacuo and the residue was used directly in the next step without any further purification. LCMS (Method 2): [MH+]=278 at 3.60 min. The solvent was removed in vacuo The mixture was partitioned between DCM (15 mL) and water (15 mL) the layers were separated The solvent was removed in vacuo the residue was used directly in the next step without any further purification at 3.60 min.

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (7-Methyl-2-propyl-3H-benzoimidazol-5-yl)methanol (3 g, 15 mmol; prepared as described in Preparation 7) was dissolved in 20 mL of dry DMF. The solution was cooled to 0° C. and sodium hydride (598 mg, 15 mmol, 60 wt % in mineral oil) was added. The mixture was stirred for 30 minutes. 4-Bromomethyl-2-fluorobenzoic acid methyl ester (3.7 g, 15 mmol; prepared as described in Preparation 3) in 50 mL of DMF was added, and the mixture was warmed to room temperature and stirred for 10 minutes. The solution was partitioned between EtOAc (300 mL) and 150 mL 10% LiCl (aqueous). The organic layer was separated, dried over MgSO4 and concentrated. The concentrate was flash chromatographed to produce Intermediate (8a) as a clear oil (2.4 g). MS m/z: [M+H+] calcd for C21H23FN2O3, 371.7. found 371.0. the mixture was warmed to room temperature stirred for 10 minutes The solution was partitioned between EtOAc (300 mL) and 150 mL 10% LiCl (aqueous) The organic layer was separated dried over MgSO4 concentrated chromatographed

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Use a method similar to the Example 428, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and methyl 4-bromomethyl-2-fluorobenzoate, to give the desired intermediate as a white solid.