1-(5-bromo-2-fluorophenyl)ethanone

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a stirred solution of compound 14 (106 g, 404 mmol) in anhydrous THF (1.7 L) was added a solution of methyl magnesium bromide in diethyl ether (3.0 M, 270 mL, 808 mmol) at 0° C. under nitrogen. After addition was completed, the reaction mixture was stirred at 0° C. for 6.5 h. After this time, the solution was poured to a cold 2 N hydrochloric acid (1 L) and warmed to room temperature. The resulting mixture was extracted with ethyl acetate (2×1 L). The combined extracts were washed with saturated aqueous NaHCO3 (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 15 (85.2 g, 97%) as an orange oil: 1H NMR (300 MHz, CDCl3) δ 7.98 (dd, J=6.4, 2.6 Hz, 1H), 7.61 (ddd, J=8.7, 4.3, 2.6 Hz, 1H), 7.05 (dd, J=10.4, 8.7, 1H), 2.64 (d, J=4.9, 3H); ESI MS m/z 217 [M+H]+. After addition warmed to room temperature The resulting mixture was extracted with ethyl acetate (2×1 L) The combined extracts were washed with saturated aqueous NaHCO3 (500 mL), brine (500 mL) dried over anhydrous sodium sulfate filtered concentrated under reduced pressure

反応条件: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Commercially available 1-(5-bromo-2-fluorophenyl)ethanone (140 g, 645 mmol, Eq: 1.0) [CAS No. 477-89-3], (R)-2-methylpropane-2-sulfinamide (78.2, 645 mmol, Eq: 1.0) and titanium(IV) ethoxide (221 g, 204 ml, 968 mmol, Eq: 1.5) were dissolved in tetrahydrofuran (1.19 l) and the mixture heated to 75° C. and stirred at this temperature overnight. The mixture was cooled to 50° C., sat. potassium sodium tartrate solution (1.17 l, 2.58 mol, Eq: 4) was added and the mixture stirred at this temperature for 1.5 hours. The mixture was diluted with TBME, the layers separated, the organic layer washed with sulfuric acid (0.05 M, 2.36 l, 118 mmol, Eq: 0.183), sat. Na2CO3-solution (645 ml, 645 mmol, Eq: 1.00) and brine, dried over Na2SO4 and the solvent evaporated leaving an dark orange solid, which was purified by trituration with n-heptane to give the first batch (144.7 g) as an off-white solid. From the mother liquor another batch (23.0 g) was obtained by trituration with pentane, yet another batch was obtained by silica gel column chromatography with n-heptane/ethyl acetate. Total yield of (R,E)-N-(1-(5-bromo-2-fluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (180.7 g, 564 mmol, 87.5% yield) as an off-white solid. MS (ISP): m/z=320.3 [M+H]+ and 322.0 [M+2+H]+. The mixture was cooled to 50° C. the mixture stirred at this temperature for 1.5 hours the layers separated dried over Na2SO4 the solvent evaporated leaving an dark orange solid, which was purified by trituration with n-heptane to give the first batch (144.7 g) as an off-white solid

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

実験手順: The reaction of commercially available 1-(5-bromo-2-fluoro-phenyl)-ethanone with potassium cyanide and ammonium carbonate in ethanol in an autoclave at 120° C. for 16 h yielded the title compound as light yellow solid. Mass (calculated) C10H8BrFN2O2 [287.087]; (found) [M−H]−=285, 287.

反応条件: temp:117.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compound (4c) (66.0 g, 304 mmol) and 350 ml anhydrous hydrazine were charged into a 1 Liter round bottom flask. The resulting reaction mixture was refluxed at 117° C. for 5 hours. After the reaction mixture was allowed to cool down to room temperature, the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 ml water was poured into the resulting solid and water was filtered off. The solid was washed with 400 ml water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 ml EtOAc and washed with 300 ml water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94%). The product was used directly for the next step without further purification. The resulting reaction mixture to cool down to room temperature the excess hydrazine was evaporated under reduced pressure to yield a white solid was filtered off The solid was washed with 400 ml water twice To remove the trace amount of hydrazine washed with 300 ml water twice The EtOAc layer was then dried over sodium sulfate Removal of the solvent

反応条件: temp:117.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compound (4c) (66.0 g, 304 mmol) and 350 ml anhydrous hydrazine were charged into a 1 Liter round bottom flask. The resulting reaction mixture was refluxed at 117° C. for 5 hours. After the reaction mixture was allowed to cool down to room temperature, the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 ml water was poured into the resulting solid and water was filtered off. The solid was washed with 400 ml water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 ml EtOAc and washed with 300 ml water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94%). The product was used directly for the next step without further purification. The resulting reaction mixture to cool down to room temperature the excess hydrazine was evaporated under reduced pressure to yield a white solid was filtered off The solid was washed with 400 ml water twice To remove the trace amount of hydrazine washed with 300 ml water twice The EtOAc layer was then dried over sodium sulfate Removal of the solvent

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compound 4b (50.0g, 228 mmol) along with 300 ml dichloromethane was charged into 2 liter round bottom flask. Crushed pyridinum dichromate (171.0 g, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 20° C. The resulting reaction mixture was filtered through celite and washed with ether (500 ml×3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica gel pad (3 inches in length) withlo% EtOAc in hexane. The resulting product (42.0 g, yield=84%) was used for the following step. both added into the flask The resulting reaction mixture was filtered through celite washed with ether (500 ml×3) The combined filtrate was concentrated under reduced pressure The crude product was eluted through a short silica gel pad (3 inches in length) withlo% EtOAc in hexane

反応条件: temp:117.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compound (4c) (66.0 g, 304 mmol) and 350 ml anhydrous hydrazine were charged into a 1 Liter round bottom flask. The resulting reaction mixture was refluxed at 117° C. for 5 hours. After the reaction mixture was allowed to cool down to room temperature, the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 ml water was poured into the resulting solid and water was filtered off. The solid was washed with 400 ml water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 ml EtOAc and washed with 300 ml water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94%). The product was used directly for the next step without further purification. The resulting reaction mixture to cool down to room temperature the excess hydrazine was evaporated under reduced pressure to yield a white solid was filtered off The solid was washed with 400 ml water twice To remove the trace amount of hydrazine washed with 300 ml water twice The EtOAc layer was then dried over sodium sulfate Removal of the solvent

反応条件: temp:117.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compound (4c) (66.0 g, 304 mmol) and 350 ml anhydrous hydrazine were charged into a 1 Liter round bottom flask. The resulting reaction mixture was refluxed at 117° C. for 5 hours. After the reaction mixture was allowed to cool down to room temperature, the excess hydrazine was evaporated under reduced pressure to yield a white solid. 400 ml water was poured into the resulting solid and water was filtered off. The solid was washed with 400 ml water twice. To remove the trace amount of hydrazine, the white solid was taken up in 600 ml EtOAc and washed with 300 ml water twice and saturated brine solution. The EtOAc layer was then dried over sodium sulfate. Removal of the solvent gave the desired product as a white amorphous solid (60.0 g, yield=94%). The product was used directly for the next step without further purification. The resulting reaction mixture to cool down to room temperature the excess hydrazine was evaporated under reduced pressure to yield a white solid was filtered off The solid was washed with 400 ml water twice To remove the trace amount of hydrazine washed with 300 ml water twice The EtOAc layer was then dried over sodium sulfate Removal of the solvent

反応条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Compound 4b (50.0 g, 228 mmol) along with 300 ml dichloromethane was charged into 2 liter round bottom flask. Crushed pyridinum dichromate (171.0 g, 456 mmol) and powdered molecular sieves (10 g) were both added into the flask. The heterogeneous reaction mixture was stirred for 16 hours at 20° C. The resulting reaction mixture was filtered through celite and washed with ether (500 ml×3). The combined filtrate was concentrated under reduced pressure. The crude product was eluted through a short silica gel pad (3 inches in length) with 10% EtOAc in hexane. The resulting product (42.0 g, yield=84%) was used for the following step. both added into the flask The resulting reaction mixture was filtered through celite washed with ether (500 ml×3) The combined filtrate was concentrated under reduced pressure The crude product was eluted through a short silica gel pad (3 inches in length) with 10% EtOAc in hexane

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

実験手順: To 1-(5-Bromo-2-fluoro-phenyl)-ethanone 103 (95.7 g, 0.441 mol) was added anhydrous hydrazine (240 mL, 7.65 mol). The reaction mixture was heated under reflux for 10 hours. The reaction mixture was allowed to cool to room temperature and was stirred for 16 hours. The reaction mixture was added to ice (1.4 L). The reaction mixture was stirred for 30 minutes. The reaction mixture was filtered and the white solid product was washed with water. The white solid was dried in a vacuum oven to afford the desired 5-bromo-3-methyl-1H-indazole 104 (86.1 g, 0.408 mol) which was used without further purification. The reaction mixture was heated under reflux for 10 hours The reaction mixture was stirred for 30 minutes The reaction mixture was filtered the white solid product was washed with water The white solid was dried in a vacuum oven