1-[[bromo(difluoro)methyl]-ethoxyphosphoryl]oxyethane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl bromodifluoromethylphosphonate (1.13 g, 4.22 mmol) was added in one portion to a cooled (−30° C.) solution of tert-butyl 5-hydroxy-3-iodo-1H-indazole-1-carboxylate and KOH (2.36 g, 42.2 mmol) in MeCN/H2O (20 mL/20 mL). The reaction mixture was allowed to warm to room temperature. After 20 min, the reaction mixture was diluted with EtOAc (15 mL), and the organic phase was separated. The water phase was extracted with EtOAc (10 mL). The combined organic layers were dried over Na2SO4. Evaporation of the solvent gave a crude product that was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1) to give tert-butyl 5-(difluoromethoxy)-3-iodo-1H-indazole-1-carboxylate (0.41 g, 47% over two steps) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.13 (d, 1H, J=9.0 Hz), 7.39 (dd, 1H, J=9, 2.4 Hz), 7.23 (d, 1H, J=2.4 Hz), 6.57 (t, 1H, J=73.2 Hz), 1.73 (s, 9H). the organic phase was separated The water phase was extracted with EtOAc (10 mL) The combined organic layers were dried over Na2SO4 Evaporation of the solvent gave a crude product that was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl bromodifluoromethylphosphonate (1.13 g, 4.22 mmol) was added in one portion to a cooled (−30° C.) solution of tert-butyl 5-hydroxy-3-iodo-1H-indazole-1-carboxylate and KOH (2.36 g, 42.2 mmol) in MeCN/H2O (20 mL/20 mL). The reaction mixture was allowed to warm to room temperature. After 20 min, the reaction mixture was diluted with EtOAc (15 mL), and the organic phase was separated. The water phase was extracted with EtOAc (10 mL). The combined organic layers were dried over Na2SO4. Evaporation of the solvent gave a crude product that was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1) to give tert-butyl 5-(difluoromethoxy)-3-iodo-1H-indazole-1-carboxylate (0.41 g, 47% over two steps) as a white solid. 1H NMR (300 MHz, CDCl3): δ 8.13 (d, 1H, J=9.0 Hz), 7.39 (dd, 1H, J=9, 2.4 Hz), 7.23 (d, 1H, J=2.4 Hz), 6.57 (t, 1H, J=73.2 Hz), 1.73 (s, 9H). the organic phase was separated The water phase was extracted with EtOAc (10 mL) The combined organic layers were dried over Na2SO4 Evaporation of the solvent gave a crude product that was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl bromodifluoromethylphosphonate (9 g, 10.9 mmol) was added in one portion to a cooled (dry ice-acetone bath) solution of 3-iodo-1-methyl-1H-indazol-5-ol (3 g, 37.8 mmol) and KOH (15 g, 267 mmol) in CH3CN (50 mL) and H2O (50 mL) with stirring, the reaction mixture was warmed to room temperature and stirred for 0.5 h, the mixture was diluted with EtOAc (50 mL), The organic layer was washed with H2O (50 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=3:1) to give 5-(difluoromethoxy)-3-iodo-1-methyl-1H-indazole (1.85 g, 53%) as a white solid. LCMS: (M+H)+=325; 1H NMR (300 MHz, CDCl3), δ 7.36-7.33 (m, 1H), 7.28-7.23 (m, 1H), 7.19 (s, 1H), 6.53 (t, 1H, J=73.5 Hz), 4.09 (s, 3H). stirred for 0.5 h The organic layer was washed with H2O (50 mL), brine (100 mL) dried over Na2SO4 concentrated under reduced pressure the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=3:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diethyl bromodifluoromethylphosphonate (9 g, 10.9 mmol) was added in one portion to a cooled (dry ice-acetone bath) solution of 3-iodo-1-methyl-1H-indazol-5-ol (3 g, 37.8 mmol) and KOH (15 g, 267 mmol) in CH3CN (50 mL) and H2O (50 mL) with stirring, the reaction mixture was warmed to room temperature and stirred for 0.5 h, the mixture was diluted with EtOAc (50 mL), The organic layer was washed with H2O (50 mL), brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=3:1) to give 5-(difluoromethoxy)-3-iodo-1-methyl-1H-indazole (1.85 g, 53%) as a white solid. LCMS: (M+H)+=325; 1H NMR (300 MHz, CDCl3), δ 7.36-7.33 (m, 1H), 7.28-7.23 (m, 1H), 7.19 (s, 1H), 6.53 (t, 1H, J=73.5 Hz), 4.09 (s, 3H). stirred for 0.5 h The organic layer was washed with H2O (50 mL), brine (100 mL) dried over Na2SO4 concentrated under reduced pressure the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=3:1)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (40 g, 714 mmol) was dissolved in water (100 mL) and acetonitrile (100 mL). The reaction mixture was cooled to −78° C. 1-(5-Fluoro-2-hydroxyphenyl)ethan-1-one (5 g, 32.44 mmol) was added to the reaction mixture and stirred for 5 minutes at −78° C. Diethyl[bromo(difluoro)methyl]phosphonate (11.5 mL, 64.88 mmol) was added dropwise to the mixture. The reaction mixture was stirred at −78° C. for 30 minutes, then warmed to room temperature over 1.5 h. The reaction mixture was diluted using EtOAc (2×100 mL). The mixture was washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude orange oil was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with 0 to 40% ethyl acetate in heptanes, to afford the title compound (4.86 g, 74%) as a clear oil. δH (500 MHz, CDCl3) 7.47 (ddd, J 0.5, 3.0, 8.5 Hz, 1H), 7.24-7.14 (m, 2H), 6.55 (t, J 73.3 Hz, 1H), 2.62 (s, 3H). Method B HPLC-MS: RT 1.84 minutes, no mass ion observed. The reaction mixture was stirred at −78° C. for 30 minutes warmed to room temperature over 1.5 h The reaction mixture was diluted The mixture was washed with brine (50 mL) The organic phase was dried over sodium sulfate concentrated in vacuo The crude orange oil was purified by chromatography on silica (Biotage, 100 g cartridge) eluting with 0 to 40% ethyl acetate in heptanes

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (40 g, 714 mmol) was dissolved in water (100 mL) and acetonitrile (100 mL). The reaction mixture was cooled to −78° C. 1-(5-Fluoro-2-hydroxyphenyl)ethan-1-one (5 g, 32.44 mmol) was added to the reaction mixture and stirred for 5 minutes at −78° C. Diethyl[bromo(difluoro)methyl]phosphonate (11.5 mL, 64.88 mmol) was added dropwise to the mixture. The reaction mixture was stirred at −78° C. for 30 minutes, then warmed to room temperature over 1.5 h. The reaction mixture was diluted using EtOAc (2×100 mL). The mixture was washed with brine (50 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude orange oil was purified by chromatography on silica (Biotage, 100 g cartridge), eluting with 0 to 40% ethyl acetate in heptanes, to afford the title compound (4.86 g, 74%) as a clear oil. δH (500 MHz, CDCl3) 7.47 (ddd, J 0.5, 3.0, 8.5 Hz, 1H), 7.24-7.14 (m, 2H), 6.55 (t, J 73.3 Hz, 1H), 2.62 (s, 3H). Method B HPLC-MS: RT 1.84 minutes, no mass ion observed. The reaction mixture was stirred at −78° C. for 30 minutes warmed to room temperature over 1.5 h The reaction mixture was diluted The mixture was washed with brine (50 mL) The organic phase was dried over sodium sulfate concentrated in vacuo The crude orange oil was purified by chromatography on silica (Biotage, 100 g cartridge) eluting with 0 to 40% ethyl acetate in heptanes

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately −20° C. 1-(2-Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl[bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3×200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes. to warm to room temperature over 1 h The mixture was extracted with ethyl acetate (3×200 mL) the combined organic layers were washed with brine (50 mL) dried over magnesium sulfate concentrated under vacuum The mixture was purified by flash chromatography

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately −20° C. 1-(2-Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl[bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes. The mixture was then allowed to warm to room temperature over 1 h. The mixture was extracted with ethyl acetate (3×200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound (16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ m/z 187, RT 1.77 minutes. to warm to room temperature over 1 h The mixture was extracted with ethyl acetate (3×200 mL) the combined organic layers were washed with brine (50 mL) dried over magnesium sulfate concentrated under vacuum The mixture was purified by flash chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-hydroxy-3,4-dihydroisoquinolin-1(2H)-one (1h, 0.1 g, 0.237 mmol) and KOH (0.265 g, 4.74 mmol) in CH3CN/H2O (10 mL/1 mL) was added diethyl [bromo(difluoro)methyl]phosphonate (0.126 g, 0.474 mmol) at −78° C. under N2 atmosphere. The resulting mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with EtOAc (20 mL) and H2O (5 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×10 mL). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by prep. TLC (petroleum ether/EtOAc, 4:1) to obtain 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-7-(difluoromethoxy)-3,4-dihydroisoquinolin-1(2H)-one (1i, 0.08 g, 72%) as a yellow oil. The organic layer was separated the aqueous layer was extracted with EtOAc (2×10 mL) washed with brine (10 mL) dried over Na2SO4 concentrated under vacuum The residue was purified by prep