5-bromo-2-fluorophenol

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

実験手順: To a stirred solution of 5-bromo-2-fluorophenol (5 g, 26.2 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.571 g, 39.3 mmol). After stirring for 10 min, chloromethyl methyl ether (2.386 mL, 31.4 mmol) was added dropwise to mixture and the mixture was then stirred for 1 hour at 0° C. The reaction was quenched with addition of saturated NH4Cl aq. and the mixture was poured into water (150 mL). The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-10% ethyl acetate in cyclohexane to give the title compound (5.90 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 3.55 (3H, s), 5.24 (2H, s), 6.95-7.02 (1H, m), 7.08-7.14 (1H, m), 7.36-7.40 (1H, m). the mixture was then stirred for 1 hour at 0° C The reaction was quenched with addition of saturated NH4Cl aq. the mixture was poured into water (150 mL) The mixture was extracted with ethyl acetate (30 mL×2) washed with brine (100 mL) dried over MgSO4 filtered evaporated in vacuo The crude residue was purified by chromatography on silica eluting with a gradient of 0-10% ethyl acetate in cyclohexane

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

実験手順: A solution of the crude 5-bromo-2-fluorophenol (4.0 g) prepared using literature procedure [EP0238272] and (2R)-glycidyl 3-nitrobenzenesulfonate (5.37 g) in dry acetone (175 mL) was treated with potassium carbonate (8.58 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chromatographed (20% ethyl acetate/hexanes) to yield the desired product (4.25 g) in 82% yield. 1H NMR (400 MHz, CDCl3): δ 7.15-6.96 (m, 3H), 4.33 and 4.30 (dd, 1H), 4.02 and 4.00 (dd, 1H), 3.41-3.37 (m, 1H), 2.97 (m, 1H), 2.78 (m, 1H). refluxed under nitrogen for 12 h The reaction was cooled filtered filtrate was concentrated in vacuo chromatographed (20% ethyl acetate/hexanes)

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

実験手順: The title compound was prepared in a similar manner as that described for Example 3 (step 4) from ethyl {5-[2-(4-hydroxypiperidin-1-yl)pyrimidin-5-yl]-2H-tetrazol-2-yl}acetate, 5-bromo-2-fluorophenol, triphenylphosphine and di-tert-butyl azodicarboxylate.

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-(tert-butyl)-1H-pyrazol-5-amine (1.00 g, 7.20 mmol) in toluene (13 mL) was added 5-bromo-2-fluorophenol (1.51 g, 7.90 mmol), potassium carbonate (2.08 g, 15.1 mmol), (1S,2S)—N,N′-bis-methyl-1,2-cyclohexane-diamine (0.20 g, 1.40 mmol) then copper (I) iodide (0.07 g, 0.36 mmol). The mixture was degassed then heated at 150° C. for 1 h using microwave irradiation. Another portion of copper (I) iodide (0.07 g, 0.36 mmol) was added and the reaction mixture heated at 150° C. for a further 1 h using microwave irradiation. The mixture was diluted with EtOAc and water and the phases separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give an impure solid. The residue was partitioned between DCM and water and the phases separated. The organic layer was evaporated in vacuo and the residue was purified by FCC, using 0-5% MeOH in DCM. Further purification by FCC, using 0-25% EtOAc in DCM, gave the title compound as an orange gum (1.25 g, 70%). LCMS (Method 3): Rt 2.33 min, m/z 250.3 [MH+]. The mixture was degassed microwave irradiation the reaction mixture heated at 150° C. for a further 1 h microwave irradiation the phases separated The aqueous layer was then extracted with EtOAc (2×) The combined organic layers were washed with brine dried (Na2SO4) filtered evaporated in vacuo to give an impure solid The residue was partitioned between DCM and water the phases separated The organic layer was evaporated in vacuo the residue was purified by FCC Further purification by FCC

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

実験手順: A solution of the crude 5-bromo-2-fluorophenol (4.0 g) prepared using literature procedure [EP0238272] and (2R)-glycidyl 3-nitrobenzenesulfonate (5.37 g) in dry acetone (175 mL) was treated with potassium carbonate (8.58 g) and refluxed under nitrogen for 12 h. The reaction was cooled, filtered and filtrate was concentrated in vacuo and the residue was flash chromatographed (20% ethyl acetate/hexanes) to yield the desired product (4.25 g) in 82% yield. 1H NMR (400 MHz, CDCl3): δ 7.15-6.96 (m, 3H), 4.33 and 4.30 (dd, 1H), 4.02 and 4.00 (dd, 1H), 3.41-3.37 (m, 1H), 2.97 (m, 1H), 2.78 (m, 1H). refluxed under nitrogen for 12 h The reaction was cooled filtered filtrate was concentrated in vacuo chromatographed (20% ethyl acetate/hexanes)

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

実験手順: To a stirred solution of 5-bromo-2-fluorophenol (5 g, 26.2 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.571 g, 39.3 mmol). After stirring for 10 min, chloromethyl methyl ether (2.386 mL, 31.4 mmol) was added dropwise to mixture and the mixture was then stirred for 1 hour at 0° C. The reaction was quenched with addition of saturated NH4Cl aq. and the mixture was poured into water (150 mL). The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-10% ethyl acetate in cyclohexane to give the title compound (5.90 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 3.55 (3H, s), 5.24 (2H, s), 6.95-7.02 (1H, m), 7.08-7.14 (1H, m), 7.36-7.40 (1H, m). the mixture was then stirred for 1 hour at 0° C The reaction was quenched with addition of saturated NH4Cl aq. the mixture was poured into water (150 mL) The mixture was extracted with ethyl acetate (30 mL×2) washed with brine (100 mL) dried over MgSO4 filtered evaporated in vacuo The crude residue was purified by chromatography on silica eluting with a gradient of 0-10% ethyl acetate in cyclohexane

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

実験手順: To a stirred solution of 5-bromo-2-fluorophenol (5 g, 26.2 mmol) in DMF (50 mL) at 0° C. was added sodium hydride (1.571 g, 39.3 mmol). After stirring for 10 min, chloromethyl methyl ether (2.386 mL, 31.4 mmol) was added dropwise to mixture and the mixture was then stirred for 1 hour at 0° C. The reaction was quenched with addition of saturated NH4Cl aq. and the mixture was poured into water (150 mL). The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined, washed with brine (100 mL), dried over MgSO4, filtered and evaporated in vacuo. The crude residue was purified by chromatography on silica, eluting with a gradient of 0-10% ethyl acetate in cyclohexane to give the title compound (5.90 g). 1H NMR (CDCl3, 400 MHz) δ ppm: 3.55 (3H, s), 5.24 (2H, s), 6.95-7.02 (1H, m), 7.08-7.14 (1H, m), 7.36-7.40 (1H, m). the mixture was then stirred for 1 hour at 0° C The reaction was quenched with addition of saturated NH4Cl aq. the mixture was poured into water (150 mL) The mixture was extracted with ethyl acetate (30 mL×2) washed with brine (100 mL) dried over MgSO4 filtered evaporated in vacuo The crude residue was purified by chromatography on silica eluting with a gradient of 0-10% ethyl acetate in cyclohexane

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-(tert-butyl)-1H-pyrazol-5-amine (1.00 g, 7.20 mmol) in toluene (13 mL) was added 5-bromo-2-fluorophenol (1.51 g, 7.90 mmol), potassium carbonate (2.08 g, 15.1 mmol), (1S,2S)—N,N′-bis-methyl-1,2-cyclohexane-diamine (0.20 g, 1.40 mmol) then copper (I) iodide (0.07 g, 0.36 mmol). The mixture was degassed then heated at 150° C. for 1 h using microwave irradiation. Another portion of copper (I) iodide (0.07 g, 0.36 mmol) was added and the reaction mixture heated at 150° C. for a further 1 h using microwave irradiation. The mixture was diluted with EtOAc and water and the phases separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give an impure solid. The residue was partitioned between DCM and water and the phases separated. The organic layer was evaporated in vacuo and the residue was purified by FCC, using 0-5% MeOH in DCM. Further purification by FCC, using 0-25% EtOAc in DCM, gave the title compound as an orange gum (1.25 g, 70%). LCMS (Method 3): Rt 2.33 min, m/z 250.3 [MH+]. The mixture was degassed microwave irradiation the reaction mixture heated at 150° C. for a further 1 h microwave irradiation the phases separated The aqueous layer was then extracted with EtOAc (2×) The combined organic layers were washed with brine dried (Na2SO4) filtered evaporated in vacuo to give an impure solid The residue was partitioned between DCM and water the phases separated The organic layer was evaporated in vacuo the residue was purified by FCC Further purification by FCC

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

実験手順: A mixture of 2-fluoro-5-bromophenol (2.40 g), potassium carbonate (2.31 m), Aliquat 336 (5 drops), sodium iodide (catalytic) and 4-bromo-1,1-difluoro-1-butene (1.79 mL) in methyl ethyl ketone was placed in a pressure vessel and heated in a 82° oil bath for 15 hours. The reaction mixture was cooled, diluted with dichloromethane, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica gel, eluant: 2.5% ethyl acetate/hexane to afford 4-bromo-2-(4,4-difluorobut-3-enyloxy)-1-fluorobenzene, 2.23 g (63% yield), identified by NMR analysis. was placed in a pressure vessel heated in a 82° oil bath for 15 hours The reaction mixture was cooled filtered evaporated in vacuo The resultant residue was purified by flash chromatography (silica gel, eluant

反応条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 3-(tert-butyl)-1H-pyrazol-5-amine (1.00 g, 7.20 mmol) in toluene (13 mL) was added 5-bromo-2-fluorophenol (1.51 g, 7.90 mmol), potassium carbonate (2.08 g, 15.1 mmol), (1S,2S)—N,N′-bis-methyl-1,2-cyclohexane-diamine (0.20 g, 1.40 mmol) then copper (I) iodide (0.07 g, 0.36 mmol). The mixture was degassed then heated at 150° C. for 1 h using microwave irradiation. Another portion of copper (I) iodide (0.07 g, 0.36 mmol) was added and the reaction mixture heated at 150° C. for a further 1 h using microwave irradiation. The mixture was diluted with EtOAc and water and the phases separated. The aqueous layer was then extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to give an impure solid. The residue was partitioned between DCM and water and the phases separated. The organic layer was evaporated in vacuo and the residue was purified by FCC, using 0-5% MeOH in DCM. Further purification by FCC, using 0-25% EtOAc in DCM, gave the title compound as an orange gum (1.25 g, 70%). LCMS (Method 3): Rt 2.33 min, m/z 250.3 [MH+]. The mixture was degassed microwave irradiation the reaction mixture heated at 150° C. for a further 1 h microwave irradiation the phases separated The aqueous layer was then extracted with EtOAc (2×) The combined organic layers were washed with brine dried (Na2SO4) filtered evaporated in vacuo to give an impure solid The residue was partitioned between DCM and water the phases separated The organic layer was evaporated in vacuo the residue was purified by FCC Further purification by FCC