4,4-difluorocyclohexan-1-ol

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: 0.213 g DTAD was added into a solution of 5-fluoro-2-nitro-phenol, 0.105 g 4,4-difluorocyclohexanol, 0.25 g triphenylphospine in 2 ml of anhydrous methylene chloride at rt. The reaction mixture was stirred at rt overnight when TLC analysis indicated the consumption of the 5-Fluoro-2-nitro-phenol. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 10% potassium carbonate solution. The aqueous layer was extracted with methylene chloride (2×25 ml) and the combined organics washed with sodium hydrogecarbonate solution (25 ml). The organic layer was passed through a phase separator and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 iso-hexane/EtOAc). the consumption of the 5-Fluoro-2-nitro-phenol The reaction mixture was diluted with methylene chloride (50 ml) washed with 10% potassium carbonate solution The aqueous layer was extracted with methylene chloride (2×25 ml) the combined organics washed with sodium hydrogecarbonate solution (25 ml) concentrated in vacuo Purification

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

実験手順: 0.361 g meta-chloro-perbenzoic acid were added into a solution of 0.262 g 1-(4,4-difluoro-cyclohexyl)-ethanone in 5 ml chloroform. The reaction was stirred at rt for 2 hours when TLC indicated consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone. The solution was poured into saturated sodium hydrogencarbonate solution and extracted with chloroform (3×50 ml). The combined organic phases were passed through a phase separator concentrated in vacuo. The crude product was resuspended in methanol (5 ml) and 10% aq. potassium carbonate solution. (5 ml) and stirred at rt over a weekend. The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution. The organic phases were separated and the aqueous phase was extracted with methylene chloride (3×25 ml). The combined organic phases were passed through a phase-separator, concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 petroleum ether/diethylether). consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone The solution was poured into saturated sodium hydrogencarbonate solution extracted with chloroform (3×50 ml) concentrated in vacuo (5 ml) and stirred at rt over a weekend The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution The organic phases were separated the aqueous phase was extracted with methylene chloride (3×25 ml) concentrated in vacuo Purification

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 from 5-fluoro-3-iodo-indazole and 4,4-difluorocyclohexanol in 17% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 1.94-2.17 (4H, m), 2.34-2.52 (4H, m), 4.67-4.73 (1H, m), 7.02 (1H, dd, J=2.4, 8.4 Hz), 7.11 (1H, td, J=2.4, 9.2 Hz), 7.67 (1H, dd, J=4.0, 9.2 Hz). The minor isomer was not isolated

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4,4-difluorocyclohexan-1-ol (162 mg, 1.19 mmol) in THF (10 mL) was added NaH (48 mg, 1.19 mmol, 60% in mineral oil) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 minutes. Then the title compound from Step 2 (200 mg, 0.6 mmol) was added and the mixture was stirred at 25° C. for 18 hours. The reaction contents were poured into ice-water (v/v=1/1) (150 mL) and stirred for 20 minutes. The aqueous phase was extracted with EA (40 mL×3). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound (57.35 mg, 22%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd, J1=8.8 Hz, J 2=2.4 Hz 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 4.90-4.84 (brs, 1H), 3.44 (s, 3H), 3.32 (q, J=7.2 Hz, 2H), 1.85-1.83 (m, 4H), 1.69-1.61 (m, 4H), 1.15 (t, J=7.2 Hz, 3H). LCMS: 452.2 (M+H)+ the mixture was stirred at 25° C. for 18 hours The reaction contents stirred for 20 minutes The aqueous phase was extracted with EA (40 mL×3) The combined organic phase was washed with brine (20 mL×2) dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by prep-HPLC

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

実験手順: To a suspension of sodium hydride (60% in oil, 19 mg) in tetrahydrofuran (5 ml) was added 4,4-difluorocyclohexanol (109 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound (75 mg). the mixture was stirred at room temperature for 5 hr the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane) recrystallized from a mixed solvent of hexane/ethyl acetate

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

実験手順: To a suspension of sodium hydride (60% in oil, 19 mg) in tetrahydrofuran (5 ml) was added 4,4-difluorocyclohexanol (109 mg) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and recrystallized from a mixed solvent of hexane/ethyl acetate to give the title compound (75 mg). the mixture was stirred at room temperature for 5 hr the mixture was extracted with ethyl acetate The extract was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane) recrystallized from a mixed solvent of hexane/ethyl acetate

反応条件: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 4,4-difluorocyclohexan-1-ol (162 mg, 1.19 mmol) in THF (10 mL) was added NaH (48 mg, 1.19 mmol, 60% in mineral oil) in one portion at 25° C. under N2. The mixture was stirred at 25° C. for 30 minutes. Then the title compound from Step 2 (200 mg, 0.6 mmol) was added and the mixture was stirred at 25° C. for 18 hours. The reaction contents were poured into ice-water (v/v=1/1) (150 mL) and stirred for 20 minutes. The aqueous phase was extracted with EA (40 mL×3). The combined organic phase was washed with brine (20 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to afford the title compound (57.35 mg, 22%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd, J1=8.8 Hz, J2=2.4 Hz 1H), 7.95 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.31 (s, 1H), 4.90-4.84 (brs, 1H), 3.44 (s, 3H), 3.32 (q, J=7.2 Hz, 2H), 1.85-1.83 (m, 4H), 1.69-1.61 (m, 4H), 1.15 (t, J=7.2 Hz, 3H). LCMS: 452.2 (M+H)+ the mixture was stirred at 25° C. for 18 hours The reaction contents stirred for 20 minutes The aqueous phase was extracted with EA (40 mL×3) The combined organic phase was washed with brine (20 mL×2) dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by prep-HPLC

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

実験手順: 0.213 g DTAD was added into a solution of 5-fluoro-2-nitro-phenol, 0.105 g 4,4-difluorocyclohexanol, 0.25 g triphenylphospine in 2 ml of anhydrous methylene chloride at rt. The reaction mixture was stirred at rt overnight when TLC analysis indicated the consumption of the 5-Fluoro-2-nitro-phenol. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 10% potassium carbonate solution. The aqueous layer was extracted with methylene chloride (2×25 ml) and the combined organics washed with sodium hydrogecarbonate solution (25 ml). The organic layer was passed through a phase separator and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 iso-hexane/EtOAc). the consumption of the 5-Fluoro-2-nitro-phenol The reaction mixture was diluted with methylene chloride (50 ml) washed with 10% potassium carbonate solution The aqueous layer was extracted with methylene chloride (2×25 ml) the combined organics washed with sodium hydrogecarbonate solution (25 ml) concentrated in vacuo Purification

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

実験手順: 0.213 g DTAD was added into a solution of 5-fluoro-2-nitro-phenol, 0.105 g 4,4-difluorocyclohexanol, 0.25 g triphenylphospine in 2 ml of anhydrous methylene chloride at rt. The reaction mixture was stirred at rt overnight when TLC analysis indicated the consumption of the 5-Fluoro-2-nitro-phenol. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 10% potassium carbonate solution. The aqueous layer was extracted with methylene chloride (2×25 ml) and the combined organics washed with sodium hydrogecarbonate solution (25 ml). The organic layer was passed through a phase separator and concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 iso-hexane/EtOAc). the consumption of the 5-Fluoro-2-nitro-phenol The reaction mixture was diluted with methylene chloride (50 ml) washed with 10% potassium carbonate solution The aqueous layer was extracted with methylene chloride (2×25 ml) the combined organics washed with sodium hydrogecarbonate solution (25 ml) concentrated in vacuo Purification

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

実験手順: 0.361 g meta-chloro-perbenzoic acid were added into a solution of 0.262 g 1-(4,4-difluoro-cyclohexyl)-ethanone in 5 ml chloroform. The reaction was stirred at rt for 2 hours when TLC indicated consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone. The solution was poured into saturated sodium hydrogencarbonate solution and extracted with chloroform (3×50 ml). The combined organic phases were passed through a phase separator concentrated in vacuo. The crude product was resuspended in methanol (5 ml) and 10% aq. potassium carbonate solution. (5 ml) and stirred at rt over a weekend. The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution. The organic phases were separated and the aqueous phase was extracted with methylene chloride (3×25 ml). The combined organic phases were passed through a phase-separator, concentrated in vacuo. Purification was achieved by silica gel column chromatography (solvent: 100%→1:1 petroleum ether/diethylether). consumption of the 1-(4,4-difluoro-cyclohexyl)-ethanone The solution was poured into saturated sodium hydrogencarbonate solution extracted with chloroform (3×50 ml) concentrated in vacuo (5 ml) and stirred at rt over a weekend The solution was diluted with chloroform (25 ml) and sat. sodium hydrogencarbonate solution The organic phases were separated the aqueous phase was extracted with methylene chloride (3×25 ml) concentrated in vacuo Purification

反応条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The inside of a reactor was sufficiently dried by vacuum heating, and the atmosphere inside the reactor was replaced with dry nitrogen. The reactor was charged with 2000 ml of dichloromethane and 128.4 ml (1.5 mol) of oxalyl chloride at −78° C. After the dropwise addition of 233 ml (3.0 mol) of DMSO, the mixture was stirred at −78° C. After 10 minutes had elapsed, a dichloromethane (300 ml) solution of 136.1 g (1.0 mol) of 4,4-difluorocyclohexanol was added dropwise to the mixture using a syringe over 10 minutes. After stirring the reaction mixture at −78° C. for 40 minutes and at −45° C. for 40 minutes, N,N-diisopropylethylamine (500 ml) was added to the reaction mixture. After stirring the mixture at 0° C. for 20 minutes, a saturated ammonium chloride aqueous solution (1000 ml) was added to the mixture to terminate the reaction. The mixture was then extracted three times with dichloromethane (3000 ml). The organic layer was washed with 1N hydrochloric acid and a saturated salt solution, and dried over magnesium sulfate. After removing anhydrous magnesium sulfate using a Buchner funnel, the solvent was evaporated. The residue was distilled under reduced pressure (30 mmHg) to obtain 4,4-difluorocyclohexanone (118.9 g (yield: 85%)). The inside of a reactor was sufficiently dried by vacuum heating over 10 minutes After stirring the reaction mixture at −78° C. for 40 minutes at −45° C. for 40 minutes After stirring the mixture at 0° C. for 20 minutes to terminate the reaction The mixture was then extracted three times with dichloromethane (3000 ml) The organic layer was washed with 1N hydrochloric acid a saturated salt solution, and dried over magnesium sulfate After removing anhydrous magnesium sulfate using a Buchner funnel the solvent was evaporated The residue was distilled under reduced pressure (30 mmHg)