2,2-difluoropropan-1-ol

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:

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

実験手順: To mixture of 2,2-Difluoro-propan-1-ol (0.26 g, 0.0027 mol) and Pyridine (0.27 mL, 0.0034 mol) in Acetonitrile (25 mL, 0.48 mol) at 0-5° C. was added dropwise Trifluoromethanesulfonic anhydride (0.48 mL, 0.0028 mol). The mixture was stirred for 30 minutes then Potassium carbonate (0.37 g, 0.0027 mol) and 7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.30 g, 0.0013 mol) were added. The reaction mixture was warmed to room temperature then heated to 50° C. for 18 hours. The mixture was evaporated. The residue was dissolved in dichloromethane (50 mL) and washed with water (50 mL), dried over magnesium sulfate, filtered and evaporated. The material was purified via silica gel chromatography using 0%→10% Methanol:Dichloromethane solvent gradient. 3-(2,2-Difluoro-propyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine isolated as a yellow solid (0.316 g, 78%). then heated to 50° C. for 18 hours The mixture was evaporated The residue was dissolved in dichloromethane (50 mL) washed with water (50 mL) dried over magnesium sulfate filtered evaporated The material was purified via silica gel chromatography

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

実験手順: The title compound is prepared in 85% yield (1.12 g, colorless oil) from 5,6-dichloronicotinic acid (1.00 g, 5.21 mmol) and 2,2-difluoropropan-1-ol (0.50 g, 5.21 mmol) in a similar manner to Step-1 of Intermediate-A3.

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

実験手順: The title compound is prepared in 85% yield (1.12 g, colorless oil) from 5,6-dichloronicotinic acid (1.00 g, 5.21 mmol) and 2,2-difluoropropan-1-ol (0.50 g, 5.21 mmol) in a similar manner to Step-1 of Intermediate-A3.

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 2,2-difluoropropan-1-ol (1.13 g, 11.7 mmol) and potassium tert-butoxide (1.43 g, 12.8 mmol) in DMF (36 mL) is added methyl 6-fluoro-5-methylnicotinate (1.80 g, 10.6 mmol, Step-1 of Amine-36). After stirring at rt for 2 hours, MeOH (30 mL), water (30 mL), and 2 M aqueous sodium hydroxide solution (15 mL) are added to the mixture, and the mixture is stirred at rt for 2 hours. After evaporation of MeOH, the mixture is acidified by 2 M hydrochloric acid, and the precipitate is collected by filtration to give 2.14 g (87%) of the title compound as white solid. the mixture is stirred at rt for 2 hours After evaporation of MeOH the precipitate is collected by filtration

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

実験手順: The title compound is prepared in >99% yield (1.79 g, orange oil) from 6-chloronicotinic acid (1.3 g, 8.25 mmol) and 2,2-difluoropropan-1-ol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-1.

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

実験手順: (R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (15.0 mg, 32 μmol), HOBt (12.8 mg, 95 μmol) and EDC (16.8 μL, 95 μmol) were combined in DCM (121 μL, 1.9 mmol) and stirred for 10 minutes. 2,2-Difluoropropanol (24.3 mg, 253 μmol) was added and the resulting mixture was stirred at room temperature until the reaction was complete (≈48 hours). The mixture was evaporated under reduced pressure and the product was purified (reverse phase column) to yield the title compound (13.8 mg, purity 96%) as a TFA salt. MS m/z [M+H]+ calc'd for C25H24ClF3N4O5, 553.14. found 553.1. the resulting mixture was stirred at room temperature until the reaction (≈48 hours) The mixture was evaporated under reduced pressure the product was purified (reverse phase column)

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

実験手順: To a solution of 2,2-difluoropropanol (0.50 g, 5.20 mmol) in dichloromethane (52.0 mL) and triethylamine (0.50 g, 0.73 mL, 5.20 mmol) at 0° C. is added p-toluenesulfonyl chloride (0.99 g, 5.20 mmol). The mixture is allowed to slowly warm to room temperature over 24 h. The mixture is concentrated and is partitioned between diethyl ether and water. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The material is purified over silica gel to obtain 1.0 g of the title compound as clear crystals. MS (m/z) 250 (M+1). The mixture is concentrated is partitioned between diethyl ether and water The organic layer is washed with water and brine dried over magnesium sulfate filtered concentrated to dryness The material is purified over silica gel

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

実験手順: To a solution of 2,2-difluoropropanol (0.50 g, 5.20 mmol) in dichloromethane (52.0 mL) and triethylamine (0.50 g, 0.73 mL, 5.20 mmol) at 0° C. is added p-toluenesulfonyl chloride (0.99 g, 5.20 mmol). The mixture is allowed to slowly warm to room temperature over 24 h. The mixture is concentrated and is partitioned between diethyl ether and water. The organic layer is washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The material is purified over silica gel to obtain 1.0 g of the title compound as clear crystals. MS (m/z) 250 (M+1). The mixture is concentrated is partitioned between diethyl ether and water The organic layer is washed with water and brine dried over magnesium sulfate filtered concentrated to dryness The material is purified over silica gel

反応条件: temp:0.00; pressure:0.00; stir: