1-氟丙烷-2-ol

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-fluoropropane-2-ol (38 mg, 0.48 mmol) and pyridine (39 μL, 0.48 mmol) were dissolved in DCM (1.5 mL), and the mixture was stirred and cooled to 0° C. Phosgene (1.9 M solution in toluene, 232 μL, 0.44 mmol) was added in one portion and the reaction was allowed to warm to rt and was stirred for 3 h during which a white precipitate formed. In a separate flask, the amine 56-b (36 mg, 0.080 mmol) and DIPEA (45 μL, 0.26 mmol) were dissolved in DCM (1 mL) and the mixture was stirred and cooled to 0° C. 250 μL of the mixture in the first flask were added to the second, and the reaction was monitored by HPLC. Another 250 μL aliquot was added after 15 min and the reaction was stirred for 15 more minutes after which it was quenched by the addition of sat aq NaHCO3 (10 mL) and Et2O (10 mL). The layers were separated and the aqueous phase was extracted with 2×5 mL EtOAc. The combined organic phases were washed with sat aq NaHCO3 (5 mL) and the solvent was removed by rotary evaporation. The product was purified by gradient column chromatography (DCM-10% MeOH in DCM). This gave the title compound as a mixture of diastereomers (22 mg, 57%). ES+ 486.3 [M+H]+. to warm to rt was stirred for 3 h during which a white precipitate formed the mixture was stirred cooled to 0° C Another 250 μL aliquot was added after 15 min the reaction was stirred for 15 more minutes after which it was quenched by the addition of sat aq NaHCO3 (10 mL) and Et2O (10 mL) The layers were separated the aqueous phase was extracted with 2×5 mL EtOAc The combined organic phases were washed with sat aq NaHCO3 (5 mL) the solvent was removed by rotary evaporation The product was purified by gradient column chromatography (DCM-10% MeOH in DCM)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-fluoropropane-2-ol (38 mg, 0.48 mmol) and pyridine (39 μL, 0.48 mmol) were dissolved in DCM (1.5 mL), and the mixture was stirred and cooled to 0° C. Phosgene (1.9 M solution in toluene, 232 μL, 0.44 mmol) was added in one portion and the reaction was allowed to warm to rt and was stirred for 3 h during which a white precipitate formed. In a separate flask, the amine 56-b (36 mg, 0.080 mmol) and DIPEA (45 μL, 0.26 mmol) were dissolved in DCM (1 mL) and the mixture was stirred and cooled to 0° C. 250 μL of the mixture in the first flask were added to the second, and the reaction was monitored by HPLC. Another 250 μL aliquot was added after 15 min and the reaction was stirred for 15 more minutes after which it was quenched by the addition of sat aq NaHCO3 (10 mL) and Et2O (10 mL). The layers were separated and the aqueous phase was extracted with 2×5 mL EtOAc. The combined organic phases were washed with sat aq NaHCO3 (5 mL) and the solvent was removed by rotary evaporation. The product was purified by gradient column chromatography (DCM-10% MeOH in DCM). This gave the title compound as a mixture of diastereomers (22 mg, 57%). ES+ 486.3 [M+H]+. to warm to rt was stirred for 3 h during which a white precipitate formed the mixture was stirred cooled to 0° C Another 250 μL aliquot was added after 15 min the reaction was stirred for 15 more minutes after which it was quenched by the addition of sat aq NaHCO3 (10 mL) and Et2O (10 mL) The layers were separated the aqueous phase was extracted with 2×5 mL EtOAc The combined organic phases were washed with sat aq NaHCO3 (5 mL) the solvent was removed by rotary evaporation The product was purified by gradient column chromatography (DCM-10% MeOH in DCM)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-fluoropropane-2-ol (38 mg, 0.48 mmol) and pyridine (39 μL, 0.48 mmol) were dissolved in DCM (1.5 mL), and the mixture was stirred and cooled to 0° C. Phosgene (1.9 M solution in toluene, 232 μL, 0.44 mmol) was added in one portion and the reaction was allowed to warm to rt and was stirred for 3 h during which a white precipitate formed. In a separate flask, the amine 56-b (36 mg, 0.080 mmol) and DIPEA (45 μL, 0.26 mmol) were dissolved in DCM (1 mL) and the mixture was stirred and cooled to 0° C. 250 μL of the mixture in the first flask were added to the second, and the reaction was monitored by HPLC. Another 250 μL aliquot was added after 15 min and the reaction was stirred for 15 more minutes after which it was quenched by the addition of sat aq NaHCO3 (10 mL) and Et2O (10 mL). The layers were separated and the aqueous phase was extracted with 2×5 mL EtOAc. The combined organic phases were washed with sat aq NaHCO3 (5 mL) and the solvent was removed by rotary evaporation. The product was purified by gradient column chromatography (DCM-10% MeOH in DCM). This gave the title compound as a mixture of diastereomers (22 mg, 57%). ES+ 486.3 [M+H]+. to warm to rt was stirred for 3 h during which a white precipitate formed the mixture was stirred cooled to 0° C Another 250 μL aliquot was added after 15 min the reaction was stirred for 15 more minutes after which it was quenched by the addition of sat aq NaHCO3 (10 mL) and Et2O (10 mL) The layers were separated the aqueous phase was extracted with 2×5 mL EtOAc The combined organic phases were washed with sat aq NaHCO3 (5 mL) the solvent was removed by rotary evaporation The product was purified by gradient column chromatography (DCM-10% MeOH in DCM)

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 0.29 g (3.77 mmol) 1-fluoro-propan-2-ol in 20 mL THF is cooled down to 0° C. 4.90 mL (1 M in THF; 4.90 mmol) LiHMDS is added drop wise. After 60 minutes of stirring at 0° C. 0.60 g (3.77 mmol) 2,4-difluoro-1-nitro-benzene is added. The mixture is stirred for 2 h. The mixture is diluted with water and EtOAc. The organic layer is washed with brine, separated, dried and evaporated giving rise to the crude 4-fluoro-2-(2-fluoro-1-methyl-ethoxy)-1-nitro-benzene. 80.0 mg palladium on charcoal (10%) and MeOH are added hydrogenated in a Parr apparatus (RT; 50 psi; 5 h). The catalyst is filtered off and the solvent is evaporated. The mixture is stirred for 2 h The organic layer is washed with brine separated dried evaporated

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 0.29 g (3.77 mmol) 1-fluoro-propan-2-ol in 20 mL THF is cooled down to 0° C. 4.90 mL (1 M in THF; 4.90 mmol) LiHMDS is added drop wise. After 60 minutes of stirring at 0° C. 0.60 g (3.77 mmol) 2,4-difluoro-1-nitro-benzene is added. The mixture is stirred for 2 h. The mixture is diluted with water and EtOAc. The organic layer is washed with brine, separated, dried and evaporated giving rise to the crude 4-fluoro-2-(2-fluoro-1-methyl-ethoxy)-1-nitro-benzene. 80.0 mg palladium on charcoal (10%) and MeOH are added hydrogenated in a Parr apparatus (RT; 50 psi; 5 h). The catalyst is filtered off and the solvent is evaporated. The mixture is stirred for 2 h The organic layer is washed with brine separated dried evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The title compound was synthesized in analogy to Example 108b, using 3-bromo-4-chloropyridine (CAN 36953-42-1), 1-fluoropropan-2-ol (CAN 430-50-2) as starting materials and sodium hydride as reagent. The title compound was isolated (7.55 g, 62%) as a yellow oil; MS (ESI, m/z): 235.9 (M+H+). The title compound was synthesized in analogy to Example 108b