(4R)-8-fluoro-3,4-dihydro-2H-chromen-4-amine;hydrochloride

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

実験手順: 2,5-diamino-4,6-dichloropyrimidine (1.5 g, 8.37 mmol), (R)-8-fluorochroman-4-amine hydrochloride (see preparation below) (1.7 g, 8.37 mmol, 1 equiv.), sodium bicarbonate (2.46 g, 29.3 mmol, 3.5 equiv.) and 1-butanol (30 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride) to give 2.01 g (78% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 6.97-6.86 (m, 2H), 6.77-6.72 (m, 1H), 5.36 (m, 1H), 4.25 (m, 2H), 2.10 (m, 2H); MS (EI) m/z 310.1 (MH)+. the solvent was removed in vacuo The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride)

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

実験手順: 2,5-diamino-4,6-dichloropyrimidine (1.5 g, 8.37 mmol), (R)-8-fluorochroman-4-amine hydrochloride (see preparation below) (1.7 g, 8.37 mmol, 1 equiv.), sodium bicarbonate (2.46 g, 29.3 mmol, 3.5 equiv.) and 1-butanol (30 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride) to give 2.01 g (78% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 6.97-6.86 (m, 2H), 6.77-6.72 (m, 1H), 5.36 (m, 1H), 4.25 (m, 2H), 2.10 (m, 2H); MS (EI) m/z 310.1 (MH)+. the solvent was removed in vacuo The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride)

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

実験手順: 2,5-diamino-4,6-dichloropyrimidine (1.5 g, 8.37 mmol), (R)-8-fluorochroman-4-amine hydrochloride (see preparation below) (1.7 g, 8.37 mmol, 1 equiv.), sodium bicarbonate (2.46 g, 29.3 mmol, 3.5 equiv.) and 1-butanol (30 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride) to give 2.01 g (78% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 6.97-6.86 (m, 2H), 6.77-6.72 (m, 1H), 5.36 (m, 1H), 4.25 (m, 2H), 2.10 (m, 2H); MS (EI) m/z 310.1 (MH)+. the solvent was removed in vacuo The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride)

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

実験手順: tert-Butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (2.0 g) was added to a solution of (R)-8-fluorochroman-4-amine hydrochloride (1.1 gram) and N,N-diisopropylethylamine (2.2 mL) in THF (anhydrous, 50 mL). The mixture was stirred for 6 hr at room temperature then partitioned between water and EtOAc and separated. The aq. layer was washed with additional EtOAc and the combined organics were dried over Na2SO4 and concentrated in vacuo to give the title product in 94% yield. MH+=515, 459 (-tBu). then partitioned between water and EtOAc separated The aq. layer was washed with additional EtOAc the combined organics were dried over Na2SO4 concentrated in vacuo

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

実験手順: A solution of (R)-8-fluorochroman-4-amine hydrochloride (1.02 g) and DIEA (2.6 mL) in DCM (10 mL) was slowly added to a solution of 2,4-dichloro-5-nitropyrimidine (0.97 g) THF (25 mL) at −78° C. The reaction mixture was stirred for 30 min at −78° C. then allowed to warm to RT overnight. The reaction was quenched with the addition of sat. NH4Cl (1 mL), the solvent volume was reduced in vacuo, and the resulting mixture partition between EtOAc and water then separated. The crude material was purified via column chromatography, elution with 30% EtOAc/Hex gave the titled product (1.43 g). 1H-NMR (300 MHz, CDCl3) δ 9.1 (s, 1H), 8.6 (br d, 1H), 7.1-6.8 (m, 3H), 5.6 (dd, 1H), 4.4 (m 1H), 4.3 (m, 1H), 2.4 (m, 1H), 2.2 (m, 1H). to warm to RT overnight The reaction was quenched with the addition of sat. NH4Cl (1 mL) the resulting mixture partition between EtOAc and water then separated The crude material was purified via column chromatography, elution with 30% EtOAc/Hex

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

実験手順: A solution of the (R)-8-fluorochroman-4-amine hydrochloride (104 mg) in DMSO (2 mL) and potassium carbonate (141 mg) were added to a stirred solution of tert-butyl 4-fluoro-2-(5-nitro-4-thiocyanatopyrimidin-2-ylamino)phenylcarbamate (140 mg) in ACN (10 mL). The mixture was stirred for 15 hr at room temperature then partitioned between brine and EtOAc and separated. The aq. layer was washed with additional EtOAc, the combined organics were evaporated and purified via column chromatography, elution with 20-30% EtOAc/H gave the titled product in 83% yield. 1H-NMR (300 MHz, CDCl3) δ 9.1 (s, 1H), 8.7 (m, 1H), 8.2 (br s, 1H), 7.7 (m, 1H), 7.3 (m, 1H), 7.3-6.8 (m, 4H), 6.5 (s, 1H), 5.5 (br s, 1H), 4.4 (m 2H), 2.4 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H); MH+=515, 459 (-tBu). then partitioned between brine and EtOAc separated The aq. layer was washed with additional EtOAc the combined organics were evaporated purified via column chromatography, elution with 20-30% EtOAc/H

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

実験手順: 2,5-diamino-4,6-dichloropyrimidine (1.5 g, 8.37 mmol), (R)-8-fluorochroman-4-amine hydrochloride (see preparation below) (1.7 g, 8.37 mmol, 1 equiv.), sodium bicarbonate (2.46 g, 29.3 mmol, 3.5 equiv.) and 1-butanol (30 mL) were heated together at 150° C. in a sealed tube. After 3 days, when the reaction appeared to be complete (by HPLC), the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride) to give 2.01 g (78% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 6.97-6.86 (m, 2H), 6.77-6.72 (m, 1H), 5.36 (m, 1H), 4.25 (m, 2H), 2.10 (m, 2H); MS (EI) m/z 310.1 (MH)+. the solvent was removed in vacuo The residue was purified by flash chromatography (silica gel, elution with 1/1 ethyl acetate/methylene chloride)