3-BROMO-4-FLUOROBENZYLAMINE HYDROCHLORIDE

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

実験手順: Triethylamine (2.52 g) was added to a suspension of 3-bromo-4-fluorobenzylamine hydrochloride (2.79 g) in chloroform (50 mL), and the mixture was stirred at room temperature for 10 min. Tetrahydro-4H-pyran-4-one (2.29 g) was added thereto and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (4.85 g) was added thereto, followed by further stirring for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was then stirred for a while and extracted with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=100:0-90:10) to afford the title compound (2.70 g). the mixture was stirred at room temperature for 30 min by further stirring for 1 hr the resulting mixture was then stirred for a while extracted with chloroform The organic phase was separated out the solvent was distilled off under reduced pressure The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=100:0-90:10)

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

実験手順: Triethylamine (2.52 g) was added to a suspension of 3-bromo-4-fluorobenzylamine hydrochloride (2.79 g) in chloroform (50 mL), and the mixture was stirred at room temperature for 10 min. Tetrahydro-4H-pyran-4-one (2.29 g) was added thereto and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (4.85 g) was added thereto, followed by further stirring for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was then stirred for a while and extracted with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=100:0-90:10) to afford the title compound (2.70 g). the mixture was stirred at room temperature for 30 min by further stirring for 1 hr the resulting mixture was then stirred for a while extracted with chloroform The organic phase was separated out the solvent was distilled off under reduced pressure The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=100:0-90:10)

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

実験手順: [(3-Bromo-4-fluorophenyl)methyl]amine hydrochloride (0.795 g, 3.29 mmol), [3-(hydroxymethyl)phenyl]boronic acid (0.5 g, 3.29 mmol), potassium carbonate (2.275 g, 16.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.114 g, 0.1 mmol) were combined in dioxane (10 mL) and water (3 mL). The mixture was microwaved at 150° C. for 30 min. The solvents were evaporated and the residue taken up in EtOAc and H2O. The aqueous phase was extracted 2× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by CombiFlash on a silica gel column eluting with 0-100% CH2Cl2/CH2Cl2: 20% MeOH:1% NH4OH to afford the title compound as a viscous oil. LC-MS m/z 231.8 (M+H)+, 1.03 min (ret time). The mixture was microwaved at 150° C. for 30 min The solvents were evaporated The aqueous phase was extracted 2× with EtOAc The combined organic phases were dried over anhydrous Na2SO4 filtered evaporated The residue was purified by CombiFlash on a silica gel column eluting with 0-100% CH2Cl2/CH2Cl2

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-(hydroxymethyl)phenyl]boronic acid (2 g, 13.2 mmol) in 1,4-dioxan (40 mL) was added [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (3.18 g, 13.2 mmol), potassium carbonate (9.1 g, 66 mmol) and tetrakis(triphenylphosphine) palladium(0) (456 mg, 0.4 mmol). The mixture was split into 4×20 mL capacity microwave vials and each was treated with water (3 mL). The mixtures were each heated at 150° C. for 20 mins. One sixth of the total reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was dried (magnesium sulphate) and evaporated to dryness and the product purified by flash chomatography on silica using 0-50% ethyl acetate/cyclohexane followed by dichloromethane/ammonia solution/methanol @8:1:1 as eluants. Product-containing fractions were combined and evaporated to dryness to afford 402 mg of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The remaining five-sixths of the reaction mixture was worked up in the same manner and purified by flash chomatography using ethyl acetate/cyclohexane @1:1 followed by dichloromethane/ammonia solution/methanol @8:1:1 as eluants. This yielded 1.97 g of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The mixture was split into 4×20 mL capacity microwave vials each was treated with water (3 mL) One sixth of the total reaction mixture extracted with ethyl acetate (2×80 mL) The combined organic phase was dried (magnesium sulphate) evaporated to dryness the product purified by flash chomatography on silica using 0-50% ethyl acetate/cyclohexane evaporated to dryness

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

実験手順: A solution of (3-bromo-4-fluorophenyl)methanamine hydrochloric acid salt (500 mg, 2.079 mmol) in pyridine (6 mL) was stirred on ice and treated with acetic anhydride (0.235 mL, 2.495 mmol). The resulting solution was stirred at rt for 17 h, then was concentrated. The residue was stirred in 1 M hydrochloric acid, forming a precipitate which was collected by filtration, rinsed with water and dried to provide N-(3-bromo-4-fluorobenzyl)acetamide as a white solid (435 mg, 85%). 1H NMR (400 MHz, chloroform-d) δ 7.47 (dd, J=6.6, 2.2 Hz, 1H) 7.20 (ddd, J=8.6, 4.6, 2.2 Hz, 1H) 7.07 (t, J=8.3 Hz, 1H) 5.84 (br. s., 1H) 4.38 (d, J=5.9 Hz, 2H) 2.04 (s, 3H). Mass spectrum m/z 246, 248 (M+H)+. was concentrated The residue was stirred in 1 M hydrochloric acid forming a precipitate which was collected by filtration rinsed with water dried

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

実験手順: A mixture of glutaric anhydride (342 mg, 3 mmol), [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride salt (721.5 mg, 3 mmol), and diisopropyl ethyl amine (2 mL) in THF (50 mL) was stirred at room temperature for 1 hour. It was concentrated, mixed with 4% HCl (50 mL) and extracted with EtOAc (50 mL, 2×). The combined organic extracts were dried and concentrated to provide the captioned product (920 mg). It was concentrated mixed with 4% HCl (50 mL) extracted with EtOAc (50 mL, 2×) The combined organic extracts were dried concentrated

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

実験手順: [(3-Bromo-4-fluorophenyl)methyl]amine hydrochloride (0.795 g, 3.29 mmol), [3-(hydroxymethyl)phenyl]boronic acid (0.5 g, 3.29 mmol), potassium carbonate (2.275 g, 16.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.114 g, 0.1 mmol) were combined in dioxane (10 mL) and water (3 mL). The mixture was microwaved at 150° C. for 30 min. The solvents were evaporated and the residue taken up in EtOAc and H2O. The aqueous phase was extracted 2× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated. The residue was purified by CombiFlash on a silica gel column eluting with 0-100% CH2Cl2/CH2Cl2: 20% MeOH:1% NH4OH to afford the title compound as a viscous oil. LC-MS m/z 231.8 (M+H)+, 1.03 min (ret time). The mixture was microwaved at 150° C. for 30 min The solvents were evaporated The aqueous phase was extracted 2× with EtOAc The combined organic phases were dried over anhydrous Na2SO4 filtered evaporated The residue was purified by CombiFlash on a silica gel column eluting with 0-100% CH2Cl2/CH2Cl2

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-(hydroxymethyl)phenyl]boronic acid (2 g, 13.2 mmol) in 1,4-dioxan (40 mL) was added [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (3.18 g, 13.2 mmol), potassium carbonate (9.1 g, 66 mmol) and tetrakis(triphenylphosphine) palladium(0) (456 mg, 0.4 mmol). The mixture was split into 4×20 mL capacity microwave vials and each was treated with water (3 mL). The mixtures were each heated at 150° C. for 20 mins. One sixth of the total reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was dried (magnesium sulphate) and evaporated to dryness and the product purified by flash chomatography on silica using 0-50% ethyl acetate/cyclohexane followed by dichloromethane/ammonia solution/methanol @8:1:1 as eluants. Product-containing fractions were combined and evaporated to dryness to afford 402 mg of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The remaining five-sixths of the reaction mixture was worked up in the same manner and purified by flash chomatography using ethyl acetate/cyclohexane @1:1 followed by dichloromethane/ammonia solution/methanol @8:1:1 as eluants. This yielded 1.97 g of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The mixture was split into 4×20 mL capacity microwave vials each was treated with water (3 mL) One sixth of the total reaction mixture extracted with ethyl acetate (2×80 mL) The combined organic phase was dried (magnesium sulphate) evaporated to dryness the product purified by flash chomatography on silica using 0-50% ethyl acetate/cyclohexane evaporated to dryness

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 8-cyclopentyl-4-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-ylboronic acid (30 mg, 0.099 mmol), 3-bromo-4-fluorobenzylamine hydrochloride (28.7 mg, 0.119 mmol), potassium carbonate (3 M, 0.10 mL) in DME (0.5 mL) and EtOH (0.5 mL) was added tetrakis(triphenylphosphine) palladium(0) (6 mg, 0.005 mmol). The mixture was degassed with N2, sealed and heated for 1 h at 100° C. in microwave. The mixture was removed under reduced pressure. The crude product was purified by chromatography to give the title compound (16.4 mg, 43.3%). The mixture was degassed with N2 sealed The mixture was removed under reduced pressure The crude product was purified by chromatography

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

実験手順: [(3-Bromo-4-fluorophenyl)methyl]amine hydrochloride (0.795 g, 3.29 mmol), [3-(hydroxymethyl)phenyl]boronic acid (0.5 g, 3.29 mmol), potassium carbonate (2.275 g, 16.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.114 g, 0.1 mmol) were combined in dioxane (10 mL) and water (3 mL). The mixture was microwaved at 150° C. for 30 min. The solvents were concentrated and the residue taken up in EtOAc and H2O. The aqueous phase was extracted 2× with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by CombiFlash on a silica gel column eluted with 0-100% CH2Cl2/CH2Cl2: 20% MeOH: 1% NH4OH to afford the title compound as viscous oil. LC-MS m/z 231.8 (M+H)+, 1.03 min (ret time). The mixture was microwaved at 150° C. for 30 min The solvents were concentrated The aqueous phase was extracted 2× with EtOAc The combined organic phases were dried over anhydrous Na2SO4 filtered concentrated The residue was purified by CombiFlash on a silica gel column eluted with 0-100% CH2Cl2/CH2Cl2

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-(hydroxymethyl)phenyl]boronic acid (2 g, 13.2 mmol) in 1,4-dioxan (40 mL) was added [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (3.18 g, 13.2 mmol), potassium carbonate (9.1 g, 66 mmol) and tetrakis(triphenylphosphine)-palladium(0) (456 mg, 0.4 mmol). The mixture was split into 4×20 mL capacity microwave vials and each was treated with water (3 mL). The mixtures were each heated at 150° C. for 20 min. One sixth of the total reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was dried (magnesium sulphate) and concentrated to dryness and the product purified by flash chromatography on silica using 0-50% ethyl acetate/cyclohexane followed by dichloromethane/ammonia solution/methanol @ 8:1:1 as eluants. Product-containing fractions were combined and concentrated to dryness to afford 402 mg of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The remaining five-sixth of the reaction mixture was worked up in the same manner and purified by flash chromatography using ethyl acetate/cyclohexane @ 1:1 followed by dichloromethane/ammonia solution/methanol @ 8:1:1 as eluants. This yielded 1.97 g of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The mixture was split into 4×20 mL capacity microwave vials each was treated with water (3 mL) One sixth of the total reaction mixture extracted with ethyl acetate (2×80 mL) The combined organic phase was dried (magnesium sulphate) concentrated to dryness the product purified by flash chromatography on silica using 0-50% ethyl acetate/cyclohexane concentrated to dryness

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-(hydroxymethyl)phenyl]boronic acid (2 g, 13.2 mmol) in 1,4-dioxan (40 mL) was added [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (3.18 g, 13.2 mmol), potassium carbonate (9.1 g, 66 mmol) and tetrakis(triphenylphosphine)-palladium(0) (456 mg, 0.4 mmol). The mixture was split into 4×20 mL capacity microwave vials and each was treated with water (3 mL). The mixtures were each heated at 150° C. for 20 min. One sixth of the total reaction mixture was treated with water (100 mL) and extracted with ethyl acetate (2×80 mL). The combined organic phase was dried (magnesium sulphate) and concentrated to dryness and the product purified by flash chromatography on silica using 0-50% ethyl acetate/cyclohexane followed by dichloromethane/ammonia solution/methanol @ 8:1:1 as eluants. Product-containing fractions were combined and concentrated to dryness to afford 402 mg of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The remaining five-sixth of the reaction mixture was worked up in the same manner and purified by flash chromatography using ethyl acetate/cyclohexane @ 1:1 followed by dichloromethane/ammonia solution/methanol @ 8:1:1 as eluants. This yielded 1.97 g of the title compound. LC-MS m/z 463 (M+H)+, 0.65 min (ret time). The mixture was split into 4×20 mL capacity microwave vials each was treated with water (3 mL) One sixth of the total reaction mixture extracted with ethyl acetate (2×80 mL) The combined organic phase was dried (magnesium sulphate) concentrated to dryness the product purified by flash chromatography on silica using 0-50% ethyl acetate/cyclohexane concentrated to dryness