(3-bromo-5-methoxyphenyl)methanamine

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

実験手順: A mixture of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (762 mg, 1.69 mmol), {[3-bromo-5-(methyloxy)phenyl]methyl}amine (529 mg, 1.86 mmol), HBTU (769 mg, 2.03 mmol) and Et3N (0.47 mL, 3.38 mmol) in DCM was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was then purified using CombiFlash chromatography eluting with 0 to 10% methanol in DCM to obtain N-{[3-bromo-5-(methyloxy)phenyl]methyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (1.05 g, 96%). LC-MS m/z 649 (M+H)+. The reaction was quenched with saturated NaHCO3 extracted with DCM twice The combined organic layers were then washed with water wash The organic layer was then concentrated under vacuum to give a crude residue It was then purified eluting with 0 to 10% methanol in DCM

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

実験手順: To a solution of 3-bromo-5-(methyloxy)benzamide (4.00 g, 17.4 mmol) in THF (60 mL), BH3.Me2S (2.64 g, 34.8 mol) was added at 0° C. After the end of the addition, the reaction mixture was kept refluxing overnight (monitored by TLC). After cooling to room temperature, EtOH was cautiously added to the reaction mixture. When there no more air bubbles appeared, the mixture was acidified with 1N HCl to pH=2. Then the mixture was stirred at 50° C. for 4 h, filtered and the filter rinsed with water (20 mL×2). The filtrate was washed with EtOAc (50 mL×3). After addition of 2N NaOH (pH=10), the filtrate was extracted with EtOAc (100 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a mixture of solid and oil. MeOH (10 mL) and conc. HCl (10 mL) were added and concentrated to afford crude material as a white solid. Recrystallization from MeOH-Et2O gave the captioned product (3.10 g, 71%), {[3-bromo-5-(methyloxy)phenyl]methyl}amine, as colorless fine needles. 1H NMR (400 MHz, D2O): δ 7.12-7.09 (m, 2 H), 6.86 (s, 1 H), 3.98 (s, 2 H), 3.69 (s, 3 H); 13C NMR (100 MHz, D2O): δ160.2, 135.8, 124.2, 123.0, 117.8, 114.0, 55.8, 42.5; HPLC: retention time: 5.452 min; purity: 97.4% (HPLC). After the end of the addition the reaction mixture was kept refluxing overnight (monitored by TLC) filtered the filter rinsed with water (20 mL×2) The filtrate was washed with EtOAc (50 mL×3) After addition of 2N NaOH (pH=10) the filtrate was extracted with EtOAc (100 mL×3) The combined extracts were washed with brine dried over anhydrous sodium sulfate concentrated to give a mixture of solid and oil concentrated to afford crude material as a white solid Recrystallization from MeOH-Et2O

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

実験手順: To a solution of 3-bromo-5-(methyloxy)benzamide (4.00 g, 17.4 mmol) in THF (60 mL), BH3.Me2S (2.64 g, 34.8 mol) was added at 0° C. After the end of the addition, the reaction mixture was kept refluxing overnight (monitored by TLC). After cooling to room temperature, EtOH was cautiously added to the reaction mixture. When there no more air bubbles appeared, the mixture was acidified with 1N HCl to pH=2. Then the mixture was stirred at 50° C. for 4 h, filtered and the filter rinsed with water (20 mL×2). The filtrate was washed with EtOAc (50 mL×3). After addition of 2N NaOH (pH=10), the filtrate was extracted with EtOAc (100 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a mixture of solid and oil. MeOH (10 mL) and conc. HCl (10 mL) were added and concentrated to afford crude material as a white solid. Recrystallization from MeOH-Et2O gave the captioned product (3.10 g, 71%), {[3-bromo-5-(methyloxy)phenyl]methyl}amine, as colorless fine needles. 1H NMR (400 MHz, D2O): δ 7.12-7.09 (m, 2 H), 6.86 (s, 1 H), 3.98 (s, 2 H), 3.69 (s, 3 H); 13C NMR (100 MHz, D2O): δ160.2, 135.8, 124.2, 123.0, 117.8, 114.0, 55.8, 42.5; HPLC: retention time: 5.452 min; purity: 97.4% (HPLC). After the end of the addition the reaction mixture was kept refluxing overnight (monitored by TLC) filtered the filter rinsed with water (20 mL×2) The filtrate was washed with EtOAc (50 mL×3) After addition of 2N NaOH (pH=10) the filtrate was extracted with EtOAc (100 mL×3) The combined extracts were washed with brine dried over anhydrous sodium sulfate concentrated to give a mixture of solid and oil concentrated to afford crude material as a white solid Recrystallization from MeOH-Et2O

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

実験手順: To a solution of 1-(3-bromo-5-methoxyphenyl)methanamine (2.57 g, 11.9 mmol) and 2,4,5-trichloropyrimidine (2.4 g, 13 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (3.3 g, 24 mmol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel column chromatography to give the desired product (3.7 g, 87%). LCMS for C12H10BrCl2N3O (M+H)+: m/z=361.9, 363.9. The reaction mixture was quenched with water EtOAc was added the layers were separated The aqueous layer was extracted with EtOAc twice The combined organic layers were washed with water and brine successively dried (Na2SO4) filtered concentrated The residue was purified by silica gel column chromatography

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 3-Bromo-5-methoxybenzonitrile (13.1 g, 61.8 mmol) was dissolved in dry tetrahydrofuran (100 mL) in a flame-dried flask and cooled in an ice bath. A solution of borane in tetrahydrofuran (100 mL, 0.10 mol, 1.0 M) was slowly added over a period of 30 minutes. After the addition was complete, the mixture was heated at 70° C. overnight and quenched slowly with ice water and Na2CO3 (saturated aqueous solution). After removal of THF, the residue was extracted with large amounts of EtOAc three times. The combined organic layers were washed with water, dried, and concentrated to give the crude product, which was purified by silica gel column chromatography to give the desired product as a white powder (2.57 g, 19%). LCMS for C8H10BrNO (M+H)+: m/z=216.9, 218.9. cooled in an ice bath After the addition quenched slowly with ice water and Na2CO3 (saturated aqueous solution) After removal of THF the residue was extracted with large amounts of EtOAc three times The combined organic layers were washed with water dried concentrated to give the crude product, which was purified by silica gel column chromatography

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

実験手順: A mixture of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (762 mg, 1.69 mmol), {[3-bromo-5-(methyloxy)phenyl]methyl}amine (529 mg, 1.86 mmol), HBTU (769 mg, 2.03 mmol) and Et3N (0.47 mL, 3.38 mmol) in DCM was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue. It was then purified using CombiFlash chromatography eluting with 0 to 10% methanol in DCM to obtain N-{[3-bromo-5-(methyloxy)phenyl]methyl}-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide as a solid (1.05 g, 96%). LC-MS m/z 649 (M+H)+. The reaction was quenched with saturated NaHCO3 extracted with DCM twice The combined organic layers were then washed with water wash The organic layer was then concentrated under vacuum to give a crude residue It was then purified eluting with 0 to 10% methanol in DCM

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

実験手順: To a solution of 3-bromo-5-(methyloxy)benzamide (4.00 g, 17.4 mmol) in THF (60 mL), BH3.Me2S (2.64 g, 34.8 mol) was added at 0° C. After the end of the addition, the reaction mixture was kept refluxing overnight (monitored by TLC). After cooling to room temperature, EtOH was cautiously added to the reaction mixture. When there no more air bubbles appeared, the mixture was acidified with 1N HCl to pH=2. Then the mixture was stirred at 50° C. for 4 h, filtered and the filter rinsed with water (20 mL×2). The filtrate was washed with EtOAc (50 mL×3). After addition of 2N NaOH (pH=10), the filtrate was extracted with EtOAc (100 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to give a mixture of solid and oil. MeOH (10 mL) and conc. HCl (10 mL) were added and concentrated to afford crude material as a white solid. Recrystallization from MeOH-Et2O gave the captioned product (3.10 g, 71%), {[3-bromo-5-(methyloxy)phenyl]methyl}amine, as colorless fine needles. 1H NMR (400 MHz, D2O): δ 7.12-7.09 (m, 2 H), 6.86 (s, 1 H), 3.98 (s, 2 H), 3.69 (s, 3 H); 13C NMR (100 MHz, D2O): δ160.2, 135.8, 124.2, 123.0, 117.8, 114.0, 55.8, 42.5; HPLC: retention time: 5.452 min; purity: 97.4% (HPLC). After the end of the addition the reaction mixture was kept refluxing overnight (monitored by TLC) filtered the filter rinsed with water (20 mL×2) The filtrate was washed with EtOAc (50 mL×3) After addition of 2N NaOH (pH=10) the filtrate was extracted with EtOAc (100 mL×3) The combined extracts were washed with brine dried over anhydrous sodium sulfate concentrated to give a mixture of solid and oil concentrated to afford crude material as a white solid Recrystallization from MeOH-Et2O