(3-bromophenyl)methanamine;hydrochloride

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

実験手順: A solution of 25 g (110 mmol) of 3-bromobenzylamine hydrochloride and 24.5 g (110 mmol) of tert-butyl dicarbonate in 250 mL of dichloromethane in the presence of 15.6 mL (110 mmol) of triethylamine is stirred at room temperature for 16 hours. The reaction medium is washed with water, the phases are separated by settling and the organic phase is dried over sodium sulfate. The solvent is evaporated off and 32.4 g (100%) of tert-butyl (3-bromobenzyl)carbamate are obtained in the form of crystals. The reaction medium is washed with water the phases are separated the organic phase is dried over sodium sulfate The solvent is evaporated off

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

実験手順: (3-Bromophenyl)methanamine hydrochloride (3.62 g, 15.64 mmol) and sodium methoxide (3.58 mL, 15.64 mmol) were added to a solution of methyl 2,2-diethoxyacetimidate (5.042 g, 31.3 mmol) in methanol (15 mL). The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellow mixture was concentrated. The residue was purified by silica gel chromatography with 100% ethyl acetate. The desired fractions were concentrated to give a yellow viscous oil (2.5 g, 51%). LCMS:R.T.=2.11; [M+2]+=317.06. The cloudy mixture was heated at 70 C for 1.5 h the resulting yellow mixture was concentrated The residue was purified by silica gel chromatography with 100% ethyl acetate The desired fractions were concentrated

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

実験手順: (3-Bromophenyl)methanamine hydrochloride (3.62 g, 15.64 mmol) and sodium methoxide (3.58 mL, 15.64 mmol) were added to a solution of methyl 2,2-diethoxyacetimidate (5.042 g, 31.3 mmol) in methanol (15 mL). The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellow mixture was concentrated. The residue was purified by silica gel chromatography with 100% ethyl acetate. The desired fractions were concentrated to give a yellow viscous oil (2.5 g, 51%). LCMS:R.T.=2.11; [M+2]+=317.06. The cloudy mixture was heated at 70 C for 1.5 h the resulting yellow mixture was concentrated The residue was purified by silica gel chromatography with 100% ethyl acetate The desired fractions were concentrated

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-bromobenzylamine hydrochloride (5.20 g) in pyridine (30 ml) was added acetic anhydride (3.2 ml) at 0° C. and the mixture was stirred at room temperature for 24 h. Water and ethyl acetate were added to the reaction mixture for partitioning, and the organic layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (4.00 g) as colorless needle crystals. for partitioning the organic layer was washed with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine dried (magnesium sulfate) concentrated under reduced pressure The residue was recrystallized from hexane-ethyl acetate

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

実験手順: The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromophenyl)methyl]amine hydrochloride (464 mg, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap and the residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (962 mg, 1.476 mmol, 73.8% yield) as a white solid. LC-MS m/z 633.6 (M+H)+, 0.97 min (ret time); mp 116-118° C. The solvent was removed on a rotavap washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine dried over anhydrous Na2SO4 filtered evaporated to give the crude residue absorbed on Isolute® Sorbent purified by Combiflash eluted with 0-10% DCM/MeOH concentrated

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

実験手順: The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromophenyl)methyl]amine hydrochloride (464 mg, 2.000 mmol), and TEA (0.558 mL, 4.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap and the residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. The residue was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give N-[(3-bromophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (962 mg, 1.476 mmol, 73.8% yield) as a white solid. LC-MS m/z 633.6 (M+H)+, 0.97 min (ret time); mp 116-118° C. The solvent was removed on a rotavap washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine dried over anhydrous Na2SO4 filtered evaporated to give the crude residue absorbed on Isolute® Sorbent purified by Combiflash eluted with 0-10% DCM/MeOH concentrated

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

実験手順: To a suspension of 10.0 g of 3-bromobenzylamine hydrochloride in chloroform (100 ml), 9.55 g of triethylamine was added at room temperature. To this solution, 4.67 g of methyl chloroformate was dropwise added under cooling with ice, followed by stirring at room temperature for 2 hours. The reaction solution was poured into a sodium chloride aqueous solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9.54 g of methyl N-(3-bromobenzyl)carbamate as white crystals. was added at room temperature under cooling with ice the organic layer was dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the residue 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 solution of 25 g (110 mmol) of 3-bromobenzylamine hydrochloride and 24.5 g (110 mmol) of tert-butyl dicarbonate in 250 mL of dichloromethane in the presence of 15.6 mL (110 mmol) of triethylamine is stirred at room temperature for 16 hours. The reaction medium is washed with water, the phases are separated by settling and the organic phase is dried over sodium sulfate. The solvent is evaporated off and 32.4 g (100%) of tert-butyl (3-bromobenzyl)carbamate are obtained in the form of crystals. The reaction medium is washed with water the phases are separated the organic phase is dried over sodium sulfate The solvent is evaporated off

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

実験手順: (3-Bromophenyl)methanamine hydrochloride (3.62 g, 15.64 mmol) and sodium methoxide (3.58 mL, 15.64 mmol) were added to a solution of methyl 2,2-diethoxyacetimidate (5.042 g, 31.3 mmol) in methanol (15 mL). The cloudy mixture was heated at 70 C for 1.5 h and the resulting yellow mixture was concentrated. The residue was purified by silica gel chromatography with 100% ethyl acetate. The desired fractions were concentrated to give a yellow viscous oil (2.5 g, 51%). LCMS:R.T.=2.11; [M+2]+=317.06. The cloudy mixture was heated at 70 C for 1.5 h the resulting yellow mixture was concentrated The residue was purified by silica gel chromatography with 100% ethyl acetate The desired fractions were concentrated

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

実験手順: To a 250 mL shaker vessel was added 2,6-dimethoxy-4-polystyrenebenzyloxy-benzaldehyde (DMHB resin) (10 g, 1.5 mmol/g, 15 mmol) and 150 mL of 1-methyl-2-pyrrolidinone (NMP). 3-Bromo-benzylamine HCl salt (17 g, 75 mmol), diisopropylethylamine (DIEA) (13 mL, 75 mmol), acetic acid (HOAc) (15 mL), and Na(OAc)3BH (19.1 g, 90 mmol) were then added. The resulting mixture was shaken at rt for overnight, and was then washed with NMP (150 mL×2), dichloromethane (DCM) (150 mL×2), MeOH (150 mL×2) and DCM (150 mL×2). The resulting resin was dried in vacuum oven at 35° C. for overnight to yield DMHB resin-bound 3-bromo-benzylamine (15 mmol). was then washed with NMP (150 mL×2), dichloromethane (DCM) (150 mL×2), MeOH (150 mL×2) and DCM (150 mL×2) The resulting resin was dried in vacuum oven at 35° C. for overnight

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

実験手順: 3-Bromo-benzylamine HCl salt (0.75 g) was dissolved in 10 mL 15% IPA in CH2Cl2. 7 drops of 10N Sodium Hydroxide (NaOH) was added and stirred for 3 minutes. To the reaction mixture, 5 mL of dH2O was added and stirred for 5 minutes. The IPA/CH2Cl2 layer was extracted. The aqueous layer was rinsed with 10 mL 15% IPA in CH2Cl2. All organic layers were added together and concentrated under vacuum. MS (ESI+) for C7H8BrN m/z 186.3 (M+H)+ To the reaction mixture, 5 mL of dH2O was added stirred for 5 minutes The IPA/CH2Cl2 layer was extracted The aqueous layer was rinsed with 10 mL 15% IPA in CH2Cl2 All organic layers were added together concentrated under vacuum

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 26.25 g of 3-Bromobenzylamine hydrochloride was suspended in 250 ml of dichloromethane, and the mixture was cooled to 0° C. 33.5 g of N,N-diisopropylethylamine and 28.3 g of t-butyl dicarbonate were added. After stirring was continued at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off, to give 31.28 g of the title compound. The solution was washed with water and saturated brine dried over anhydrous magnesium sulfate filtered the solvent was distilled off