(3S)-3-methylmorpholine;hydrochloride

反応条件: temp:175.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (712 mg, 2.81 mmol), diisopropylethylamine (0.98 mL, 5.61 mmol), and (S)-3-methylmorpholin hydrochloride (579 mg, 4.21 mmol) were stirred in 2-butanol (3 mL) in a closed 5 mL microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 175° C. for 48 hours. The organic layer was diluted with 200 mL of CH2Cl2 and washed with brine. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aq NH3 in a gradient from 100/0/0.1 to 90/10/0.1) to give the product as a solid (588 mg, 66%). were dissolved washed with brine Drying over Na2SO4 filtering concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aq NH3 in a gradient from 100/0/0.1 to 90/10/0.1)

反応条件: temp:175.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (712 mg, 2.81 mmol), diisopropylethylamine (0.98 mL, 5.61 mmol), and (S)-3-methylmorpholin hydrochloride (579 mg, 4.21 mmol) were stirred in 2-butanol (3 mL) in a closed 5 mL microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 175° C. for 48 hours. The organic layer was diluted with 200 mL of CH2Cl2 and washed with brine. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aq NH3 in a gradient from 100/0/0.1 to 90/10/0.1) to give the product as a solid (588 mg, 66%). were dissolved washed with brine Drying over Na2SO4 filtering concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aq NH3 in a gradient from 100/0/0.1 to 90/10/0.1)

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

実験手順: 4-Bromo-2,5-difluorobenzaldehyde (331 mg, 1.5 mmol), (S)-3-methylmorpholine hydrochloride (206 mg, 1.50 mmol) and sodium triacetoxyborohydride (461 mg, 2.18 mmol) were mixed in dichloroethane (5 mL). Triethylamine (0.230 mL, 1.65 mmol) was added and the resulting mixture was stirred at RT under argon atmosphere for 24 h. NaHCO3 (25 mL) was added and the mixture was extracted with dichloromethane (3×25 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated to give (S)-4-(4-bromo-2,5-difluorobenzyl)-3-methylmorpholine (432 mg, 94%) as a solid. the mixture was extracted with dichloromethane (3×25 mL) The combined organic extracts were dried over MgSO4 filtered 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 (3S)-3-methylmorpholine hydrochloride (0.2059 g, 1.496 mmol) in DMF (7.5 mL) was added tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.7451 g, 1.498 mmol), and N,N-diisopropylethylamine (0.575 mL, 3.301 mmol). The solution was stirred overnight, and then diluted with Et2O (150 mL). The mixture was washed with water (2×50 mL), and the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL). This Et2O layer was washed with a fresh portion of water (50 mL), and the combined organic phase was diluted with DCM (50 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and azeotroped with EtOAc. The solid was collected by vacuum filtration and washed with hexanes. The supernatant was concentrated in vacuo, and purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N). The desired fractions were concentrated in vacuo, and the resulting solid was collected by vacuum filtration, washed with hexanes, and combined with the first crop of solid to give tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3S)-3-methyl-4-morpholinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.6610 g, 79%) as a white solid. LCMS: (M+H)+: 562.2. The mixture was washed with water (2×50 mL) the combined aqueous phase was extracted with a fresh portion of Et2O (50 mL) This Et2O layer was washed with a fresh portion of water (50 mL) the combined organic phase was diluted with DCM (50 mL) dried over anhydrous Na2SO4 filtered concentrated in vacuo azeotroped with EtOAc The solid was collected by vacuum filtration washed with hexanes The supernatant was concentrated in vacuo purified by gradient silica gel chromatography (0% to 100% EtOAc in hexanes; 1% Et3N) The desired fractions were concentrated in vacuo the resulting solid was collected by vacuum filtration washed with hexanes

反応条件: temp:175.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (712 mg, 2.81 mmol), diisopropylethylamine (0.98 mL, 5.61 mmol), and (S)-3-methylmorpholin hydrochloride (579 mg, 4.21 mmol) were stirred in 2-butanol (3 mL) in a closed 5 mL microwave tube under argon at 50° C., until all ingredients were dissolved. The reaction was then stirred at 175° C. for 48 hours. The organic layer was diluted with 200 mL of CH2Cl2 and washed with brine. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aq NH3 in a gradient from 100/0/0.1 to 90/10/0.1) to give the product as a solid (588 mg, 66%). were dissolved washed with brine Drying over Na2SO4 filtering concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, CH2Cl2/EtOH/aq NH3 in a gradient from 100/0/0.1 to 90/10/0.1)