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Stage #1: With N-Bromosuccinimide In chloroform for 15 h; Stage #2: With sodium hydroxide In dichloromethane; chloroform; water
[0242] To a solution of 4-methylpyrimidine-2-ylamine (10.9 g, lOO mmol) in chloroform (400 mL) was added N-bromosuccinimide (17.8 g, 100 mmol). The solution was stirred in the dark for 15 hours, at which time it was added to CH2Cl2 (140O mL), washed with IN NaOH (3x200 mL) and NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 5-bromo-4-methylpyrimidine-2-ylamine (18.8 g, 99percent). LCMS (m/z): 188.0/190.0 (MH+). 1H NMR (CDCl3): δ 8.22 (s, IH), 5.02 (bs, 2H), 2.44 (s, 3H).
91%
With N-Bromosuccinimide In chloroform at 20℃; for 2 h;
Step 44a: 5-Bromo-4-methylpyrimidin-2-amine (Compound 0601-125)A mixture of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), NBS (7.18 g, 40.3 mmol) in chloroform (100 mL) was stirred for 2 h at room temperature, then the solvent was removed in vacuum. Water (100 mL) was added and stirred for 30 min at room temperature, filtered. The solid was washed with water and dried to get compound 0601- 125 (6.3 g, 91percent) as a white solid. LCMS: 188 [M+l]+, 1H NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H), 6.79 (s, 2H), 8.21 (s, 1H).
91%
With N-Bromosuccinimide In chloroform at 20℃; for 2 h;
Step 44a: 5-Bromo-4-methylpyrimidin-2-amine (Compound 0601-125)[0378]A mixture of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), NBS (7.18 g, 40.3 mmol) in chloroform (100 mL) was stirred for 2 h at room temperature, then the solvent was removed in vacuum. Water (100 mL) was added and stirred for 30 min at room temperature, filtered. The solid was washed with water and dried to get compound 0601-125 (6.3 g, 91percent) as a white solid. LCMS: 188 [M+1]+, 1H NMR (400 MHz, DMSO-d6) δ 2.32 (s, 3H), 6.79 (s, 2H), 8.21 (s, 1H).
91%
With N-Bromosuccinimide In chloroform at 20℃; for 2 h;
Chloroform (100 mL) solution of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), a mixture of NBS (7.18g, 40.3mmol) was stirred at room temperature for 2 hours, then the solvent was removed under vacuum. Water (100 mL) was added and stirred for 30 min at room temperature and filtered. The solid was washed with water, to give the compound 0601-125 and dried as a white solid (6.3g, 91percent).
86%
With N-Bromosuccinimide In chloroform for 18 h; Darkness
To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with IN NaOH aq solution and brine, dried over MgS04, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
86%
With N-Bromosuccinimide In chloroform for 18 h; Darkness
To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with 1N NaOH aq solution and brine, dried over MgSO4, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
86%
With N-Bromosuccinimide In chloroform for 18 h; Darkness
Example 6 4-methyl-5-(4, 4, 5, 5-tetramethyl (1, 3, 2-dioxaborolan-2-yl)) pyrimidine-2-ylamine 42 [0204] To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with IN NaOH aq solution and brine, dried over MgSO4, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
81%
With N-Bromosuccinimide In dichloromethane at 25℃; for 16 h; Darkness
To a solution of compound 22 (500mg, 4.6 mmol) in DCM (50 mL) was added NBS (820mg, 4.6 mmol). The mixture was stirred in the dark for 16 hours at room temperature. The reaction was quenched with DCM (50 mL) and iN NaOH (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound 23 as a white solid (700 mg, 81percent yield), which was used directly in the next step without further purification.
[0242] To a solution of 4-methylpyrimidine-2-ylamine (10.9 g, lOO mmol) in chloroform (400 mL) was added N-bromosuccinimide (17.8 g, 100 mmol). The solution was stirred in the dark for 15 hours, at which time it was added to CH2Cl2 (140O mL), washed with IN NaOH (3x200 mL) and NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 5-bromo-4-methylpyrimidine-2-ylamine (18.8 g, 99percent). LCMS (m/z): 188.0/190.0 (MH+). 1H NMR (CDCl3): delta 8.22 (s, IH), 5.02 (bs, 2H), 2.44 (s, 3H).
91%
With N-Bromosuccinimide; In chloroform; at 20℃; for 2h;
Step 44a: 5-Bromo-4-methylpyrimidin-2-amine (Compound 0601-125)A mixture of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), NBS (7.18 g, 40.3 mmol) in chloroform (100 mL) was stirred for 2 h at room temperature, then the solvent was removed in vacuum. Water (100 mL) was added and stirred for 30 min at room temperature, filtered. The solid was washed with water and dried to get compound 0601- 125 (6.3 g, 91percent) as a white solid. LCMS: 188 [M+l]+, 1H NMR (400 MHz, DMSO-d6) delta 2.32 (s, 3H), 6.79 (s, 2H), 8.21 (s, 1H).
91%
With N-Bromosuccinimide; In chloroform; at 20℃; for 2h;
Step 44a: 5-Bromo-4-methylpyrimidin-2-amine (Compound 0601-125)[0378]A mixture of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), NBS (7.18 g, 40.3 mmol) in chloroform (100 mL) was stirred for 2 h at room temperature, then the solvent was removed in vacuum. Water (100 mL) was added and stirred for 30 min at room temperature, filtered. The solid was washed with water and dried to get compound 0601-125 (6.3 g, 91percent) as a white solid. LCMS: 188 [M+1]+, 1H NMR (400 MHz, DMSO-d6) delta 2.32 (s, 3H), 6.79 (s, 2H), 8.21 (s, 1H).
91%
With N-Bromosuccinimide; In chloroform; at 20℃; for 2h;
Chloroform (100 mL) solution of 2-amino-4-methylpyrimidine (4.0 g, 36.7 mmol), a mixture of NBS (7.18g, 40.3mmol) was stirred at room temperature for 2 hours, then the solvent was removed under vacuum. Water (100 mL) was added and stirred for 30 min at room temperature and filtered. The solid was washed with water, to give the compound 0601-125 and dried as a white solid (6.3g, 91percent).
86%
With N-Bromosuccinimide; In chloroform; for 18h;Darkness;
To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with IN NaOH aq solution and brine, dried over MgS04, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
86%
With N-Bromosuccinimide; In chloroform; for 18h;Darkness;
To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with 1N NaOH aq solution and brine, dried over MgSO4, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
86%
With N-Bromosuccinimide; In chloroform; for 18h;Darkness;
Example 6 4-methyl-5-(4, 4, 5, 5-tetramethyl (1, 3, 2-dioxaborolan-2-yl)) pyrimidine-2-ylamine 42 [0204] To a solution of 4-methylpyrimidine-2-ylamine (8.0 g, 0.073 mol) in chloroform (320 mL) was added N-bromosuccinimide (13.7 g, 0.077 mol). The reaction mixture was stirred in the dark for 18 hrs. LC/MS indicated the reaction was completed. The mixture was diluted with DCM, then washed with IN NaOH aq solution and brine, dried over MgSO4, filtered and concentrated to yield 5-bromo-4-methylpyrimidine-2-ylamin (12 g, Yield: 86percent).
81%
With N-Bromosuccinimide; In dichloromethane; at 25℃; for 16h;Darkness;
To a solution of compound 22 (500mg, 4.6 mmol) in DCM (50 mL) was added NBS (820mg, 4.6 mmol). The mixture was stirred in the dark for 16 hours at room temperature. The reaction was quenched with DCM (50 mL) and iN NaOH (50 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound 23 as a white solid (700 mg, 81percent yield), which was used directly in the next step without further purification.
With N-Bromosuccinimide; at 20℃; for 1h;
Intermediate C; 5-Bromo-4 methyl-pyrimidin-2-ylamine2-Amino-4-methylpyrimidine; (10 g, 91.6 mmol), n-bromosuccinimide (17.9 g, 100.8 mmol) and CHCI3 are mixed together and stirred at room temperature for 1 hour. The <n="66"/>solvent is removed in vacuo, water is added and the mixture is stirred at room temperature for 30 minutes. The resulting precipitate is collected by filtration and dried under vacuum oven to afford the title compound.
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 18.25h;Heating / reflux;
[0244] To a dry 1 L flask was added 5-bromo-4-methylpyrimidine-2~ylamine(18.8 g, 100 mmol), potassium acetate (29.45 g, 300 mmol), 4,4,5,5-tetramethyl-2- (4,4,5 ,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (26.7 g, 105 mmol) and dioxane (500 mL). Argon was bubbled through the solution for 15 minutes, at which time l,r-bis(diphenylphosphino)ferrocene palladium(II) chloride dichloromethane adduct (4.07 g, 5 mmol) was added. The reaction was refluxed in a 115 0C oil bath for 18 hours under argon. After cooling to room temperature, EtOAc (500 mL) was added and the resulting slurry was sonicated and filtered. Additional EtOAc (500 mL) was used to wash the solid. The combined organic extracts were washed with H2O (2x300 mL), NaCl(sat.) (30O mL), dried over Na2SO4, concentrated and purified by SiO2 chromatography (EtOAc eluent) yielding 18.1 g of an off-white solid. By 1H NMR the material was a 5:1 mixture of boronate ester and 4-methylpyrimidine-2-ylamine as a <n="95"/>7 001708byproduct. The material was used as is in subsequent Suzuki reactions. LCMS {m/z): 154 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC). 1H NMR (CDCl3): delta 8.52 (s, IH), 5.14 (bs, 2H), 2.56 (d, 3H), 1.32 (s, 12H).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 115℃; for 16h;Inert atmosphere;
To a dry flask was added compound 23 (50 mg, 0.27 mmol), potassium acetate (79 mg, 0.81 mmol), bis(pinacolato)diboron (81 mg, 0.32 mmol) and dioxane (1.5mL). N2 was bubbled through the solution for 1.5 minutes, at which time 1 ,1- bis(diphenylphosphino)ferrocene-palladium(ll) (22 mg, 30 iimol) was added. The reaction was stirred at 115°C for 16 hours under N2. After cooling to room temperature, the dioxane was removed in vacuo. EA was added and the resulting slurry was sonicated and filtered. Additional EA was used to wash the solid. The combined organic was concentrated and the crude was purified by prep-TLC affording to a white solid (40mg). By ?H NMR the material was a 2:1 mixture of compound 24 and compound 22 byproduct. The mixture was used in the subsequent Suzuki reactions. ?H NIVIR (400 MHz, CDC13): 8.53 (s, 1H), 5.77 (bs, 2H), 2.56 (s, 3H), 1.32 (s, 12H)
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