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Stage 1 - (7R)-2-[(4-Bromo-2-fluorophenyl)amino]-8-cyclopentyl-7-ethyl-5-methyl-7,8- dihydropteridin-6(5H)-oneTo a suspension of 4-bromo-2-fluoro-phenylamine (388mg, 2.04mmol) in ethanol (2.5ml) and water (10ml) was added concentrated HCI (0.26ml) and intermediate A (300mg, 1.02mmol). The mixture was heated at 800C for 18 hours, cooled and the solvent was removed under reduced pressure. The residue was diluted with EtOAc (10ml) and washed with saturated NaHCO3 (2 x 10 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography (20 - 50% EtOAc in heptane) to afford the title product as a yellow oil (90mg, 20%). ESMS: m/z 448, 449, 450 [Br splitting].
A. (4-Bromo-2-fluoro-phenyl)-(l-pyrimidin-2-yl-piperidin-4-yl)-amine: To the mixture of bromoaniline (285 mg, 1.5 mmol) and ketone (266 mg, 1.5 mmol) in MeOH/AcOH (10:1, 5 ml) was added BH3-Py in THF (8M, 188 mul). The mixture was stirred at rt for 2h. The reaction mixture was concentrated and to the residue was added HCl (10%, 10 ml). The resulting mixture was stirred at rt for 30 min., then with cooling, the mixture was adjusted to alkaline with solid Na2CO3 and water. The aq. layer was extracted with EtOAc (5x 30 ml). The EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO to give the titled compound as a white solid (230 mg).
With [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(ll) dichloride; potassium tert-butylate; In isopropyl alcohol; at 20℃; for 15h;Inert atmosphere;
(1) Isopropanol (60 mL) was added to PEPPSI-IPr catalyst (161 mg, 0.24 mmol) and tert-butoxy potassium (2.65 g, 23.6 mmol) under an argon atmosphere, and the mixture was stirred at room temperature for 15 min. To the reaction mixture were added <strong>[57002-01-4]trans-(2-cyclohexylvinyl)boronic acid</strong> (2.00 g, 13.0 mmol) and 4-bromo-2-fluoroaniline (2.24 g, 11.8 mmol) successively and the mixture was stirred at room temperature for 15 hr. Water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to afford 4-[(E)-2-cyclohexylethenyl]-2-fluoroaniline as a reddish brown oil (2.58 g).
N-(4-bromo-2-fluorophenyl)-6-iodoquinazolin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
In isopropyl alcohol; at 20 - 80℃; for 2h;
General procedure: To a solution of compound 9 (5.8 g, 20 mmol) in 2-propanol was added anilines (22 mmol) at room temperature (r.t.). Then the reaction mixture was heated to 80 C for 2 hours. After the start material was completed, the mixture was filtered through celite, and the cake was washed by 2-propanol, then dried to obtain the desired compounds 10a-10d. N-(4-Bromo-2-fluorophenyl)-6-iodoquinazolin-4-amine (10a): Yield 96%; mp 240-242C; 1H NMR (400MHz, DMSO-d6): δ 12.02 (s, 1H), 9.35 (d, 1H, J=1.5Hz), 8.94 (s, 1H), 8.40 (dd, 1H, J=8.8, 1.6Hz), 7.84-7.76 (m, 2H), 7.61-7.50 (m, 2H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene;Inert atmosphere; Reflux;
Toluene (9 mL), ethanol (6 mL) and water (3 mL) were added into the mixture of M3(0.95 g, 5 mmoi), 3Methyiboronic acid (0.82 g, 5 mmoi) and potassium carbonate (1.73g, 12.5 mmol), stirred with nitrogen replacement for three times. Additional replacementwith nitrogen was performed for three times after 0.3 g of tetraphenylphenylphosphinepalladium was added. Then the reaction was warmed up for reflux reaction overnight.The product was filtered and concentrated, then 20 mL of dichloromethane and 10 mL ofwater were added and stilTed for 10 mitt The liquid was separated and washed with 10mL of water twice, dried with anhydrous sodium sulfate, filtered, concentrated andpurified by column chromatography. 0.77 g of M8 was achieved.
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