反应详情

温度

130 °C

To a solution of trans-N2-{4-[(4-bromo-2-trifluoromethoxy-benzylamino)-methyl]-cyclohexylmethyl}-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step B of example 15 (300 mg, 0.529 mol) in toluene (6.6 mL) were added MeOH (2.2 mL), 2 M aqueous K2CO3 (2.2 mL), phenylboronic acid (77 mg, 0.635 mmol), and tetrakis (triphenylphosphine) palladium (61 mg, 0.053 mmol). The reaction mixture was stirred at 130° C. for 12 hr. The mixture was poured into water, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated and, purified by flash chromatography (NH-silica gel, 33% CHCl3 in hexane and silica gel, 9% MeOH in CHCl3) to give pale yellow oil. To a solution of above oil in EtOAc (2 mL) was added 4 M hydrogen chloride in EtOAc (0.1 mL). The mixture was stirred at ambient temperature for 20 min and concentrated. A solution of the residue in Et2O (2 mL) was stirred at ambient temperature for 30 min. The precipitate was collected by filtration, washed with Et2O, and dried under reduced pressure to give trans-N4,N4-dimethyl-N2-(4-{[(3-trifluoromethoxy-biphenyl-4-ylmethyl)-amino]-methyl}-cyclohexylmethyl)-quinazoline-2,4-diamine dihydrochloride (70 mg, 21%) as a white solid.

1. extractionthe aqueous layer was extracted with CHCl3 (three times)
2. dry with materialThe combined organic layer was dried over MgSO4
3. filtrationfiltered
4. concentrationconcentrated
5. custompurified by flash chromatography (NH-silica gel, 33% CHCl3 in hexane and silica gel, 9% MeOH in CHCl3)
6. customto give pale yellow oil
7. stirringThe mixture was stirred at ambient temperature for 20 min
8. concentrationconcentrated
9. stirringA solution of the residue in Et2O (2 mL) was stirred at ambient temperature for 30 min
10. filtrationThe precipitate was collected by filtration
11. washwashed with Et2O
12. customdried under reduced pressure