反应详情

To a suspension of cis-[4-(4-methylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester obtained in step B of example 50 (8.68 g, 23.4 mmol) in CHCl3 (87 mL) was added 4 M hydrogen chloride in EtOAc (100 mL). The reaction mixture was stirred at ambient temperature for 2 hr, and concentrated. The residue was alkalized with saturated aqueous NaHCO3 and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated (10.57 g). To a suspension of the above residue (594 mg) in MeOH (6 mL) were added 3-(4-bromo-2-trifluoromethoxy-phenyl)-propionaldehyde obtained in step C of example 62 (650 mg, 2.19 mmol), AcOH (132 mg, 2.19 mmol), and NaBH3CN (207 mg, 3.29 mmol). The reaction mixture was stirred at ambient temperature for 16 hr, poured into saturated aqueous NaHCO3, and the aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, purified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane and silica gel, 16% MeOH in CHCl3) to give a yellow oil. To a solution of the residue in EtOAc (6 mL) was added 4 M hydrogen chloride in EtOAc (0.14 mL). The reaction mixture was stirred at ambient temperature for 30 min, and concentrated. A solution of the residue in Et2O (10 mL) was stirred at ambient temperature for 1 hr and the precipitate was collected by filtration to give cis-N2-{4-[3-(4-bromo-2-trifluoromethoxy-phenyl)-propylamino]-cyclohexyl}-N4-methyl-quinazoline-2,4-diamine dihydrochloride (59 mg, 7%) as a white solid.

1. concentrationconcentrated
2. extractionthe aqueous layer was extracted with CHCl3 (three times)
3. dry with materialThe combined organic layer was dried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated (10.57 g)
6. additionTo a suspension of the above residue (594 mg) in MeOH (6 mL)
7. stirringThe reaction mixture was stirred at ambient temperature for 16 hr
8. extractionthe aqueous layer was extracted with CHCl3 (three times)
9. dry with materialThe combined organic layer was dried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated
12. custompurified by medium-pressure liquid chromatography (NH-silica gel, 50% EtOAc in hexane and silica gel, 16% MeOH in CHCl3)
13. customto give a yellow oil
14. stirringThe reaction mixture was stirred at ambient temperature for 30 min
15. concentrationconcentrated
16. stirringA solution of the residue in Et2O (10 mL) was stirred at ambient temperature for 1 hr
17. filtrationthe precipitate was collected by filtration