反应详情

To a solution of 1-((1,3-dioxoisoindolin-2-yl)methyl)-6,7-dimethoxyisoquinolin-3-yl acetate SIL 32166 (297 mg, 0.73 mmol) in dry CH2Cl2 (9 mL) in a 25 mL round-bottomed flask equipped with a magnetic stirrer was added a 7 N NH3 solution in MeOH (1 mL) and the reaction mixture was stirred for 4 h at RT then concentrated to dryness at 40° C. under vacuum. The solid was taken up in THF (7 mL) and transferred in a 20 mL microwave vial equipped with a magnetic stirrer before addition of a 2 N aq. LiOH solution (0.37 mL, 0.74 mmol) and 3-(chloromethyl)-N-ethyl-6-methoxyquinolin-2-amine SLA 28166 free base (240 mg, 0.96 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave 2-((4-((2-(ethylamino)-6-methoxyquinolin-3-yl)methyl)-3-hydroxy-6,7-dimethoxyisoquinolin-1-yl)methyl)isoindoline-1,3-dione CCH 42006-1 as a yellow oil (75 mg, 32%).

1. concentrationthen concentrated to dryness at 40° C. under vacuum
2. stirringthe mixture was stirred at 150° C. for 1.5 h under microwave irradiation
3. temperatureAfter cooling to RT
4. washMeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL)
5. dry with materialdried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated at 40° C. under vacuum
8. customPurification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3)
9. customfollowed by a second purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100)