反应详情

温度

160 °C

To a stirred solution of 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (362 mg, 1.46 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41070 (500 mg, 1.47 mmol) at RT followed by a 2 N aq. solution of LiOH (1.47 mL, 2.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 161 mg of 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 51 as a yellow solid (130 mg, 15% yield).

1. temperatureAfter cooling to RT
2. washMeOH=9:1 (150 mL), washed with brine (20 mL)
3. dry with materialdried over Na2SO4
4. filtrationfiltered
5. concentrationconcentrated at 40° C. under vacuum
6. customPurification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5)
7. customfollowed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3)
8. customprovided
9. customafter evaporation, 161 mg of 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid
10. dissolutionThis free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask
11. customequipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.5 mL)
12. stirringThe reaction mixture was stirred for 5 min at RT
13. concentrationthen concentrated at 40° C. under vacuum