反应详情

温度

150 °C

To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (250 mg, 1.07 mmol) in p-cymene (11 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-propylquinolin-2-amine hydrochloride SLA 28178 (323 mg, 1.07 mmol) at RT followed by a 2 N aq. LiOH solution (1.07 mL, 2.14 mmol) and the mixture was stirred at 150° C. for 1 h before addition of a new portion of SLA 28178 (323 mg, 1.07 mmol, done 3 times). After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and 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 92:8) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation, 14.8 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)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 (0.26 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum, to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 42 as a yellow solid (6 mg, 10% yield).

1. temperatureAfter cooling to RT
2. washMeOH=9:1 (150 mL) and 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 92:8)
7. customfollowed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5)
8. customprovided
9. customafter evaporation, 14.8 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(propylamino)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 (0.26 mL)
12. stirringThe reaction mixture was stirred for 5 min at RT
13. concentrationthen concentrated at 40° C. under vacuum