反应详情

The title compound 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (2) was prepared by the following procedure: To phenol (22.6 mg, 0.24 mmol) in DMF (2 mL) was added NaH (60% oil dispersion) (24 mg, 0.6 mmol). After stirring at rt for 5 minutes, ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-iodopropyl)thiazole-4-carboxylate (2C) (127 mg, 0.2 mmol) was added and stirring was continued for 1 hour. The reaction mixture was acidified with 1N HCl and the precipitate was filtered and washed with water. The precipitate was slurried in Et2O, filtered and washed with additional Et2O. The resulting solid was purified by column chromatography on silica gel eluting with a gradient of 0 to 2% MeOH in DCM. To the purified material in DMF (1 mL) was added NaOH (4N aq) (0.5 mL, 2 mmol), heated at 50° C. for 5 hours, cooled to rt, and acidified with 1N HCl. The precipitate was filtered, washed with water, slurried in Et2O, filtered, washed with Et2O and dried in a vacuum oven to provide the desired product 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (2) in 37% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.89 (s, 1H), 12.49 (1H, s), 8.04 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.44 (4H, m), 7.25 (2H, m), 6.88 (3H, m), 4.82 (2H, s), 3.96 (2H, t), 3.72 (2H, t), 3.17 (2H, m), 3.03 (2H, t), 2.00 (2H, m). MS (ESI(+)): m/z 571 (M+H).

1. customThe title compound 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-phenoxypropyl)thiazole-4-carboxylic acid (2) was prepared by the following procedure
2. stirringstirring
3. waitwas continued for 1 hour
4. filtrationthe precipitate was filtered
5. washwashed with water
6. filtrationfiltered
7. washwashed with additional Et2O
8. customThe resulting solid was purified by column chromatography on silica gel eluting with a gradient of 0 to 2% MeOH in DCM
9. temperatureheated at 50° C. for 5 hours
10. temperaturecooled to rt
11. filtrationThe precipitate was filtered
12. washwashed with water
13. filtrationfiltered
14. washwashed with Et2O
15. customdried in a vacuum oven