Ammonia → ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloropropyl)thiazole-4-carboxylate

Participants

Reaction Steps

To N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride (1B) (11.5 g, 30 mmol) in DMF (125 mL) was added TEA (16.7 mL, 120 mmol) and stirred at rt for 15 minutes. Di(1H-imidazol-1-yl)methanethione (6.53 g, 33 mmol) was added and the reaction mixture was stirred at rt for 1 hour. 7N Ammonia in MeOH (171 mL, 1.2 mol) was added and the mixture was stirred at rt overnight. The reaction mixture was concentrated to remove ammonia, TEA, and MeOH. To the concentrate was added a solution of ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) (11.4 g, 42 mmol) in EtOH (40 mL). The reaction mixture was heated at 50° C. under nitrogen for 4.5 hours. Additional ethyl 3-bromo-6-chloro-2-oxohexanoate (2A) (0.815 g, 3 mmol) in EtOH (3 mL) was added and heating was continued for 1.5 hours. The reaction mixture was concentrated under reduced pressure to remove EtOH and then extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography on silica gel eluting with a gradient of 30 to 50% EtOAc in hexanes to provide the desired product ethyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-5-(3-chloropropyl)thiazole-4-carboxylate (2B) in 69% yield. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.89 (1H, s), 8.04 (1H, d), 7.79 (1H, d), 7.67 (1H, d), 7.42 (4H, m), 4.83 (2H, s), 4.19 (2H, q), 3.72 (2H, t), 3.64 (2H, t), 3.13 (2H, m), 3.04 (2H, t), 2.00 (2H, m), 1.21 (3H, t).

Provenance & Evidence