反应详情

1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g), 4-(1,1-dioxido-4-thiomorpholinyl)benzoic acid (0.186 g) in DCM (5 ml). EDC (0.165 g) was then added and the reaction was stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was then loaded directly onto a silica column and eluted with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min. The mixture was evaporated (co-evaporated with acetone 2×10 ml), triturated with acetone, then dried at 50° C. under high vacuum for 16 h to yield the title compound (E9) as a pale solid (0.086 g). MS electrospray (+ion) 392 (MH+). 1H NMR δ (DMSO-d6): 10.5 (1H, s), 7.37 (2H, d, J=8.4 Hz), 7.07 (2H, d, J=8.8 Hz), 4.18-3.24 (10H, m), 3.11 (4H, m), 3.10-2.85 (2H, m), 2.45-1.98 (7H, m), 1.80-2.54 (2H, m).

1. filtrationwas filtered off
2. additionthe filtrate was diluted with DCM (10 ml)
3. washwashed with saturated sodium hydrogen carbonate (2×15 ml)
4. washeluted with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM
5. dissolutionThe isolated free base product was dissolved in DCM (5 ml)
6. additiontreated with excess 1N HCl/diethyl ether solution (1 ml)
7. stirringstirred for 10 min
8. customThe mixture was evaporated (co-evaporated with acetone 2×10 ml)
9. customtriturated with acetone
10. customdried at 50° C. under high vacuum for 16 h