反应详情

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl N-(4-[[(12S)-12-(carbamoylmethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (80 mg, 0.17 mmol, 1.00 equiv) in dichloromethane (5 mL) at 0° C. Then hydrochloric acid (6 M, 0.5 mL) was added and the resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum to give 86 mg (crude) of 2-[(12S)-3-[(4-aminocyclohexyl)oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetamide hydrochloride as a yellow solid. The crude hydrochloride dissolved in 5 mL of methanol was added HCHO (37%, 1 mL) and AcOH (0.5 mL). After stirring for 30 min, NaCNBH3 (34 mg, 0.54 mmol, 2.50 equiv) was added and the resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product (80 mg) was purified by preparative HPLC under the following conditions (Waters): column: X bridge Prep C18 5 um, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (5.0% CH3CN up to 41.0% in 9 min, up to 95.0% in 2 min, down to 5.0% in 2 min); flow rate: 20 mL/min; UV detection at 220/254 nm. This resulted in 21.5 mg (26%) of 2-[(12S)-3-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetamide as a white solid. MS: m/z 389 (M+H)+. 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 5.47-5.40 (d, 2H), 5.25-5.19 (m, 1H), 3.31-3.25 (m, 1H), 2.92-2.90 (m, 2H), 2.61-2.55 (m, 1H), 2.41-2.29 (m, 11H), 2.20-2.15 (m, 1H), 2.13-2.00 (m, 2H), 1.69-1.56 (m, 6H).

1. customInto a 50-mL round-bottom flask purged
2. temperaturemaintained with an inert atmosphere of nitrogen
3. customat 0° C
4. concentrationThe resulting mixture was concentrated under vacuum