反应详情

温度

65 °C

(2R,4R)-tert-butyl 2-((2-amino-phenyl)carbamoyl)-4-(3-(4-cyanophenyl)ureido)piperidine-1-carboxylate (1600 mg, 3.34 mmol) was dissolved in acetic acid (10 mL) and stirred at 65° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove acetic acid. Trifluoroacetic acid (10 mL) was added to the residue. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to remove TFA and the resulting product was used in the next step without further purification. 37% formaldehyde solution (1.24 mL, 16.7 mmol) in water was added to a solution of the residue in methanol (20 mL) and the reaction mixture was stirred at room temperature for 1 hour, then 1M sodium cyanoborohydride in THF (10.5 mL, 10.5 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 18 hours and the solvent was evaporated under vacuum. Saturated sodium bicarbonate solution (50 mL), water (100 mL) and ethyl acetate (200 mL) were added and the mixture was stirred about 30 min. The organic layer was separated, dried over MgSO4, and concentrated. The resulting product was purified by Companion (ReadySep 40 g, silica gel packed) using CH3OH/CH2Cl2 from 1-5% as eluent to provide the title compound as an off-white solid 915 mg (73%). LC-MS: 375.3, 373.3 (t=1.5 min). 1H NMR (acetone-D6): δ 1.81 (m, 2H), 1.9-2.05 (m, 2H), 2.10 (m, 1H), 2.17 (s, 3H), 2.52 (m, 1H), 2.94 (m, 1H), 3.86 (m, 1H), 4.2 (m, 1H), 6.4 (d, 1H), 7.16 (m, 2H), 7.52 (m, 2H), 7.60 (m, 2H), 7.62 (m, 2H), 8.46 (s, 1H).

1. concentrationThe reaction mixture was concentrated under reduced pressure
2. customto remove acetic acid
3. additionTrifluoroacetic acid (10 mL) was added to the residue
4. stirringThe resulting solution was stirred at room temperature for 2 hours
5. concentrationThe reaction mixture was concentrated
6. customto remove TFA
7. customthe resulting product was used in the next step without further purification
8. stirringthe reaction mixture was stirred at room temperature for 1 hour
9. stirringThe reaction mixture was stirred at room temperature for 18 hours
10. customthe solvent was evaporated under vacuum
11. additionSaturated sodium bicarbonate solution (50 mL), water (100 mL) and ethyl acetate (200 mL) were added
12. stirringthe mixture was stirred about 30 min
13. customThe organic layer was separated
14. dry with materialdried over MgSO4
15. concentrationconcentrated
16. customThe resulting product was purified by Companion (ReadySep 40 g, silica gel packed)