反应详情

A 2 L three neck flask fitted with a thermometer, a mechanical stirrer and an addition funnel was charged with a suspension of tert-butyl 2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-carboxylate (18.01 g, 86.5 mmol) in anhydrous acetonitrile (1.0 L). Sodium hydride (60% dispersion in oil, 4.15 g, 104 mmol) was added to the suspension in one portion under nitrogen. The reaction was stirred at room temperature for 2 h. The resulting white suspension was then cooled in an ice bath and iodoacetamide (31.95 g, 173 mmol) was added. The ice bath was then removed and the mixture was stirred 18 h at room temperature. The mixture was quenched with water (50 mL) and the solvent was removed under reduced pressure. The residue was partitioned between diluted NaCl (50 mL brine and 100 mL water) and 1.0 L EtOAc. The aqueous layer was extracted with 2×1.0 L EtOAc. The organic layers were combined and dried over Na2SO4 and solvent was evaporated under reduced pressure. Crude material was purified on silica gel eluting with 20-50% EtOAc/CH2Cl2 to wash out excess iodoacetamide, and then with 2-10% MeOH/CH2Cl2 to afford a mixture of the two products which were separated on a chiral AD column by eluting with 30% MeOH/CO2 to afford the title compound (less mobile fraction). LC-MS=267.32 [M+1].

1. temperatureThe resulting white suspension was then cooled in an ice bath
2. customThe ice bath was then removed
3. stirringthe mixture was stirred 18 h at room temperature
4. customThe mixture was quenched with water (50 mL)
5. customthe solvent was removed under reduced pressure
6. customThe residue was partitioned between diluted NaCl (50 mL brine and 100 mL water) and 1.0 L EtOAc
7. extractionThe aqueous layer was extracted with 2×1.0 L EtOAc
8. dry with materialdried over Na2SO4 and solvent
9. customwas evaporated under reduced pressure
10. customCrude material was purified on silica gel eluting with 20-50% EtOAc/CH2Cl2
11. washto wash out excess iodoacetamide
12. customwith 2-10% MeOH/CH2Cl2 to afford
13. additiona mixture of the two products which
14. customwere separated on a chiral AD column
15. washby eluting with 30% MeOH/CO2