反应详情

A mixture of benzimidazole (0.351 g, 2.97 mmol) and triisopropyl orthoformate (3.9 mL, 17.61 mmol) in toluene (25 mL) was heated in a 100 mL round bottom flask equipped with a Dean-Stark trap and reflux condenser under an atmosphere of nitrogen. After 1 h the solvent was removed in vacuo. The residue was dissolved in THF (8 mL) and to the solution was added a solution of tert-butyl 4-(2-(4-(ethoxycarbonyl)phenoxy)pyridin-3-yl)piperidine-1-carboxylate (1.07 g, 2.509 mmol) in THF (8 mL). The mixture was cooled (−78° C.) and lithium diisopropylamide (2.0M solution in heptane/THF/ethylbenzene, 1.80 mL, 3.60 mmol) was added dropwise resulting in a reddish solution. After 2 h the reaction was quenched with saturated NH4Cl and allowed to warm to rt. The mixture was partitioned between EtOAc/saturated NaHCO3. The organic layer was washed with brine and dried over Na2SO4. The solution was filtered and the filtrate was evaporated onto silica gel and purified by flash chromatography (Isco, (120 gram)) eluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97) to give a white amorphous solid. MS (ESI, pos. ion) m/z: 499.1 (M+1). IC50 (uM) +++++.

1. temperaturewas heated in a 100 mL round bottom flask
2. customequipped with a Dean-Stark trap
3. temperaturereflux condenser under an atmosphere of nitrogen
4. customAfter 1 h the solvent was removed in vacuo
5. dissolutionThe residue was dissolved in THF (8 mL) and to the solution
6. additionwas added dropwise
7. customresulting in a reddish solution
8. customAfter 2 h the reaction was quenched with saturated NH4Cl
9. customThe mixture was partitioned between EtOAc/saturated NaHCO3
10. washThe organic layer was washed with brine
11. dry with materialdried over Na2SO4
12. filtrationThe solution was filtered
13. customthe filtrate was evaporated onto silica gel
14. custompurified by flash chromatography (Isco, (120 gram))
15. washeluting with 2M NH3 in MeOH:CH2Cl2 (0:1→3:97)
16. customto give a white amorphous solid