反应详情

2-(2,2,2-Trifluoroethoxy)ethanol (0.57 mL, 3.60 mmol) was dissolved in THF (5 mL), NaH (146 mg, 60% dispersion in mineral oil, 3.60 mmol) was added and the reaction mixture was stirred for 10 min. 4-Nitrophenyl chloroformate (726 mg, 3.60 mmol) was added and the reaction mixture was stirred for 16 h. Intermediate 1 (297 mg, 1.80 mmol) was dissolved in THF (5 mL) and added to the reaction mixture which was stirred at room temperature. Three additional such portions of NaH, 2-(2,2,2-trifluoroethoxy)ethanol and 4-nitrophenyl chloroformate in THF were added after 8, 24 and 32 h, respectively. After 104 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in MeOH (10 mL) and 1 M aq NaOH solution (6 mL) and stirred for 1.5 h. The solvents were removed in vacuo and the residue dissolved in EtOAc (100 mL). The organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water to give 2-(2,2,2-trifluoroethoxy)ethyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-e]pyridine-5-carboxylate (3 mg, 0.5%) as a pale yellow gum.

1. stirringthe reaction mixture was stirred for 16 h
2. additionadded to the reaction mixture which
3. stirringwas stirred at room temperature
4. customAfter 104 h the reaction mixture was quenched with water (10 mL)
5. customthe solvents were removed in vacuo
6. dissolutionThe residue was dissolved in MeOH (10 mL)
7. stirring1 M aq NaOH solution (6 mL) and stirred for 1.5 h
8. customThe solvents were removed in vacuo
9. dissolutionthe residue dissolved in EtOAc (100 mL)
10. washThe organic layer was washed with 1 M aq Na2CO3 solution (6×50 mL), brine (2×50 mL)
11. dry with materialdried (MgSO4)
12. customthe solvents were removed in vacuo
13. customThe residue was purified by reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 50% (over 12 min) to 100% (over 3 min) MeOH in water