反应详情

Methyl 1-ethyl-5-oxo-prolinate (0.135 g, 0.79 mmol, prepared as described below) was dissolved in methanol (4 ml) and treated with 2M aqueous sodium hydroxide (0.592 ml, 1.18 mmol). The mixture was stirred for 4 hrs at room temperature and then evaporated to give a residue which was then treated with an excess of 1M hydrogen chloride in ether (˜5 ml) for 10 minutes. The mixture was evaporated once more and the residue was dissolved in dichloromethane (4 ml) and dimethylformamide (2 ml) and filtered to remove solids. The resulting solution was transferred to a reaction tube and 1-hydroxybenzotriazole (0.117 g, 0.87 mmol), [(2-chloro-4-fluorophenyl)methyl]amine (0.138 g, 0.87 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.167 g, 0.87 mmol) were then added. The mixture was flushed with argon and then stirred at room temperature over the weekend. The mixture was then diluted with dichloromethane and washed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was filtered through a phase separator and then evaporated to give the crude product. The crude material was purified by mass-directed automated HPLC to give pure N-[(2-chloro-4-fluorophenyl)methyl]-1-ethyl-5-oxo-prolinamide (0.086 g) as a white solid. LC/MS [M+H]+=299.1, retention time=2.13 minutes.

1. customevaporated
2. customto give a residue which
3. customThe mixture was evaporated once more
4. dissolutionthe residue was dissolved in dichloromethane (4 ml)
5. filtrationdimethylformamide (2 ml) and filtered
6. customto remove solids
7. customThe resulting solution was transferred to a reaction tube
8. customThe mixture was flushed with argon
9. stirringstirred at room temperature over the weekend
10. additionThe mixture was then diluted with dichloromethane
11. washwashed sequentially with 2M aqueous hydrogen chloride and saturated aqueous sodium hydrogen carbonate
12. filtrationThe organic layer was filtered through a phase separator
13. customevaporated
14. customto give the crude product
15. customThe crude material was purified