反应详情

Sodium hydride (39.98 g as a 50% mineral oil suspension, 883 mmole) was suspended in dry DMF (500 ml). 1-Acetyl-4-ethynyl-4-hydroxypiperidine (126.5 g; 758 mmole), dissolved in 500 ml of DMF, was added dropwise to the sodium hydride suspension at such a rate as to maintain the solvent temperature below 30° C. After evolution of hydrogen had ceased, 2-fluorobenzylchloride (120.8 g; 99 ml; 833 mmole), dissolved in 200 ml of DMF, was added dropwise, maintaining the temperature below 25° C. After allowing the mixture to react for 3 hours, 2 l. of water was added to quench the reaction. The mixture was extracted with ether and the combined ether extracts were back extracted with 5% hydrochloric acid. The organic phase was finally extracted with saturated aqueous sodium chloride and dried over anhydrous potassium carbonate. The mixture was filtered and the volatile components removed in vacuo. A residue of material, slightly impure by TLC, remained (193 g; 700 mmole; 84.3%). A 10 g sample was purified by preparative high performance liquid chromatography (HPLC) using hexane:ethylacetate (2:1) and finally ethylacetate as the effluents on silica gel. The residue was an oil which crystallized upon standing. Recovery was 7 g of material which appeared pure by TLC on silica gel in hexane:ethylacetate (2:1), Rf =0.1 and in chloroform:methanol (9:1), Rf =0.6, MS (ci MH+ =276), NMR-CDCl3 and IR-CHCl3 are consistent with the structure, m.p.=59°-62° C.

1. temperatureto maintain the solvent temperature below 30° C
2. additionwas added dropwise
3. temperaturemaintaining the temperature below 25° C
4. customto react for 3 hours
5. customto quench
6. customthe reaction
7. extractionThe mixture was extracted with ether
8. extractionthe combined ether extracts were back extracted with 5% hydrochloric acid
9. extractionThe organic phase was finally extracted with saturated aqueous sodium chloride
10. dry with materialdried over anhydrous potassium carbonate
11. filtrationThe mixture was filtered
12. customthe volatile components removed in vacuo
13. customA 10 g sample was purified by preparative high performance liquid chromatography (HPLC)
14. customcrystallized