反应详情

Sodium hydride (50% mineral oil dispersion, 10.7 g, 223 mmole) was suspended in 100 ml DMF. A solution of 1-acetyl-4-ethynyl-4-hydroxypiperidine (37.4 g, 0.223 mole) in 125 ml DMF was added to the sodium hydride suspension at 20° C. After the complete evolution of hydrogen gas, the solution was cooled to 5° C. and a mixture of 50 g 4-chloro-2-fluorobenzylbromide in 50 ml DMF was added dropwise. The temperature was not allowed to exceed 10° C. during the addition. The mixture was allowed to equilibrate to ambient temperature and after 2 hrs. the reaction was determined to be complete. The mixture was quenched with ice water and extracted with ether. The ether extracts were combined and dried over anhydrous magnesium sulfate. This was filtered and the solvent removed in vacuo. The oily residue was purified by preparative HPLC, eluting with hexane:ethylacetate (1:1). The material was contained in fractions 8-12. When combined and the solvent removed, these fractions afforded 52.6 g 1-acetyl-4-(4-chloro-2-fluorobenzyloxy)-4-ethynylpiperidine (170 mmole, 76.23%). This material appeared pure by TLC on silica gel in chloroform:methanol (9:1), Rf =0.6 and in hexane:ethylacetate (1:1) Rf =0.2, MS(MH+ =310), NMR-CDCl3 and IR-CHCl3 are consistent with the structure; mp=70°-74° C.

1. additionwas added dropwise
2. additionto exceed 10° C. during the addition
3. customThe mixture was quenched with ice water
4. extractionextracted with ether
5. dry with materialdried over anhydrous magnesium sulfate
6. filtrationThis was filtered
7. customthe solvent removed in vacuo
8. customThe oily residue was purified by preparative HPLC
9. washeluting with hexane:ethylacetate (1:1)
10. customthe solvent removed