反应详情

To a stirred suspension of NaH (60% in oil, 21.0 g, 0.525 mol) in DMF (300 ml) was added portionwise 1,2,4-triazole (43.3 g, 0.627 mol) at the inner temperature from 2° C. to 11° C. over 30 min. The resulting mixture was stirred at r.t. for 1.5 hrs. To this mixture was added a solution of 2-(2,5-Difluorophenyl)-2-[(1R)-1-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane (48.3 g, 0.170 mol) in DMF (50 ml). The mixture was stirred at 60° C. for 1 hr. and then at 65° C. for 14 hrs. The reaction mixture was cooled down to 10° C. and then poured into ice-water (800 mL ). The resulting mixture was extracted with EtOAc (400 ml+200 ml×2 ). The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silicagel (n-hexane: EtOAc=4:1˜1:5) to give (3R)-2-(2,5difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (43.9 g, 73% ) and recovered starting material (13.2 g, 27%). Physical form: colorless syrup; FAB-MS: m/z 354 (M+H)+; 1H-NMR(CDCl3): 1.00(3H×½,d,J=6.6Hz),1.13(3H×½,d,J=6.6Hz), 1.42˜1.88(6H,m)3.38˜3.60(1H,m),3.80˜4.00(1H,m),4.32˜5.02(5H,m),6.83˜6.99 (2H,m),7.14˜7.21(1H,m),7.73(1H×½,s),7.74(1H×½,s),7.92(1H×½,s)7.95(1H×½,s),

1. stirringThe mixture was stirred at 60° C. for 1 hr
2. waitand then at 65° C. for 14 hrs
3. temperatureThe reaction mixture was cooled down to 10° C.
4. extractionThe resulting mixture was extracted with EtOAc (400 ml+200 ml×2 )
5. dry with materialThe combined organic layer was dried over Na2SO4
6. concentrationconcentrated in vacuo
7. customThe residue was chromatographed on silicagel (n-hexane: EtOAc=4:1˜1:5)