反应详情

3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (28.9 g) was dissolved in 30 mL dry NMP and 270 mL dry diglyme under nitrogen and heated to 142° C. internal temperature. A suspension of sodium hydride (2.676 g of 60% NaH in mineral oil) in 6 mL of dry NMP and 54 mL of dry diglyme was added all at once via cannula while stirring. After 15 min the reaction was removed from heating and cooled 5 min, then poured into ice/1 L EtOAc/0.5 L 1 N HCl. The layers were separated and the organic layer washed twice with water, once with brine and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc) to provide 31 g of partially purified solid which was then crystallized from refluxing 3:1 MeOH/DCM, to give 15 g of desired product. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.33 (m, 2H), 7.28-7.24 (m, 1H), 7.23 (d, 1H) 7.19 (m, 1H), 7.0 (m, 3H), 5.12 (m, 1H), 5.04 (s, 2H), 4.37 (m, 1H), 4.03 (m, 1H).

1. additionwas added all at once via cannula
2. customAfter 15 min the reaction was removed
3. temperaturefrom heating
4. temperaturecooled 5 min
5. additionpoured into ice/1 L EtOAc/0.5 L 1 N HCl
6. customThe layers were separated
7. washthe organic layer washed twice with water, once with brine
8. dry with materialdried over Na2SO4
9. customThe residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc)
10. customto provide 31 g of partially purified solid which
11. customwas then crystallized
12. temperaturefrom refluxing 3:1 MeOH/DCM