反应详情

Iron powder (710 mg, 13 mmol) was added to a stirred solution of ethyl 2-(5-bromo-2-nitrophenyl)-3-(4-fluorophenyl)-3-hydroxyacrylate (1.0 g, 2.4 mmol) in EtOH (20 mL)/AcOH (16 mL) in a 250 mL round bottomed flask. The flask was immediate placed in a preheated (100° C.) oil bath under an air condenser and the slurry was stirred vigorously. After 1.5 h, the reaction was cooled to r.t., diluted with EtOAc (200 mL), and the solids were removed by filtration. The filtrate was washed with water repeatedly until the organic phase was no longer red. The organic phase was then washed with sat'd NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated (PhMe azeotrope to remove residual AcOH) to give an off-white solid. The crude product was triturated with 1:1 CH2Cl2/hexanes and the filtrate purified by silica gel chromatography with a Biotage 40+M cartridge (gradient elution 10% to 40% EtOAc/hexanes over 10 column volumes, fraction collection at λ=254 nm). The off-white ppt. from above was further triturated with CH2Cl2 to give a white solid, and the filtrate was concentrated to give an off-white solid. Both ppt. and filtrate were chromatographed separately with the same method as above, but with fraction collection at λ=320 nm. Each of the three columns afforded two major peaks. The combined first peaks elute were concentrated to give the title compound (335 mg, 38% yield). 1H NMR (300 MHz, CDCl3) δ ppm 8.67 (br. s., 1H) 8.36 (br. s., 1H) 7.54-7.70 (m, 2H) 7.36 (d, J=7.68 Hz, 1H) 7.25 (t, J=7.68 Hz, 1H) 7.11 (t, J=8.23 Hz, 2H) 4.31 (q, J=6.83 Hz, 2H) 1.33 (t, J=7.14 Hz, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.73, (ES+) ink (MH+)=362, 364 (1:1 ratio).

1. customThe flask was immediate placed in a preheated (100° C.) oil bath under an air condenser
2. customthe solids were removed by filtration
3. washThe filtrate was washed with water repeatedly until the organic phase
4. washThe organic phase was then washed with sat'd NaHCO3 and brine
5. dry with materialdried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated
8. custom(PhMe azeotrope to remove residual AcOH)
9. customto give an off-white solid
10. customThe crude product was triturated with 1:1 CH2Cl2/hexanes
11. customthe filtrate purified by silica gel chromatography with a Biotage 40+M cartridge (gradient elution 10% to 40% EtOAc/hexanes over 10 column volumes, fraction collection at λ=254 nm)
12. customfrom above was further triturated with CH2Cl2
13. customto give a white solid
14. concentrationthe filtrate was concentrated
15. customto give an off-white solid
16. customand filtrate were chromatographed separately with the same method as above, but
17. customwith fraction collection at λ=320 nm
18. customEach of the three columns afforded two major peaks
19. washThe combined first peaks elute
20. concentrationwere concentrated