反应详情

温度

2 °C

Add tetrahydrofuran (2.7 L) to a 22-L, 3-neck flask fitted with a stirrer, temperature probe and an addition funnel fitted with a gas inlet adapter for N2, and cool to about 2° C. Add sodium ethoxide (0.409 kg, 6.02 mol, 2.0 equiv.) in one portion. One observes a slight exotherm to 2.7° C. Stir the mixture for 20 min, add diethyl oxalate (1.22 L, 9.03 mol, 3.0 equiv.) at −0.34° C. over 50 min (slightly exothermic) and then stir the mixture for 10 min. Add a solution of 2-methyl-3-nitropyridine (2a-1, 0.415 kg, 3.01 mol, 1.0 equiv.) and THF (0.625 L) at 4-9° C. over 22 min without cooling. Allow the mixture to warm to rt over 1 h. Monitor progress of the reaction by HPLC (Agilent series 1100 using the following conditions: Waters Symmetry C8 (5μ) column (3.9×150 mm), flow rate at 1.0 mL/min; CH3CN/0.1% aq. TFA, 55/45; λ=210 nm; RT: 2-methyl-3-nitropyridine 2a-1=1.8 min, 3a-1=2.7 min). Typically one observes >99% conversion to product within 2-3 h. During the reaction, a thick red precipitate forms. Cool the reaction mixture to about 1° C. and add saturated NH4Cl solution (2.0 L) at 1° C. to 9° C. Add water (5.9 L) (pH 7.4) and then add IPA (3.5 L). Stir the mixture for 1 h and collect the red colored solid by filtration. Wash the filter cake with IPA/H2O (1:4, 8.0 L), H2O (15 L) and air dry. Dry the filter cake (40° C./0.1 in Hg) to give 3a-1 (0.635 kg, 89%). 1H NMR (CDCl3) δ 1.40 (t, 3H, J=7 Hz), 4.38 (q, 2H, J=7 Hz), 7.36 (m, 2H), 8.42 (dd, 1H J=1.5, 8.4 Hz), 8.66 (dd, 1H, J=1.5, 4.8 Hz), 14.52 (2, 1H, OH).

1. customfitted with a stirrer
2. customto 2.7° C
3. stirringthen stir the mixture for 10 min
4. temperaturewithout cooling
5. temperatureAllow the mixture to warm to rt over 1 h
6. customMonitor progress of the reaction by HPLC (Agilent series 1100 using the following conditions
7. customRT
8. customwithin 2-3 h
9. customDuring the reaction
10. temperatureCool the reaction mixture to about 1° C.
11. stirringStir the mixture for 1 h
12. customcollect the red colored solid
13. filtrationby filtration
14. washWash the filter cake with IPA/H2O (1:4, 8.0 L), H2O (15 L) and air
15. customdry
16. customDry the filter cake (40° C./0.1 in Hg)
17. customto give 3a-1 (0.635 kg, 89%)