反应详情

温度

7.5 °C

A 12-L 3-neck round-bottom flask was equipped with an overhead air-driven stirrer apparatus, condenser, nitrogen inlet, thermometer/thermocouple, and heating mantle. The flask was charged with ethyl acetate (450 mL) and 21% (wt.) sodium ethoxide in ethanol solution (3318 mL, 8.87 moles, 2 eq). The resulting mixture was heated to reflux under a nitrogen atmosphere and maintained at reflux for 30 min. The mixture was then allowed to cool slightly below reflux, and 4-(4-hydroxyphenyl)butyric acid (800 g, 4.43 moles) was added. The flask contents were re-heated to reflux for 30 min, at which point ethyl 2-bromoisobutyrate (EBIB, 1954 mL, 13.32 moles, 3.0 eqs.) was added. After 1 h at reflux, the flask was equipped with a 2-L addition funnel, which was charged sodium ethoxide in ethanol solution (1660 mL, 4.43 moles, 1 eq.). The sodium ethoxide solution was added dropwise to the refluxing reaction over 1 h. After an additional 30 min at reflux, HPLC analysis showed the reaction was complete. The heat source was removed and the flask contents were cooled to 5-10° C. and then transferred to a 22-L bottom-outlet flask. While stirring, the mixture was quenched with dilute phosphoric acid (6000 mL), transferred to a 20-L Buchi flask, and concentrated in vacuo to remove ethanol. The resulting aqueous mixture of crystals and excess EBIB was refrigerated overnight. The crystals were then filtered and washed with water (2000 mL). The solids were removed from the funnel and placed in a 20-L Buchi flask equipped with an overhead stirring apparatus. After the addition of water (2000 mL), the solids were stirred at ambient temperature for 30 min, then filtered and washed with heptane (2×2500 mL)). The solids were then placed in the vacuum oven and dried at 45° C. to afford the title compound as an off-white solid (1247 g, 95.5%). 1H NMR (500 MHz, CDCl3) δ 1.25 (t, 3 H), 1.57 (s, 6 H), 1.92 (m, 2 H), 2.35 (t, 2 H), 2.60 (t, 2 H), 4.23 (q, 2 H), 6.76 (d, 2 H), 7.03 (d, 2 H). 13C NMR (CDCl3) δ 14.1, 25.4, 26.3, 33.3, 34.2, 61.4, 119.4, 129.1, 134.9, 153.7, 174.4, 179.7.

1. customA 12-L 3-neck round-bottom flask was equipped with an overhead air-driven stirrer apparatus, condenser, nitrogen inlet
2. temperaturethermometer/thermocouple, and heating mantle
3. temperatureThe resulting mixture was heated
4. temperatureto reflux under a nitrogen atmosphere
5. temperaturemaintained
6. temperatureat reflux for 30 min
7. temperatureto cool slightly
8. temperaturebelow reflux
9. temperatureThe flask contents were re-heated
10. additionwas added
11. temperatureAfter 1 h at reflux
12. temperatureAfter an additional 30 min at reflux
13. customThe heat source was removed
14. customtransferred to a 22-L bottom-outlet flask
15. customthe mixture was quenched with dilute phosphoric acid (6000 mL)
16. concentrationconcentrated in vacuo
17. customto remove ethanol
18. additionThe resulting aqueous mixture of crystals and excess EBIB
19. filtrationThe crystals were then filtered
20. washwashed with water (2000 mL)
21. customThe solids were removed from the funnel
22. customequipped with an overhead
23. stirringstirring apparatus
24. additionAfter the addition of water (2000 mL)
25. stirringthe solids were stirred at ambient temperature for 30 min
26. filtrationfiltered
27. washwashed with heptane (2×2500 mL))
28. customdried at 45° C.