反应详情

温度

45 °C

A 20-L reaction vessel was charged with magnesium ethoxide (3.61 moles; 413.52 g) and THF (6.6 L), and the resulting mixture was stirred as ethyl hydrogen malonate (7.23 moles; 888.89 mL; 994.67 g; diluted with 20 mL of THF) was added and the mixture was heated at 45° C. for 4 hours. Meanwhile, a 20 L reactor was charged with 2,5-dimethoxybenzoic acid (3.29 moles; 600.00 g) and THF (3.6 L). To this mixture stirring at room temperature was added 1,1′-carbonyldiimidazole (3.61 moles; 585.98 g) in portions to avoid excess foaming. After stirring for 3 hours at room temperature the second solution was added gradually to the first solution. After addition the reaction mixture was heated to 45° C. After 20 hours, the reaction mixture was concentrated under reduced pressure before adding ethyl acetate (6 L) followed by 2 N HCl (3 L). After mixing, the layers were separated and the organic phase was washed sequentially with 2 N HCl (3 L), saturated sodium bicarbonate (3 L), and water (3 L). The organic phase was concentrated under reduced pressure, the residue taken up in ethyl acetate (6 L) and concentrated again to afford an oil, which was transferred to a 20 L reaction vessel with 5 L of ethyl acetate and treated with sodium methoxide (3.45 moles; 793.00 mL of a 4.35 M solution in methanol). After stirring at room temperature for 3 hours, an additional 6 L of ethyl acetate was added and the solid collected by vacuum filtration and dried overnight in a vacuum oven at 40° C. to give 661 grams of the title product. MS (ES+) 253.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.92 (d, J=3.0 Hz, 1 H) 6.84 (d, J=8.8 Hz, 1 H) 6.73 (dd, J=8.8, 3.0 Hz, 1 H) 4.67 (s, 1 H) 3.88 (q, J=7.0 Hz, 2 H) 3.67 (s, 6 H) 1.12 (t, J=7.0 Hz, 3 H).

1. additionwas added
2. stirringAfter stirring for 3 hours at room temperature the second solution
3. additionwas added gradually to the first solution
4. additionAfter addition the reaction mixture
5. temperaturewas heated to 45° C
6. concentrationthe reaction mixture was concentrated under reduced pressure
7. additionbefore adding ethyl acetate (6 L)
8. additionAfter mixing
9. customthe layers were separated
10. washthe organic phase was washed sequentially with 2 N HCl (3 L), saturated sodium bicarbonate (3 L), and water (3 L)
11. concentrationThe organic phase was concentrated under reduced pressure
12. concentrationconcentrated again
13. customto afford an oil, which
14. stirringAfter stirring at room temperature for 3 hours
15. filtrationthe solid collected by vacuum filtration
16. customdried overnight in a vacuum oven at 40° C.