反应详情

温度

30 °C

Charge a 100-L reactor with ethyl 3-(4-bromophenyl)-4-cyano-5-ethyl-1-methylpyrrole-2-carboxylate (6.0 kg, 16.61 mol, 1 eq, prepared in step DI above), potassium carbonate powder (5.050 kg, 36.54 mol, 2.2 eq), THF (63 L, peroxide test: <0.5 mg/L) and water (23 L). Degas the mixture by sparging with nitrogen for 20 min (oxygen sensor: 0.01 ppm). Continue sparging with argon for 24 min (oxygen sensor: 0.01 ppm). Heat the mixture to 30° C. and add 2-cyanophenylboronic acid (2.7 kg, 18.37 mol, 1.1 eq, prepared in preparation 53). Degas the mixture by continuing to sparging with argon for additional 10 min (oxygen sensor: 0.00 ppm). Add tri-t-butylphosphonium tetrafluoroborate (25.33 g, 0.087 mol, 0.005 eq) and tris(dibenzylideneacetone)dipalladium(0) (40.13 g, 0.044 mol, 0.0025 eq) at 30° C. Stir the resulting mixture for 50 min at 30° C. (an exotherm to 45° C. is observed). Separate the aqueous layer and extract with THF (17 L). Combine the organic layers (green) and filter through THF-wet (9 L) Celite® (2.21 kg). Wash the filter cake with THF (2×8.5 L). Filter the combined organic solution through a charcoal inline filter element. Change the filter element after the first half of the solution. Rinse the filter elements twice with THF (9 L and 11 L). Concentrate the resulting clear orange solution (133 L). Concentrate at reduced pressure (50° C. jacket temperature) to remove 50 L of the solvent. Add a solution of potassium carbonate powder (233.9 g) in water (23 L) to the residual mixture. Continue distillation until the THF is removed and the distillation ceases at 50° C. jacket temperature, 80 mbar pressure. Cool the suspension to 20-22° C. in 15 min and stir for additional 25 min. Collect the product by filtration, wash with water (2×8.5 L), and dry at 50° C. under reduced pressure to obtain 6.112 kg of crude title compound. Suspend the crude title compound in ethyl acetate (29 L). Heat the suspension to reflux for 1 h. Add heptane (30 L) over a period of 35 min at reflux temperature. Cool the suspension in 90 min to 0° C. and stir at that temperature for 30 min. Collect the product by filtration. Wash with a cold (0° C.) mixture of ethyl acetate (6 L) and heptane (6 L). Dry at 50° C. in a rotary evaporator under reduced pressure for 9 h to obtain 5.862 kg of title compound as a slightly yellow powder (92% yield). 1H NMR (CDCl3, 500.0 MHz): δ 1.08 (t, J=7.1 Hz, 3H), 1.37 (t, J=7.7 Hz, 3H), 2.91 (q, J=7.1 Hz, 2H), 3.96 (s, 3H), 4.16 (q, J=7.7 Hz, 2H), 7.48-7.53 (m, 3H), 7.60-7.64 (m, 3H), 7.69-7.73 (td, 1H), 7.81-7.83 (dd, 1H); 13C NMR (DMSO-d6, 125.7 MHz): δ 12.99, 13.79, 18.81, 33.47, 60.21, 92.04, 110.15, 115.40, 118.44, 120.15, 128.09, 128.25, 129.78, 130.09, 132.33, 133.21, 133.51, 133.90, 137.11, 144.03, 147.90, 159.99. Anal Calcd for C24H21N3O2: C, 75.17; H, 5.52; N, 10.96. Found: C, 75.26; H, 5.48; N, 11.08. IR (KBr): 3067, 2978, 2901, 2232, 2218, 1693, 1486, 1476, 1396, 1385, 1268, 1249, 1211, 1160, 1104, 756 cm−1.

1. customDegas the mixture
2. customby sparging with nitrogen for 20 min (oxygen sensor: 0.01 ppm)
3. customContinue sparging with argon for 24 min (oxygen sensor: 0.01 ppm)
4. customDegas the mixture
5. customto sparging with argon for additional 10 min (oxygen sensor: 0.00 ppm)
6. customat 30° C
7. customSeparate the aqueous layer
8. extractionextract with THF (17 L)
9. filtrationCombine the organic layers (green) and filter through THF-wet (9 L) Celite® (2.21 kg)
10. washWash the filter cake with THF (2×8.5 L)
11. filtrationFilter the combined organic solution through a charcoal inline filter element
12. washRinse the filter elements twice with THF (9 L and 11 L)
13. concentrationConcentrate the resulting clear orange solution (133 L)
14. concentrationConcentrate at reduced pressure (50° C. jacket temperature)
15. customto remove 50 L of the solvent
16. additionAdd a solution of potassium carbonate powder (233.9 g) in water (23 L) to the residual mixture
17. distillationdistillation until the THF
18. customis removed
19. distillationthe distillation
20. customceases at 50° C.
21. temperatureCool the suspension to 20-22° C. in 15 min
22. stirringstir for additional 25 min
23. customCollect the product
24. filtrationby filtration
25. washwash with water (2×8.5 L)
26. customdry at 50° C. under reduced pressure
27. customto obtain 6.112 kg of crude title compound
28. temperatureHeat the suspension
29. temperatureto reflux for 1 h
30. temperatureCool the suspension in 90 min to 0° C.
31. stirringstir at that temperature for 30 min
32. customCollect the product
33. filtrationby filtration
34. washWash with a cold (0° C.) mixture of ethyl acetate (6 L) and heptane (6 L)
35. customDry at 50° C. in a rotary evaporator under reduced pressure for 9 h