反应详情

温度

60 °C

Mix propane-2-sulfonic acid {2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl) -phenyl]-thiophen-3-yl}-amide (1.00 equiv; 441.02 mmoles; 196.60 g), 3-ethoxy-4-iodo -benzoic acid ethyl ester (1.00 equiv; 441.47 mmoles; 141.27 g), DME (15.15 moles; 1.57 L; 1.37 kg), PdCl2(dppf) (2.42 mmoles; 1.97 g), and ethanol (13.57 moles; 790.00 mL; 625.13 g) under a N2 atmosphere. Then add Na2CO3 2M in water (1.89 equiv; 833.06 mmoles; 416.53 mL; 504.00 g) and heat the reaction mixture to reflux until HPLC monitoring indicates reaction completion. Cool reaction mixture to RT then add water (109.13 moles; 1.97 L). Separate the organic layer, filter through diatomaceous earth, then concentrate organic layer under reduced pressure. Add ethanol (2.36 L), and remove solvent under reduced pressure. Add 3-Mercaptopropyl-functionalized Silica Gel (50.00 g), and heat to 60° C. for 30 minutes. Cool to RT then filter over diatomaceous earth. Rinse cake with ethanol, then combine ethanol washes and filtrate. Add 14% Sodium Hydroxide (4.89 moles; 1.27 L; 1.43 kg) and heat the reaction mixture at 55° C. until monitoring by HPLC indicates the end of the reaction. Cool to RT then add 7N HCl to the reaction mixture. Stir the resulting precipitate overnight. Filter the reaction mixture and wash cake with EtOH/Water (40/60-v/v) (180.78 g), EtOH (155.49 g), and n-heptane (262 g). Redissolve cake in acetone (2.18 kg) and add activated charcoal (46 g). Heat the reaction mixture at 50° C. for 30 minutes. Cool to RT, filter over diatomaceous earth (765.59 mmoles; 200.00 g), and concentrate under reduced pressure. Cool to RT, then add n-Heptane (7.73 moles; 1.13 L; 775. 00 g) and stir for 1 h. Fltere and wash cake with n-heptane/acetone 60/40 (2.58 moles; 354.79 mL) and dry under reduced pressure to yield 124 g of the title compound.

1. temperatureto reflux until HPLC monitoring
2. customreaction completion
3. temperatureCool
4. customreaction mixture to RT
5. customSeparate the organic layer
6. filtrationfilter through diatomaceous earth
7. customAdd ethanol (2.36 L), and remove solvent under reduced pressure
8. temperatureCool to RT
9. filtrationthen filter over diatomaceous earth
10. washRinse cake with ethanol
11. temperatureheat the reaction mixture at 55° C. until monitoring by HPLC
12. customthe end of the reaction
13. temperatureCool to RT
14. filtrationFilter the reaction mixture
15. washwash cake with EtOH/Water (40/60-v/v) (180.78 g), EtOH (155.49 g), and n-heptane (262 g)
16. dissolutionRedissolve cake in acetone (2.18 kg)
17. additionadd activated charcoal (46 g)
18. temperatureHeat the reaction mixture at 50° C. for 30 minutes
19. temperatureCool to RT
20. filtrationfilter over diatomaceous earth (765.59 mmoles; 200.00 g)
21. concentrationconcentrate under reduced pressure
22. temperatureCool to RT
23. customdry under reduced pressure