反应详情

温度

3 °C

4-[2-(4-Aminophenyl)ethoxy]phenyl methanesulfonate (15.9 g, 37.7 mmol) was added to a suitably serviced reaction vessel under nitrogen, followed by copper (I) iodide (0.36 g, 1.9 mmol), acetone (103 mL), and water (2.5 mL) and stirred to form a mobile slurry. Concentrated hydrochloric acid (9.3 mL of 37% w/w, 113 mmol) was added in one portion to form a brown solution, followed by acrylic acid (19.4 mL, 283 mmol) in one portion, and the resulting solution cooled to 3° C. A solution of sodium nitrite (2.95 g, 41.5 mmol) dissolved in water (6.3 mL) was added smoothly to the reaction mixture over at least 10 hours, keeping the reaction temperature at 3° C. Water (1.0 mL) was added as a line wash over at least 1.5 hours, then the reaction mixture stirred at 3° C. for 3 hours before warming to 20° C. over 10 hours. Once all the diazonium chloride had been consumed (<0.1% as determined by HPLC), an aqueous solution of urea (2.0 mL of 20% w/w in water) was added and the reaction mixture stirred for 30 minutes. Ethyl acetate (32 mL), toluene (63 mL), brine (63 mL) and water (32 mL) were added to the reaction mixture, which was stirred for 20 minutes, allowed to settle and the lower green aqueous layer separated and discarded. Brine (63 mL) and water (32 mL) were added to the remaining organic phase. The mixture was stirred for 20 minutes, allowed to settle and the lower colourless aqueous layer separated and discarded. The water/brine washes were repeated. Water (63 mL) was added to the organic phase, stirred for 20 minutes, allowed to settle and the lower colourless aqueous layer separated and discarded. The water wash was repeated four times. Water (127 mL) was added followed by aqueous sodium carbonate (59 mL of a 10% w/w solution in water) carefully in portions, stirred, and the phases allowed to separate (the solution can be heated briefly to 40° C. to improve the separation). The upper organic phase was removed and discarded and the lower aqueous phase returned to the vessel. Ethyl acetate (127 mL) was added followed by concentrated hydrochloric acid (8.8 mL of 37% w/w solution, 107 mmol) in portions to acidify the solution (CO2 may be evolved). After stirring for 20 minutes, the phases were separated and the lower aqueous phase discarded (the solution can be heated briefly to 40° C. to improve the separation). The organic phase was washed with water (63 mL) as described above, and then dried by azeotropic distillation at atmospheric pressure to remove water (106 mL distillate collected on this scale; residual water content of the ethyl acetate solution was 0.5% w/w). The solution was cooled to 20° C. and ammonia in dioxane (85 mL of a 0.5 M solution, 42.7 mmol) added smoothly over 90 minutes at 22° C., during which period a mobile slurry formed. After a minimum of 4 hours at 22° C., the reaction mixture was cooled to 0° C. for 75 minutes, and the solid isolated by filtration under a nitrogen pad. The product was washed by displacement with chilled (0° C.) ethyl acetate (30 mL) and dried in a vacuum oven at 40° C. to yield the title compound as a buff-coloured solid (9.2 g corrected for strength, 58.9%). HPLC (Rt 9.5 mins); m.p. 148-150° C.; 1H NMR (400 MHz, d6-DMSO) δ 6.9-7.8 (˜3H, vbs), 7.25 (2H, d, J=9.2 Hz), 7.22 (2H, d, J=8.4 Hz), 7.17 (2H, d, J=8.0 Hz), 7.02 (2H, d, J=9.2 Hz), 4.16-4.22 (3H, m), 3.31 (3H, s), 3.26 (1H, dd, J=14.0, 5.6 Hz), 3.00 (2H, t, J=7.0 Hz), 2.88 (1H, dd, J=14.0, 8.8 Hz); 13C NMR (100.6 MHz, d6-DMSO) δ 170.54, 157.15, 142.45, 136.66, 135.89, 129.20, 128.58, 123.28, 115.48, 68.56, 63.91, 41.37, 36.89 and 34.44; MS (ES+) 416 (M+NH4+, 60%).

1. customto form a mobile slurry
2. customto form a brown solution
3. additionwas added smoothly to the reaction mixture over at least 10 hours
4. customat 3° C
5. washwash over at least 1.5 hours
6. stirringthe reaction mixture stirred at 3° C. for 3 hours
7. temperaturebefore warming to 20° C. over 10 hours
8. customOnce all the diazonium chloride had been consumed (<0.1% as determined by HPLC)
9. additionan aqueous solution of urea (2.0 mL of 20% w/w in water) was added
10. stirringthe reaction mixture stirred for 30 minutes
11. additionEthyl acetate (32 mL), toluene (63 mL), brine (63 mL) and water (32 mL) were added to the reaction mixture, which
12. stirringwas stirred for 20 minutes
13. customthe lower green aqueous layer separated
14. additionBrine (63 mL) and water (32 mL) were added to the remaining organic phase
15. stirringThe mixture was stirred for 20 minutes
16. customthe lower colourless aqueous layer separated
17. additionWater (63 mL) was added to the organic phase
18. stirringstirred for 20 minutes
19. customthe lower colourless aqueous layer separated
20. washThe water wash
21. additionWater (127 mL) was added
22. stirringstirred
23. customto separate (the solution
24. temperaturecan be heated briefly to 40° C.
25. customthe separation)
26. customThe upper organic phase was removed
27. additionEthyl acetate (127 mL) was added
28. stirringAfter stirring for 20 minutes
29. customthe phases were separated
30. temperaturecan be heated briefly to 40° C.
31. customthe separation)
32. washThe organic phase was washed with water (63 mL)
33. customthen dried by azeotropic distillation at atmospheric pressure
34. customto remove water (106 mL
35. distillationdistillate collected on this scale
36. temperatureThe solution was cooled to 20° C.
37. additionammonia in dioxane (85 mL of a 0.5 M solution, 42.7 mmol) added smoothly over 90 minutes at 22° C., during which period a mobile slurry
38. customformed
39. temperatureAfter a minimum of 4 hours at 22° C., the reaction mixture was cooled to 0° C. for 75 minutes
40. customthe solid isolated by filtration under a nitrogen pad
41. washThe product was washed by displacement
42. temperaturewith chilled (0° C.) ethyl acetate (30 mL)
43. customdried in a vacuum oven at 40° C.