反应详情

温度

80 °C

A solution of 4-hydroxyphenyl methanesulfonate (7.04 g @ 82% strength, 30.6 mmol, (prepared by methanesulfonylation of quinol)) dissolved in acetonitrile (72 mL) was added to a mixture of 2-[4-(tert-Butoxycarbonylamino)phenyl]ethyl 4-methylbenzenesulfonate (prepared as described in WO 99/62871) (12.0 g, 30.6 mmol) and potassium carbonate (6.42 g of −325 mesh, 46.0 mmol) under nitrogen and the resulting mixture gently stirred. Acetonitrile (36 mL) and water (12 mL) were added, the stirring rate increased and the reaction mixture was boiled under reflux (80° C.) for 11 to 24 hours. After cooling back to 60° C., the solvent volume was reduced by 6 volumes (˜72 mL) by distillation at reduced pressure. Toluene (108 mL) and water (24 mL) were added and the mixture stirred for 5 minutes at 60° C. The solution was filtered through Celite™ (and/or 5% w/w charcoal) and returned to the reaction vessel at 60° C. The phases were allowed to separate and the lower aqueous phase run off and discarded. Dilute aqueous sodium hydroxide solution (10.2 mL of 2.5%, 0.625 M) was added and the mixture stirred at 60° C. for 5 minutes. The phases were allowed to separate and the lower aqueous phase was run off and discarded. Water (24 mL) was added and stirred at 60° C. for 5 minutes, before the phases were allowed to separate and the lower aqueous phase was run off and discarded. The solvent volume was reduced by distillation at atmospheric pressure until a still-head temperature of ˜110° C. was achieved. Fresh toluene was added to make the total volume up to 8 volumes (96 mL). The solution was cooled to 60° C., filtered and then cooled to 45° C. Iso-hexane (143 mL) was added dropwise over 1 hour, maintaining the temperature at 45° C., and then the solution cooled to 20° C. at 1° C./minute. The resulting solid was isolated by filtration, washed by displacement with iso-hexane (29 mL) and dried in a vacuum oven at 50° C. to yield the title compound as a buff solid (9.9 g, 79%). HPLC (Rt 10.9 mins); m.p. 117-118° C.; 1H NMR (400 MHz, d6-DMSO) δ 9.22 (˜1H, s), 7.36 (2H, d, J=8.0 Hz), 7.23 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.4 Hz), 6.98 (2H, d, J=9.2 Hz), 4.13 (2H, t, J=6.6 Hz), 3.29 (3H, s), 2.93 (2H, t, J=6.6 Hz), 1.44 (9H, s); 13C NMR (100.6 MHz, d6-DMSO) δ 157.18, 152.77, 142.44, 137.80, 131.62, 129.04, 124.01, 123.28, 118.15, 115.45, 78.83, 68.69, 36.89, 34.14 and 28.10; MS (ES+) 425 (M+NH4+, 5%), 308 (10%), 120 (100%).

1. temperaturethe stirring rate increased
2. temperatureAfter cooling back to 60° C.
3. distillationthe solvent volume was reduced by 6 volumes (˜72 mL) by distillation at reduced pressure
4. additionToluene (108 mL) and water (24 mL) were added
5. stirringthe mixture stirred for 5 minutes at 60° C
6. filtrationThe solution was filtered through Celite™ (and/or 5% w/w charcoal)
7. customreturned to the reaction vessel at 60° C
8. customto separate
9. additionDilute aqueous sodium hydroxide solution (10.2 mL of 2.5%, 0.625 M) was added
10. stirringthe mixture stirred at 60° C. for 5 minutes
11. customto separate
12. additionWater (24 mL) was added
13. stirringstirred at 60° C. for 5 minutes, before the phases
14. customto separate
15. distillationThe solvent volume was reduced by distillation at atmospheric pressure until a still-head temperature of ˜110° C.
16. additionFresh toluene was added
17. temperatureThe solution was cooled to 60° C.
18. filtrationfiltered
19. temperaturecooled to 45° C
20. additionIso-hexane (143 mL) was added dropwise over 1 hour
21. temperaturemaintaining the temperature at 45° C.
22. temperaturethe solution cooled to 20° C. at 1° C./minute
23. customThe resulting solid was isolated by filtration
24. washwashed by displacement with iso-hexane (29 mL)
25. customdried in a vacuum oven at 50° C.