反应详情

温度

60 °C

Concentrated sulfuric acid (2.2 mL, 60.0 mmol) was added smoothly over 30 minutes to a slurry of ammonium 2-chloro-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]-propanoate (15.0 g @ 91.4% strength, 33.0 mmol) in methanol (60 mL) and trimethyl orthoformate (10.9 mL, 39.6 mmol), followed by a line wash of methanol (7.5 mL). The reaction mixture was heated to 60° C. for 2 hours to form a dark solution, and then cooled back to 50° C. 2-(4-Hydroxyphenyl)ethyl thiobenzoate (10.4 g @ 97.9%, 39.6 mmol) was added in one portion and the reaction vessel thoroughly purged with nitrogen. Sodium methoxide (19.0 mL of 25% strength solution in methanol, 82.4 mmol) was added smoothly over 30 minutes followed by a methanol line wash (7.5 mL), and the reaction stirred at 50° C. for 5 hours, during which time a slightly cloudy precipitate formed. The reaction mixture was cooled to 35° C., water (98 mL) was added with vigorous stirring, followed by MTBE (98 mL), the mixture stirred for 15 minutes, allowed to settle, and the lower aqueous phase removed and discarded. The remaining MTBE phase was washed with dilute aqueous hydrochloric acid solution (0.03 mL of 32% w/w in 49 mL of water), and then with water (49 mL), both at 35° C. The MTBE solution was reduced in volume by distillation to ˜3 volumes (47 mL in this case). A solution of tert-butanol/water (95 mL of a 9:1 solution, 6 volumes) was added and the distillation was continued to remove a further 4 volumes of distillate (˜63 mL in this case), before cooling to 25° C. A further 1 volume of tert-butanol/water (16 mL of a 9:1 solution) was added, followed by Lipozyme RM IM (1.6 g of immobilized enzyme, 10% w/w with starting ester). The reaction mixture was heated to 35° C. and stirred gently for more than 16 hours until ˜30-35% conversion had occurred. The enzyme was removed by filtration and the solid washed with tert-butanol/water (16 mL of a 9:1 solution). Chiral HPLC of the product (S)-Acid solution was typically 91-93% e.e. The product (S)-Acid solution was reduced in volume by atmospheric distillation to half volume (50 mL in this case). Toluene (100 mL) was added and distillation continued until a still-head temperature of 109° C. achieved (a further 80 mL of distillate was collected in this case). The solution was cooled to 60° C. and fresh toluene (80 mL) and water (50 mL) added, followed by a solution of sodium carbonate (18 mL of a 10% w/w solution in water). The solution was stirred at 60° C. for 10 minutes, allowed to settle and the lower aqueous layer removed and retained; the upper organic phase containing (R)-Ester was removed. The aqueous phase was returned to the vessel followed by butyronitrile (20 mL) and stirred vigorously for 20 minutes. The phases were allowed to separate and the highly-coloured upper organic phase removed and discarded. Butyronitrile (100 mL) was added, followed by aqueous hydrochloric acid (35 mL of 1.0M solution) smoothly over 10 minutes with good stirring at 50° C., before being allowed to settle and the lower aqueous phase removed and discarded. Water (25 mL) was added at 50° C., stirred vigorously for 5 minutes, allowed to settle and the lower aqueous phase removed and discarded. The butyronitrile solution was then dried by azeotropic distillation at atmospheric pressure to remove water (5.5 mL collected on this scale; residual water content of the butyronitrile solution was measured at 0.1%), before cooling to 20° C. tert-Butylamine (0.83 g, 1.19 mL, 11.3 mmol) was added, the solution warmed to 45° C., and product seed (6 mg, 0.1% w/w) added. The solution was stirred at 45° C. for 86 hours, and then cooled smoothly to 20° C. at 0.1° C./hour, during which time a solid crystallised. The solid was isolated by filtration, washed sequentially by displacement with butyronitrile (10.6 mL) and MTBE (10.6 mL), and dried in a vacuum oven at 50° C. to yield the title compound as a white solid (4.7 g, 24% based on starting salt). HPLC (Rt 9.8 min); chiral HPLC (typically 95% e.e.); m.p. 132-134° C.; 1H NMR (400 MHz, d6-DMSO) δ 7.19 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=9.2 Hz), 7.10 (2H, d, J=9.2 Hz), 6.95 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.0 Hz), 6.59 (2H, d, J=8.4 Hz), 4.10 (2H, t, J=6.8 Hz), 3.25 (3H, s), 3.20 (1H, dd, J=8.4, 6.0 Hz), 3.02 (1H, dd, J=13.6, 8.8 Hz), 2.92 (2H, t, J=6.8 Hz), 2.44-2.72 (5H, m), 1.13 (9H, s); 13C NMR (100.6 MHz, d6-DMSO) δ 173.86, 157.15, 155.71, 142.44, 138.39, 135.39, 130.84, 129.18, 128.95, 128.45, 123.27, 115.45, 114.96, 68.63, 51.21, 49.93, 36.88, 34.80, 34.45, 32.65, 27.65; MS (ES+) 534 (M+NH4+, 40%), 517 (M+H+, 27%), 471 (M-CO2H+, 100%).

1. washwash of methanol (7.5 mL)
2. customto form a dark solution
3. temperaturecooled back to 50° C
4. customthe reaction vessel thoroughly purged with nitrogen
5. washwash (7.5 mL)
6. customformed
7. temperatureThe reaction mixture was cooled to 35° C.
8. stirringthe mixture stirred for 15 minutes
9. customthe lower aqueous phase removed
10. washThe remaining MTBE phase was washed with dilute aqueous hydrochloric acid solution (0.03 mL of 32% w/w in 49 mL of water)
11. customat 35° C
12. distillationThe MTBE solution was reduced in volume by distillation to ˜3 volumes (47 mL in this case)
13. additionA solution of tert-butanol/water (95 mL of a 9:1 solution, 6 volumes) was added
14. distillationthe distillation
15. customto remove a further 4 volumes of distillate (˜63 mL in this case),
16. temperaturebefore cooling to 25° C
17. additionA further 1 volume of tert-butanol/water (16 mL of a 9:1 solution) was added
18. temperatureThe reaction mixture was heated to 35° C.
19. stirringstirred gently for more than 16 hours until ˜30-35% conversion
20. customThe enzyme was removed by filtration
21. washthe solid washed with tert-butanol/water (16 mL of a 9:1 solution)
22. distillationThe product (S)-Acid solution was reduced in volume by atmospheric distillation to half volume (50 mL in this case)
23. additionToluene (100 mL) was added
24. distillationdistillation
25. customcontinued until a still-head temperature of 109° C.
26. customwas collected in this case)
27. temperatureThe solution was cooled to 60° C.
28. additionfresh toluene (80 mL) and water (50 mL) added
29. stirringThe solution was stirred at 60° C. for 10 minutes
30. customthe lower aqueous layer removed
31. additionthe upper organic phase containing (R)-Ester
32. customwas removed
33. stirringstirred vigorously for 20 minutes
34. customto separate
35. customthe highly-coloured upper organic phase removed
36. additionButyronitrile (100 mL) was added
37. waitfollowed by aqueous hydrochloric acid (35 mL of 1.0M solution) smoothly over 10 minutes
38. stirringwith good stirring at 50° C.
39. customthe lower aqueous phase removed
40. additionWater (25 mL) was added at 50° C.
41. stirringstirred vigorously for 5 minutes
42. customthe lower aqueous phase removed
43. dry with materialThe butyronitrile solution was then dried by azeotropic distillation at atmospheric pressure
44. customto remove water (5.5 mL
45. customcollected on this scale
46. additionwas added
47. temperaturethe solution warmed to 45° C.
48. additionproduct seed (6 mg, 0.1% w/w) added
49. stirringThe solution was stirred at 45° C. for 86 hours
50. temperaturecooled smoothly to 20° C. at 0.1° C./hour, during which time a solid
51. customcrystallised
52. customThe solid was isolated by filtration
53. washwashed sequentially by displacement with butyronitrile (10.6 mL) and MTBE (10.6 mL)
54. customdried in a vacuum oven at 50° C.