反应详情

温度

30 °C

Ammonium 2-chloro-3-[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenyl]propanoate (90%, 1.55 g, 25.0 mmol) and 2-(4-hydroxyphenyl)ethyl thiobenzoate (98%, 8.57 g, 32.5 mmol, 1.3 eq) were charged to a reaction vessel under nitrogen. Tetrahydrofuran (THF) (60 mL, 5 vol) was added and the mixture was warmed to 30° C. To the resulting suspension was added a solution of sodium methoxide (25% wt/vol in methanol) (17 mL, 74 mmol, 3 eq.) at a rate of 0.25 mL/min. The resulting grey suspension was heated to 40° C. for 2 hours and allowed to stand at ambient temperature overnight without stirring. The mixture was re-heated to 40° C. and the progress of the reaction was monitored by HPLC. After 4 hours, 97% conversion was achieved and the mixture was quenched by the addition of toluene (50 mL, 5 vol) and water (10 mL, 1 vol) and the mixture was vigorously stirred until all two clear phases were obtained. The pH of the lower aqueous phase was adjusted from ˜12 to ˜10.0 by addition of hydrochloric acid (˜4 mL @ 6 N) and the mixture was allowed to settle. The lower aqueous phase was separated and retained; the toluene phase was re-extracted with water (10 mL). The combined aqueous phases were washed with toluene (twice, 10 mL) (this gave three phases when allowed to settle: a lower oily phase containing product, clear aqueous middle phase, upper toluene phase). The lower phase was collected, the middle and upper phase were discarded, and this was allowed to stand overnight (no degradation observed as judged by HPLC). The aqueous phase was acidified to pH ˜1.0 by addition of 6 N hydrochloric acid and the product was extracted into butyronitrile (2×30 mL, 1×20 mL). The butyronitrile solution was dried by azeotropic distillation under reduced pressure (45° C., 60 mbar). The resulting clear brown solution (75 mL, 7.5 vol) was held at 45° C. and tert-butylamine (2.9 mL, 27.5 mmol, 1.1 eq.) was added, before seeding with an authentic sample of title material (100 mg). As the resulting suspension thickened iso-butyl acetate (40 mL) was charged and the mixture was allowed to settle overnight. After filtration, the cake was washed with iso-butyl acetate (2×10 mL), 1:1 iso-hexane/iso-butyl acetate (20 mL) and iso-hexane (25 mL). The product was dried in vacuo at 40° C. to give the title compound as an off-white solid (13.41 g, 91%). HPLC (Rt 9.8 min); m.p. 125-129° C. Other physical and spectral data were consistent with those reported above.

1. temperatureThe resulting grey suspension was heated to 40° C. for 2 hours
2. temperatureThe mixture was re-heated to 40° C.
3. waitAfter 4 hours
4. customthe mixture was quenched by the addition of toluene (50 mL, 5 vol) and water (10 mL, 1 vol)
5. stirringthe mixture was vigorously stirred until all two clear phases
6. customwere obtained
7. customThe lower aqueous phase was separated
8. extractionthe toluene phase was re-extracted with water (10 mL)
9. washThe combined aqueous phases were washed with toluene (twice, 10 mL) (
10. customthis gave three phases when
11. customThe lower phase was collected
12. waitto stand overnight
13. additionThe aqueous phase was acidified to pH ˜1.0 by addition of 6 N hydrochloric acid
14. extractionthe product was extracted into butyronitrile (2×30 mL, 1×20 mL)
15. dry with materialThe butyronitrile solution was dried by azeotropic distillation under reduced pressure (45° C., 60 mbar)
16. customwas held at 45° C.
17. additionwas charged
18. waitto settle overnight
19. filtrationAfter filtration
20. washthe cake was washed with iso-butyl acetate (2×10 mL), 1:1 iso-hexane/iso-butyl acetate (20 mL) and iso-hexane (25 mL)
21. customThe product was dried in vacuo at 40° C.