反应详情

温度

35 °C

The ethyl acetate/toluene solution of ketone 3 (118 g, 765 mmol in 1.2 L of 5:1 v:v ethyl acetate/toluene) was charged to a 5-L three-necked round-bottomed flask equipped with an overhead mechanical stirrer, 250-mL pressure-equalizing dropping funnel, and thermocouple temperature probe. The mixture was stirred and water (35 mL) was added to saturate the organic phase. A solution of sodium tungstate dihydrate (11.7 g, 77 mmol) dissolved in water (35 mL) was then added (caution: there is an induction period of several minutes before an exotherm). The mixture was heated to 35° C. and hydrogen peroxide (30%, 250 mL, 2.43 mole) was added over 45 minutes. The temperature of the reaction was allowed to rise to 55°-58° C. until judged complete by HPLC: 4.1×254 mm Altex C-8, 5-micron ultrasphere column at 45° C. (2 mL/min, gradient from 65:35 to 20:80 0.1% H3PO4 in H2O: CH3CN over 20 minutes, then isocratic for 5 minutes 230 nm) R1 (sulfoxide) 6.9 minutes, (sulfone) 10.6 minutes, (sulfide) 15.8 minutes. On completion the mixture was cooled to 0°-5° C. and excess hydrogen peroxide was decomposed by the slow addition of aqueous sodium sulfite (205 g, 1.63 mole dissolved in 700 mL water). The temperature of the reaction mixture was maintained at <20° C. When the reaction mixture tested negative for peroxides with acidified starch-iodide paper, the layers were separated. The upper organic layer was concentrated under vacuum at 45° C. bath temperature to a volume of 400 mL. Hexanes (400 mL) were then added over approximately 10 minutes and the batch was aged for one hour. The product was filtered, washed with hexanes, and dried under vacuum at 60° C. with a nitrogen sweep to constant weight. The yield of crude ketosulfone 4 was 113 g (76% from 3-bromopropionic acid). Crude ketosulfone was then recrystallized from methanol in the following procedure. A quantity of 113 g crude ketosulfone was dissolved in 3 L of anhydrous methanol at 55°-60° C. The solution was cooled to 40° C. and 10 g of Calgon ADP® carbon was added. The mixture was aged at 40° C. for a minimum of 4 hours. The batch was then filtered warm at 40° C. through a well-washed pad of SuperCel®. The filter cake was washed with two 500 mL portions of methanol at 40° C. and filtrates were combined. The batch was then concentrated under vacuum to a volume of 500 mL and aged at 0°-5° C. for 4 hours. Crystallization ensued during concentration. The batch was filtered, washed with 75 mL cold methanol, sucked dry under nitrogen, and dried under vacuum (25" Hg) at 80° C. with a nitrogen sweep for 12 hours. The recovery yield was 100 g (89%) assayed @ 99.6 wt % by HPLC against an external standard. R∫ =0.30 (dichloromethane). m.p. 121°-121.5° C. 1H NMR: δ 7.60 (d, J=5.1, H2); 7.50 (d, J=5.1, H3); 3.76 (m, C5H2); 3.36 (m, C6H2). 13C NMR: δc 186.3 (C4), 147.2 (C3a), 139.3 (C7a), 130.2 (C2), 126.3 (C3), 52.8 (C6), 37.0 (C5). MS (EI, 70 eV): 202 (M+,35), 174 (38), 138 (15), 110 (100), 84 (30), 82 (25), Anal Calcd for C7H6O3S2 : C, 41.57; H, 2.99; S, 31.70. Found: C, 41.49; H, 3.02; S, 31.60.

1. customequipped with an overhead mechanical stirrer
2. concentrationto saturate the organic phase
3. additionwas then added (caution
4. customan induction period of several minutes
5. customto rise to 55°-58° C.
6. temperatureOn completion the mixture was cooled to 0°-5° C.
7. temperatureThe temperature of the reaction mixture was maintained at <20° C
8. customthe layers were separated
9. concentrationThe upper organic layer was concentrated under vacuum at 45° C. bath temperature to a volume of 400 mL
10. additionHexanes (400 mL) were then added over approximately 10 minutes
11. filtrationThe product was filtered
12. washwashed with hexanes
13. customdried under vacuum at 60° C. with a nitrogen sweep to constant weight
14. customCrude ketosulfone was then recrystallized from methanol in the following procedure
15. dissolutionA quantity of 113 g crude ketosulfone was dissolved in 3 L of anhydrous methanol at 55°-60° C
16. temperatureThe solution was cooled to 40° C.
17. addition10 g of Calgon ADP® carbon was added
18. customwas aged at 40° C. for a minimum of 4 hours
19. filtrationThe batch was then filtered
20. temperaturewarm at 40° C. through a well-washed pad of SuperCel®
21. washThe filter cake was washed with two 500 mL portions of methanol at 40° C.
22. concentrationThe batch was then concentrated under vacuum to a volume of 500 mL
23. waitaged at 0°-5° C. for 4 hours
24. customCrystallization
25. concentrationensued during concentration
26. filtrationThe batch was filtered
27. washwashed with 75 mL cold methanol
28. customsucked dry under nitrogen
29. customdried under vacuum (25" Hg) at 80° C. with a nitrogen sweep for 12 hours