反应详情

温度

0 °C

To a stirred suspension of trans-2-chloro-N-(4-hydroxymethyl-cyclohexyl)-5-trifluoromethyl-benzamide (step 2)(24 g, 71.5 mmol) in DCM (72 mL) under N2 supply at RT, is added triethylamine (29.7 mL, 214 mmol) followed by DMSO (24 mL), giving an almost homogenous solution. The mixture is cooled to 0° C. (ice/salt bath), and to this is added dropwise a solution/suspension of sulfur trioxide-pyridine complex (34.1 g, 214 mmol) in DMSO (30 mL): DCM (20 mL) over a period of ˜90 min. The mixture is stirred at 0-5° C. over a 1 h period then allowed to warm to RT over 2 h. The mixture is cooled to 0° C. in an ice bath and is quenched by the addition of 1M HCl (aq) (40 mL) dropwise over 30 min. The mixture is then diluted with water (60 mL) and DCM (150 mL). 2 M HCl is added to give pH˜1-2. The organic phase is separated, washed again with 2 M HCl (100 mL), followed by sat. NaHCO3 (100 mL). The organic layer is diluted with EtOAc (800 mL) and is vigourously stirred at RT. The mixture is then filtered removing some insoluble material in the process. The now clear two phase mixture is separated, the organic (EtOAc) layer is dried over over MgSO4 and is filtered and concentrated to give an off white solid. The crude solid is suspended in diethylether (500 mL) and is triturated, removing some brown/yellow colour. The solid is allowed to settle, and the liquors are decanted off. The solid is then triturated in iso-hexane (300 mL), using the same procedure twice, then the solid is transferred to a small flask in iso-hexane slurry and is dried in vacuo to give an off-white solid; [MH+ 334]

1. customgiving an almost homogenous solution
2. additionto this is added dropwise
3. temperatureto warm to RT over 2 h
4. temperatureThe mixture is cooled to 0° C. in an ice bath
5. customis quenched by the addition of 1M HCl (aq) (40 mL) dropwise over 30 min
6. additionThe mixture is then diluted with water (60 mL) and DCM (150 mL)
7. addition2 M HCl is added
8. customto give pH˜1-2
9. customThe organic phase is separated
10. washwashed again with 2 M HCl (100 mL)
11. additionThe organic layer is diluted with EtOAc (800 mL)
12. stirringis vigourously stirred at RT
13. filtrationThe mixture is then filtered
14. customremoving some insoluble material in the process
15. customThe now clear two phase mixture is separated
16. dry with materialthe organic (EtOAc) layer is dried over over MgSO4
17. filtrationis filtered
18. concentrationconcentrated
19. customto give an off white solid
20. customis triturated
21. customremoving some brown/yellow colour
22. customthe liquors are decanted off
23. customThe solid is then triturated in iso-hexane (300 mL)
24. customthe solid is transferred to a small flask in iso-hexane
25. customslurry and is dried in vacuo
26. customto give an off-white solid