反应详情

To a solution of 3-(4-methoxyphenyl)-4-methylisothiazol-5-ylamine (280 g, 1.00 equivalent) and pyridine (catalytic, 0.03 equivalent) in anhydrous THF (350 mL) is added the above acid chloride solution dropwise over 30 min at 6 to 13° C.; and the reaction mixture is stirred at room temperature 1 h. (The progress of the reaction may be followed by HPLC, and acid chloride addition terminated if monitoring indicates complete reaction of the amine.) Water (2.5 L) is added, the phases are separated and aqueous phase is re-extracted with dichloromethane. The combined organic phase is washed (aqueous NaOH (1 L), then water (1 L)). partially evaporated to about 1 kg, and then diluted with THF (2 L) to give an homogeneous solution, from which some water separates. The mixture is allowed to stand overnight at room temperature during which the two phases separate, with the aqueous phase above the organic phase. The phases are separated, THF is added to each phase, water is added to the upper (organic) phase, and each layer is reequilibrated, with very slow phase separation and the organic phase as the top layer. The combined organic phase is charged to a rotary evaporator (10-L flask) through a clarifying membrane (5 μm), toluene (4 L) is added, resulting in opacification of the mixture, and THF/water are evaporated (160 mbar, bath temp 45° C.). As the THF/water are evaporated, crystals begin to form. When 2 L has been distilled, toluene (2 L) is added and distillation continued (85 mbar, bath temp 45° C.). After distillation of a further 2 L of solvent, the system is set to atmospheric pressure, cooled to ambient temperature, and, after 1 h, the resulting suspension is filtered. The filter cake is resuspended in toluene (1 L), refiltered, and washed with toluene (1 L) before it is dried overnight to afford (R,R)—N-[3-(4-methoxyphenyl)-4-methylisothiazol-5-yl]-2-methylcyclopropanecarboxamide. Yield: 357 g, 92%.

1. customThe progress of the reaction
2. customterminated if monitoring
3. customreaction of the amine
4. customthe phases are separated
5. extractionaqueous phase is re-extracted with dichloromethane
6. washThe combined organic phase is washed (aqueous NaOH (1 L)
7. custompartially evaporated to about 1 kg
8. additiondiluted with THF (2 L)
9. customto give an homogeneous solution
10. waitto stand overnight at room temperature during which
11. customthe two phases separate, with the aqueous phase above the organic phase
12. customThe phases are separated
13. additionTHF is added to each phase, water
14. additionis added to the upper (organic) phase
15. customeach layer is reequilibrated, with very slow phase separation
16. additionThe combined organic phase is charged to a rotary evaporator (10-L flask) through a clarifying membrane (5 μm), toluene (4 L)
17. additionis added
18. customresulting in opacification of the mixture, and THF/water
19. customare evaporated (160 mbar, bath temp 45° C.)
20. customAs the THF/water are evaporated
21. customto form
22. distillationWhen 2 L has been distilled
23. additiontoluene (2 L) is added
24. distillationdistillation
25. custom(85 mbar, bath temp 45° C.)
26. distillationAfter distillation of a further 2 L of solvent
27. temperaturecooled to ambient temperature
28. waitafter 1 h
29. filtrationthe resulting suspension is filtered
30. washwashed with toluene (1 L) before it
31. customis dried overnight