反应详情

To a mixture of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine, hydrochloride (37.1 g, 0.10 mol, see Example 1b, step 5) and phenyl pyridazin-3-ylcarbamate (21.5 g, 0.10 mol, see Example 39, steps 1 and 2) in acetonitrile (400 mL) was added dropwise diisopropylethyl amine (25.8 g, 0.20 mol). A solution formed after 2 h of stirring. The slightly turbid solution was stirred at ambient temperature for 17 h. It was poured into 2.5 L of stirred ice-water. The resulting mixture was stirred for 1 h. The solid was filtered off, rinsed with 300 mL of water and pressed dry under suction. This was dissolved in 400 mL of dichloromethane. Water was removed using a sep funnel and then the solution was dried over magnesium sulfate and concentrated in vacuo to ˜50 mL. The viscous solution was diluted with 65 mL of ethyl acetate and then with 85 mL of methyl t-butyl ether. A solution formed, and then a solid began separating. The crystallizing mixture was kept at −10° C. for 2 h and filtered. The solid was rinsed with EtOAc:MTBE (40 mL) and pressed dry under suction. Further drying in vacuo at 40° C. for 7 h provided 30.3 g (66%) of product. The mother liquor was concentrated in vacuo to 19 g of a viscous oil. This was dissolved in 15 mL of ethyl acetate. The solution was diluted with 60 mL of methyl t-butyl ether, seeded and kept at 5° C. for 18 h. The solid which crystallized was filtered off, rinsed with 10 mL of methyl t-butyl ether, and pressed dry under suction. 9.0 g (20%) of additional product was obtained. Total yield=39.3 g (86%).

1. customA solution formed after 2 h
2. stirringThe slightly turbid solution was stirred at ambient temperature for 17 h
3. stirringThe resulting mixture was stirred for 1 h
4. filtrationThe solid was filtered off
5. washrinsed with 300 mL of water
6. custompressed dry under suction
7. dissolutionThis was dissolved in 400 mL of dichloromethane
8. customWater was removed
9. dry with materialthe solution was dried over magnesium sulfate
10. concentrationconcentrated in vacuo to ˜50 mL
11. additionThe viscous solution was diluted with 65 mL of ethyl acetate
12. customA solution formed
13. customa solid began separating
14. filtrationfiltered
15. washThe solid was rinsed with EtOAc
16. dry with materialMTBE (40 mL) and pressed dry under suction
17. customFurther drying in vacuo at 40° C. for 7 h