PF-04457845

1020327-61-0

1020325-53-4

1020315-31-4

General procedure for the large-scale synthesis of N-(pyridazin-3-yl)-4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzylidene)piperidine-1-carboxamide in Example 5b: To a mixture of 2-(3-(piperidin-4-ylidenemethyl)phenoxy)-5-trifluoromethylpyridine hydrochloride (37.1 g, 0.10 mol, see Example 1b, step 5) and phenylpyridazin- 3-ylcarbamate (21.5 g, 0.10 mol, see Example 39, Step 1) in acetonitrile (400 mL) was added dropwise to a mixture of diisopropylethylamine (25.8 g, 0.20 mol). The solution was formed by stirring for 2 hours. The slightly cloudy solution was stirred at ambient temperature for 17 hours. It was poured into 2.5 L of stirred ice water. The resulting mixture was stirred for 1 hour. The solid was filtered out, rinsed with 300mL of water and pressed dry under suction. Dissolve it in 400mL of dichloromethane. The water was removed using a partition funnel, then the solution was dried with magnesium sulfate and concentrated under vacuum to about 50 mL. the viscous solution was diluted with 65 mL of ethyl acetate and then 85 mL of methyl tert-butyl ether. A solution was formed and then the solids began to separate. The crystalline mixture was kept at -10°C for 2 hours and filtered. The solid was rinsed with EtOAc:MTBE (40mL) and pressure dried under suction. It was further dried under vacuum at 40 °C for 7 h to give 30.3 g (66%) of product. The mother liquor was concentrated under vacuum to 19 g of a viscous oil. It was dissolved in 15 mL of ethyl acetate. The solution was diluted with 60 mL of methyl tert-butyl ether, inoculated and kept at 5°C for 18 hours. The crystallized solid was filtered out, rinsed with 10 mL of methyl tert-butyl ether and pressed dry under suction. 9.0 g (20%) of additional product was obtained. Total yield = 39.3 g (86%).