Doramapimod

317806-87-4

317806-88-5

285983-48-4

Step 4 Synthesis of 1-(3-tert-butyl-1-tosyl-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea (Compound 4): to a mixed solution of 4-(2-((4-nitronaphthalen-1-yl)oxy)ethyl)morpholine (11.18 g, 36.9 mmol) in methanol (90 mL) and THF (30 mL) , 5% palladium/activated carbon (0.500 g) was added. The resulting mixture was stirred at room temperature in a hydrogen atmosphere for 23 hours. Upon completion of the reaction, the insoluble material was removed by filtration and the solvent was evaporated under reduced pressure. The resulting residue was mixed with 2,2,2-trichloroethyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (16.1 g, 39.7 mmol), N,N-diisopropylethylamine (8.50 mL) and DMSO (30 mL) and stirred at 60 °C for 18 hours. After completion of the reaction, the reaction solution was cooled to room temperature and saturated brine was added. The aqueous layer was extracted with ethyl acetate and the organic phase was dried with anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=50/50 to ethyl acetate/methanol=90/10) to afford 13.58 g of the target product 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-(2-morpholinoethoxy)naphthalen-1-yl)urea in 69% yield.