反应详情

3-Fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1, 612 mg, 1.7 mmol), tert-butyl 4-(aminomethyl)-4-(pyridin-4-yl)piperidine-1-carboxylate (amine intermediate “L”, 640 mg, 2.2 mmol), EDAC (649 mg, 3.4 mmol), HOBt (297 mg, 2.8 mmol) and diisopropyl-ethyl-amine (1.47 ml, 8.4 mmol) were dissolved in 15 ml NMP and stirred until LCMS showed complete consumption of acid starting material. (usually overnight) The product was precipitated out of the reaction mixture by addition of water, filtered, rinsed with water and dried. The title compound was isolated as a solid (1.01 g, 90% pure by HPLC, 83% yield). An analytical sample was purified by prep HPLC (C-18 reversed phase column, water/MeOH gradient, buffered with 0.1% TFA). Alternatively a water/acetonitrile gradient, buffered with 10 mM NH4OAc can be used. Product containing fractions were filtered through a cartridge filled with cation exchange resin (MCX from Waters or STRATA X-C from Phenomenex), rinsed with methanol, eluted with 2 M solution of ammonia in methanol and evaporated. The residue was dissolved in methanol, 1.0 equiv. aq. of 1.00 N HCl were added and the title compound was isolated as the mono-HCl salt by evaporation. LC/MS (M+H)+: 636. Ret. time: 1.66 min. (Condition M); analytical HPLC Ret. time: 16.74 min (Condition N).

1. customconsumption of acid
2. custom(usually overnight) The product was precipitated out of the reaction mixture by addition of water
3. filtrationfiltered
4. washrinsed with water
5. customdried