Dimethylformamide → N-[4-(2-Amino-4-methoxypyridin-3-yl)phenyl]-5-(4-fluorophenyl)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-3-carboxamide

COMU (391 mg) and DIPEA (159 μl) were added to a solution of the compound obtained in Step 2 of Example 9 (216 mg) in DMF (2 ml) at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (100 mg) was added to the reaction mixture at room temperature. The reaction mixture was stirred at 50° C. overnight, and then at 80° C. for two days. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [hexane:ethyl acetate=1:1->1:3->0:100 (v/v)], and the eluate was concentrated under reduced pressure. 3-Iodo-4-methoxypyridine-2-amine (47 mg), tetrakis(triphenylphosphine)palladium (14 mg) and potassium carbonate (52 mg) were added to a solution of part of the resulting oily substance (65 mg) in dioxane (3 ml) and water (0.3 ml) at room temperature. The reaction mixture was stirred at 100° C. overnight, returned to room temperature and diluted by adding ethyl acetate. After purification by silica gel column chromatography (NH) (developed with ethyl acetate), the eluate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC [acetonitrile:water:formic acid] to give 5.6 mg of the title compound as a solid.

1. stirringThe reaction mixture was stirred at 50° C. overnight
2. waitat 80° C. for two days
3. extractionfollowed by extraction with ethyl acetate
4. dry with materialThe organic layer was dried over sodium sulfate
5. filtrationfiltered
6. concentrationthe filtrate was then concentrated under reduced pressure
7. customThe residue was purified by silica gel column chromatography [hexane:ethyl acetate=1:1->1:3->0:100 (v/v)]
8. concentrationthe eluate was concentrated under reduced pressure
9. addition3-Iodo-4-methoxypyridine-2-amine (47 mg), tetrakis(triphenylphosphine)palladium (14 mg) and potassium carbonate (52 mg) were added to a solution of part of the resulting oily substance (65 mg) in dioxane (3 ml)
10. customat room temperature
11. stirringThe reaction mixture was stirred at 100° C. overnight
12. customreturned to room temperature
13. additiondiluted
14. additionby adding ethyl acetate
15. customAfter purification by silica gel column chromatography (NH) (developed with ethyl acetate)
16. concentrationthe eluate was concentrated under reduced pressure
17. customThe residue was purified by reverse phase HPLC [acetonitrile:water:formic acid]

ORD record

ord-98d143bc0da84a9fbcd99665cba09131

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08933103B2