反应详情

温度

70 °C

Under a N2 atmosphere, 146 mg (0.5 mmol) of 5-chloro-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine (contains a little 5-chloro-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine as an impurity) in 2.0 ml of tbutanol/dioxane 1:5 are mixed with 160 mg (1 mmol) of 3-trifluoromethyl-aniline and 0.12 ml of 4 N HCl/dioxane and stirred for 14 h at 70° C. The cooled reaction mixture is dissolved in diluted Na2CO3 solution and EtOAc whilst adding ethanol. The water phase is separated and extracted twice with EtOAc. The organic phases are dried (Na2SO4) and concentrated by evaporation. The resulting oil is separated by reversed phase medium-pressure chromatography (water/-acetonitrile/TFA). The fractions are partially concentrated by evaporation, then solid NaHCO3 is added to the aqueous residue. Extraction with 3 portions of EtOAc, drying (Na2SO4) and concentration by evaporation yields 5-(3-trifluoromethyl-anilino)-8-[(6-hydroxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36a (FAB-MS: (M+H)+=397; HPLC(gradient20-100) tRet=8.5); 5-(3-trifluoromethyl-anilino)-8-[(6-methoxy-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36b (FAB-MS: (M+H)+=411; HPLC(gradient20-100) tRet=10.0) and 5-(3-trifluoromethyl-anilino)-8-[(6-chloro-pyridin-3-yl)-methyl]-[1,6]naphthyridine 36c (FAB-MS: (M+H)+=415; HPLC(gradient20-100) tRet=1.5).

1. customThe cooled reaction mixture
2. customThe water phase is separated
3. extractionextracted twice with EtOAc
4. dry with materialThe organic phases are dried (Na2SO4)
5. concentrationconcentrated by evaporation
6. customThe resulting oil is separated by reversed phase medium-pressure chromatography (water/-acetonitrile/TFA)
7. concentrationThe fractions are partially concentrated by evaporation
8. additionsolid NaHCO3 is added to the aqueous residue
9. extractionExtraction with 3 portions of EtOAc
10. customdrying
11. concentration(Na2SO4) and concentration
12. customby evaporation