反应详情

To a 5 mL microwave tube was added N-{[2-[(4-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 61, 31 mg, 0.073 mmol), 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinyl]piperazine (21.13 mg, 0.073 mmol), potassium carbonate (30.3 mg, 0.219 mmol), and tetrakis(triphenylphosphine)palladium (0) (2.53 mg, 2.192 μmol) in 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (10 ml) and acidified with 1N HCl. The mixture was then extracted with ethyl acetate (2×50 mL) and the organic layers combined, dried over magnesium sulfate, filtered, and solvents removed by rotary evaporation. The mixture of products, by tlc, was purified by HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA)). However, the product was not there but found in the aqueous extract, 100% clean, which was evaporated to afford the title compound N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2-({4-[2-(1-piperazinyl)-4-pyridinyl]phenyl}methyl)-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (26 mg, 0.049 mmol, 66.7% yield) as a tfa salt. 1H NMR (400 MHz, DMSO-d6) d ppm 15.89 (s, 1H), 10.18 (t, J=5.81 Hz, 1H), 8.80 (br. s., 2H), 8.21 (d, J=5.56 Hz, 1H), 7.78 (d, J=8.34 Hz, 2H), 7.43 (d, J=8.34 Hz, 2H), 7.23 (s, 1H), 7.09 (dd, J=5.31, 1.01 Hz, 1H), 5.32 (s, 2H), 4.11 (d, J=5.81 Hz, 2H), 3.76-3.87 (m, 4H), 3.13-3.29 (m, 5H), 1.22 (d, J=7.07 Hz, 6H). MS (ES+) m/e 507 [M+H]+.

1. customThe mixture was irradiated at 100° C. for 20 minutes
2. extractionThe mixture was then extracted with ethyl acetate (2×50 mL)
3. dry with materialdried over magnesium sulfate
4. filtrationfiltered
5. customsolvents removed by rotary evaporation
6. additionThe mixture of products
7. customby tlc, was purified by HPLC chromatography (ODS silica, gradient 10-100% acetonitrile/water (0.1% TFA))
8. customwhich was evaporated