反应详情

4-(1-(4-Methoxybenzyl)-3-(1-methyl-1H-imidazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.213 g, 0.479 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (0.561 g, 2.40 mmol, prepared in Example 19, step C), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.459 g, 2.40 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.367 g, 2.40 mmol), N-ethyl-N-isopropylpropan-2-amine (0.310 g, 2.40 mmol) and CH2Cl2 (5 mL) were charged in a 50 mL single-neck, round-bottomed flask. The reaction mixture was stirred at room temperature until LC-MS shows that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (CH2Cl2/MeOH from 100/1 to 50/1, v/v) to afford product (0.201 g, 63.5%). LRMS (APCI pos): >95% purity, 254 nm, m/e 661 (M+1). 1H NMR (400 MHz, CDCl3 δ 11.75 (s, 1H), 8.31 (d, 1H), 8.25 (d, 1H), 8.14 (d, 1H), 7.87 (dd, 1H), 7.60 (s, 1H), 7.52 (m, 2H), 7.42 (s, 1H), 7.28 (m, 3H), 7.13 (m, 3H), 6.75 (m, 2H), 6.20 (d, 1H), 5.56 (s, 2H), 3.83 (s, 3H), 3.67 (s, 3H).

1. customhad been consumed (overnight)
2. customThen the reaction was partitioned between EtOAc (50 mL) and water (50 mL)
3. customThe phases were separated
4. extractionthe aqueous phase was extracted with EtOAc (3×50 mL)
5. dry with materialThe combined organic layers were dried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated
8. customto yield a crude product
9. customThe crude product was purified by silica gel chromatography (CH2Cl2/MeOH from 100/1 to 50/1