反应详情

A round-bottomed flask was charged with 4-(2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (100.0 mg, 0.256 mmol), 2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (Example 104, Step C, 70.53 mg, 0.301 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (144.3 mg, 0.753 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (101.7 mg, 0.753 mmol), N-ethyl-N-isopropylpropan-2-amine (162.2 mg, 1.255 mmol) and DMF (10 mL). The reaction mixture was stirred at room temperature until LC-MS showed that the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 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 (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (103 mg, 66.8%). LRMS (APCI pos): >99% purity, 254 nm, m/e 615 (M+1). 1H NMR (400 MHz, CDCl3) δ 11.82 (s, 1H), 8.41 (m, 2H), 8.23 (d, 1H), 7.98 (d, 1H), 7.60 (m, 2H), 7.39 (m, 2H), 7.24 (m, 3H), 6.46 (d, 1H), 6.28 (m, 1H), 4.04 (s, 4H), 2.78 (m, 2H), 2.52 (m, 2H), 1.98 (m, 2H).

1. customhad been consumed (overnight)
2. customThen the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL)
3. customThe phases were separated
4. extractionthe aqueous phase was re-extracted with EtOAc (3×100 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 (DCM/7 M NH3 in MeOH from 50/1 to 10/1