反应详情

温度

80 °C

A solution of 2-[4-(benzotriazol-1-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (Example 109, Step 1, 0.50 g, 0.95 mmol) in N,N-dimethylformamide (4 mL, 0.24M) was treated with cesium carbonate (0.62 g, 1.90 mmol) and 1H-indol-4-ol (0.15 g, 1.13 mmol). The resulting reaction mixture was stirred at 80° C. overnight. The reaction mixture was then concentrated in vacuo, diluted with water (100 mL), and acidified with a 1N aqueous hydrochloric acid solution. Ethyl acetate (75 mL) was added, and the mixture was filtered through filter paper, rinsing with water and ethyl acetate. The layers were separated, and the aqueous layer was back extracted with ethyl acetate (75 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (100 mL), dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 40 g, 1-10% methanol/methylene chloride) followed by chromatography (Pursuit C-18 column 5×25 cm, 0.05% trifluoroacetic acid/water/acetonitrile linear gradient, 50 ml/min, 45 min run) afforded impure 2-[4-(4-hydroxy-indol-1-yl)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (66 mg).

1. customThe resulting reaction mixture
2. concentrationThe reaction mixture was then concentrated in vacuo
3. additiondiluted with water (100 mL)
4. additionEthyl acetate (75 mL) was added
5. filtrationthe mixture was filtered
6. filtrationthrough filter paper
7. washrinsing with water and ethyl acetate
8. customThe layers were separated
9. extractionthe aqueous layer was back extracted with ethyl acetate (75 mL)
10. washThe combined organics were washed with a saturated aqueous sodium chloride solution (100 mL)
11. dry with materialdried over magnesium sulfate
12. filtrationfiltered
13. washrinsed
14. concentrationconcentrated in vacuo
15. customfollowed by chromatography (Pursuit C-18 column 5×25 cm, 0.05% trifluoroacetic acid/water/acetonitrile linear gradient, 50 ml/min, 45 min run)