Dimethylformamide → 2-[4-(1H-indol-4-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

温度

25 °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, 0.25 g, 0.47 mmol) in acetonitrile (10 mL, 0.048M) was treated with cesium carbonate (0.31 g, 0.95 mmol) and 1H-indol-4-ol (75.4 mg, 0.56 mmol). The resulting reaction mixture was stirred at 25° C. for 3.5 h. At this time, the reaction was treated with N,N-dimethylformamide (1.0 mL) and the reaction was heated at 80° C. overnight. The reaction mixture was then concentrated in vacuo and partitioned between water (75 mL) and ethyl acetate (75 mL). The emulsified bilayer was filtered through filter paper and rinsed with water and ethyl acetate. The layers were separated, and the organics were washed with a saturated aqueous sodium chloride solution (50 mL). The combined aqueous layers were acidified with a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, rinsed, and concentrated in vacuo. Silica gel column chromatography (AnaLogix 24 g, 1-10% methanol/methylene chloride) afforded 2-[4-(1H-indol-4-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 (207.1 mg, 81%) as a viscous brown/black oil as a mixture of diastereomers.

1. customThe resulting reaction mixture
2. temperaturethe reaction was heated at 80° C. overnight
3. concentrationThe reaction mixture was then concentrated in vacuo
4. custompartitioned between water (75 mL) and ethyl acetate (75 mL)
5. filtrationThe emulsified bilayer was filtered
6. filtrationthrough filter paper
7. washrinsed with water and ethyl acetate
8. customThe layers were separated
9. washthe organics were washed with a saturated aqueous sodium chloride solution (50 mL)
10. extractionextracted with ethyl acetate (50 mL)
11. dry with materialThe combined organic layers were dried over magnesium sulfate
12. filtrationfiltered
13. washrinsed
14. concentrationconcentrated in vacuo

ORDレコード

ord-8b43dc4df3124b3c8837dfcb2b4d0c24

出典データセット

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08258134B2