反应详情

温度

120 °C

In a 25 mL container, 1-(3-bromo-2-formylphenyl)-1H-pyrazole-4-carbonitrile (100 mg, 362 μmol, Eq: 1.00), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (160 mg, 724 μmol, Eq: 2) and copper (I) iodide (138 mg, 724 μmol, Eq: 2.00) were combined with DMSO (2.00 ml) to give a yellow suspension. Sodium bicarbonate (76.1 mg, 906 μmol, Eq: 2.5) was added to it. The mixture was heated in a microwave at 120° C. for 1 hr. The reaction mixture was poured into 25 mL sat NH4Cl and extracted with EtOAc (3×25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The organic layer was concentrated and purified through ISCO flash column chromatography using ethyl acetate (containing 5% methanol) in hexanes (5% to 80% linear gradient in 15 minutes, 24 g silica gel) to give the pure desired product which was triturated with ether in hexanes and filtered to obtain 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-1H-pyrazole-4-carbonitrile (110 mg, 73%). Step 3. The aldehyde is reduced to the alcohol as in Example 22. Step 4. In a 25 mL round-bottomed flask, 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrazole-4-carbonitrile (89 mg, 213 μmol, Eq: 1.00) and hydrido(dimethylyphosphinous acid-kP) (4.58 mg, 10.7 μmol, Eq: 0.05) were combined with Ethanol (1 ml) and Water (1.00 ml) to give a colorless solution. The reaction mixture was heated to 85° C. and stirred for 45 min. Mixture was allowed to come to room temperature and the solvent was removed under vacuum. Purification by reverse phase HPLC gave 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrazole-4-carboxylic acid amide (51 mg, 56%, [M+H]+ 436)

1. customto give a yellow suspension
2. additionThe reaction mixture was poured into 25 mL
3. extractionextracted with EtOAc (3×25 mL)
4. dry with materialThe organic layers were dried over MgSO4
5. concentrationconcentrated in vacuo
6. concentrationThe organic layer was concentrated
7. custompurified through ISCO flash column chromatography
8. customethyl acetate (containing 5% methanol) in hexanes (5% to 80% linear gradient in 15 minutes, 24 g silica gel)