反应详情

An oven-dried vial was charged with 3-amino-2,3-dimethylbutan-2-ol (Example 35A) (0.063 g, 0.540 mmol), and 4-fluoro-3-((trimethylsilyl)ethynyl)phthalonitrile (Example 40C) (0.109 g, 0.45 mmol) and sealed with a rubber septum. DIEA (0.157 mL, 0.900 mmol) and anhyd DMSO (2 mL) were added via syringe and the mixture was stirred at rt under N2. After 18 h, the temperature was increased to 60° C. and stirring continued an additional 30 h. Upon cooling the mixture was poured into water and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo to a dark, oily residue. An oven-dried vial was charged with the residue, followed by CuI (0.043 g, 0.225 mmol) and sealed with a rubber septum. Anhyd DMF (3 mL) was added via syringe and the septum was replaced with a PTFE-faced crimp top. The mixture was subjected to microwave heating (140° C.) for 20 min. The mixture was poured into satd NH4Cl and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution) followed by preparative HPLC (C18 stationary phase, MeCN/water gradient with 0.1% TFA additive) affording 1-(3-hydroxy-2,3-dimethylbutan-2-yl)-1H-indole-4,5-dicarbonitrile (0.0093 g, 8% yield) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 8.21 (dd, J=9.0, 0.8 Hz, 1H), 7.65 (d, J=3.5 Hz, 1H), 7.42 (d, J=9.0 Hz, 1H), 6.81 (dd, J=3.5, 0.8 Hz, 1H), 1.88 (s, 6H), 1.21 (s, 6H); MS (LCMS ES+) m/z 268 ([M+H]+, 29%), 309 ({[M+H]+MeCN}+, 100%).

1. customsealed with a rubber septum
2. temperaturethe temperature was increased to 60° C.
3. stirringstirring
4. waitcontinued an additional 30 h
5. temperatureUpon cooling the mixture
6. extractionextracted with EtOAc (×3)
7. washCombined organics were washed (water, brine)
8. dry with materialdried over Na2SO4
9. concentrationconcentrated in vacuo to a dark, oily residue
10. additionAn oven-dried vial was charged with the residue
11. customsealed with a rubber septum
12. temperatureheating (140° C.) for 20 min
13. extractionextracted with EtOAc (×3)
14. washCombined organics were washed (water, brine)
15. dry with materialdried over Na2SO4
16. concentrationconcentrated in vacuo
17. customThe residue was purified by low pressure liquid chromatography (silica gel, EtOAc/hexanes, gradient elution)