反应详情

Potassium tert-butoxide (1.0 M in THF, 6.4 ml, 6.4 mmol, 3.0 equiv) is added dropwise at room temperature under an atmosphere of argon to a solution of 2-(7-methyl-1H-indol-3-yl)-acetamide (400 mg, 2.13 mmol, 1.0 equiv) and of [5-(tert-butyl-diphenyl-silanyloxymethyl)-2-methyl-pyrazolo[1,5-a]pyridin-3-yl]-oxo-acetic acid methyl ester (1.04 g, 2.13 mmol, 1.0 equiv) in anhydrous tetrahydrofuran (10 ml, dried over molecular sieves). The reaction mixture is stirred for 15 minutes at room temperature. It is then diluted with EtOAc and poured into a saturated aqueous NH4Cl solution. After three extractions with EtOAc, the combined organic layers are dried over Na2SO4, filtered and concentrated in vacuo. The residue is dissolved in N,N-dimethylformamide (20 ml), treated with DBU (3.2 ml, 21.3 mmol, 10 equiv) and stirred under an atmosphere of argon for 10 minutes at 100° C. After cooling, the reaction mixture is diluted with water and extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (gradient of hexane/EtOAc 100:0 to 50:50) affords the title compound (750 mg, 56%). 1H NMR (400 MHz, d6-DMSO): δ=11.83 (br s, 1H), 11.02 (br s, 1H), 8.54 (d, J=7.8 Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.61-7.59 (m, 4H), 7.48-7.39 (m, 6H), 7.34 (s, 1H), 6.82 (d, J=7.1 Hz, 1H), 6.74 (dd, J=7.1/1.7 Hz, 1H), 6.52 (t, J=7.1 Hz, 1H), 6.20 (d, J=8.1 Hz, 1H), 4.69 (s, 2H), 2.44 (s, 3H), 1.91 (s, 3H), 1.01 (s, 9H). MS (ES+): 625 (M+H)+.

1. extractionAfter three extractions with EtOAc
2. dry with materialthe combined organic layers are dried over Na2SO4
3. filtrationfiltered
4. concentrationconcentrated in vacuo
5. dissolutionThe residue is dissolved in N,N-dimethylformamide (20 ml)
6. stirringstirred under an atmosphere of argon for 10 minutes at 100° C
7. temperatureAfter cooling
8. extractionextracted three times with EtOAc
9. washThe combined organic layers are washed with brine
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. customPurification of the residue via flash chromatography (gradient of hexane/EtOAc 100:0 to 50:50)