| 71% |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water at 110℃; for 1.5h; Inert atmosphere; Microwave irradiation; |
23 Synthesis of 2-(2-(3-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)-4-ethylphenyl) propan-2-yl)-1H-indole-6-carbonitrile (25)
A mixture of 23 (350 mg, 0.68 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (422 mg, 1.36 mmol), Pd(PPh3)4 (158 mg, 0.136 mmol), and Na2CO3 (2 M in water, 1.5 mL) in dioxane (4.5 mL) was degassed with nitrogen for 5 min and then heated at 110 °C under microwave for 1.5 h. After the completion of the reaction, the mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was concentrated and purified by chromatograph (petroleum/acetoacetate) to afford a yellow solid (275 mg, 71% yield): 1H NMR (300 MHz, CDCl3) δ 9.12 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.41 (dd, J = 8.4, 1.2 Hz, 1H), 7.16-7.07 (m, 2H), 6.98-6.91 (m, 1H), 5.52-5.45 (m, 1H), 4.04-3.94 (m, 2H), 3.59 (t, J = 5.5 Hz, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.36-2.24 (m, 2H), 1.91 (s, 6H), 1.48 (s, 9H), 1.37 (s, 9H), 1.16 (t, J = 7.5 Hz, 3H). The obtained solid was dissolved in toluene/TFA (5 mL/5 mL). The mixture was heated at 80 °C for 3 h under nitrogen atmosphere. After being cooled to room temperature, the reaction mixture was evaporated in vacuum, and basified with saturated sodium bicarbonate until pH > 7. After extraction with EtOAc, the combined mixture was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by chromatograph (CHCl3/MeOH) to give the corresponding intermediate as a pale yellow solid (80 mg, 45%): 1H NMR (300 MHz, CDCl3 + CD3OD) δ 7.60-7.48 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 7.10-6.99 (m, 2H), 6.94 (s, 1H), 6.42 (s, 1H), 5.53-5.43 (m, 1H), 3.40-3.30 (m, 2H), 2.96 (t, J = 5.6 Hz, 2H), 2.53 (q, J = 7.5 Hz, 2H), 2.21-2.10 (m, 2H), 1.70 (s, 6H), 1.11 (t, J = 7.5 Hz, 3H). The intermediate (80 mg, 0.22 mmol) was dissolved in 2 mL of pyridine. Ac2O (0.24 mL, 2.6 mmol) and DMAP (3 mg, 0.025 mmol) were added. The solution was stirred at room temperature overnight until the completion of the reaction. After removal of the solventunder vacuum, DCM (80 mL) was added and the solution was washed with diluted hydrochloric acid (1 N) followed by brine, dried over sodium sulfate, and then ltered. After evaporation of the solvent, the residue was puried by chromatograph (CHCl3/ MeOH) to yield the title product 25 as a white solid (81 mg, 91%yield) (29% overall yield in three steps): 1H NMR (300 MHz, CDCl3)d 8.51 (s, 1H), 7.60 (d, J 8.1Hz, 1H), 7.55 (s, 1H), 7.33e7.27 (m, 1H),7.18e7.05 (m, 2H), 6.97 (s, 1H), 6.51 (s, 1H), 5.60e5.43 (m, 1H),4.20e4.12 (m, 1H), 4.11e4.00 (m, 1H), 3.82-3.72 (m, 1H), 3.66-3.58 (m, 1H), 2.56 (q, J 7.5 Hz, 2H), 2.41-2.26 (m, 2H), 2.17-2.07 (m,3H), 1.76 (s, 6H), 1.17 (t, J 7.5 Hz, 3H). 13C NMR (126 MHz, CDCl3)d 169.6 and 169.4 (1C), 152.0, 144.4, 141.9, 139.6 and 139.5 (1C),138.8, 136.7, 134.9, 131.7, 128.7, 126.0 and 125.9 (1C), 125.5, 123.0 and 122.8 (1C), 121.3, 120.8, 115.2, 103.4, 99.7, 45.5 and 43.5 (1C),41.8 and 38.4 (1C), 39.7, 31.2 and 30.5 (1C), 29.7, 25.6, 22.0 and 21.6 (1C), 15.7. MS (EI) 411 (M). HRMS: calcd for C27H29N3O (M),411.2311; found 411.2313. |
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