78% |
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 12h; |
5 Preparation of 4-(2,6-dichlorobenzamido)-N-(1-(N-glycyl-L- valyl)piperidin-4-yl)-1H-pyrazole-3-carboxamide hydrochloride (compound 5)
N-(tert-Butoxycarbonyl)glycyl-L-valine (274 mg, 1.0 mmol, 1.0 eq.) and Et3N (202 mg, 2.0 mmol, 2.0 eq.) were added to a solution of 4-(2,6- dichlorobenzamido)-N-(piperidin-4-yl)-1H-pyrazole-3-carboxamide hydrochloride (417 mg, 1.0 mmol, 1.0 eq.) in DMF (10 mL), followed by addition of HATU (418 mg, 1.1 mmol, 1.1 eq.). The mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure. The residual material was purified by flash column chromatography (silica-gel; eluent, ethyl acetate), giving 4-(2,6- dichlorobenzamido)-N-(1-(N-(N-tBoc-glycyl)-L-valyl)piperidin-4-yl)-1H-pyrazole-3- carboxamide (500 mg, 78%). The material thus obtained (500 mg, 1.27 mmol, 1.0 eq.) was dissolved in dioxane (10 mL), followed by addition of 4M HCl in dioxane (5 mL). The mixture was stirred at room temperature for 12 h, and then concentrated under reduced pressure. The residual material was purified by flash column chromatography (silica-gel; eluent: DCM:MeOH, 20:1), affording compound 5 (100 mg, 14%): 1H NMR (D2O, 500 MHz) d ppm 0.92-0.97 (m, 6H), 1.50 (s, 1H), 1.66 (d, J=8 Hz, 1H), 2.05-2.09 (m, 3H), 2.96 (s, 1H), 3.35 (s, 1H), 3.84-3.94 (m, 2H), 4.10 (t, J=12 Hz, 2H), 4.35 (d, J=12 Hz, 1H), 4.79 (s, 1H), 7.46 (s, 3H), 8.30 (d, J=8 Hz, 1H); 13C NMR (CD3OD, 125 MHz) d ppm 18.15, 19.84, 31.75, 32.30, 33.09, 41.47, 42.32, 45.95, 47.39, 55.66, 122.70, 122.83, 129.38, 132.76, 133.21, 134.15, 136.41, 163.13, 164.43, 167.15, 171.41; m/z (ESI+) 537.9 (M+H). |