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With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 100℃; for 1.0h; |
The residue was suspended in diisopropylethylamine (7 ml), phosphorus oxychloride (1.5 ml) was added to the suspension, and the mixture was stirred at 100C for one hr. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an acetone-chloroform system to give 8-chloro-2-methoxy-[1,5]naphthyridine (572 mg, yield 29%) (3 steps). 8-Chloro-2-methoxy-[1,5]naphthyridine (50 mg), 5,6-dimethyl-[2,2']bipyridinyl-3-ol (51 mg), and 4-dimethylaminopyridine (94 mg) were dissolved in dimethylsulfoxide (1.5 ml), cesium carbonate (251 mg) was added to the solution, and the mixture was stirred at 130C overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (70 mg, yield 75%). 1H-NMR (CDCl3, 400 MHz): delta 2.34 (s, 3H), 2.66 (s, 3H), 3.92 (s, 3H), 6.92 (d, J = 5.4 Hz, 1H), 7.17 - 7.26 (m, 3H), 7.65 (dd, J = 7.6, 7.6 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.36 (s, 1H), 8.53 (d, J = 5.9 Hz, 1H), 8.58 (m, 1H) Mass spectrometric value (ESI-MS, m/z): 381 (M+Na)+ |
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With trichlorophosphate; at 110℃; for 12.0h;Inert atmosphere; |
Step 3: 8-Chloro-2-methoxy-1,5-naphthyridine To the intermediate 6-methoxy-1,5-naphthyridin-4(1H)-one (15.0 g, 0.085 mumol) was added POCl3 (300 mL) dropwise under nitrogen atmosphere at RT. The reaction mixture was heated to 110 C. with constant stirring. After 12 h, the mixture was concentrated in vacuo and azeotroped with toluene (2*100 mL). The residue was dissolved in ice-water (100 mL) and adjusted pH of the solution to 7 using 10% NaHCO3 solution, and extracted with EtOAc (4*100 mL). The combined organic extracts were washed with water (2*100 mL), saturated NaCl solution (100 mL), dried (Na2SO4), filtered and concentrated in vacuo. |
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Step 3: 8-Chloro-2-methoxy-1.5-naphthyridine; To the intermediate 6-methoxy-l,5-naphthyridin-4(lH)-one (15.0 g, 0.085mol) was added POCI3 (300 mL) dropwise under nitrogen atmosphere at RT. The reaction mixture was heated to 110 C with constant stirring. After 12 h, the mixture was concentrated in vacuo and azeotroped with toluene (2 * 100 mL). The residue was dissolved in ice-water (100 mL) and adjusted pW of the solution to 7 using 10% NaHCO3 solution, and extracted with EtOAc (4 x 100 mL). The combined organic extracts were washed with water (2 x 100 mL), saturated NaCl solution ( 100 mL), dried (Na2SO4), filtered and concentrated in vacuo. |
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