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Stage #1: With chloro-trimethyl-silane In methanol at 20℃; for 8 h; Stage #2: for 0.5 h; Heating / reflux
Step 9A: Methyl 6-oxo-1,6-dihydropyrimidine-4-carboxylate; To 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (36.0 g, 257 mmol) in MeOH (360 mL) was dropwise added chlorotrimethylsilane (56 g, 554 mmol) and then stirred for 8 h at room temperature. The solvent was evaporated off and the solid was refluxed with 200 mL MeOH for 30 minutes. The reaction mixture was cooled, the precipitated solid was filtered off and washed with a small amount of MeOH and dried under vacuum at 35° C. to afford 27.9 g (70percent) of the subtitle compound.1H NMR (300 MHz, DMSO-d6): δ (ppm) 12.50 (broad s, 1H), 8.23 (s, 1H), 6.83 (s, 1H), 3.80 (s, 3H).
Example 33.2Pyridazine-4-carboxylic acid ethyl ester To 6-pyrimidine-4-carboxylic acid (36.0 g, 257 mmol) in methanol (360 mL) was dropwise added chlorotrimethylsilane (56 g, 554 mmol) and then stirred for 8 hours at room temperature. The solvent was evaporated off and the solid was refluxed with 200 mL methanol for 30 minutes. The reaction mixture was cooled, the precipitated solid was filtered off and washed with a small amount of methanol and dried under vacuum at 35° C. to afford 27.9 g (70percent) of the title compound.1H NMR (300 MHz, (CD3)2SO): δ (ppm) 12.50 (broad s, 1H), 8.23 (s, 1H), 6.83 (s, 1H), 3.80 (s, 3H).
[0778] Into a 2000-mL 4-necked round-bottom flask was placed methyl 6-hydroxypyrimidine-4- carboxylate (115 g, 746.16 mmol, 1.00 equiv), CH3CN (1200 mL), and POC13 (340 g, 2.22 mol, 3.00 equiv). The resulting solution was stirred at 80C overnight, cooled to room temperature, concentrated under vacuum, diluted with 1000 mL of EA, and quenched with 1000 mL of water/ice. The resulting solution was extracted with 3x500 mL of ethyl acetate. The combined organic layers were washed with lx 1000 mL of water and lx 1000 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel colunm eluted with ethyl acetate/petroleum ether (1:4) to afford 76 g (59%) of methyl 6-chloropyrimidine-4-carboxylate as a white solid. LCMS [M+H] 173.
76 g
With trichlorophosphate; In acetonitrile; at 80℃;
Into a 2000-mL 4-necked round-bottom flask was placed methyl 6-hydroxypyrimidine-4- carboxylate (1 15 g, 746.16 mmol, 1.00 equiv), CH3CN (1200 mL), and POCl3 (340 g, 2.22 mol, 3.00 equiv). The resulting solution was stirred at 80C overnight, cooled to room temperature, concentrated under vacuum, diluted with 1000 mL of EA, and quenched with 1000 mL of water/ice. The resulting solution was extracted with 3x500 mL of ethyl acetate. The combined organic layers were washed with 1x1000 mL of water and 1x1000 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column eluted with ethyl acetate/petroleum ether (1 :4) to afford 76 g (59%) of methyl 6-chloropyrimidine-4-carboxylate as a white solid. LCMS [M+H]+ 173.
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