Methyl 6-HydroxypyriMidine-4-carboxylate

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.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.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.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.Step 1: Methyl 1-(1-(tert-butoxycarbonyl)-2, 6-dioxopiperidin-3-yl)-6-oxo-1, 6- dihydropyrimidine-4-carboxylate. (1511) tert-Butyl 3-bromo-2, 6-dioxopiperidine-1-carboxylate (1.0 equiv.) and methyl 6-oxo-1, 6- dihydropyrimidine-4-carboxylate (1.0 equiv.) are mixed in DMF (0.2M) and cesium carbonate is added (2.0 equiv.). The reaction mixture is stirred at 60 oC for 16 hours. The reaction mixture is partitioned between brine and ethyl acetate. The organic layer is dried with sodium sulfate, filtered and evaporated under reduced pressure. The crude residue is purified by silica gel column chromatography to afford methyl 1-(1-(tert-butoxycarbonyl)-2, 6-dioxopiperidin-3-yl)-6-oxo-1, 6- dihydropyrimidine-4-carboxylate.Step 9A: Example 96-Oxo-1, 6-dihydropyrimidine-4-carbohydrazide; The subtitle compound of step 9A was stirred as a slurry in anhydrous methanol and hydrazine monohydrate (3 eq.) was added. The solid first dissolved but within 5 minutes the product started to precipitate. More methanol was added and the slurry was stirred at it overnight, filtered, washed with methanol, and dried in vacuo to give the title product (91%).1H NMR (400 MHz, DMSO-d6): delta 12.36 (broad s, 1H), 9.88 (s, 1H), 8.23 (s, 1H), 6.67 (s, 1H), 4.67 (s, 2H).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 (70%) of the title compound.1H NMR (300 MHz, (CD3)2SO): delta (ppm) 12.50 (broad s, 1H), 8.23 (s, 1H), 6.83 (s, 1H), 3.80 (s, 3H).