4-Pyrimidinecarboxylic acid, 5-amino-2,6-dichloro-, ethyl ester

A suspension of ethyl 2, 6-dichloro-5-nitropyrimidine-4-carboxylate (1 g, 3.76 mmol, 1.00 equiv) and stannous chloride dihydrate (3.38 g, 14.98 mmol, 1.00 equiv) in ethyl acetate (30 mL) in a 50-mL sealed tube was stirred for 5 hours at 70° C. A suspension of ethyl 2, 6-dichloro-5-nitropyrimidine-4-carboxylate (1 g, 3.76 mmol, 1.00 equiv)and stannous chloride dihydrate (3.38 g, i4.98 mmol, 1.00 equiv) in ethyl acetate (30 mL) in a50-mL sealed tube was stirred for 5 hours at 70 °C. The resulting solution was diluted with 50 mLof water, the pH value of the solution was adjusted to 9 with sodium carbonate, extracted with3x 100 mL of ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:5) to give the title compound (572 mg, 64percent) as a light yellow solid. LC-MS (ES, mlz): 236 [M+H].General procedure: To a solution ofnitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) inN, N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). Thereaction was heated to 100 C. and stirred at this temperature for 2 hours. Thereaction was then cooled to room temperature and acidified to pH=1 with 10%aqueous HCl solution if product contains a carboxylic acid, or diluted withwater if neutral. The solution was extracted with twice with dichloromethane.The organic layers were combined, dried with sodium sulfate and concentratedunder vacuum. The crude material was either used directly in subsequentreactions or purified by flash chromatography.Similar to as described in General Procedure A, A suspension of ethyl 2, 6-dichloro-5-nitropyrimidine-4-carboxylate (1 g, 3.76 mmol, 1.00 equiv) and stannous chloride dihydrate (3.38 g, 14.98 mmol, 1.00 equiv) in ethyl acetate (30 mL) in a 50-mL sealed tube was stirred for 5 hours at 70 C. The resulting solution was diluted with 50 mL of water, the pH value of the solution was adjusted to 9 with sodium carbonate, extracted with 3*100 mL of ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:5) to give the title compound (572 mg, 64%) as a light yellow solid. LC-MS (ES, m/z): 236 [M+H]+.A suspension of ethyl 2, 6-dichloro-5-nitropyrimidine-4-carboxylate (1 g, 3.76 mmol, 1.00 equiv)and stannous chloride dihydrate (3.38 g, i4.98 mmol, 1.00 equiv) in ethyl acetate (30 mL) in a50-mL sealed tube was stirred for 5 hours at 70 C. The resulting solution was diluted with 50 mLof water, the pH value of the solution was adjusted to 9 with sodium carbonate, extracted with3x 100 mL of ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:5) to give the title compound (572 mg, 64%) as a light yellow solid. LC-MS (ES, mlz): 236 [M+H].General procedure: To a solution of nitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) in N, N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). Thereaction was heated to 100 C. and stirred at this temperature for 2 hours. Thereaction was then cooled to room temperature and acidified to pH=1 with 10%aqueous HCl solution if product contains a carboxylic acid, or diluted withwater if neutral. The solution was extracted with twice with dichloromethane.The organic layers were combined, dried with sodium sulfate and concentratedunder vacuum. The crude material was either used directly in subsequentreactions or purified by flash chromatography.General procedure: Similar to as described in General Procedure A, ethyl5-amino-2, 6-dichloropyrimidine-4-carboxylate was reacted with 2-methoxyethan-1-ol to give the title compound (216 mg, 65%) as a light yellow solid. LC-MS (ES, mlz): 306 [M+H]. To a solution of nitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) in N, N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). The reaction washeated to 100 C and stirred at this temperature for 2 hours. The reaction was then cooled to room temperature and acidified to pH = 1 with 10 % aqueous HCl solution if product contains a carboxylic acid, or diluted with water if neutral. The solution was extracted with twice with dichloromethane. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The crude material was either used directly in subsequent reactions or purified byflash chromatography.General procedure: To a solution of nitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) in N, N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). Thereaction was heated to 100 C. and stirred at this temperature for 2 hours. Thereaction was then cooled to room temperature and acidified to pH=1 with 10%aqueous HCl solution if product contains a carboxylic acid, or diluted withwater if neutral. The solution was extracted with twice with dichloromethane.The organic layers were combined, dried with sodium sulfate and concentratedunder vacuum. The crude material was either used directly in subsequentreactions or purified by flash chromatography.Similar to as described in General Procedure A, ethyl5-amino-2, 6-dichloropyrimidine-4-carboxylate was reacted with ]H-pyrazole to give the titlecompound (170 mg, 28%) as a light yellow solid. LC-MS (ES, m/z): 268 [M+H]. To a solution of nitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) in N, N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). The reaction washeated to 100 C and stirred at this temperature for 2 hours. The reaction was then cooled to room temperature and acidified to pH = 1 with 10 % aqueous HCl solution if product contains a carboxylic acid, or diluted with water if neutral. The solution was extracted with twice with dichloromethane. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The crude material was either used directly in subsequent reactions or purified byflash chromatography.