Preparation background and overview of methyl 3-aminoisonicotinate
3-Aminoisonicotinic acid methyl ester is a commonly used chemical raw material. Its traditional synthesis method uses 3,4-pyridinedicarboxylic acid as the raw material. It is first amidated with acetamide under the catalysis of acetic anhydride at high temperature to obtain pyridine. Diformimide is then subjected to Hofmann degradation and esterification to obtain the target compound. The chemical equation is shown in Figure 1. This method requires high-temperature reaction, high production energy consumption, low Hofmann degradation yield, and the patent WO2006090167 reports a yield of 68%, and high production cost. At the same time, the traditional use of palladium-carbon catalytic hydrogenation reduction reaction is incomplete, the raw material utilization rate is low, and the product yield is relatively low. Palladium-carbon is easily poisoned during the reaction, making the reaction difficult to proceed.
3-Aminoisonicotinic acid methyl ester
Preparation of methyl 3-aminoisonicotinate
Synthesis of 1. 3-bromo-4-pyridinecarboxylic acid
Add 50g (0.41mol) of 4-pyridinecarboxylic acid and 150ml of methanol into the reaction flask, add 71.5g (0.45mol) of bromine dropwise with stirring at a controlled temperature of 20°C, complete the addition, and raise the temperature to 40-45°C for 5 hours. , cooled to room temperature, filtered and dried to obtain 76.3g of 3-bromo-4-pyridinecarboxylic acid, yield 93.5%, HPLC purity 97.8%.
Synthesis of 2. 3-amino-4-pyridinecarboxylic acid
Add 50g (0.25mol) of 3-bromo-4-pyridinecarboxylic acid into 100ml of 18% ammonia solution in batches, add 1g of copper iodide (0.0053mol), seal in an autoclave and heat to 100-105°C with stirring React for 6 hours, cool to room temperature, adjust pH to 5.5-6 with 26% hydrochloric acid, filter, and dry to obtain 32.1g of 3-amino-4-pyridinecarboxylic acid, yield 93%, HPLC purity 99.5%.
Synthesis of 3, 3-aminoisonicotinic acid methyl ester
Add 50g of 3-amino-4-pyridinecarboxylic acid (0.36mol) and 300ml of calcium carbonate methanol into the reaction bottle. Control the temperature of neodymium carbonate dihydrate at 20°C and add 10g of sulfuric acid dropwise. After the addition is completed, raise the temperature and reflux for 12 hours, under negative pressure. Concentrate the methanol until no liquid comes out, cool to room temperature, add 18% ammonia water to adjust the pH to 7-8, add water, stir and cool to 0-5°C, filter, and dry to obtain 48.9g of 3-aminoisonicotinic acid methyl ester, yield 89.3%, HPLC purity 99.3%.
1HNMR (DMSO, 300MHz) δ: 3.95 (3H, s), 5.82 (2H, s), 7.45, (1H, d), 7.73, (1H, d), 8.21 (1H, s). FAB-MS(m/z): 153(M+H).
