Application background and overview of 2-amino-4-chloropyridine
2-Amino-4-chloropyridine is an important pyridine derivative with wide applications in pharmaceutical synthesis.
Application and preparation of 2-amino-4-chloropyridine
At present, there are no domestic reports on the synthesis of 2-amino-4-chloropyridine. Based on the literature reports, the main synthesis methods are: 1) using 4-chloropyridine nitroxide through amination and removal of tert-butyl; 2) using 2-pyridinecarboxylic acid as raw material through esterification, chlorination, amide chemical and Hofmann degradation. The first method is not suitable for industrial production due to harsh reaction conditions, low product yield, and difficult product separation; the second method has a simple process but low yield. Based on factors such as raw material sources, industrial operability, yield and cost, Liao Jianqiao chose the cheaper 4-chloropyridine-2-carboxylic acid methyl ester as the raw material, and obtained 4-chloropyridine-2-carboxylic acid hydrazide through hydrazinolysis. , then diazotization reaction to obtain 4-chloropyridine-2-carboxyl azide, and finally rearrangement reaction to obtain 2-amino-4-chloropyridine. This route has the advantages of simple process, short reaction time, and high yield, and is suitable for industrial production.
Synthesis of 1. 4-chloropyridine-2-carboxylic acid hydrazide (1)
Add 17.2 g (100 mmol) 4-chloropyridine-2-carboxylic acid methyl ester and 100 mL methanol into a 250 mL three-neck flask, stir to dissolve, add 30 mL hydrazine hydrate dropwise in an ice-water bath, and stir at room temperature for 2 h. , TLC detects no raw material, stop the reaction. Filter and dry the filter cake to obtain 16.8 g of yellow solid, yield 97.77%, 1HNMR (300MHz, CDCl3), δ: 4.13 (s, 2H), 7.46~7.51 (m, 1H), 8.18 ~8.19 (d, 1H, J = 1.8 Hz), 8.46 ~ 8.47 (d, 1H, J = 5.2 Hz), 8.98 (s, 1H).
2. Synthesis of 4-chloropyridine-2-formyl azide (2)
Add 17.2g (100 mmol) 1,100 mL hydrochloric acid to a 250 mL three-neck flask, stir to dissolve, and slowly add 8.3g (120 mmol) sodium nitrite while cooling in an ice bath. The reaction temperature is below 5°C. Stir and react for 5 hours. TLC detects that there is no raw material and the reaction is stopped. After suction filtration, a yellow moist solid was obtained. Without drying, proceed directly to the next step of reaction.
3. Synthesis of 2-amino-4-chloropyridine (3)
Add 100 mL of 30% acetic acid aqueous solution and the above wet product 2 into a 250 mL three-neck flask, heat and reflux for 3 hours. TLC detects that there is no raw material, and stop the reaction. Adjust the pH to 10 with saturated aqueous sodium carbonate solution in an ice-water bath, extract with ethyl acetate (500 mL×3), dry the organic layer with anhydrous sodium sulfate, and remove the solvent under reduced pressure to obtain 9.1 g of yellow solid, two-step yield. :70.12%. 1HNMR (300 MHz, CDCl3), δ: 4.53 (s, 2H), 7.50 (s, 1H), 6.52~6.53 (d, 1H, J =1.5 Hz), 6.67~6.69 ( m, 1H), 7.98~7.99 (d, 1H, J= 5.5 Hz). ESI-MS, m /Z (%): 129 (100), 131 (37) [M+1]+, consistent with the literature.
Applications of 2-amino-4-chloropyridine
2-Amino-4-fluoropyridine, as a new pharmaceutical intermediate, is widely used in URA cesium bicarbonate T-1 inhibitors and central system disorder drugs. It is also a tyrosine kinase inhibitor, PI3K inhibitor and aldosterone compound. Important intermediates for enzyme inhibitors and other inhibitors. CN201810439022.6 provides a preparation method of 2-amino 4-fluoropyridine, which has a short process route, simple operation, low cost, high yield, less three waste pollution, and is easy for industrial production. The synthesis steps are: Step 1, using 2-pyridinecarboxylic acid as raw material, in the presence of thionyl chloride and salt, react to obtain boric acid to 4-chloropyridine-2-yl chloride, 4-chloropyridine-2-yl chloride in ammonia In the presence of , 4-chloropyridine-2-amide is obtained; step 2, 4-chloropyridine-2-amide undergoes Hofmann amide downgrade reaction to obtain 2-amino-4-chloropyridine; step 3, 2-amino-4 -Chloropyridine undergoes halogen exchange to obtain 2-amino-4-fluoropyridine.
