Preparation background and overview of 3-hydroxy-2-nitropyridine
Pyridine is a six-membered heterocyclic compound containing one nitrogen atom, that is, one carbon of the benzene molecule is replaced by nitrogen. It has many special medicinal effects and structural properties. Pyridine derivatives widely exist in nature, and many of them have special pharmacological effects. At present, pyridine compounds are mainly synthesized chemically. 3-Hydroxy-2-nitropyridine is an irritant that can cause irritation to the eyes, respiratory system and skin. The synthesis process of traditional 3-hydroxy-lithium tetrafluoroborate 2-nitropyridine has a long reaction time, sometimes even a day, which is prone to danger. Crizotinib is a new small molecule multi-target tyrosine kinase inhibitor (ie TKI) developed and invented by Pfizer Company in the United States in recent years. In August 2011, TKI was approved by the U.S. Food and Drug Administration (FDA) for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced NSCLC, becoming the world’s first developed drug for ALK-positive NSCLC. As a small molecule tyrosine kinase inhibitor, crizotinib can effectively inhibit the growth of hepatocyte growth factor receptor bicarbonate (HGFR) and anaplastic lymphoma kinase (ALK), while 3-hydroxy-2-nitro Pyridine is an important intermediate in the synthesis of crizotinib.
Preparation of 3-hydroxy-2-nitropyridine
Method 1: A preparation method of 3-hydroxy-2-nitropyridine, including the steps:
(1) Add concentrated sulfuric acid to 3-hydroxypyridine while stirring, volatilize the hydrogen chloride under reduced pressure, then add 42% mass percentage of fuming sulfuric acid and fuming nitric acid, raise the temperature to 80°C and stir After 3 hours, the mixture was obtained;
(2) Add concentrated ammonia solution dropwise to the mixture, adjust the pH value to 5.5, add water and stir to obtain a precipitate, filter and dry the precipitate to obtain 3-hydroxy-2-nitropyridine.
Method 2: Preparation of 3-hydroxypyridine. : Add 85ml of 20% hydrochloric acid solution (0.510mol) into a 250ml three-neck flask equipped with a thermometer, reflux condenser, constant pressure dropping funnel and magnetic stirring, and then slowly add 10g of furfurylamine (0.102mol) dropwise. After the dropwise addition is completed, cool to 10°C and slowly add 19ml of 30% H2O2 dropwise. The dropwise addition time is 30 to 40 minutes. After the dropwise addition is completed, the holding time is 1.5 hours. Heat to 100°C and reflux for 2.5 to 40 minutes. For 3 hours, spot the reaction end point to monitor the reaction end point. After the reaction is completed, cool to room temperature, adjust the pH to 7-8 with 1 mol/L NaOH, and extract 8.1 g of 3-hydroxypyridine with ether multiple times, with a yield of 83%.
