Synthesis process and application of 3-hydroxy-2-nitropyridine_Industrial additives

Synthesis process and application background and overview of 3-hydroxy-2-nitropyridine

3-Hydroxy-2-nitropyridine is an important intermediate in the synthesis of crizotinib. 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. The small molecule tyrosine kinase inhibitors sodium bicarbonate and crizotinib can effectively inhibit the growth of hepatocyte growth factor receptor (HGFR) and anaplastic lymphoma kinase (ALK).

Synthesis process and application preparation of 3-hydroxy-2-nitropyridine

Preparation of 3-hydroxypyridine: Add 85ml of 20% concentration (mass fraction) hydrochloric acid solution into a 250ml three-neck flask equipped with a thermometer, reflux condenser, constant pressure dropping funnel and magnetic stirring, and then slowly add it dropwise After the dropwise addition of 10g of furfurylamine is completed, cool to 10°C, and slowly add 19ml of 30% concentration (mass fraction) H₂O₂ dropwise. The time is 30 to 40 minutes. After the dripping is completed, the holding time is 1.5 hours. Heat to 100°C and reflux for 2.5 to 3 hours. Spot a sample to monitor the end point of the reaction. After the reaction is completed, cool to room temperature and adjust the pH to 7~ with 1 mol/L NaOH. 8. Extract 3-hydroxypyridine 8 sodium tetraborate .1g through multiple extractions with diethyl ether, with a yield of 83%.

Preparation of 3-hydroxy-2-nitropyridine: Add 10g of 3-hydroxypyridine and 80ml of ethyl acetate, 4.2g of KNO₃ and 21ml of acetic anhydride into a 250mL three-port In the bottle, heat the reaction with magnetic stirring at a temperature of 45°C. Monitor the end point of the reaction by spotting. After the reaction is completed, cool to room temperature, filter with suction, and wash 1 to 2 times with a small amount of ethyl acetate. Take the filtrate and adjust the pH to medium with a saturated solution of NaOH. Properties, extract with ethyl acetate 3 to 4 times, add activated carbon to the extract and heat to reflux for 1 hour, then cool and filter, take the filtrate and dry it with anhydrous magnesium sulfate, filter, place it on a rotary evaporator to concentrate, and then place it in a drying box drying. 11.9 g of 3-hydroxy-2-nitropyridine was obtained, with a yield of 81%.

The synthesis process and application of 3-hydroxy-2-nitropyridine

CN201210488.0 discloses a synthesis method of 6-bromo-2,2-dimethyl-2H-pyrido[3,2-B][1,4]oxazin-3(4H)-one , the synthetic method of 6-bromo-2,2-dimethyl-2H-pyrido[3,2-B][1,4]oxazin-3(4H)-one is 3-hydroxy-2 – Dissolve nitropyridine and sodium methoxide in methanol, add liquid bromine dropwise at a low temperature and continue the reaction for half an hour. After the addition, add some acetic acid, continue stirring for 10 minutes and then concentrate to obtain a crude product. After purification, mix with 2-bromo-2 , 2-dimethylethyl acetate is converted into ether in N,N-dimethylformamide in the presence of alkali. The purified intermediate is reduced and purified with iron powder in acetic acid to obtain white 6-bromo-2,2 -Dimethyl-2H-pyrido[3,2-B][1,4]oxazin-3(4H)-one.

References

[1][China invention, China invention authorization] CN201510769632.9 A synthesis process of 3-hydroxy-2-nitropyridine

[2]CN201210488.0 Synthesis of 6-bromo-2,2-dimethyl-2H-pyrido[3,2-B][1,4]oxazin-3(4H)-one Method