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A kind of synthesis technique of 3-hydroxy-2-nitropyridine

A technology of nitropyridine and hydroxypyridine, applied in the field of synthesis technology of 3-hydroxy-2-nitropyridine, can solve the problems of low yield, excessive use of strong acid, etc., and achieves improved reaction yield, improved yield, The effect of shortening the post-processing process

Active Publication Date: 2018-09-28
ZHEJIANG ZHONGXIN FLUORIDE MATERIALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The purpose of the present invention is to provide a synthesis process of 3-hydroxy-2-nitropyridine, to solve the problem of using too much strong acid in the synthesis process and the problem of low yield

Method used

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  • A kind of synthesis technique of 3-hydroxy-2-nitropyridine
  • A kind of synthesis technique of 3-hydroxy-2-nitropyridine
  • A kind of synthesis technique of 3-hydroxy-2-nitropyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Example 1: Preparation of 3-hydroxypyridine.

[0034] A thermometer, a reflux condenser, a constant pressure dropping funnel, and a magnetically stirred 250ml three-necked flask were added with 85ml of 20% hydrochloric acid solution (0.510mol), and then slowly added dropwise 10g of furfurylamine (0.102mol). After the addition is completed, cool to between 10°C and slowly add 19ml of 30% concentration of H 2 o 2 , the dropping time is 30-40 minutes. After the dropping, the holding time is 1.5 hours, heated to 100°C, heated to reflux for 2.5-3 hours, spotting the sample to monitor the reaction end point, cooling to room temperature after the reaction, and using 1mol / L NaOH The pH was adjusted to 7-8, and 8.1 g of 3-hydroxypyridine was obtained by repeated extraction with ether, with a yield of 83%.

[0035] Replacement example 1-1-1-9:

[0036] The preparation method is the same as in Example 1, except that the concentration of hydrochloric acid is adjusted, the temper...

Embodiment 2

[0040] Example 2: Preparation of 3-hydroxy-2-nitropyridine.

[0041] 10g of 3-hydroxypyridine (105mmol) and 80ml of ethyl acetate and 4.2g of KNO 3 (42mmol) and 21ml of acetic anhydride (0.210mol) were added to a 250mL three-neck flask, heated at a temperature of 45°C with magnetic stirring to react, and the sample was monitored to monitor the end of the reaction. Wash the ester 1-2 times, take the filtrate and adjust the pH to neutral with NaOH saturated solution, extract 3-4 times with ethyl acetate, take the extract and add activated carbon and heat it under reflux for 1 hour, cool and filter, take the filtrate with anhydrous magnesium sulfate Dry, filter, concentrate on a rotary evaporator, and dry in a drying oven. 11.9 g of 3-hydroxy-2-nitropyridine was obtained with a yield of 81%.

[0042]The nuclear magnetic resonance spectrum and high performance liquid chromatography of the product are as follows: figure 1 , figure 2 shown.

[0043] Replacement examples 2-1 to...

Embodiment 3

[0048] Example 3: Preparation of 3-hydroxy-2-nitropyridine.

[0049] 50g of 3-hydroxypyridine (0.525mol) and 400ml of ethyl acetate and 74g of KNO 3 (0.735mol) and 367ml of acetic anhydride (3.675mol) were added to a 1L three-neck flask, heated and stirred mechanically at a temperature of 45°C to react, and the sample was monitored to monitor the end of the reaction. Wash 1-2 times with ethyl ester, take the filtrate and adjust the pH to neutral with NaOH saturated solution, extract 3-4 times with ethyl acetate, take the extract and add activated carbon to reflux for 1 hour, cool and filter, take the filtrate with anhydrous sulfuric acid Magnesium was dried, filtered, concentrated on a rotary evaporator, and then dried in a drying oven. 66 g of 3-hydroxy-2-nitropyridine was obtained with a yield of 90%.

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Abstract

The invention discloses a synthesizing technology for 3-hydroxy-2-nitropyridine. The synthesizing technology is characterized by comprising the following steps that furfuryl amine and hydrogen peroxide are added into a hydrochloric acid solution with the mass fraction of 20%-30%, the mole ratio of hydrochloric acid to the furfuryl amine to the hydrogen peroxide is 1:5:1-2, and 3-hydroxy pyridine is obtained after reacting is completed; the 3-hydroxy pyridine, ethyl acetate, nitrate and acetic anhydride react at the temperature of 35 DEG C-55 DEG C, the mole ratio of the 3-hydroxy pyridine to the nitrate to the acetic anhydride is 1-2:1-2:10, and the 3-hydroxy-2-nitropyridine is obtained. According to the synthesizing technology for the 3-hydroxy-2-nitropyridine, by studying a furfuryl amine oxidation hydrolysis technology, the furfuryl amine oxidation hydrolysis technology and a nitration reaction form a telescopic reaction, and therefore the aftertreatment process of the reaction is greatly shortened; meanwhile, metal nitrate is adopted to replace mix acid to perform the nitration reaction, usage of concentrated sulfuric acid and concentrated nitric acid is avoided, and not only are equipment corrosion and environmental problems solved, but also the reaction yield is greatly increased.

Description

Technical field: [0001] The invention relates to a synthesis process of 3-hydroxy-2-nitropyridine, which belongs to the technical field of chemical synthesis. Background technique: [0002] Crizotinib is a small molecule novel multi-target tyrosine kinase inhibitor (ie TKI) developed and invented by Pfizer Corporation of the United States in recent years. In August 2011, TKI was approved by the U.S. Food and Drug Administration (FDA), which can be used to treat anaplastic lymphoma kinase (ALK)-positive advanced NSCLC, as the world's first drug developed for ALK-positive NSCLC. Small molecule tyrosine kinase inhibitor, crizotinib can effectively inhibit the growth of hepatocyte growth factor receptor (HGFR) and anaplastic lymphoma kinase (ALK), while 3-hydroxy-2-nitropyridine is An important intermediate in the synthesis of crizotinib. [0003] At present, there have been many reports on the synthesis method of 3-hydroxy-2-nitropyridine. Most of the synthetic reactions adop...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/65
CPCC07D213/65
Inventor 沈永淼袁其亮袁少岚黄炜朱露露王超陈寅镐
Owner ZHEJIANG ZHONGXIN FLUORIDE MATERIALS CO LTD
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