Simple 2-amino-5-halogenated pyridine preparation method

A technology of halopyridine and ammonia via pyridine, which is applied in the field of simple preparation of 2-amino-5-halopyridine, which can solve the problems of unfavorable industrial production application, easy flushing or even explosion, and high temperature control requirements, and achieve low cost , easy operation, high selectivity effect

Active Publication Date: 2019-08-06
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In the above synthetic route 1 method, nitric acid-sulfuric acid nitration produces a large amount of acid waste water, is unfavorable for environmental protection, and reaction selectivity is poor simultaneously, needs to carry out the separation of 2-amino-5-nitropyridine and 2-amino-3-nitropyridine, 2 - The yield of amino-5-nitropyridine is only 41%; the diazonium salt has poor stability, high temperature control requirements, improper operation is easy to charge or even explode, poor operation safety, and low total yield, which is not conducive to industrial production and application

Method used

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  • Simple 2-amino-5-halogenated pyridine preparation method

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Experimental program
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Effect test

Embodiment 1

[0029] Embodiment 1: the preparation of 2-amino-5-chloropyridine

[0030] In the 500 milliliter four-neck flask that is connected with stirring, thermometer, reflux condenser and 20wt% sodium hydroxide aqueous solution tail gas absorption device, add 90 grams of 1,2-dichloroethane, 15.8 grams (0.2 moles) of 4-cyano -1-butyne, 0.2 g of ferric chloride (0.0012 mol), under stirring, intermittently feed chlorine gas at 40-45 ° C, and feed 30 g of chlorine gas in total for 2 hours, after ventilation is completed, stir and react at 40-45 ° C for 2 hours Nitrogen was then bubbled for 2 hours to replace residual chlorine and hydrogen chloride. Add 100 grams of 17wt% ammonia water, stir and react at 60-65°C for 5 hours, cool to 20°C, separate layers, extract the water layer three times with 1,2-dichloroethane, 20 grams each time, combine the organic phases, and use 20 1 g of saturated brine, then dried with 5 g of anhydrous sodium sulfate, and 1,2-dichloroethane was recovered by rotar...

Embodiment 2

[0033] Embodiment 2: the preparation of 2-amino-5-bromopyridine

[0034] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser and 20wt% aqueous sodium hydroxide tail gas absorption device, add 90 grams of dichloromethane, 15.8 grams (0.2 moles) of 4-cyano-1-butyne , 0.3 grams of 40wt% hydrobromic acid aqueous solution (0.0015 moles), under stirring, dropwise add 65.0 grams of bromine and 50 grams of dichloromethane mixture at 30-35 ° C, dropwise for about 1 hour, and stir at 40-45 ° C for reaction 4 hours, then nitrogen bubbles for 2 hours to displace residual bromine and hydrogen bromide. Add 140 grams of 17wt% ammonia water, stir and react at 50-55°C for 4 hours, cool to 20°C, separate layers, extract the aqueous layer three times with dichloromethane, 20 grams each time, combine the organic phases, and wash with 20 grams of saturated brine , and then dried with 5 grams of anhydrous sodium sulfate, and the dichloromethane wa...

Embodiment 3

[0037] Embodiment 3: Preparation of 2-amino-5-fluoropyridine

[0038]Add 120 grams of 1,2-ethylene dichloride, 15.8 grams (0.2 mole) 4-cyano-1-butyne, 0.5 gram cuprous chloride (0.005 mole), under stirring, at 30-35 ℃ intermittently pass into the fluorine gas diluted with nitrogen (the mass concentration of fluorine gas is 2-5wt%), A total of 8 grams of fluorine gas was fed in equivalent to fluorine gas within 5 hours, then stirred and reacted at 35-40°C for 3 hours, and samples were taken at the same time to detect the completion of the addition reaction, and then nitrogen gas was bubbled for 2 hours to replace residual fluorine gas and hydrogen fluoride. Add 120 grams of 17wt% ammonia water, stir and react at 60-65°C for 5 hours, cool to 20°C, separate layers, extract the water layer three times with 1,2-dichloroethane, 20 grams each time, combine the organic phases, and use 20 Wash with 5 g of saturated brine, then dry with 5 g of anhydrous sodium sulfate, and recover 1,2-...

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Abstract

The invention provides a 2-amino-5-halogenated pyridine preparation method, which comprises: carrying out an addition reaction on 4-cyano-1-butyne and a halogen element X2 in a solvent under the catalysis of an acidic catalyst to obtain 4,4,5,5-tetrahalogenated n-valeronitrile, and carrying out cyclization on the 4,4,5,5-tetrahalogenated n-valeronitrile and ammonia through pyridine to obtain 2-amino-5-halogenated pyridine. According to the present invention, the preparation method has advantages of mild preparation condition, safety, environmental protection, low cost, high selectivity, less by-products and high product yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a convenient preparation method of 2-amino-5-halopyridine, which belongs to the technical field of medicinal chemistry. Background technique [0002] 2-Amino-5-halopyridines include 2-amino-5-chloropyridine, 2-amino-5-fluoropyridine and 2-amino-5-bromopyridine; 2-amino-5-chloropyridine can be used in the preparation of betrid Shaban, Etosibu, Zopiclone and other drugs, in addition, other drugs can be prepared from 2-amino-5-fluoropyridine, 2-amino-5-bromopyridine, it can be seen that 2-amino-5-halogenated Pyridine is an important class of pyridine derivatives. [0003] Most of the preparation methods of 2-amino-5-halopyridine reported at present are starting raw materials with 2-aminopyridine with higher price: [0004] For example, the Chinese patent document CN106432069A uses 2-aminopyridine as a raw material to prepare 2-amino-5-chloropyridine through hydrochloric acid and sodium hypochlorite chlorination, with a single-st...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 戚聿新鞠立柱屈虎胡金山
Owner XINFA PHARMA
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