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Preparation method of 2-chloro-5-nitropyridine

A nitropyridine and alkyl technology, which is applied in the field of preparation of 2-chloro-5-nitropyridine, can solve problems such as large waste water, unfavorable production scale-up and safe operation, and not meeting green production requirements.

Active Publication Date: 2020-05-19
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In the above-mentioned synthetic route 1, 2-aminopyridine will produce a large amount of waste water in the mixed acid nitration treatment process, pollutes greatly, does not meet the green production requirement; Simultaneously nitration reaction produces more by-products, as 2-amino-3-nitropyridine (the ratio is as high as 15%), the separation and purification are cumbersome; the diazotization hydrolysis reaction has poor safety and operability, which is not conducive to production amplification and safe operation

Method used

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  • Preparation method of 2-chloro-5-nitropyridine
  • Preparation method of 2-chloro-5-nitropyridine
  • Preparation method of 2-chloro-5-nitropyridine

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Effect test

Embodiment 1

[0073] Embodiment 1: Preparation of 2-hydroxyl-5-nitropyridine (Ⅴ) (approach 1 of step (1))

[0074] To a 500 ml four-necked flask connected with stirring, a thermometer, and a reflux condenser, add 200 g of dichloromethane, 27.0 g (0.2 moles) of 2-nitroacetaldehyde dimethyl acetal (II1), 0.5 g of piperidine, 25.3 gram (0.21 moles) of methyl 2-chloroacrylate (Ⅲ1), stirred and reacted at 40-45°C for 3 hours, lowered the reaction solution to 25°C, added 5.0 grams of ammonium chloride, 100 grams of 17% ammonia water, 35-40°C The reaction was stirred for 5 hours. Add 100 grams of water, recover dichloromethane under reduced pressure, cool to 20-25°C, filter, wash once with 20 grams of water, and dry to obtain 25.8 grams of 2-hydroxy-5-nitropyridine with a liquid phase purity of 99.6% , yield 92.1%.

Embodiment 2

[0075] Embodiment 2: the preparation of 2-hydroxyl-5-nitropyridine (Ⅴ) (way 1 of step (1))

[0076] In a 500 ml four-necked flask connected with stirring, a thermometer and a reflux condenser, add 200 grams of tetrahydrofuran, 26.6 grams (0.2 moles) of 2-nitroacetaldehyde ethylene acetal (II2), 0.5 grams of DBU, 34.7 grams ( 0.21 moles) methyl 2-bromoacrylate (Ⅲ2), stirred and reacted at 40-45°C for 3 hours, lowered the reaction solution to 25°C, added 3.5 grams of ammonium chloride, 100 grams of 17% ammonia in methanol solution, 50-55 The reaction was stirred at °C for 3 hours. Add 150 grams of water, recover tetrahydrofuran and methanol under reduced pressure, cool to 20-25°C, filter, wash once with 20 grams of water, and dry to obtain 26.2 grams of 2-hydroxy-5-nitropyridine, with a liquid phase purity of 99.5% , yield 93.6%.

Embodiment 3

[0077] Embodiment 3: Preparation of 2-hydroxyl-5-nitropyridine (Ⅴ) (way 1 of step (1))

[0078] To a 500 ml four-necked flask connected with stirring, a thermometer, and a reflux condenser, add 200 g of 1,2-dichloroethane, 27.0 g (0.2 moles) of 2-nitroacetaldehyde dimethyl acetal (II1), 0.5 Kepiperidine, 28.2 grams (0.21 moles) of ethyl 2-chloroacrylate (Ⅲ3), stirred and reacted at 55-60°C for 2 hours, lowered the reaction solution to 25°C, added 3.5 grams of ammonium chloride, 100 grams of 17% ammonia water , Stir the reaction at 50-55°C for 3 hours. Add 100 grams of water, recover 1,2-dichloroethane under reduced pressure, cool to 20-25°C, filter, wash once with 20 grams of water, and dry to obtain 25.3 grams of 2-hydroxy-5-nitropyridine, liquid The phase purity was 99.2%, and the yield was 90.4%.

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Abstract

The invention provides a preparation method of 2-chloro-5-nitropyridine. The preparation method comprises the following steps: preparing 2-hydroxy-5-nitropyridine by taking 2-nitroacetaldehyde diethylacetal as an initial raw material through two methods; and then carrying out a chlorination reaction on the 2-hydroxy-5-nitropyridine and a chlorination reagent to prepare the 2-chloro-5-nitropyridine. The method has the advantages of cheap and accessible raw materials and low cost, does not use a diazotization hydrolysis reaction, is safe, simple and convenient to operate, does not use mixed acid, is less in wastewater yield and environmentally-friendly, does not use a nitration reaction, is high in reaction selectivity, few in side reactions, simple in post-treatment and high in product yield and product, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a preparation method of 2-chloro-5-nitropyridine, which belongs to the technical field of medicinal chemistry. Background technique [0002] 2-Chloro-5-nitropyridine is an important pharmaceutical intermediate, which can be used to prepare drugs such as pyronaridine, sononejib and other fine chemicals. Research and optimize the preparation method of 2-chloro-5-nitropyridine It is of great significance to the development of its downstream products. [0003] 2-Chloro-5-nitropyridine (I), the molecular formula is C 5 h 3 ClN 2 o 2 (The English name is 2-Chloro-5-Nitropyridine), the CAS number is 4548-45-2, and the structural formula is as follows: [0004] [0005] At present, the synthesis of 2-chloro-5-nitropyridine is mainly prepared from 2-aminopyridine through nitration reaction, diazotization hydrolysis reaction and chlorination reaction. [0006] For example, patent documents CN102040554A and CN105523995A use 2-ami...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/61
CPCC07D213/61
Inventor 徐欣戚聿新王保林王全龙
Owner XINFA PHARMA
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