Preparation method for 5-chlorine-2-hydroxyl-3-nitroacetophenone

A technology of nitroacetophenone and hydroxyacetophenone, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of large solvent consumption, safety accidents, environmental pollution, and high cost, and achieve simple and convenient follow-up processing, reduce production costs, The effect of a short reaction cycle

Inactive Publication Date: 2015-03-11
SHANDONG JINCHENG PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The use of chloroform and carbon tetrachloride in this process has strong toxicity, which is easy to cause safety accidents and environmental pollution, and the cost of using solvents is relatively high; the third step needs to be concentrated to remove solvents to separate intermediates, and more solvents are used, which increases production costs. , and the yield is low
[0006] The patent document JP03095144 is similar to the reaction route of WO09734885. The same solvent is used in each step. The difference is that the final system is crystallized at low temperature, which improves the yield. The amount of solvent is large, the cost is high, the process operation is cumbersome, and the product purity is not high.
[0007] Document CN102304052 discloses the synthetic method of 5-bromo-2-hydroxyl-3-nitroacetophenone, adopts the same solvent tetrachloroethylene as solvent, but the follow-up treatment is more loaded down with trivial details, and the cost of solvent is higher, and reaction raw material p-bromophenol Higher cost, lower yield

Method used

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  • Preparation method for 5-chlorine-2-hydroxyl-3-nitroacetophenone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 77.2g (0.6mol) of p-chlorophenol and 73.4g (0.72mol) of acetic anhydride into a 500mL three-neck flask, add 5g of concentrated sulfuric acid dropwise into the flask, stir, react at 110°C for 1.5h, and carry out vacuum distillation. The fraction is glacial acetic acid, and the fraction at 90°C is collected to obtain 100 g of p-chlorophenol acetate with a purity of 98.2%;

[0030] Add 34.2g (0.2mol) of p-chlorophenol acetate into a 500mL three-neck flask, slowly add 79.5g (about 0.6mol) of anhydrous aluminum trichloride to the flask and stir for 1 hour at 130°C. Slowly add 200 mL of water into the flask, stir for 0.5 h, filter, heat the filter cake with methanol to dissolve, decolorize with activated carbon, and recrystallize to obtain 30.8 g of 5-chloro-2-hydroxyacetophenone with a purity of 99.68%.

[0031] Add 43g (0.25mol) of 5-chloro-2-hydroxyacetophenone into a 500mL three-necked flask, slowly add 200mL glacial acetic acid to the flask, stir, and slowly dissolve...

Embodiment 2

[0033] Add 77.2g (0.6mol) of p-chlorophenol and 73.4g (0.72mol) of acetic anhydride into a 500mL three-neck flask, add 5g of potassium carbonate into the flask, stir, react at 100°C for 1.5h, filter, and conduct vacuum distillation , the previous fraction was glacial acetic acid, and the fraction collected at 90°C was 98.7g of p-chlorophenol acetate, with a purity of 98.7%;

[0034] Add 34.2g (0.2mol) of p-chlorophenol acetate into a 500mL three-necked flask, slowly add 79.5g (about 0.6mol) of anhydrous aluminum trichloride to the flask, stir and react at 120°C for 1h, Slowly add 200 mL of water into the flask, stir for 0.5 h, filter, heat the filter cake with methanol to dissolve, decolorize with activated carbon, and recrystallize to obtain 30.5 g of 5-chloro-2-hydroxyacetophenone with a purity of 99.68%.

[0035] Add 43g (0.25mol) of 5-chloro-2-hydroxyacetophenone into a 500mL three-necked flask, slowly add 200mL of glacial acetic acid into the flask, stir, and slowly disso...

Embodiment 3

[0037] Add 77.2g (0.6mol) of p-chlorophenol and 73.4g (0.72mol) of acetic anhydride into a 500mL three-necked flask, add 5g of triethylamine into the flask, stir, react at 120°C for 1.5h, filter, and decompress Distillation, the front fraction is glacial acetic acid, and the fraction at 90°C is collected to obtain 96.7 g of p-chlorophenol acetate with a purity of 98.3%;

[0038] Add 34.2g (0.2mol) of p-chlorophenol acetate into a 500mL three-necked flask, slowly add 79.5g (about 0.6mol) of anhydrous aluminum trichloride to the flask, stir and react at 140°C for 1h, Slowly add 200 mL of water into the flask, stir for 0.5 h, filter, heat the filter cake with methanol to dissolve, decolorize with activated carbon, and recrystallize to obtain 31 g of 5-chloro-2-hydroxyacetophenone with a purity of 99.58%.

[0039] Add 43g (0.25mol) of 5-chloro-2-hydroxyacetophenone into a 500mL three-necked flask, slowly add 200mL glacial acetic acid into the flask, stir, and slowly dissolve, then...

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Abstract

The invention belongs to the technical field of preparation of medical intermediates, and particularly relates to a preparation method for 5-chlorine-2-hydroxyl-3-nitroacetophenone. The preparation method comprises the steps: under the existence of a catalyst, reacting parachlorophenol with an acetylation reagent in a solvent-free condition, and performing decompression distillation to obtain acetic acid parachlorophenol and glacial acetic acid serving as a byproduct; adding lewis acid into acetic acid parachlorophenol to perform Fries rearrangement reaction, adding water into a system after the reaction is completed, stirring the mixture to obtain solid sediments, performing recrystallization by using methyl alcohol to obtain 5-chlorine-2-hydroxyacetophenone, adding glacial acetic acid for dissolving, then dropping a nitration reagent, and stirring and filtering to obtain 5-chlorine-2-hydroxyl-3-nitroacetophenone. According to the preparation method, the production cost is lowered, the reaction period is short, the purity is high, the yield is high, the operation is simple and convenient, and industrialization is easily realized.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical intermediates, and in particular relates to a preparation method of 5-chloro-2-hydroxyl-3-nitroacetophenone. Background technique [0002] 3-Amino-2-hydroxyacetophenone is the key drug intermediate for the synthesis of Pranlukast, which has potential application value in the research of new drugs. Leukotriene receptor antagonist, launched in Japan in 1995. Registered in Europe and America in 1996. It is mainly used clinically as an anti-asthma and anti-allergy drug, and is an effective drug for the treatment of asthma. It was launched in Mexico in 2002 and is currently in phase III clinical trials in the United States and the United Kingdom. [0003] Pranlukast is a new type of anti-asthma drug, which belongs to leukotriene receptor antagonist. Prankast has quickly occupied the anti-asthma drug market since it was launched due to its high efficiency, low toxicity, wide ra...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C201/08C07C205/45
Inventor 叶德坤刘娜阴华冻李佳钱长健
Owner SHANDONG JINCHENG PHARMA & CHEM
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