Preparation method of 3,5-dihalogenated-4-pyridone-1-acetic acid

A technology of pyridone and dihalogenation, which is applied in the field of preparation of 3,5-dihalogeno-4-pyridone-1-acetic acid, and can solve the problem of high price of 4-aminopyridine, poor stability of diazonium salt, and operational requirements Advanced problems, to achieve the effect of high target reaction selectivity, good stability and high reaction selectivity

Active Publication Date: 2019-11-22
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the price of the raw material 4-aminopyridine used in the synthetic route 2 is relatively high, the obtained diazonium salt has poor stability, high operation requirements, and a large amount of waste water, which is not suitable for industrialization

Method used

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  • Preparation method of 3,5-dihalogenated-4-pyridone-1-acetic acid
  • Preparation method of 3,5-dihalogenated-4-pyridone-1-acetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1: Preparation of 4-piperidone-1-acetic acid (III)

[0051] To the 500-milliliter four-necked flask connected with stirring, thermometer, reflux condenser and constant-pressure dropping funnel, add 60 g of water, 34.5 g (0.25 mol) of potassium carbonate, 21.8 g (0.23 mol) of chloroacetic acid, heat, keep Between 60-65°C, a solution of 27.1 g (0.2 mol) piperidin-4-one hydrochloride and 60 g of water was added dropwise, and the dropwise addition was completed in about 2 hours, after which the reaction was stirred at 70-75°C for 4 hours, and cooled to 20-25°C, 30wt% hydrochloric acid acidification system with pH value of 2.5-3.0, filtered and dried to obtain 28.95 g of white solid 4-piperidone-1-acetic acid with a yield of 92.2% and a liquid phase purity of 99.3%.

Embodiment 2

[0052] Example 2: Preparation of 3,5-dichloro-4-pyridone-1-acetic acid (I1)

[0053] To the 500-milliliter four-necked flask connected with stirring, thermometer, reflux condenser and constant pressure dropping funnel, add 100 grams of water, 15.7 grams (0.1 moles) of 4-piperidone-1- Acetic acid, 47.0 g (0.45 mol) 35wt% hydrochloric acid, 52.0 (0.46 mol) 30wt% hydrogen peroxide was added dropwise at 50-55°C for about 3 hours, after that, the reaction was stirred at 55-60°C for 5 hours, cooled to 20-25 ℃, add 35.0 grams (0.35 moles) of 40wt% sodium hydroxide aqueous solution, 0.5 grams of activated carbon, stir at 50-55 ℃ for 2 hours, filter, wash the filter cake with 20 grams of water, combine the filtrates, cool to 20-25 ℃, 30wt % The pH value of the acidification system with hydrochloric acid was 1.5-2.0, filtered and dried to obtain 20.09 g of white solid 3,5-dichloro-4-pyridone-1-acetic acid (I1) with a yield of 90.5% and a liquid phase purity of 99.6%.

[0054] The NMR d...

Embodiment 3

[0056] Example 3: Preparation of 3,5-dichloro-4-pyridone-1-acetic acid (I1) (one-pot method)

[0057] To the 500-milliliter four-necked flask connected with stirring, thermometer, reflux condenser and constant-pressure dropping funnel, add 60 grams of water, 8.8 grams (0.22 moles) of sodium hydroxide, 10.5 grams (0.11 moles) of chloroacetic acid, heat, Keep between 60-65 ℃, add dropwise a solution of 13.6 g (0.1 mol) piperidin-4-one hydrochloride (II) and 30 g of water, the dropwise addition is completed in about 2 hours, and then the reaction is stirred at 70-75 ℃ for 4 hour, cooled to 20-25 ℃, added 52.0 g (0.5 mol) of 35wt% hydrochloric acid, added dropwise 56.7 (0.5 mol) of 30 wt% hydrogen peroxide at 50-55 ℃, dripped in about 3 hours, after that, stirred the reaction at 55-60 ℃ 5 hours, cooled to 20-25 ° C, added 38.0 g (0.38 mol) 40wt% sodium hydroxide aqueous solution, 0.5 g activated carbon, stirred at 50-55 ° C for 2 hours, filtered, washed the filter cake with 20 g o...

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Abstract

The invention provides a preparation method of 3, 5-dihalogenated-4-pyridone-1-acetic acid, and particularly relates to a preparation method of 3,5-dichloro-4-pyridone-1-acetic acid. The method comprises the following steps: performing a substitution reaction on piperidine-4-ketone hydrochloride (II) with chloroacetic acid in the presence of a proper solvent and an acid-binding agent to obtain 4-piperidone-1-acetic acid (III), carrying out a halogenation reaction on the 4-piperidone-1-acetic acid (III) and a halogenation reagent to obtain 3,3,5,5-tetrahalogenated-4-piperidone-1-acetic acid (IV), carrying out an elimination reaction in the presence of an alkali to remove hydrogen halide, and performing acidification with hydrochloric acid to obtain the 3,5-dihalo-4-pyridinone-1-acetic acid.The method has the advantages of cheap and easily available raw materials, low cost, simple operation, easy realization, less wastewater generation amount, environmental protection, high reaction selectivity, high product yield and purity, and suitableness for industrial production.

Description

technical field [0001] The invention relates to a preparation method of 3,5-dihalogenated-4-pyridone-1-acetic acid, belonging to the technical field of medicine and chemical industry. Background technique [0002] 3,5-Dihalo-4-pyridone-1-acetic acid (I) including 3,5-dichloro-4-pyridone-1-acetic acid (I1), 3,5-dibromo-4-pyridone -1-acetic acid (I2) and 3,5-diiodo-4-pyridone-1-acetic acid (I3), wherein 3,5-dichloro-4-pyridone-1-acetic acid (3,5-Dichloro- 4-pyridone-N-acetic acid) is an important intermediate for the preparation of cefoxidone, and its structural formula is as follows: [0003] [0004] In the current prior art, there have been reports on the synthesis method of the intermediate 3,5-dichloro-4-pyridone-1-acetic acid. [0005] For example, Chinese patent document CN104230958A takes 4-pyridone as starting material, and obtains 3,5-dichloro-4-pyridone through hypochlorite chlorination reaction, and then uses water as solvent, 70-78°C and pH= Under the reacti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/68
CPCC07D213/68
Inventor 张明峰戚聿新鞠立柱吕强三王全龙
Owner XINFA PHARMA
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