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A kind of preparation method of 3,5-dihalo-4-pyridone-1-acetic acid

A pyridone and dihalogenated technology, which is applied in the field of preparation of 3,5-dihalogenated-4-pyridone-1-acetic acid, 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: 2021-05-14
XINFA PHARMA
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  • Summary
  • 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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  • A kind of preparation method of 3,5-dihalo-4-pyridone-1-acetic acid
  • A kind of preparation method of 3,5-dihalo-4-pyridone-1-acetic acid
  • A kind of preparation method of 3,5-dihalo-4-pyridone-1-acetic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0051] In the 500 milliliter four-necked flask that is connected with stirring, thermometer, reflux condenser and constant pressure dropping funnel, add 60 grams of water, 34.5 grams (0.25 moles) of potassium carbonate, 21.8 grams (0.23 moles) of chloroacetic acid, heat, keep Between 60-65°C, add dropwise a solution of 27.1 grams (0.2 moles) of piperidin-4-one hydrochloride and 60 grams of water, and the dropwise addition is completed in about 2 hours, then stir and react at 70-75°C for 4 hours, and cool to 20-25°C, 30wt% hydrochloric acid acidified the pH value of the system to 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] In the 500 milliliter four-neck flask that is connected with stirring, thermometer, reflux condenser and constant pressure dropping funnel, add 100 grams of water, 15.7 grams (0.1 mole) 4-piperidone-1- Acetic acid, 47.0 grams (0.45 moles) of 35wt% hydrochloric acid, 52.0 (0.46 moles) of 30wt% hydrogen peroxide was added dropwise at 50-55°C for about 3 hours. ℃, add 35.0 grams (0.35 mole) 40wt% sodium hydroxide aqueous solution, 0.5 gram of activated carbon, 50-55 ℃ of stirring reaction 2 hours, filter, wash filter cake with 20 gram of water, combine filtrate, cool to 20-25 ℃, 30wt The pH value of the hydrochloric acid acidification system 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 data of the product are as follows:

[0055] 1 H NMR (DMSO-d 6 ,δ,ppm):...

Embodiment 3

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

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

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Abstract

The invention provides a preparation method of 3,5-dihalo-4-pyridone-1-acetic acid, especially a preparation method of 3,5-dichloro-4-pyridone-1-acetic acid. This method utilizes piperidone-4-one hydrochloride (II) and chloroacetic acid in the presence of a suitable solvent and an acid-binding agent to obtain 4-piperidone-1-acetic acid (III) through a substitution reaction, and then 4-piperidone Pyridone-1-acetic acid and halogenated reagent obtain 3,3,5,5-tetrahalo-4-piperidone-1-acetic acid (Ⅳ) through halogenation reaction, and then remove through elimination reaction in the presence of base Acidification with hydrogen halide and hydrochloric acid gives 3,5-dihalo-4-pyridone-1-acetic acid (I). The method of the invention has cheap and easy-to-obtain raw materials, low cost, simple and easy operation, less waste water generation, environmental protection, high reaction selectivity, high product yield and purity, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of 3,5-dihalo-4-pyridone-1-acetic acid, which belongs to the technical field of medicine and chemical industry. Background technique [0002] 3,5-Dihalo-4-pyridone-1-acetic acid (I) includes 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), in which 3,5-dichloro-4-pyridone-1-acetic acid (3,5-Dichloro- 4-pyridone-N-acetic acid) is an important intermediate for the preparation of cefazedone, 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, the Chinese patent document CN104230958A uses 4-pyridone as a starting material to obtain 3,5-dichloro-4-pyridone through hypochlorite chlorination reaction, and then uses water as a solvent, 70-78 ° C and pH = Under the re...

Claims

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Application Information

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Patent Type & Authority Patents(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