Preparation method of 4-methylpyrazole

A technology of methylpyrazole and hydrazine sulfate, applied in the direction of organic chemistry, can solve the problems of insufficient purity, many impurities, black color, etc., and achieve the effect of simple preparation method

Inactive Publication Date: 2013-03-20
郑州大明药物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the shortcoming of this synthetic method is that due to the existence of concentrated sulfuric acid in the reaction process, more impurities are produced in the reaction, the color is darker, and the purity is not enough.

Method used

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  • Preparation method of 4-methylpyrazole
  • Preparation method of 4-methylpyrazole
  • Preparation method of 4-methylpyrazole

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation method of 4-methylpyrazole of the present invention, the detailed steps of this preparation method are as follows:

[0033] a, the preparation of hydrazine sulfate:

[0034] Concentrated sulfuric acid (98% by mass) and hydrazine hydrate (80% by mass) are used as raw materials, and the two raw materials are weighed according to the mass ratio between concentrated sulfuric acid and hydrazine hydrate of 1:1.0 , first add the weighed concentrated sulfuric acid into the reaction vessel, and stir, put the reaction vessel with the concentrated sulfuric acid into the low-temperature reactor to cool down, so that the temperature in the reactor drops to -10°C, and slowly add Hydrazine hydrate, hydrazine hydrate was added dropwise for 1 hour, the temperature was controlled at 0°C and the reaction was continuously stirred for 2 hours, suction filtration was performed after the reaction, the obtained filter cake was washed with absolute ethanol, and the washed filter...

Embodiment 2

[0044] The preparation method of 4-methylpyrazole of the present invention, the detailed steps of this preparation method are as follows:

[0045] a, the preparation of hydrazine sulfate:

[0046]Concentrated sulfuric acid (98% by mass) and hydrazine hydrate (80% by mass) are used as raw materials, and the two raw materials are weighed according to the mass ratio between concentrated sulfuric acid and hydrazine hydrate of 1:1.3 , first add the weighed concentrated sulfuric acid into the reaction vessel, and stir, put the reaction vessel with the concentrated sulfuric acid into the low-temperature reactor to cool down, so that the temperature in the reactor drops to -5°C, and slowly add Hydrazine hydrate, hydrazine hydrate was added dropwise for 1.5 hours, the temperature was controlled at 5°C and the reaction was continuously stirred for 2.2 hours, suction filtration was performed after the reaction, the obtained filter cake was washed with absolute ethanol, and the washed fil...

Embodiment 3

[0056] The preparation method of 4-methylpyrazole of the present invention, the detailed steps of this preparation method are as follows:

[0057] a, the preparation of hydrazine sulfate:

[0058] Concentrated sulfuric acid (98% by mass) and hydrazine hydrate (80% by mass) are used as raw materials, and the two raw materials are weighed according to the mass ratio between concentrated sulfuric acid and hydrazine hydrate of 1:1.5 , first add the weighed concentrated sulfuric acid into the reaction vessel, and stir, put the reaction vessel with the concentrated sulfuric acid into the low-temperature reactor to cool down, so that the temperature in the reactor drops to 0°C, and slowly add the hydration Hydrazine, hydrazine hydrate was added dropwise for 2 hours, the temperature was controlled at 10°C and the reaction was continuously stirred for 2.5 hours, suction filtration was performed after the reaction, the obtained filter cake was washed with absolute ethanol, and the washe...

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Abstract

The invention discloses a preparation method of 4-methylpyrazole. According to the method, concentrated sulfuric acid and hydrazine hydrate are utilized as raw materials. The method comprises the following steps of: performing a heating reflux reaction to generate hydrazine sulfate; adding sulfuric acid, hydrazine sulfate and potassium iodide into a reactor; adding isobutyraldehyde while stirring continuously so as to conduct a heating reflux reaction; after the reaction, adjusting the pH value of the reaction liquid to 7; sequentially extracting, drying and evaporating out a solvent to obtain a crude product of 4-methylpyrazole; performing primary reduced-pressure distillation of the crude product, and purifying; adding the product after primary purification into the mixed liquid of ethyl acetate and petroleum ether, and recrystallizing; and finally performing reduced-pressure distillation again to obtain a refined product of 4-methylpyrazole. According to the invention, the preparation of 4-methylpyrazole can be performed under normal pressure; the preparation method is simple and favorable for industrial production; and moreover, the product 4-methylpyrazole has relatively high purity, the impurity content of a single product is less than 0.1%, and the quality requirements are completely met.

Description

technical field [0001] The invention relates to a preparation method of medicine, which belongs to the field of medicinal chemistry, in particular to a preparation method of 4-methylpyrazole. Background technique [0002] Methylpyrazole is an alcohol dehydrogenase inhibitor approved by the U.S. FDA in early 1998 and produced by Orphan Medical Company. It is mainly used for the rescue of alcohol poisoning such as ethylene glycol, ethanol, and methanol. [0003] At present, there are also relevant literature reports on methylpyrazole. For example: 1. H.R.Merkle et al. conducted in-depth research on methyl-substituted pyrazoles. The synthesis of methylpyrazole in this document is obtained by reacting isobutyraldehyde and hydrazine hydrate in the presence of sulfuric acid, and the yield is 49%. The disadvantage of this synthesis method is that the boiling point of isobutyraldehyde is only 64°C, so Merkle et al. used an autoclave to add isobutyraldehyde into the reaction kettle...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/12
Inventor 王斐张宝国张宏波朱赞梅
Owner 郑州大明药物科技有限公司
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