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Method for preparing 5-ethyl-5-(1-methylbutyl)malonylurea

A technology of methyl butyl and malonyl urea, which is applied in the field of drug synthesis, can solve the problems of many by-products, long reaction time, and high cost, and achieve the effects of mild reaction conditions, simple post-processing, and low production cost

Inactive Publication Date: 2016-05-04
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Ethyl-(1-methylbutyl) diethyl malonate compound (II) is also difficult to remove by rectification with the isomer ethyl-(1-ethylpropyl) diethyl malonate. The pentobarbital isomer product generated in the reaction is more difficult to separate and remove, thus having a strong impact on product purity, many by-products, and the isomer impurity content is at least more than 0.5% in the target compound (I)
Moreover, compound (II) and urea have strict requirements on the reaction concentration of sodium alkoxide in the condensation and ring-closure reaction, the operation is cumbersome, the reaction time is long, the energy consumption is high, the appearance of the obtained product is poor, a large amount of activated carbon is required for decolorization, and the crude mother cannot be used mechanically, and the three wastes many, high cost

Method used

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  • Method for preparing 5-ethyl-5-(1-methylbutyl)malonylurea

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] (1) Add 453.3g sodium ethoxide ethanol solution (15% content) and an appropriate amount of ethyl acetate into the reaction flask, heat up to 60-70° C. under stirring, and react for 30 minutes. Add 188.2g of diethyl ethyl malonate. After the addition is complete, ethanol is distilled out during the heating reaction process until the internal temperature reaches about 125°C, then the heating is stopped, and then the alcohol is distilled under reduced pressure until there is no effluent, and the internal temperature is 105°C. pressure, keep the negative pressure in the bottle (in the kettle), add 564.6g of toluene, start to add 182.2g of (2-pentyl) methanesulfonate dropwise, and distill the residual ethanol by fractional distillation while adding dropwise, the maximum temperature does not exceed 78°C, The internal temperature rises gradually, the highest is not more than 110°C, and it takes about 3 hours to complete the addition. After the addition, keep the reflux reaction...

Embodiment 2

[0033] (1) Add 420 g of sodium ethoxide ethanol solution (content 17%) and an appropriate amount of ethyl acetate into the reaction flask, heat up to 60-70° C. under stirring, and react for 30 minutes. Add 188.2g of diethyl ethyl malonate. After the addition is complete, ethanol is distilled out during the heating reaction process until the internal temperature reaches about 125°C, then the heating is stopped, and then the alcohol is distilled under reduced pressure until there is no effluent, and the internal temperature is 105°C. pressure, keep the negative pressure in the bottle (in the kettle), add 564.6g of toluene, start to add 236.9g of (2-pentyl) methanesulfonate dropwise, and distill the residual ethanol by fractional distillation while adding dropwise, the maximum temperature does not exceed 78°C, The internal temperature rises gradually, the highest is not more than 110°C, and it takes about 3 hours to complete the addition. After the addition, keep the reflux reacti...

Embodiment 3

[0037](1) Add 346.8 g of sodium ethoxide ethanol solution (20% content) and an appropriate amount of ethyl acetate into the reaction flask, heat up to 60-70° C. under stirring, and react for 30 minutes. Add 188.2g of diethyl ethyl malonate. After the addition is complete, ethanol is distilled out during the heating reaction process until the internal temperature reaches about 125°C, then the heating is stopped, and then the alcohol is distilled under reduced pressure until there is no effluent, and the internal temperature is 105°C. pressure, keep the negative pressure in the bottle (in the kettle), add 564.6g of toluene, start to add 236.9g of (2-pentyl) methanesulfonate dropwise, and distill the residual ethanol by fractional distillation while adding dropwise, the maximum temperature does not exceed 78°C, The internal temperature rises gradually, the highest is not more than 110°C, and it takes about 3 hours to complete the addition. After the addition, keep the reflux react...

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Abstract

The invention belongs to the technical field of drug synthesis and particularly relates to a method for preparing 5-ethyl-5-(1-methylbutyl)malonylurea. A mixture which is obtained after ethyl-propanedioic acid diethyl ester (III) reacts with an alcohol solution of sodium ethoxide reacts with methanesulfonic acid (2-pentyl) ester under the condition that toluene exists, and an ethyl-(1-methylbutyl) diethyl malonate compound (II) is obtained through rectification; the compound (II) reacts with urea under the condition that a methanol solution of sodium methoxide exists, and a fine 5-ethyl-5-(1-methylbutyl)malonylurea (I) product is obtained through hydrochloric acid acidizing and re-crystallization. The technology is stable, reaction conditions are moderate, control is easy, the obtained product is high in purity and high in yield, the conversion rate nearly reaches 100%, post-processing is easy and convenient, energy consumption is low, three wastes are few, mother liquor can be continuously used, production cost is low, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of 5-ethyl-5-(1-methylbutyl)malonylurea. Background technique [0002] 5-Ethyl-5-(1-methylbutyl)malonylurea (I) is mainly used for sedation, hypnosis, administration before anesthesia and anticonvulsant. [0003] Existing preparation technology, its step is that diethyl ethyl malonate reacts with 2-bromopentane in the alcoholic solution of sodium ethylate to obtain ethyl-(1-methylbutyl) diethyl malonate compound (II), the latter reacts with urea in an alcoholic solution of sodium ethoxide to obtain compound (I). The 2-bromopentane used in this process contains the isomer 3-bromopentane. Due to the unavoidable simultaneous production of isomer 3-bromopentane during the preparation of 2-bromopentane, the physical and chemical properties of 2-bromopentane and 3-bromopentane are almost completely similar, and the difference in boiling poi...

Claims

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Application Information

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IPC IPC(8): C07D239/60
CPCC07D239/60
Inventor 朱连博郑忠辉毕娜娜鹿慧
Owner SHANDONG XINHUA PHARMA CO LTD
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