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Method for preparing 4-ethyl-2,3-dioxypiperazine-1-formate

A bisoxopiperazine and formate technology, applied in the field of intermediate preparation, can solve the problems of high price, high product cost, cumbersome post-processing route, etc., and achieve simple process operation, high atom utilization rate, and equipment utilization high rate effect

Active Publication Date: 2010-12-22
山东艾孚特科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its synthesis method uses two kinds of expensive dioxane and tetrahydrofuran as solvents, and in the whole process, equimolar trimethylchlorosilane needs to be introduced into the reaction system, which only plays the role of activating the amide, and does not Changes, and finally generated as a by-product, resulting in cumbersome post-processing routes and low atom utilization
These factors lead to high product costs, difficulties in the treatment of "three wastes", and restrictions on industrial production. Therefore, a new technology is urgently needed to solve the existing problems and meet market demand.

Method used

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  • Method for preparing 4-ethyl-2,3-dioxypiperazine-1-formate
  • Method for preparing 4-ethyl-2,3-dioxypiperazine-1-formate

Examples

Experimental program
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Effect test

Embodiment 1

[0018] Add 14.2 g of 1-ethyl-2,3-dioxopiperazine, 100 mL of acetone, and 28.8 mL (0.2 mol) of triethylamine in sequence in the three-necked flask, cool down to -10 °C, and slowly add ethyl chloroformate 11 mL, control the reaction system temperature < -5 ℃. After the dropwise addition, keep warm for 5h. Suction filtration to remove triethylamine hydrochloride, the filter cake was washed once with 15 mL of acetone, the filtrate was collected and decolorized with an appropriate amount of activated carbon, and the solvent was removed under reduced pressure to obtain 4-ethyl-2, 3-dioxopiperazine-1-carboxylic acid Crude ethyl ester. Ethyl acetate was recrystallized to obtain a white powder with a product yield of 95.2% and a purity of 99.3% as determined by HPLC. Example 2

Embodiment 2

[0019] Add 14.2 g of 1-ethyl-2,3-dioxopiperazine, 100 mL of acetone, and 28.8 mL (0.2 mol) of triethylamine in sequence in the three-necked flask, cool down to -10 °C, and slowly add methyl chloroformate 9.3 mL, control the reaction system temperature < -5 ℃. After the dropwise addition, keep warm for 5h. Suction filtration to remove triethylamine hydrochloride, the filter cake was washed once with 15 mL of acetone, the filtrate was collected and decolorized with an appropriate amount of activated carbon, and the solvent was removed under reduced pressure to obtain 4-ethyl-2, 3-dioxopiperazine-1-carboxylic acid Crude methyl ester. Ethyl acetate was recrystallized to obtain a white powder with a product yield of 96% and a purity of 99.1% as determined by HPLC.

Embodiment 3

[0021] Add 14.2 g of 1-ethyl-2,3-dioxopiperazine, 100 mL of dichloromethane, and 34.8 mL (0.25 mol) of triethylamine in sequence in the three-neck flask, cool down to -20 °C, and slowly add ethyl chloroformate dropwise 11 mL, control the temperature of the reaction system < -15 ℃. After the dropwise addition, keep warm for 5h. Suction filtration to remove triethylamine hydrochloride, the filter cake was washed once with 15 mL of acetone, the filtrate was collected and decolorized with an appropriate amount of activated carbon, and the solvent was removed under reduced pressure to obtain 4-ethyl-2, 3-dioxopiperazine-1-carboxylic acid Crude ethyl ester. 1:1 (volume ratio) acetone / petroleum ether was recrystallized to obtain a white powder with a product yield of 95% and a purity of 99.4% as determined by HPLC.

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Abstract

The invention discloses a method for preparing 4-ethyl-2,3-dioxypiperazine-1-formate. In the method, 1-ethyl-2,3-dioxypiperazine and chloro-formate are used as raw materials and reacted in an organic solvent system in the presence of an acid binding agent to form 4-ethyl-2,3-dioxypiperazine-1-formate, wherein the molar ratio of the 1-ethyl-2,3-dioxypiperazine to the acid binding agent to the chloro-formate is 1:1.0-3.0:1.0-2.0; the chloro-formate is methyl chloroformate or ethyl chloroformate; and the 4-ethyl-2,3-dioxypiperazine-1-formate is 4-ethyl-2,3-dioxypiperazine-1-methyl formate or 4-ethyl-2,3-dioxypiperazine-1-ethyl formate. The method greatly reduces cost, simplifies process, reduces byproducts, improves product purity and reduces solvent separation processes; and the prepared product can be used as an intermediate for piperacillin and cefoperazone and is suitable for industrial production.

Description

technical field [0001] The present invention relates to a kind of preparation method of the intermediate of synthetic oxygenpiperazine penicillin, cefoperazone, particularly a kind of 4-ethyl-2,3-dioxopiperazine-1-carboxylate (methyl ester, ethyl The preparation method of ester) belongs to the technical field of organic synthesis. Background technique [0002] In recent years, piperacillin (oxypiperazine penicillin) and cefoperazone, as the third type of broad-spectrum antibacterial cephalosporin antibiotics, can coordinate and inhibit the action of lacton amidase, expand the antibacterial spectrum and enhance the antibacterial effect. Anti-infection therapy has received more and more attention. Its synthesis requires the use of the intermediate 4-ethyl-2,3-dioxopiperazine-1-acyl chloride, but the preparation of the intermediate requires the use of a large amount of highly toxic substance phosgene or its substitute diphosgene , triphosgene, and trimethylchlorosilane, a gro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/08
Inventor 岳涛高爱红柳泽岳魏凤胡玲胡波杨旭
Owner 山东艾孚特科技有限公司
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