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Preparation method of N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine)

A technology of bisoxypiperazine and bisoxopiperazine, which is applied in the preparation of N,N'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine), HO-EPCP intermediate In the field of preparation of bisoxypiperazine chloride, it can solve the problems of difficult separation and extraction of bisoxypiperazine chloride, unstable activity of bisoxypiperazine chloride, increase equipment and power facilities, etc., and achieve the effect of saving post-processing costs, less side reactions, and reducing treatment costs

Active Publication Date: 2016-04-27
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

[0004] There are many problems in the above route: 1. Using a large amount of triphosgene and trimethylchlorosilane as raw materials, bisoxypiperazinyl chloride is easy to hydrolyze, and requires a strict anhydrous operating environment; 2. Dioxypiperazinyl chloride is unstable and has strong activity , so the reaction needs to be carried out at low temperature; 3. Dioxypiperazine chloride is difficult to separate and extract, resulting in an increase in by-products, which increases the corresponding equipment and power facilities for post-treatment
[0006] At present, the reports on N,N'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine) are all protected by trimethylchlorosilane with 4-ethyl-2,3-dioxypiperazine It is prepared by reacting with phosgene or its substitute triphosgene (the reaction is as follows), such as EP0317484, this method also uses a large amount of trimethylchlorosilane, which produces a large amount of waste water containing regulations, and has no obvious advantages compared with the acid chloride route

Method used

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  • Preparation method of N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine)
  • Preparation method of N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine)

Examples

Experimental program
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Effect test

Embodiment 1

[0030] Triphosgene solution configuration: Dissolve 9.9g of triphosgene into 100ml of ethylene glycol dimethyl ether, and add 0.7g of imidazole, stir until fully dissolved and set aside.

[0031] Add 500ml of ethylene glycol dimethyl ether and 28.4g of 4-ethyl-2,3-dioxypiperazine in sequence in a 1L three-necked flask, stir evenly, add 4.6g of sodium metal, heat to reflux, and react for 10 hours, then cool down to 5°C, add the prepared triphosgene solution in batches under stirring, control the reaction temperature not to exceed 10°C, continue to stir and react for 10h after addition, concentrate in vacuo, remove the solvent, add 300ml of isopropanol, stir for 30min, filter to remove the solid, the filtrate Add activated carbon for decolorization, remove the activated carbon by filtration, spin dry the filtrate in vacuo, and dry to obtain a white solid, which is 59.6g of N,N'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine). The yield of 4-ethyl-2,3-dioxypiperazine was 96.1%, and th...

Embodiment 2

[0033] The preparation method is the same as in Example 1, except that the amount of sodium metal used is 4.4g, and the obtained N,N'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine) is 53.1g, and the amount of 4 -Ethyl-2,3-dioxypiperazine yield was 85.6%. The purity was determined to be 91.6% by HPLC.

Embodiment 3

[0035] The preparation method is the same as in Example 1, except that the amount of triphosgene used is 9 g, and the obtained N,N'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine) is 53.0 g, calculated as triphosgene The yield was 95.1%. The purity was determined to be 98.3% by HPLC.

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Abstract

The invention discloses a preparation method of N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine). 4-ethyl-2, 3-dioxopiperazine as a raw material and metallic sodium undergo a reaction to produce a sodium salt of 4-ethyl-2, 3-dioxopiperazine and the sodium salt and triphosgene undergo a reaction in the presence of a catalyst to produce N, N'-carbonyl-bis-(4-ethyl-2, 3-dioxopiperazine). 4-ethyl-2, 3-dioxopiperazine as a raw material and metallic sodium as a hydrogen removal reagent undergo a reaction to produce a sodium salt of 4-ethyl-2, 3-dioxopiperazine so that trimethylchlorosilane use is avoided, side reactions are less, product purity is high, a large amount of siliceous waste water is not produced, a post-treatment cost is saved and a three-waste treatment cost is greatly reduced. The preparation method has simple processes and a simple route, satisfies clean production requirements and is suitable for industrialization.

Description

technical field [0001] The invention relates to a preparation method of HO-EPCP intermediate, in particular to a preparation method of N,N'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine), which belongs to organic synthesis technology field. Background technique [0002] Cephalosporin is the representative of the third-generation cephalosporin antibiotics. It is a broad-spectrum antibacterial drug and is the first-line drug against Pseudomonas aeruginosa. It has a huge international and domestic market. N,N'-carbonyl-bis-(4-ethyl Base-2,3-dioxypiperazine) and D(-)-p-hydroxyphenylglycine can be condensed to prepare cefoperazone (pioneer must), an important intermediate HO-EPCP of piperacillin sodium. Regarding the synthesis of HO-EPCP, the route of N-ethyl-2,3-dioxypiperazine chloride (abbreviated as EOCP) is mostly reported. Piperazine and triphosgene are used as raw materials, and N-ethyldioxypiperazine chloride (hereinafter referred to as dioxypiperazine chloride) is prepared...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/08
CPCC07D241/08
Inventor 高爱红冯维春张剑文纪晓红刘丽秀刘茂岭王立芹
Owner 山东艾孚特科技有限公司