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A kind of preparation method of n,n'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine)

A technology of dioxypiperazine and dioxopiperazine, applied in the preparation of HO-EPCP intermediate, N,N'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine) 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: 2018-04-06
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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  • A kind of preparation method of n,n'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine)
  • A kind of preparation method of n,n'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0031] In a 1L three-necked flask were added 500ml of ethylene glycol dimethyl ether and 28.4g of 4-ethyl-2,3-dioxypiperazine in sequence, stirred evenly, added 4.6g of sodium metal, heated to reflux, and after reaction for 10h, cooled to Add the prepared triphosgene solution in batches under stirring at 5°C. Control the reaction temperature to not exceed 10°C. After the addition, continue to stir and react for 10h, concentrate in vacuo, remove the solvent, add 300ml isopropanol, stir for 30min, filter to remove solids, and filtrate Add activated carbon for decolorization, filter to remove the activated carbon, and the filtrate is spin-dried and dried to obtain a white solid, which is 59.6 g of N,N'-carbonyl-bis-(4-ethyl-2,3-dioxypiperazine), and The calculated yield of 4-ethyl-2,3-dioxypiperazine was 9...

Embodiment 2

[0033] The preparation method is the same as that 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-dioxopiperazine) 53.1g, with 4 -Ethyl-2,3-dioxypiperazine yield was 85.6%. The purity determined by HPLC is 91.6%.

Embodiment 3

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

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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 present 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 Technical field. Background technique [0002] Cephalosporin is a representative of the third-generation cephalosporin antibiotics. It is a broad-spectrum antibacterial. It is a first-line drug against Pseudomonas aeruginosa. It has a huge market both at home and abroad. N,N'-Carbonyl-bis-(4-B Hydroxy-2,3-dioxypiperazine) and D(-)-p-hydroxyphenylglycine can be condensed to prepare HO-EPCP, an important intermediate of cefoperazone (Xianfeng Bi) and piperacillin sodium. Regarding the synthesis of HO-EPCP, the N-ethyl-2,3-dioxypiperazine chloride (EOCP) route is mostly reported, such as CN101508679B, CN1446807A, JP59036668A, DE215194001, GB15008062. Piperazine and triphosgene are used as raw materials. In the presence of trimethylchlorosilane and triethylam...

Claims

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Application Information

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Patent Type & Authority Patents(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