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Synthesizing and purifying methods of 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione

A technology of ethylpiperazine and synthesis method, which is applied in the field of drug synthesis, can solve the problems of synthesis, separation and characterization, and achieve the effects of high purity, simple process and high yield

Active Publication Date: 2015-04-22
JIANGXI FUSHINE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are no relevant literature and patent reports on the synthesis, separation and characterization of this impurity

Method used

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  • Synthesizing and purifying methods of 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione
  • Synthesizing and purifying methods of 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione
  • Synthesizing and purifying methods of 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Preparation of 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione

[0034] Add 4-ethyl-2,3-dioxypiperazine (14.2g, 0.1mol), dichloromethane (60ml), trimethylchlorosilane (13.0g, 0.12mol) to the four-necked flask, and control the temperature- 10~-20℃, dropwise addition of triethylamine (25.5g, 0.25mol) was completed, raised to -5~0, stirred for 12min; ) was dissolved in 20ml of dichloromethane, controlled temperature 0 ℃ ~ -5 ℃ and added dropwise for 40 minutes, heated to 25 ℃ and kept for 8 hours, and cooled to -15 ℃ after the reaction, filtered, and the filter cake was cooled with pre-cooled dichloromethane (8ml) was rinsed, the mother liquors were combined, and concentrated (30°C-40°C, vacuum <0.1MPa) to obtain 30.4g of crude product (98.6% yield, 95% purity).

[0035] (2) Purification of 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione

[0036] Add 10g of crude 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione and dichloromethane (50ml) into a four-neck flask, heat and reflux fo...

Embodiment 2

[0038] (1) Preparation of 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione

[0039]Add 4-ethyl-2,3-dioxypiperazine (14.2g, 0.1mol), 1,2-dichloroethane (60ml), trimethylbromosilane (18.2g, 0.12mol) into the four-necked flask ), control the temperature at -10~-20°C, add triethylamine (25.5g, 0.25mol) dropwise, rise to -5~0 and stir for 12min; 4-ethyl-2,3-dioxypiperazine chloride (22.4 g, 0.11mol) was dissolved in 20ml of 1,2-dichloroethane, controlled temperature 0℃~-5℃, added dropwise for 40min, raised the temperature to 25℃ and kept the reaction for 6h, cooled to -15℃ after the reaction, filtered, The filter cake was rinsed with pre-cooled 1,2-dichloroethane (10ml), the mother liquors were combined, and concentrated (40°C-50°C, vacuum <0.1MPa) to obtain 28.5g of crude product (92.0% yield, 89% purity). %).

[0040] (2) Purification of 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione

[0041] Add 10 g of crude 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione and 1,2-dichloroethane (50 ml) ...

Embodiment 3

[0043] (1) Preparation of 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione

[0044] Add 4-ethyl-2,3-dioxypiperazine (14.2g, 0.1mol), chloroform (50ml), tert-butyldiphenylchlorosilane (32.9.0g, 0.12mol) to the four-necked flask, control Temperature -10~-20°C, after adding pyridine (19.8g, 0.25mol) dropwise, rise to -5~0 and stir for 12min; 4-ethyl-2,3-dioxypiperazine chloride (22.4g, 0.11mol) Dissolve in 20ml of chloroform, add dropwise at a temperature of 0°C to -5°C for 40min, heat up to 25°C and keep the temperature for 6h, cool down to -15°C after the reaction, filter, and rinse the filter cake with pre-cooled chloroform (5ml) , combined the mother liquors, concentrated (40°C-50°C, vacuum <0.1MPa) to obtain 27.9g of crude product (80.0% yield, 95.2% purity).

[0045] (2) Purification of 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione

[0046] Add 10g of crude product of 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione and chloroform (45ml) into a four-neck flask, heat and reflux for 30...

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Abstract

The invention discloses a synthesizing method of 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione. The method comprises the following steps: firstly carrying out reaction on 4-ethyl-2, 3-dioxopiperazine and a silylating reagent in an organic solvent; and then carrying out condensation reaction with 4-ethyl-2, 3-dioxo-piperazine acyl chloride under an alkaline condition to obtain 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione. The invention further provides a refining method of 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione. The methods disclosed by the invention are high in product purity, simple in process, high in yield and suitable for industrial production. The 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione obtained provides a high purity reference substance (the purity is over 98%) for production of 4-ethyl-2, 3-dioxo-piperazine acyl chloride or piperacillin and meanwhile, the 4, 4'-carbonyl di-1-ethyl piperazine-2, 3-dione can be used as a commercial organic chemical intermediate to be sold.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for synthesizing 4-ethyl-2,3-dioxypiperazine chloride impurity 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione and purification methods. Background technique [0002] 4-Ethyl-2,3-dioxypiperazine chloride is an intermediate of Oxypiperazine Penicillin, which is widely used in the production of antibiotic drugs. Oxypiperazine penicillin has a strong antibacterial effect on Gram-positive bacteria and negative bacteria, especially for infections caused by Pseudomonas aeruginosa, Proteus, Escherichia coli and Serratia, etc. Pseudomonas aeruginosa resistant to antibiotics and ampicillin is also effective, with low toxicity and relatively safe. 4,4'-carbonyldi-1-ethylpiperazine-2,3-dione impurity will inevitably be produced during the synthesis of 4-ethyl-2,3-dioxypiperazine chloride, which has been reported in relevant literature The possibility of this impurity (Synth...

Claims

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Application Information

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IPC IPC(8): C07D241/08
CPCC07D241/08
Inventor 郑裕义吴晓峰周忠波谢永居王冬冬
Owner JIANGXI FUSHINE PHARMA CO LTD
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