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Synthesis of 4-ethyl-(2,3-dioxo piperazinyl)formyl chloride-1 and preparation of crystal thereof

A technology of dioxopiperazine and formyl chloride is applied in the field of preparation of 4-ethyl-formyl chloride-1 crystallization, which can solve the problems of inability to be placed, not easy to commercialize, poor solid stability, etc., and achieves stable quality and high quality. The effect of high and short synthesis process route

Active Publication Date: 2009-04-29
山西新天源药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This is because the solid stability of 4-ethyl-(2,3-dioxopiperazinyl) formyl chloride-1 obtained after dichloromethane is evaporated to dryness is poor, cannot be placed, and is not easy to realize commercialization, so it has to Immediately proceed to the next reaction

Method used

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  • Synthesis of 4-ethyl-(2,3-dioxo piperazinyl)formyl chloride-1 and preparation of crystal thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Add 700L dichloromethane and 80Kg (0.563kmol) 4-ethyl-2,3-dioxypiperazine into a dry 1000L enamel reaction kettle, start stirring, cool to 5°C, and dropwise add 67.3Kg (0.62kmol) Tris Methyl chlorosilane, after stirring for 30 minutes, add 62.7Kg (0.62kmol) triethylamine solution dropwise at the same temperature, keep it warm for 1h after the dropwise addition, continue cooling to -30°C, add 55Kg (0.185kmol) bis- (Trichloromethyl)carbonate, control the temperature rise during the addition process not to exceed 5°C. After the addition, the temperature was naturally raised to room temperature, and the reaction was incubated for 1 h, and the insoluble matter was removed by filtration.

[0022] The filtrate was returned to the reaction kettle, cooled to -10°C, and 400Kg dipropyl ether was added dropwise. After the crystals were precipitated, the addition of dipropyl ether was temporarily stopped, stirred until a large amount of crystals were precipitated, then all the remai...

Embodiment 2

[0025] Add 28.4g (0.2mol) 4-ethyl-2,3-dioxypiperazine and 300mL chloroform in sequence to a dry 500mL three-necked flask, start stirring, cool to 0°C, add 28.2mL (0.22mol) trimethyl Chlorosilane, add 30.5mL (0.22mol) triethylamine solution dropwise through the dropping funnel, keep it warm for 1h after the dropwise addition, cool to -30°C, add 23.7g (0.08mol) bis-(trichloromethyl) Carbonic acid ester, the temperature is controlled not to exceed 5°C during the addition process, and after the addition is completed, the temperature is naturally raised to room temperature, and the reaction is kept for 1.5 hours, and the insoluble matter is removed by filtration.

[0026] Return the filtrate to the three-necked flask, cool down to -10°C, add 200mL of n-hexane, precipitate crystals under stirring, continue to stir for 1h, filter and dry to obtain 30.6g of 4-ethyl-(2,3-dioxopiperazine Base) formyl chloride-1, yield 75%, purity 97.6%.

Embodiment 3

[0028] In a dry 500mL three-necked flask, 300mL of dichloromethane was used instead of chloroform as a solvent, 200mL of petroleum ether (80-120° C.) was used as a crystallization reagent, and other conditions were the same as in Example 2 to obtain 32g of 4-ethyl-(2,3- Dioxopiperazinyl) formyl chloride-1, yield 78.3%, purity 98.2%.

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Abstract

The invention relates to a method for synthesizing 4-ethyl-(2, 3-dioxo)-1-piperazine formyl chloride, which comprises the following steps: using 4-ethyl-2, 3-dioxopiperazine as a starting raw material, di-(trichloromethyl) carbonate as a formyl chloridizing reagent, trimethyl chlorosilane as an activator and a prptectant, triethylamine as an acid-binding agent and a catalyst which are reacted with each other to prepare the 4-ethyl-(2, 3-dioxo)-1-piperazine formyl chloride; and adding crystallizing agents such as n-hexane, petroleum ether, hexamethyl disiloxane, dipropyl ether, cyclohexane into a reaction liquid of the 4-ethyl-(2, 3-dioxo)-1-piperazine formyl chloride to separate out 4-ethyl-(2, 3-dioxo)-1-piperazine formyl chloride crystal. The method for synthesizing and crystallizing the 4-ethyl-(2, 3-dioxo)-1-piperazine formyl chloride provides a more appropriate intermediate for producing piperacillin and cefoperazone, and can shorten the synthesizing process and improve the quality thereof.

Description

technical field [0001] The invention relates to a synthesis method of 4-ethyl-(2,3-dioxopiperazinyl) formyl chloride-1, the compound is mainly used as a pharmaceutical intermediate for the synthesis of β-lactam antibiotics piperacillin, Cefoperazone. The invention also relates to a preparation method of 4-ethyl-(2,3-dioxopiperazinyl) formyl chloride-1 crystal. Background technique [0002] β-lactam antibiotics are the most clinically used drugs against various infectious diseases. Piperacillin and cefoperazone are one of the most effective varieties of penicillins and cephalosporins respectively. They have high efficiency, broad spectrum, low It is effective against both Gram-positive bacteria and Gram-negative bacteria, and has a wide range of clinical applications. [0003] 4-Ethyl-(2,3-dioxopiperazinyl)formyl chloride-1 is an important intermediate for the synthesis of cefoperazone and piperacillin, and it is used as a starting material for the synthesis of cefoperazone...

Claims

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Application Information

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IPC IPC(8): C07D241/08
Inventor 苏斌林陈万成高志伟褚丕明苏蔚康福堂
Owner 山西新天源药业有限公司
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