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Continuous synthesis method of metronidazole

A technology for metronidazole and chemical synthesis, applied in chemical instruments and methods, organic chemistry, chemical/physical processes, etc., can solve the problems of inaccurate feed amount, easy generation of impurities, high impurity content, etc., to achieve increased reaction temperature, The effect of convenient feeding and large specific surface area

Pending Publication Date: 2022-06-03
ANHUI BIOCHEM UNITED PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0007] According to experimental phenomena and literature reports, impurity 1 is very easy to produce in alkaline environment (as under tetrabutylammonium bromide catalyzed condition); Long average is easy to produce. The hydroxyethylation reaction of 2-methyl-5-nitroimidazole is an exothermic reaction. Under the condition that the rate of feeding ethylene oxide is too fast or the cooling fails, the temperature in the system rises too sharply. Until the raw materials are completely consumed, it is easy to produce impurities 2
[0008] Therefore, the preparation of metronidazole by the reaction of 2-methyl-5-nitroimidazole and ethylene oxide has the problems that the feed is not easy and the feed amount is inaccurate and the impurity content is higher

Method used

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  • Continuous synthesis method of metronidazole
  • Continuous synthesis method of metronidazole
  • Continuous synthesis method of metronidazole

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preparation example Construction

[0025] The invention provides a continuous synthesis method of metronidazole, which comprises the following reactions:

[0026] S1. Synthesis of 2-methylimidazole.

[0027] For the flow chart of the synthesis equipment, please refer to figure 1 :

[0028] After mixing the aldehyde mixture of glyoxal and acetaldehyde and ammonia water, it is pre-cooled to 10-20 ℃, and then enters the SK type tubular reactor to react at 1.8-2.0 Mpa, and the temperature of the reaction liquid is 55-60 ℃; The time is 18-22min; after the reaction is completed, the temperature is lowered to 10-15°C, and then concentrated, the concentration temperature is 58-62°C, and the concentration time is 1-3h, followed by crystallization; 2-methylimidazole is obtained by filtration and washing.

[0029] Specifically, in the present application, acetaldehyde and glyoxal are pre-mixed at a temperature below 20° C. and then placed in the aldehyde water bucket 102 . They are respectively sent to the jacket mixer...

Embodiment 1

[0063] Example 1: Synthesis of 2-methylimidazole.

[0064] After pre-mixing 10kg of 40% glyoxal and 9.1kg of 40% acetaldehyde below 20°C, they were sent to the jacket mixer with the aqueous ammonia solution through the feed pump, pre-cooled to 15°C, and then entered into the fan-tooth mixer. , after mixing again, enter the first tubular reactor 107 of Φ8 50m built-in SK type to carry out the reaction at 2.0Mpa, the oil temperature of the first tubular reactor 107 is controlled at 55 ° C, the temperature of the reaction liquid is controlled at 55 ° C, the reaction The time is 18-22min. When the reaction solution flows out from the first tubular reactor 107, after temperature sensing (monitoring the reaction temperature at any time), it enters the cooling pipe 108, is cooled to 15 ° C, and the reaction solution is concentrated under reduced pressure, and the concentrated temperature is 60 ° C, and the concentrated The time was 2h, cooling, crystallization, pressure filtration, ...

Embodiment 2

[0065] Example 2: Synthesis of 2-methyl-5-nitroimidazole by nitration reaction

[0066] The imidazole sulfuric acid solution that is mixed with 2-methylimidazole and sulfuric acid is sent into the second reaction preheating channel 2031 with a flow rate of 20g / min, and the nitric acid is divided into 10 strands and enters 10 second reaction channels 2032 with a flow rate of 15g / min respectively ( The inner temperature is 120-140°C), the temperature of the imidazole sulfuric acid solution in the second reaction preheating channel 2031 reaches 110°C and then enters the first second reaction channel 2032 to mix with the first nitric acid, and the reaction mixture flows out of the first second reaction channel 2032. After the second reaction channel 2032, enter the second second reaction channel 2032 and the second nitric acid to mix and react, and so on, until the reaction mixture flows out from the last second reaction channel 2032, and the reaction mixture is in the nitrificatio...

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Abstract

The invention discloses a metronidazole continuous synthesis method, and relates to the technical field of chemical synthesis. The metronidazole continuous synthesis method comprises the following steps: heating an acidic solution containing 2-methyl-5-nitroimidazole and 2-chloroethanol to carry out a hydroxyethylation reaction, cooling a reaction solution flowing out of a hydroxyethylation microchannel reactor after the reaction is completed, adjusting the pH value of the reaction solution to 3-4, carrying out solid-liquid separation, taking a filtrate, adjusting the pH value of the filtrate to 9-11, and carrying out solid-liquid separation to obtain the metronidazole. And crystallizing to obtain a metronidazole crude product, and recrystallizing to obtain metronidazole. The 2-methyl-5-nitroimidazole and the 2-chloroethanol are in a dissolved and clarified state under the acidic condition and can be fed together, so that feeding and accurate metering are facilitated. In addition, the hydroxyethylation microchannel reactor is large in reaction specific surface area and high in heat exchange efficiency, the reaction temperature can be increased through pressurization, and after the reaction is completed, the remaining 2-chloroethanol is distilled off under reduced pressure, so that generation of a large amount of salt and wastewater is avoided.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, in particular to a method for continuous synthesis of metronidazole. Background technique [0002] Metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol) is an antibiotic and antiprotozoal agent. It is mainly used to treat or prevent systemic or local infections caused by anaerobic bacteria, such as anaerobic bacterial infections in the abdominal cavity, digestive tract, female reproductive system, lower respiratory tract, skin and soft tissues, bones and joints, etc. Inflammation, meningeal infections, and colitis caused by antibiotic use are also effective. The treatment of tetanus is often combined with tetanus antitoxin (TAT). It can also be used for oral anaerobic infection. [0003] The conventional production method of metronidazole is obtained by the addition of 2-methyl-5-nitroimidazole and ethylene oxide. 2-methyl-5-nitroimidazole was dissolved in formic acid, ethylene o...

Claims

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Application Information

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IPC IPC(8): C07D233/94B01J19/00B01J19/24
CPCC07D233/94B01J19/0093B01J19/2415B01J19/002B01J2219/00873B01J2219/0869Y02A50/30
Inventor 杨海洋徐友杰张伟王志邦王哲王小连江积旺邹春伟陈小峰刘安友
Owner ANHUI BIOCHEM UNITED PHARMA CO LTD
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