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On-line nitroimidazole derivative synthesis method by adopting enzymatic means

A technology for nitroimidazoles and derivatives, which is applied in the field of on-line enzymatic synthesis of nitroimidazole derivatives, can solve the problems of unsatisfactory conversion rate of specific substrate reaction, high price, long reaction time and the like, and shorten the reaction time. effect of time, reduced reaction costs, high conversion and selectivity

Inactive Publication Date: 2019-05-03
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] So far, the enzymatic Michael addition reaction in China is in the initial research stage, and there are still some shortcomings, and this method is mostly catalyzed by acylase, which is expensive and requires a long reaction time (24-96h). , and the conversion rate for the specific substrate reaction is not particularly ideal

Method used

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  • On-line nitroimidazole derivative synthesis method by adopting enzymatic means
  • On-line nitroimidazole derivative synthesis method by adopting enzymatic means
  • On-line nitroimidazole derivative synthesis method by adopting enzymatic means

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: 3-(2-methyl-4-nitroimidazole) butyl propionate

[0032]

[0033] device reference figure 1 : Dissolve 2-methyl-4-nitroimidazole (1.0mmol) in 10mL DMSO, and butyl acrylate (4.0mmol) in 10mL DMSO, and then put them in 10mL syringes for use. 0.87g of lipase LipozymeRM IM was evenly filled in the reaction channel, driven by the PHD2000 syringe pump, the two reaction solutions were separated at 7.3 μL min -1 The flow rate enters the reaction channel through the "Y" joint for reaction, and the temperature of the reactor is controlled at 45°C by a water bath thermostat. The reaction solution flows continuously in the reaction channel for 35 minutes, and the reaction results are tracked and detected by thin-layer chromatography (TLC).

[0034] The reaction solution was collected online by a product collector, the solvent was distilled off under reduced pressure, and the column was wet-packed with 200-300 mesh silica gel. The elution reagent was petroleum ether...

Embodiment 2-4

[0038] Change the temperature of the microfluidic channel reactor, others are the same as in Example 1, and the reaction results are as shown in Table 1:

[0039] Table 1: Effect of Temperature on Reaction

[0040]

[0041] The results in Table 1 show that when the flow rate is 7.3 μL min -1 , when the reaction time is 35min, the conversion rate increases significantly with the increase of the reaction temperature. When the reaction temperature reaches 45°C, the conversion rate of the reaction is the best. If the temperature continues to rise at this time, the enzyme activity will decrease. , thereby causing the conversion rate and selectivity of reaction to reduce to some extent, so the optimal reaction temperature of 3-(2-methyl-4-nitroimidazole) butyl propionate in the microfluidic microchannel reactor of the present invention is 45°C.

Embodiment 5-8

[0043] Based on the amount of 2-methyl-4-nitroimidazole, change the ratio of the amount of substrate substance of 2-methyl-4-nitroimidazole and butyl acrylate in the microfluidic microchannel reactor, and control the temperature 45 DEG C, other with embodiment 1, the result is as shown in table 2:

[0044] Table 2: Effect of 2-methyl-4-nitroimidazole and butyl acrylate substrate molar ratio on reaction

[0045] Example

[0046] The results in Table 2 show that when the flow rate is 7.3 μL min -1 , the reaction time is 35min, and the reaction temperature is 45°C. The reactor uses DMSO as the organic solvent. With the increase of the reactant butyl acrylate, the conversion rate of the reaction also increases. When the ratio of the substrate to 2-methyl- When the ratio of 4-nitroimidazole and butyl acrylate is 1:4, the conversion rate of the reaction is optimal, so the ratio of the amount of the optimal substrate substance in the microfluidic microchannel reactor in th...

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Abstract

The invention discloses an on-line nitroimidazole derivative synthesis method by adopting lipase catalysis. The on-line nitroimidazole derivative synthesis method by adopting lipase catalysis comprises the following steps: taking imidazole compounds and acrylate compounds as raw materials, wherein mass ratio of the imidazole compounds to the acrylate compounds is 1 to (1-5); taking 0.5-1.0 gram oflipase Lipozyme RM IM as a catalyst, as well as a DMSO solvent as a reaction solvent; uniformly filling a reaction channel of a microfluidic channel reactor with the lipase Lipozyme RM IM, wherein the inner diameter of the reaction channel of the microfluidic channel reactor is 0.8-2.4 millimeters and the length of the reaction channel is 0.5-1.0 meter; continuously introducing the raw materialsand the reaction solvent into the reaction channel so as to be subjected to Michael addition reaction for 25-40 minutes, wherein the temperature of the Michael addition reaction is controlled at 40-55DEG C; collecting reacted solution on line; and then, performing conventional post-processing on the reacted solution so as to obtain nitroimidazole derivatives. The on-line nitroimidazole derivativesynthesis method disclosed by the invention has the advantages of being short in reaction time, excellent in selectivity and high in yield.

Description

(1) Technical field [0001] The invention relates to an online enzymatic method for synthesizing nitroimidazole derivatives. (2) Background technology [0002] Imidazole is an important class of five-membered aromatic heterocyclic rings. Due to its unique electric-rich structure, it exhibits excellent biological activity and is widely used in pesticides, medicines, artificial materials, artificial receptors, supramolecular ligands, and biomimetic catalysts. field. Especially in medicinal chemistry, a large number of mature imidazole compounds are used clinically as anticancer drugs, antimicrobial drugs, anti-inflammatory drugs, antihistamine drugs, antineurotic drugs and blood pressure lowering drugs, which have a significant effect on the treatment of diseases. Efficacy. [0003] Michael addition is one of the important tools for forming C-C, C-N, C-O, C-X bonds, and is a classic addition reaction in organic synthesis. The Michael addition reaction generally needs to be c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P17/10C12M1/40C12M1/02C12M1/00
Inventor 杜理华薛苗陈平锋董振罗锡平周娜妮陈昱晗龙瑞杰
Owner ZHEJIANG UNIV OF TECH
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