CN110988176A - Method for monitoring nitration reaction in metronidazole production process - Google Patents
Method for monitoring nitration reaction in metronidazole production process Download PDFInfo
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- CN110988176A CN110988176A CN201911299165.2A CN201911299165A CN110988176A CN 110988176 A CN110988176 A CN 110988176A CN 201911299165 A CN201911299165 A CN 201911299165A CN 110988176 A CN110988176 A CN 110988176A
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Abstract
The invention provides a method for monitoring nitration reaction in a metronidazole production process, which adopts a chiral chromatographic column: a Crownpak CR (+) or Crownpak CR (-) chiral column; perchloric acid-water is used as a mobile phase; a detection wavelength of 220nm is adopted; the column temperature was set at 25 ℃ and the flow rate of the liquid chromatography was set at 1.0mL/min, and monitoring was carried out by high performance liquid chromatography. The method provided by the invention has the advantages of low equipment investment and operation cost, short analysis time and strong practicability, can be used for rapid detection and online monitoring of industrial products, and has great significance for guiding production and preventing accidents.
Description
Technical Field
The invention belongs to the field of analytical chemistry, and particularly relates to a method for monitoring nitration reaction in a metronidazole production process.
Background
Metronidazole is used to treat or prevent systemic or local infections caused by anaerobic bacteria, such as infections of the abdominal cavity, digestive tract, female reproductive system, lower respiratory tract, skin and soft tissues, bones and joints, and it also has therapeutic effects on septicemia, endocarditis, meningeal infections and colitis caused by antibiotics. An important intermediate 2-methyl-5-nitroimidazole is used in the production process of metronidazole, and the 2-methyl-5-nitroimidazole is obtained by nitration reaction of 2-methylimidazole through mixed acid. The reaction principle is as follows:
as is known, nitration reaction is one of dangerous unit operation reactions in organic chemical industry, material spraying can be caused by heating, feeding and improper operation, high-temperature concentrated sulfuric acid and nitric acid are sprayed out of a reaction kettle to cause heavy personnel and property loss, and explosion can be caused if the reaction kettle is closed to cause serious consequences. People know dangerousness deeply, and the material spraying mechanism is that: the nitration reaction belongs to exothermic reaction, the nitration reaction rate increases along with the temperature of the nitration reaction, the concentration of sulfuric acid and the dripping speed of nitric acid, and the material spraying is finally uncontrollable due to mutual promotion.
Therefore, in the process of nitration by mixed acid in 2-methylimidazole nitration, the concentration of nitric acid in the reaction kettle and the temperature of the reaction kettle must be strictly controlled, otherwise, danger occurs, and therefore, the concentration of nitric acid in the reaction system needs to be monitored. In addition, the extent to which the nitration reaction proceeds and the conversion of the starting materials also need to be monitored. The reaction system comprises four substances of raw materials of 2-methylimidazole, sulfuric acid, nitric acid and a reaction product of 2-methyl-5-nitroimidazole. If the four substances can be separated and analyzed, the relative contents of the 2-methylimidazole and the 2-methyl-5-nitroimidazole in the reaction system can be monitored on line, and the conversion rate of the raw material 2-methylimidazole in the reaction system can be known; meanwhile, the quantity of the nitric acid and the quantity of the raw material 2-methylimidazole are quantitatively detected, so that accidents caused by the accumulation of the quantity of the nitric acid in a system can be avoided. However, it is difficult to simultaneously separate 2-methylimidazole, nitric acid and the reaction product 2-methyl-5-nitroimidazole in the system. No literature is available for the isolation process.
Aiming at the practical requirement of monitoring the nitration reaction of the 2-methylimidazole, the patent develops a method for monitoring the relative content of various substances in a 2-methylimidazole nitration reaction system by using a high performance liquid chromatography, and the method is used for measuring the conversion rate of raw materials in the reaction system and preventing accidents caused by the accumulation of nitric acid in the system. The method has the advantages of low detection cost, simple and easy operation, convenience and rapidness, capability of well guiding industrial production and strong practicability.
Disclosure of Invention
The invention aims to provide a method for monitoring nitration reaction in a metronidazole production process, which adopts a high performance liquid chromatography to monitor the relative content of each component in a 2-methylimidazole nitration reaction system. The method utilizes a proper chiral chromatographic column and a mobile phase with proper components and proportion, can separate and quantify three substances, namely nitric acid, 2-methylimidazole and 2-methyl-5-nitroimidazole in a spectrogram, and has great significance in production monitoring.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for monitoring nitration reaction in the metronidazole production process is characterized by comprising the following steps: a chiral chromatographic column is used: a Crownpak CR (+) or Crownpak CR (-) chiral column; perchloric acid-water is used as a mobile phase; a detection wavelength of 220nm is adopted; setting the column temperature to be 25 ℃ and the flow rate of the liquid chromatogram to be 1.0mL/min, and monitoring by using the high performance liquid chromatogram, wherein the method comprises the following steps:
step 1: after the baseline of the liquid chromatographic system is balanced, a mobile phase blank sample is fed to ensure that the mobile phase blank has no peak within the analysis time;
step 2: after the step 1 is finished, injecting a nitric acid standard solution, a 2-methylimidazole standard solution sample, a 2-methyl-5-nitroimidazole standard solution and a standard mixed solution thereof, determining that the three solutions can be subjected to baseline separation, and recording the retention time of each peak as a qualitative basis;
and step 3: after the step 2 is finished, taking the reaction solution diluted by the mobile phase as a sample solution, and determining the relative contents of the reaction solution, the mobile phase and the sample solution by a peak area normalization method;
and 4, step 4: and (3) analyzing according to the results of the step (2) and the step (3), taking the basic disappearance of the 2-methylimidazole peak as the basis for the completion of the reaction, and taking the ratio of the peak area of the nitric acid peak to the peak area of the 2-methylimidazole peak as the basis for the excess of the nitric acid in the reaction solution, thereby realizing the monitoring of the reaction system.
Further, the pH value of the mobile phase is 0-5.
Further, the pH of the mobile phase was 1.0.
Compared with the prior art, the method has the following beneficial effects:
the invention is novel in that on the basis of widely screening chromatographic columns and optimizing the composition and the proportion of a mobile phase, a proper chiral chromatographic column and a mobile phase with proper components and proportion are found, three substances, namely nitric acid, 2-methylimidazole and 2-methyl-5-nitroimidazole, can be well separated in a spectrogram, and are quantified. And the other chromatographic columns can not separate the nitric acid and the 2-methylimidazole. The method has the advantages of low equipment investment and operation cost, short analysis time and strong practicability, and can be used for rapid detection and online monitoring of industrial products. The application of the method has great significance for guiding production and preventing accidents.
Drawings
FIG. 1 is a chromatogram of a standard of nitric acid, sulfuric acid, 2-methylimidazole and 2-methyl-5-nitroimidazole prepared in an example of the present invention;
in the figure: t is tR1.165min, nitric acid; t is tR1.711min, 2-methylimidazole; t is tR3.117min, 2-methyl-5-nitroimidazole;
FIG. 2 is a control chromatogram of a reaction solution in an example of the present invention; in the figure, tR1.165min, nitric acid; t is tR1.711min, 2-methylimidazole; t is tR3.117min, 2-methyl-5-nitroimidazole.
Detailed Description
The features and advantages of the present invention will be further understood from the following detailed description taken in conjunction with the accompanying drawings. The examples provided are merely illustrative of the method of the present invention and do not limit the remainder of the disclosure in any way.
Example 1
1. Instruments and conditions:
shimadzu 20a (shimadzu) high performance liquid chromatography system and workstation; an autosampler; a chromatographic column: CrownpakCR (+)150 × 4.0mm, 5 μm; mobile phase: ultrapure water having a pH of 1.0 adjusted with perchloric acid; detection wavelength: 204 nm;
2. the method comprises the following steps:
(1) preparing a reaction solution sample solution: transferring 10ul of reaction solution by using a micro-pipette, adding the reaction solution into a 50mL volumetric flask, diluting the reaction solution to a scale by using a mobile phase, transferring 1mL of the reaction solution, and diluting the reaction solution to 25mL by using the mobile phase;
(2) preparing a standard solution: accurately weighing 10.0mg of 2-methyl-5-nitroimidazole standard substance, adding a mobile phase for dissolving to 100mL, wherein the concentration is 0.1 mg/mL; precisely weighing 10.0mg of 2-methylnitroimidazole standard substance, adding a mobile phase for dissolving to a constant volume of 100mL, wherein the concentration of the standard substance is 0.1 mg/mL;
(3) preparing a standard mixed solution: respectively weighing 10.0mg of 2-methyl-5-nitroimidazole standard substance and 10.0mg of 2-methylnitroimidazole standard substance into a 100mL volumetric flask, and adding a mobile phase to the volume of 100 mL;
(4) preparing a sulfuric acid and nitric acid standard solution: weighing 100mg of ammonium sulfate into a 100mL volumetric flask, adding a mobile phase to fix the volume to 100mL, weighing 50mg of ammonium nitrate into the 100mL volumetric flask, and adding the mobile phase to fix the volume to 100 mL;
(5) sample introduction volume: 5 mu l of the solution;
(6) cleaning a sample injection needle, injecting a mobile phase into the sample injection needle, and recording the blank of the mobile phase;
(7) respectively injecting sulfuric acid, nitric acid, 2-methylimidazole and 2-methyl-5-nitroimidazole standard solutions, keeping for 5min, recording the peak time of each substance, and realizing baseline separation;
(8) sample solution is injected and parallelly injected into two needles.
3. As a result:
from the retention time of the standard chromatogram of each substance shown in fig. 1, the components of each peak can be qualitatively judged, and the change of the normalized content of the peak area of each peak can roughly judge the progress of the reaction, thereby achieving the purpose of monitoring the reaction. FIG. 2 is a graph for monitoring the reaction solution, showing that the peak areas of nitric acid and 2-methylimidazole are large and the peak area of 2-methyl-5 nitroimidazole is small, indicating that the reaction is in the initial stage of the nitration reaction and the product 2-methyl-5 nitroimidazole is small.
The method of the invention skillfully adopts a chiral chromatographic column to effectively separate the nitric acid, the 2-methylimidazole and the 2-methyl-5-nitroimidazole, has short analysis time and low detection cost, can meet the monitoring requirement in the nitration reaction of the 2-methylimidazole, eliminates the potential safety hazard of nitration, and is suitable for industrial enterprises.
Claims (3)
1. A method for monitoring nitration reaction in the metronidazole production process is characterized by comprising the following steps: a chiral chromatographic column is used: a Crownpak CR (+) or Crownpak CR (-) chiral column; perchloric acid-water is used as a mobile phase; a detection wavelength of 220nm is adopted; setting the column temperature to be 25 ℃ and the flow rate of the liquid chromatogram to be 1.0mL/min, and monitoring by using the high performance liquid chromatogram, wherein the method comprises the following steps:
step 1: after the baseline of the liquid chromatographic system is balanced, a mobile phase blank sample is fed to ensure that the mobile phase blank has no peak within the analysis time;
step 2: after the step 1 is finished, injecting a nitric acid standard solution, a 2-methylimidazole standard solution sample, a 2-methyl-5-nitroimidazole standard solution and a standard mixed solution thereof, determining that the three solutions can be subjected to baseline separation, and recording the retention time of each peak as a qualitative basis;
and step 3: after the step 2 is finished, taking the reaction solution diluted by the mobile phase as a sample solution, and determining the relative contents of the reaction solution, the mobile phase and the sample solution by a peak area normalization method;
and 4, step 4: and (3) analyzing according to the results of the step (2) and the step (3), taking the basic disappearance of the 2-methylimidazole peak as the basis for the completion of the reaction, and taking the ratio of the peak area of the nitric acid peak to the peak area of the 2-methylimidazole peak as the basis for the excess of the nitric acid in the reaction solution, thereby realizing the monitoring of the reaction system.
2. The method for monitoring nitration reaction during metronidazole production process as claimed in claim 1, characterised in that: the pH value of the mobile phase is 0-5.
3. The method for monitoring nitration reaction during metronidazole production process as claimed in claim 2, characterised in that: the pH of the mobile phase was 1.0.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102565271A (en) * | 2012-01-10 | 2012-07-11 | 扬子江药业集团南京海陵药业有限公司 | Quality control method for ornidazole |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102565271A (en) * | 2012-01-10 | 2012-07-11 | 扬子江药业集团南京海陵药业有限公司 | Quality control method for ornidazole |
Non-Patent Citations (2)
| Title |
|---|
| H.Y.ABOUI-ENEIN ET AL.: "Enantiomeric Resolution of Some Imidazole Antifungal Agents on ChiralpakWH Chiral Stationary Phase Using HPLC", 《CHROMATOGRAPHIA》 * |
| HONG MENG ET AL.: "Functionalized Assembly of Solid Membranes for Chiral Separation using Polyelectrolytes and Chiral Ionic Liquid", 《AICHE JOURNAL》 * |
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