CN116008435B - Method for measuring content of 2, 4-dibromo-5-chlorobenzoic acid by high performance liquid chromatography - Google Patents
Method for measuring content of 2, 4-dibromo-5-chlorobenzoic acid by high performance liquid chromatography Download PDFInfo
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- BHWZSQKCDWJPSY-UHFFFAOYSA-N 2,4-dibromo-5-chlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=C(Br)C=C1Br BHWZSQKCDWJPSY-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000004128 high performance liquid chromatography Methods 0.000 title claims abstract description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 61
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims abstract description 26
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 239000011259 mixed solution Substances 0.000 claims abstract description 12
- 238000004458 analytical method Methods 0.000 claims abstract description 8
- 238000002347 injection Methods 0.000 claims abstract description 3
- 239000007924 injection Substances 0.000 claims abstract description 3
- 239000000523 sample Substances 0.000 claims description 14
- 239000012488 sample solution Substances 0.000 claims description 10
- 239000012086 standard solution Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- NYKJNEOPRRCYLB-UHFFFAOYSA-N 1,5-dibromo-2-chloro-4-methylbenzene Chemical compound CC1=CC(Cl)=C(Br)C=C1Br NYKJNEOPRRCYLB-UHFFFAOYSA-N 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 238000012360 testing method Methods 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 238000005259 measurement Methods 0.000 claims description 5
- 238000011002 quantification Methods 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 3
- 239000012895 dilution Substances 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000012043 crude product Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000004811 liquid chromatography Methods 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 2
- 238000001514 detection method Methods 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 5
- LVASCWIMLIKXLA-LSDHHAIUSA-N halofuginone Chemical compound O[C@@H]1CCCN[C@H]1CC(=O)CN1C(=O)C2=CC(Cl)=C(Br)C=C2N=C1 LVASCWIMLIKXLA-LSDHHAIUSA-N 0.000 abstract description 3
- 229950010152 halofuginone Drugs 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000003908 quality control method Methods 0.000 abstract description 2
- PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 abstract 1
- 238000010812 external standard method Methods 0.000 abstract 1
- 238000012417 linear regression Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method for measuring the content of 2, 4-dibromo-5-chlorobenzoic acid by high performance liquid chromatography relates to a method for measuring the content of 2, 4-dibromo-5-chlorobenzoic acid, which adopts a method for measuring the content of 2, 4-dibromo-5-chlorobenzoic acid by high performance liquid chromatography, adopts an acetonitrile-trifluoroacetic acid aqueous solution mixed solution system, and adopts an external standard method to quantitatively analyze the content of 2, 4-dibromo-5-chlorobenzoic acid. The chromatographic conditions are as follows: chromatographic column: ZORBAXEclipseXDB-C18; mobile phase: aqueous solution of trifluoroacetic acid, B acetonitrile, A, B= (50-5): (50-95); flow rate: 1.000mL/min; detection wavelength: 210nm; sample injection amount: 10.0. Mu.L; column temperature: 30.0 ℃. The method has the advantages of simple sample treatment and analysis process, high accuracy of analysis results, good reproducibility and the like. The method can accurately measure the content of the 2, 4-dibromo-5-chlorobenzoic acid, is used for evaluating the quality of the 2, 4-dibromo-5-chlorobenzoic acid prepared by an Amoco method, and is beneficial to realizing the quality control of subsequent intermediates and product halofuginone.
Description
Technical Field
The invention relates to a method for measuring the content of 2, 4-dibromo-5-chlorobenzoic acid, in particular to a method for measuring the content of 2, 4-dibromo-5-chlorobenzoic acid by using high performance liquid chromatography.
Background
2, 4-Dibromo-5-chlorobenzoic acid is an organic aromatic carboxylic acid which is white solid at room temperature and can be dissolved in acetone, methanol, ethanol and N, N-dimethylamide. 2, 4-dibromo-5-chlorobenzoic acid is one of the important intermediates for preparing veterinary halofuginone. The compound is obtained by oxidizing 2, 4-dibromo-5-chlorotoluene, has wide application in drug synthesis, and the quality of the intermediate has great influence on subsequent intermediates and final products.
Therefore, research and development of a method for detecting 2, 4-dibromo-5-chlorobenzoic acid is a subject to be solved urgently.
Disclosure of Invention
The invention aims to provide a method for measuring the content of 2, 4-dibromo-5-chlorobenzoic acid by using high performance liquid chromatography. The method has the characteristics of simple sample treatment and analysis process, high accuracy of analysis results and good reproducibility. The high performance liquid chromatography analysis method capable of accurately measuring the content of the 2, 4-dibromo-5-chlorobenzoic acid is used for evaluating the quality of the 2, 4-dibromo-5-chlorobenzoic acid prepared by an Amoco method, and is beneficial to realizing the quality control of subsequent intermediates and product halofuginone.
The invention aims at realizing the following technical scheme:
A method for determining the content of 2, 4-dibromo-5-chlorobenzoic acid by high performance liquid chromatography, said method comprising the steps of:
1) Liquid chromatography conditions: chromatographic column: ZORBAXEclipseXDB-C18; mobile phase: 0.01mol/L trifluoroacetic acid aqueous solution, B acetonitrile, A: B= (50-5): (50-95); flow rate: 1.000mL/min; wavelength: 210nm; column temperature: 30.0 ℃; sample injection amount: 10.0. Mu.L;
2) Precisely weighing a2, 4-dibromo-5-chlorobenzoic acid standard substance, and preparing standard solutions with different concentrations by using a mixed solution of 0.01mol/L trifluoroacetic acid aqueous solution and acetonitrile for dissolution and quantification;
3) Moving a base line by using a mobile phase until the fluctuation is less than 0.5mAu, analyzing the standard solution in the step 2), and drawing a standard curve;
4) Accurately weighing a sample to be measured, and using a mixed solution of 0.01mol/L trifluoroacetic acid aqueous solution and acetonitrile to fix the volume to form a sample solution to be measured; and (3) carrying out analysis and test on the sample solution to be tested, and calculating the content of the 2, 4-dibromo-5-chlorobenzoic acid.
The method for measuring the content of the 2, 4-dibromo-5-chlorobenzoic acid by using high performance liquid chromatography is characterized in that the ZORBAXEclipse XDB-C18 chromatographic column is 4.6mm multiplied by 150mm and 5.0 mu m,
The method for measuring the content of the 2, 4-dibromo-5-chlorobenzoic acid by using high performance liquid chromatography comprises the steps of 2) and 4), wherein the mixed solution of 0.01mol/L trifluoroacetic acid aqueous solution and acetonitrile is equal volume mixed solution of the two.
The method for measuring the content of the 2, 4-dibromo-5-chlorobenzoic acid by using high performance liquid chromatography comprises the steps of 2) respectively obtaining standard solutions with different concentrations of 0.25 mug/mL, 0.50 mug/mL, 0.75 mug/mL, 1.00 mug/mL and 1.50 mug/mL.
The method for measuring the content of the 2, 4-dibromo-5-chlorobenzoic acid by using the high performance liquid chromatography is characterized in that the sample to be measured in the step 4) is a crude product of the 2, 4-dibromo-5-chlorobenzoic acid obtained by oxidizing 2, 4-dibromo-5-chlorotoluene by using an Amoco method.
The method for measuring the content of the 2, 4-dibromo-5-chlorobenzoic acid by using high performance liquid chromatography comprises the steps of precisely weighing 0.1g of a sample to be measured in the step 4), using acetonitrile to fix the volume to 50mL, taking 10mL of the solution, using a mixed solution of 0.01mol/L trifluoroacetic acid aqueous solution and acetonitrile for secondary dilution, and fixing the volume to 50mL.
In the step 4), after the instrument baseline is stable, standard solution is injected first, and after the deviation between the measurement result and the theoretical value is less than or equal to 1%, the solution to be measured is analyzed and tested.
In the method for measuring the content of the 2, 4-dibromo-5-chlorobenzoic acid by using high performance liquid chromatography, in the test, after the target peak of the 2, 4-dibromo-5-chlorobenzoic acid is completely out of peak, the volume ratio of acetonitrile in a mobile phase is increased to 95 percent until the 2, 4-dibromo-5-chlorotoluene is separated from a chromatographic column, the mobile phase is restored to be 50 percent of acetonitrile, and the next test is performed after a base line is stabilized.
The invention has the advantages and effects that:
The chromatographic conditions of the high performance liquid chromatography analysis of the invention are adopted to realize the retention of the 2, 4-dibromo-5-chlorobenzoic acid on a chromatographic column, and the chromatographic conditions can be fully separated from the raw material 2, 4-dibromo-5-chlorobenzoic acid used for preparing the chromatographic column, so that the chromatographic conditions can be used for the content measurement of the 2, 4-dibromo-5-chlorobenzoic acid and the reaction central control of the 2, 4-dibromo-5-chlorobenzoic acid prepared from the 2, 4-dibromo-5-chlorobenzoic acid to monitor the conversion progress of the reaction. The method has the advantages of high accuracy, good reproducibility, good linearity, high sensitivity, low detection lower limit of 0.02 mug/mL and good signal peak symmetry. The method can be used for rapidly and accurately measuring the content of the 2, 4-dibromo-5-chlorobenzoic acid.
Drawings
FIG. 1 is a linear regression equation obtained in example 1;
FIG. 2 is a chromatogram of a sample solution to be measured of 2, 4-dibromo-5-chlorobenzoic acid obtained in example 1;
FIG. 3 is a chromatogram of a2, 4-dibromo-5-chlorotoluene solution determined using the method described in example 1;
FIG. 4 is a diagram showing the lower limit of detection obtained in example 2.
Detailed Description
The present invention will be further illustrated with reference to the following examples, which are not intended to limit the scope of the invention.
Example 1
Preparing a 2, 4-dibromo-5-chlorobenzoic acid sample solution:
Taking a2, 4-dibromo-5-chlorobenzoic acid sample, precisely weighing 0.1g, using acetonitrile to fix the volume to 50mL, taking 10mL of the solution, and using a mixed solution of 0.01mol/L trifluoroacetic acid aqueous solution and acetonitrile to perform secondary dilution and fix the volume to 50mL to obtain the 2, 4-dibromo-5-chlorobenzoic acid sample solution.
The measuring process comprises the following steps:
1) Taking a2, 4-dibromo-5-chlorobenzoic acid standard substance, dissolving the standard substance in acetonitrile, and then preparing standard substance solutions with the concentration of 0.25 mug/mL, 0.50 mug/mL, 0.75 mug/mL, 1.00 mug/mL and 1.50 mug/mL by using a mixed solution of 0.01mol/L trifluoroacetic acid aqueous solution and acetonitrile to a constant volume;
2) And (3) respectively loading 10 mu L of the multiple standard substance solutions into high performance liquid chromatography, eluting with ZORBAXEclipse XDB-C18 chromatographic columns and trifluoroacetic acid aqueous solution-acetonitrile (50:50, V/V) with a mobile phase of 0.01mol/L at a flow rate of 1.000mL/min, and detecting 210nm signals by using a diode array detector to obtain a chromatogram corresponding to each standard substance solution.
3) And (3) plotting by taking the concentration of the chromatogram corresponding to each standard solution as an abscissa and the peak area of the 2, 4-dibromo-5-chlorobenzoic acid in the corresponding chromatogram as an ordinate to obtain a linear regression equation (as shown in figure 1, the content of the 2, 4-dibromo-5-chlorobenzoic acid has a good linear relationship in the concentration range of 0.25-1.50 mu g/mL), wherein the linear regression equation is specifically as follows:
y＝14364.86×x+658.11，R2＝09990。
4) Loading the 2, 4-dibromo-5-chlorobenzoic acid sample solution into high performance liquid chromatography, detecting by adopting a method consistent with the step 2) to obtain a chromatogram of the sample, and taking the peak area of the 2, 4-dibromo-5-chlorobenzoic acid chromatogram peak into a linear regression equation belonging to the step 3), thereby obtaining the content of the 2, 4-dibromo-5-chlorobenzoic acid in the sample to be detected.
The chromatogram of the sample solution to be detected of the 2, 4-dibromo-5-chlorobenzoic acid is shown in figure 2; the chromatogram of the 2, 4-dibromo-5-chlorotoluene solution at a concentration of 0.5. Mu.g/mL is shown in FIG. 3. As can be seen from FIG. 3, the retention time of the main impurity 2, 4-dibromo-5-chlorotoluene in the sample solution to be detected exceeds 10.0min, while the retention time of 2, 4-dibromo-5-chlorobenzoic acid in FIG. 2 is 5.93min, and the 2, 4-dibromo-5-chlorobenzoic acid and the 2, 4-dibromo-5-chlorotoluene are well separated under the chromatographic condition, which shows that the method has good specificity.
The sample solution to be measured was measured in parallel for 5 times, and the content of 2, 4-dibromo-5-chlorobenzoic acid in the sample was calculated, and the results are shown in Table 1.
TABLE 1 sample measurement results
The experimental results in the table show that the content of 2, 4-dibromo-5-chlorobenzoic acid in the sample to be detected is 98.68%, and the relative standard deviation RSD is 0.18%.
Example 2
Lower limit of detection and lower limit of quantification
Under the chromatographic conditions, the lower limit of detection of 2, 4-dibromo-5-chlorobenzoic acid was measured by a stepwise dilution method and found to be 0.02. Mu.g/mL as shown in FIG. 4. As a result, the lower limit of detection by this method was 0.02. Mu.g/mL, and the lower limit of quantification was 0.25. Mu.g/mL.
Example 3
1) Precision of instrument
Under the chromatographic conditions, the standard solutions of 0.25. Mu.g/mL, 0.50. Mu.g/mL, 0.75. Mu.g/mL, 1.00. Mu.g/mL and 1.50. Mu.g/mL were measured 5 times each, and the results are shown in Table 2.
TABLE 2 precision of
As can be seen from Table 2, the relative standard deviation of the precision of the instrument is 0.43% -0.68% within the linear range of 0.25-1.50 mug/mL, which meets the precision requirement.
2) Precision of the method
The content of the samples was measured 6 times in two groups, and the measurement results are shown in tables 3 and 4.
TABLE 3 within-day precision
TABLE 4 daytime precision
As shown in tables 3 and 4, the daily precision RSD is 0.18% -0.27%, and the daily precision RSD is 0.14% -0.42%, which proves that the method has good reproducibility.
Claims (1)
1. A method for determining the content of 2, 4-dibromo-5-chlorobenzoic acid by high performance liquid chromatography, comprising the steps of:
Liquid chromatography conditions: chromatographic column: ZORBAX Eclipse XDB-C18; mobile phase: 0.01 mol/L trifluoroacetic acid aqueous solution, B acetonitrile, A: B= (50-5): (50-95); flow rate: 1.000 mL/min; wavelength: 210 nm; column temperature: 30.0 o C; sample injection amount: 10.0 Mu L; the ZORBAX Eclipse XDB-C18 chromatographic column is 4.6 mm ×150mm, 5.0 μm, 80A;
Precisely weighing 2, 4-dibromo-5-chlorobenzoic acid standard substance, and preparing standard solutions with different concentrations by using 0.01 mol/L mixed solution of trifluoroacetic acid aqueous solution and acetonitrile for dissolution and quantification; standard solutions with different concentrations are respectively 0.25 mug/mL, 0.50 mug/mL, 0.75 mug/mL, 1.00 mug/mL and 1.50 mug/mL;
moving a base line by using a mobile phase until the fluctuation is less than 0.5 mAu, analyzing the standard solution in the step 2), and drawing a standard curve;
Precisely weighing a sample to be measured, namely 0.1 g, using acetonitrile to fix the volume to 50 mL, taking 10 mL of the solution, and using a mixed solution of 0.01 mol/L trifluoroacetic acid aqueous solution and acetonitrile to perform secondary dilution and fixing the volume to 50 mL; after the instrument baseline is stable, firstly injecting a standard solution, and after the deviation between the measurement result and the theoretical value is less than or equal to 1%, feeding a sample solution to be measured for analysis and test, and calculating the content of 2, 4-dibromo-5-chlorobenzoic acid; the sample to be detected is a crude product of 2, 4-dibromo-5-chlorobenzoic acid obtained by oxidizing 2, 4-dibromo-5-chlorotoluene by an Amoco method;
During testing, after the target peak of 2, 4-dibromo-5-chlorobenzoic acid is completely out of the peak, increasing the volume proportion of acetonitrile in the mobile phase to 95 percent until the 2, 4-dibromo-5-chlorotoluene is separated from the chromatographic column, recovering the mobile phase to be acetonitrile with 50 percent of the ratio, and carrying out the next test after the base line is stable;
The mixed solution of the 0.01 mol/L trifluoroacetic acid aqueous solution and acetonitrile in the step 2) and the step 4) is equal volume mixed solution of the two.
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