CN113219085A - Detection method of 2, 3-dimethyl bromobenzene related substances - Google Patents
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Abstract
The invention relates to a method for detecting 2, 3-dimethyl bromobenzene related substances, which mainly comprises the steps of taking a sample 2, 3-dimethyl bromobenzene, adding acetonitrile for dissolving, and preparing a sample solution; dissolving a reference substance of related substances of 2, 3-dimethyl bromobenzene in acetonitrile to prepare a reference substance solution; the content of the 2, 3-dimethyl bromobenzene related substances can be measured by detecting the test solution and the reference solution by adopting a gas chromatography, so that the purity of the 2, 3-dimethyl bromobenzene related substances can be effectively controlled. The method has the advantages of strong specificity, low detection limit and quantitative limit, good linear relation, high recovery rate, good repeatability, strong stability, good durability and simple and quick operation.
Description
Technical Field
The invention relates to the field of analytical chemistry, in particular to a detection method of 2, 3-dimethyl bromobenzene related substances.
Background
Dexmedetomidine hydrochloride is a highly selective alpha 2-adrenoceptor agonist, has the effects of tranquilizing, hypnotizing, resisting anxiety, relieving pain and blocking sympathetic nerves, and has alpha 2/alpha 1 selectivity as high as 45000. Dexmedetomidine hydrochloride is a dextroisomer of alpha 2-adrenoceptor agonist medetomidine, and compared with medetomidine, the dexmedetomidine hydrochloride has stronger selectivity on central alpha 2-adrenoceptor agonist, short half-life, good curative effect and small side effect, has unique advantages compared with other sedatives, and is clinically suitable for the start of intubation and the sedation of patients using breathing machines during intensive care treatment.
2, 3-dimethyl bromobenzene is an important starting material in the synthesis of dexmedetomidine hydrochloride, and is limited by the current production technology and control technology level, and related substances such as o-xylene, 3-nitro-o-xylene, 2, 3-dimethyl aniline, 4-bromo-1, 2-xylene, 2-bromo-1, 4-xylene, 2, 6-dimethyl bromobenzene, 2, 4-dimethyl bromobenzene and 5-bromo-m-xylene inevitably appear in the actual production process of 2, 3-dimethyl bromobenzene, and the related substances and the 2, 3-dimethyl bromobenzene are involved in the subsequent synthesis of dexmedetomidine hydrochloride to seriously affect the quality of the medicine and the health of a patient.
However, no relevant report exists on the quality evaluation method of 2, 3-dimethylbromobenzene at present, and in order to control the relevant substances in the 2, 3-dimethylbromobenzene, ensure the quality of dexmedetomidine hydrochloride synthesized by using the 2, 3-dimethylbromobenzene as a starting material and further ensure the medication safety of patients, a reasonable detection method needs to be invented to effectively determine the content of the relevant substances in the 2, 3-dimethylbromobenzene.
Disclosure of Invention
Aiming at the situation that no method for detecting the content of 2, 3-dimethyl bromobenzene related substances exists at present, the invention provides a method for detecting the content of eight substances including o-xylene, 3-nitro-o-xylene, 2, 3-dimethylaniline, 4-bromo-1, 2-xylene, 2-bromo-1, 4-xylene, 2, 6-dimethyl bromobenzene, 2, 4-dimethyl bromobenzene and 5-bromo-m-xylene related substances in 2, 3-dimethyl bromobenzene, so that the quality stability and the clinical medication safety of dexmedetomidine hydrochloride synthesized by using 2, 3-dimethyl bromobenzene as a starting material are improved.
In order to achieve the purpose of the invention, the embodiment of the invention adopts the following technical scheme:
a detection method of 2, 3-dimethyl bromobenzene related substances specifically comprises the following steps: dissolving a sample 2, 3-dimethyl bromobenzene in acetonitrile to prepare a sample solution; dissolving a reference substance of related substances of 2, 3-dimethyl bromobenzene in acetonitrile to prepare a reference substance solution; detecting the test solution and the reference solution by adopting gas chromatography;
the related substances comprise o-xylene, 3-nitro-o-xylene, 2, 3-dimethylaniline, 4-bromo-1, 2-xylene, 2-bromo-1, 4-xylene, 2, 6-dimethyl bromobenzene, 2, 4-dimethyl bromobenzene and 5-bromo-m-xylene.
The chromatographic conditions of the gas chromatography include:
the chromatographic column is a fused quartz column capillary chromatographic column;
the temperature-raising procedure of the gas chromatography is as follows: the initial temperature is 50-70 ℃, the temperature is increased to 90-110 ℃ at the speed of 5-15 ℃/min, the temperature is maintained for 15-25 min, the temperature is increased to 180-220 ℃ at the speed of 5-15 ℃/min, and the temperature is maintained for 5-10 min;
the temperature of a sample inlet is 230-270 ℃;
the carrier gas is nitrogen;
the detector is a hydrogen flame ionization detector.
Compared with the prior art, the detection method of the 2, 3-dimethyl bromobenzene related substance provided by the invention has the following advantages:
according to the invention, 2, 3-dimethyl bromobenzene is detected by adopting a gas chromatography, so that accurate detection of relevant substances such as p-o-xylene, 3-nitro-o-xylene, 2, 3-dimethylaniline, 4-bromo-1, 2-xylene, 2-bromo-1, 4-xylene, 2, 6-dimethyl bromobenzene, 2, 4-dimethyl bromobenzene and 5-bromo-m-xylene can be realized simultaneously, and thus the quality of 2, 3-dimethyl bromobenzene is effectively controlled. The detection method provided by the invention has the advantages of high detection sensitivity, low detection limit and short detection time, obviously improves the detection working efficiency, is simple to operate, easy to control, low in detection cost and accurate and reliable in detection result, and provides guarantee for monitoring the quality stability and the clinical medication safety of dexmedetomidine hydrochloride synthesized by taking 2, 3-dimethyl bromobenzene as a starting material.
Preferably, the concentration of the test solution is 8-12 mg/ml.
Preferably, the concentration of the control solution is 10-100 mug/ml.
Preferably, in the gas chromatography, the split ratio is 5-20: 1.
preferably, the capillary chromatography column is of the type Astec CHIRALDEX B-DA.
Preferably, the capillary chromatographic column has a column length of 15-60 m and an inner diameter of 0.25-0.53 mm.
Preferably, the thickness of the liquid film of the stationary phase coating of the capillary chromatographic column is 0.10-0.25 μm.
Preferably, the chromatographic conditions of the gas chromatograph further comprise a sample injection amount of 0.9-1.1 muL.
Preferably, the temperature of the gas chromatography-hydrogen flame ionization detector is 200-300 ℃.
Drawings
FIG. 1 is a gas chromatogram of a space-time white solvent (acetonitrile) according to example 1;
FIG. 2 is a gas chromatogram of a control solution of example 1;
FIG. 3 is a gas chromatogram of the sample solution added with the standard in example 1;
in the figure, chromatographic peak 1 is o-xylene, chromatographic peak 2 is 5-bromo-m-xylene, chromatographic peak 3 is 2-bromo-1, 4-xylene, chromatographic peak 4 is 2, 6-dimethyl bromobenzene, chromatographic peak 5 is 2, 4-dimethyl bromobenzene, chromatographic peak 6 is 4-bromo-1, 2-xylene, chromatographic peak 7 is 2, 3-dimethylaniline, chromatographic peak 8 is 3-nitro-o-xylene; chromatographic peak 9 was 2, 3-dimethylbromobenzene.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1:
a detection method of 2, 3-dimethyl bromobenzene related substances specifically comprises the following steps:
taking acetonitrile as a blank solvent; taking a proper amount of the crude 2, 3-dimethyl bromobenzene, adding acetonitrile for dissolving, and preparing a 10mg/ml 2, 3-dimethyl bromobenzene solution as a test solution; taking a proper amount of o-xylene, 3-nitro-o-xylene, 2, 3-dimethylaniline, 4-bromo-1, 2-xylene, 2-bromo-1, 4-xylene, 2, 6-dimethyl bromobenzene, 2, 4-dimethyl bromobenzene and 5-bromo-m-xylene, adding acetonitrile to dissolve the mixture to prepare a solution containing 20 mu g of o-xylene, 10 mu g of 3-nitro-o-xylene, 10 mu g of 2, 3-dimethylaniline, 100 mu g of 4-bromo-1, 2-xylene, 30 mu g of 2-bromo-1, 4-xylene, 30 mu g of 2, 6-dimethyl bromobenzene, 30 mu g of 2, 4-dimethyl bromobenzene and 20 mu g of 5-bromo-m-xylene per 1ml as a reference solution;
the chromatographic conditions for gas chromatography were:
chromatograph: shimadzu GC 2030;
a chromatographic column: 2, 6-di-O-amyl-3-methoxyl derivative modified beta-cyclodextrin is a capillary chromatographic column of stationary liquid;
the type of the chromatographic column: astec CHIRALDEX B-DA;
specification of chromatographic column: 30m 0.25mm 0.12 μm;
a detector: a hydrogen Flame Ionization (FID) detector;
detector temperature: 280 ℃;
sample inlet temperature: 250 ℃;
carrier gas: nitrogen gas;
the split ratio is as follows: 10: 1;
sample introduction volume: 1 mu L of the solution;
temperature rising procedure: the initial temperature is 50-70 ℃, the temperature is increased to 90-110 ℃ at the speed of 5-15 ℃/min, the temperature is maintained for 15-25 min, the temperature is increased to 180-220 ℃ at the speed of 5-15 ℃/min, and the temperature is maintained for 5-10 min.
Performing methodological verification on the chromatographic conditions of the detection method of the 2, 3-dimethyl bromobenzene related substances:
1. specialization inspection
Taking the blank solvent and the reference solution; analysis was performed according to the above detection conditions and the chromatogram was recorded. The blank solvent chromatogram is shown in figure 1; the chromatogram of the control solution is shown in figure 2; as can be seen from the attached drawing, under the chromatographic condition, the detection is not interfered by the solvent and other impurities in the sample, the separation degree of the 2, 3-dimethyl bromobenzene related substances meets the requirement, and the method has good specificity.
2. Detection limit and quantitative limit investigation
Precisely weighing each component reference solution of the related substances of the 2, 3-dimethyl bromobenzene, detecting according to the chromatographic conditions, recording a chromatogram, wherein the peak height is 10 times of the baseline noise and is a quantitative limit, the peak height is 3 times of the baseline noise and is a detection limit, and specific detection results are shown in the following table.
TABLE 1 quantitation Limit and detection Limit test results
The data in the table show that the detection method provided by the invention has low detection limit and quantification limit for detecting related substances in the 2, 3-dimethyl bromobenzene, and has the characteristic of high sensitivity for detecting the related substances in the 2, 3-dimethyl bromobenzene.
TABLE 2 quantitative limit repeatability test results
The data in the table show that the Relative Standard Deviation (RSD) range of the 2, 3-dimethyl bromobenzene related substances determined by the detection method provided by the invention is 1.51-8.66%, and the quantitative limit has good repeatability.
3. Linear survey
Precisely weighing 2, 3-dimethyl bromobenzene, and preparing 11 concentration levels of standard solutions; and precisely weighing each component reference substance of the 2, 3-dimethyl bromobenzene related substances, respectively preparing standard solutions with 6 concentration levels, injecting the standard solutions according to the chromatographic conditions, measuring peak areas, drawing a standard working curve by taking the concentrations of the components in the standard solutions as horizontal coordinates and the peak areas as vertical coordinates, and establishing a linear equation.
TABLE 3 results of the linearity test of each component
The data in the table show that the detection method provided by the invention has a wide linear range, and the concentrations of the 2, 3-dimethyl bromobenzene and related substances thereof have a good linear relation with the peak area measured by gas chromatography.
4. Investigation of recovery
Precisely weighing 9 parts of a sample and each component reference of related substances of 2, 3-dimethyl bromobenzene, respectively adding low, medium and high three different levels of each component reference into the sample to prepare a standard sample solution, detecting the original content of the corresponding 8 types of reference and the measured amount in the standard sample solution under the chromatographic condition, measuring in parallel for 3 times, calculating the recovery rate of the detection method according to the measurement result and the addition amount of the reference, and taking a chromatogram of the standard sample solution at the medium level as a figure 3.
TABLE 4 results of recovery test with addition of standard
The data in the table show that the recovery rate of the standard addition is 95.38-111.38% when the detection method provided by the invention detects the related substances of the 2, 3-dimethyl bromobenzene under 3 standard addition levels, which indicates that the recovery rate of the method is good; the Relative Standard Deviation (RSD) is 0.79-3.96%, which shows that the repeatability of the method is good.
5. Repeatability survey
And respectively taking different batches of 2, 3-dimethyl bromobenzene crude products, preparing a test solution according to the method, carrying out sample injection measurement under the chromatographic condition, and calculating the repeatability for detecting the content of each related substance in the 2, 3-dimethyl bromobenzene.
TABLE 5 repeatability results
| Composition (I) | 1 | 2 | 3 | 4 | 5 | 6 | Mean value of | RSD％ |
| Ortho-xylene | 0.045 | 0.045 | 0.046 | 0.046 | 0.046 | 0.046 | 0.046 | 0.70 |
| 5-bromo-m-xylene | Not detected out | Not detected out | Not detected out | Not detected out | Not detected out | Not detected out | Not detected out | - |
| 2-bromo-1, 4-xylene | 0.029 | 0.031 | 0.031 | 0.031 | 0.032 | 0.031 | 0.031 | 3.38 |
| 2, 6-dimethyl bromobenzene | 0.0083 | 0.0089 | 0.010 | 0.010 | 0.010 | 0.010 | 0.010 | 7.55 |
| 2, 4-dimethyl bromobenzene | 0.077 | 0.078 | 0.079 | 0.079 | 0.077 | 0.079 | 0.078 | 1.18 |
| 4-bromo-1, 2-xylene | 0.32 | 0.32 | 0.32 | 0.32 | 0.32 | 0.33 | 0.32 | 1.11 |
| 2, 3-dimethylaniline | Not detected out | Not detected out | Not detected out | Not detected out | Not detected out | Not detected out | Not detected out | - |
| 3-nitro-o-xylene | 0.020 | 0.020 | 0.020 | 0.020 | 0.020 | 0.020 | 0.020 | 1.16 |
| Purity% | 99.337 | 99.339 | 99.334 | 99.334 | 99.338 | 99.333 | 99.336 | 0.002 |
| Maximum single hetero% | 0.098 | 0.097 | 0.098 | 0.100 | 0.098 | 0.099 | 0.098 | 1.05 |
| Total miscellaneous | 0.663 | 0.661 | 0.666 | 0.666 | 0.662 | 0.667 | 0.664 | 0.37 |
The data in the table show that the Relative Standard Deviation (RSD) of the detection method provided by the invention for detecting the 2, 3-dimethyl bromobenzene related substances is 0.37-3.38%, which indicates that the repeatability of the method is good.
6. Stability survey
Precisely weighing each component reference substance of the related substances of the 2, 3-dimethyl bromobenzene, preparing a reference substance solution according to the preparation method of the reference substance solution, and detecting the solution under the chromatographic conditions at 0h, 2h, 4h, 8h, 12h, 24h and 48h respectively, wherein the stability result of the solution is shown in the following table.
TABLE 6 solution stability results
| Composition (I) | 0 |
2 hours | 4 |
8 hours | 12 hours | 24 hours | 48 hours | RSD％ |
| Ortho-xylene | 36543 | 41025 | 39959 | 38662 | 41669 | 34353 | 34266 | 8.04 |
| 5-bromo-m-xylene | 23932 | 25925 | 25260 | 25036 | 26547 | 22713 | 23251 | 5.73 |
| 2-bromo-1, 4-xylene | 34132 | 36836 | 36420 | 35462 | 37756 | 32148 | 32572 | 6.16 |
| 2, 6-dimethyl bromobenzene | 31887 | 35505 | 34091 | 32673 | 35038 | 30009 | 30406 | 6.63 |
| 2, 4-dimethyl bromobenzene | 31362 | 33779 | 33431 | 32784 | 34643 | 29618 | 29943 | 6.05 |
| 4-bromo-1, 2-xylene | 111939 | 121969 | 119290 | 116498 | 123709 | 105419 | 107606 | 6.14 |
| 2, 3-dimethylaniline | 10010 | 10864 | 10762 | 10994 | 11572 | 9727 | 9670 | 6.86 |
| 3-nitro-o-xylene | 14528 | 15711 | 15541 | 14979 | 15924 | 13666 | 13845 | 6.07 |
As can be seen from the table, when the detection method provided by the method is used for detecting the 2, 3-dimethyl bromobenzene related substances, the Relative Standard Deviation (RSD) is 5.73-8.04% under 0h, 2h, 4h, 8h, 12h, 24h and 48h, and the method is good in stability.
7. Durability examination
Precisely weighing each component reference substance of the 2, 3-dimethyl bromobenzene related substances, preparing a reference substance solution according to the preparation method of the reference substance solution, taking acetonitrile as a blank solvent, and respectively changing the injection port temperature, the initial temperature, the heating rate and the detector temperature for detection, wherein other detection conditions are unchanged. The durability results are shown in the following table.
TABLE 7 temperature separation at different injection ports
| Composition (I) | A sample inlet of 250 DEG C | A sample inlet of 245 DEG C | Sample inlet 255 deg.C |
| Acetonitrile | N/A | N/A | N/A |
| Ortho-xylene | 12.888 | 13.521 | 18.384 |
| 5-bromo-m-xylene | 80.140 | 81.336 | 80.370 |
| 2-bromo-1, 4-xylene | 7.573 | 7.747 | 7.595 |
| 2, 6-dimethyl bromobenzene | 1.198 | 1.211 | 1.187 |
| 2, 4-dimethyl bromobenzene | 3.480 | 3.405 | 3.396 |
| 4-bromo-1, 2-xylene | 24.413 | 23.977 | 23.573 |
| 2, 3-dimethylaniline | 37.279 | 37.174 | 37.025 |
| 3-nitro-o-xylene | 12.060 | 11.976 | 11.975 |
TABLE 8 degrees of separation at different initial temperatures
TABLE 9 degrees of separation at different heating rates
| Composition (I) | The heating rate is 10 ℃/min | The heating rate is one 9 ℃/min | The heating rate is 11 ℃/min |
| Acetonitrile | N/A | N/A | N/A |
| Ortho-xylene | 12.888 | 13.156 | 13.261 |
| 5-bromo-m-xylene | 80.140 | 80.586 | 80.601 |
| 2-bromo-1, 4-xylene | 7.573 | 7.548 | 7.669 |
| 2, 6-dimethyl bromobenzene | 1.198 | 1.198 | 1.192 |
| 2, 4-dimethyl bromobenzene | 3.480 | 3.387 | 3.405 |
| 4-bromo-1, 2-xylene | 24.413 | 23.891 | 23.454 |
| 2, 3-dimethylaniline | 37.279 | 36.814 | 37.289 |
| 3-nitro-o-xylene | 12.060 | 12.078 | 11.921 |
TABLE 10 degrees of separation at different ramp rates
| Composition (I) | The heating rate is two 10 ℃/min | The heating rate is two 9 ℃/min | The heating rate is two 11 ℃/min |
| Acetonitrile | N/A | N/A | N/A |
| Ortho-xylene | 12.888 | 18.282 | 18.266 |
| 5-bromo-substituted benzene radicalXylene | 80.140 | 82.006 | 81.719 |
| 2-bromo-1, 4-xylene | 7.573 | 7.693 | 7.637 |
| 2, 6-dimethyl bromobenzene | 1.198 | 1.185 | 1.174 |
| 2, 4-dimethyl bromobenzene | 3.480 | 3.377 | 3.401 |
| 4-bromo-1, 2-xylene | 24.413 | 23.495 | 23.638 |
| 2, 3-dimethylaniline | 37.279 | 37.507 | 36.346 |
| 3-nitro-o-xylene | 12.060 | 12.177 | 11.728 |
TABLE 11 temperature resolution of different detectors
The data in the table show that the separation degrees of the 2, 3-dimethyl bromobenzene related substances are detected by changing the factors of the temperature of the injection port, the initial temperature, the temperature rise rate and the temperature of the detector to be higher than 1.2, and the method meets the requirement of researching the impurity separation degree of the related substances, and has good durability.
As can be seen from the methodological investigation of the aspects of FIGS. 1-3 and the above 7, the detection method provided by the invention can quickly and effectively separate and measure the related substances of the 2, 3-dimethyl bromobenzene, thereby achieving the effective detection of the purity and the related substance content of the 2, 3-dimethyl bromobenzene.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A method for detecting 2, 3-dimethyl bromobenzene related substances is characterized by comprising the following steps: dissolving a sample 2, 3-dimethyl bromobenzene in acetonitrile to prepare a sample solution; dissolving a reference substance of related substances of 2, 3-dimethyl bromobenzene in acetonitrile to prepare a reference substance solution; detecting the test solution and the reference solution by adopting gas chromatography;
the related substances comprise o-xylene, 3-nitro-o-xylene, 2, 3-dimethylaniline, 4-bromo-1, 2-xylene, 2-bromo-1, 4-xylene, 2, 6-dimethyl bromobenzene, 2, 4-dimethyl bromobenzene and 5-bromo-m-xylene;
the chromatographic conditions of the gas chromatography include:
the chromatographic column is a fused quartz column capillary chromatographic column;
the temperature-raising procedure of the gas chromatography is as follows: the initial temperature is 50-70 ℃, the temperature is increased to 90-110 ℃ at the speed of 5-15 ℃/min, the temperature is maintained for 15-25 min, the temperature is increased to 180-220 ℃ at the speed of 5-15 ℃/min, and the temperature is maintained for 5-10 min;
the temperature of a sample inlet is 230-270 ℃;
the carrier gas is nitrogen;
the detector is a hydrogen flame ionization detector.
2. The method for detecting 2, 3-dimethylbromobenzene related substances according to claim 1, wherein the concentration of the test solution is 8-12 mg/ml.
3. The method for detecting 2, 3-dimethylbromobenzene related substances according to claim 1, wherein the concentration of the control solution is 10-100 μ g/ml.
4. The method for detecting 2, 3-dimethylbromobenzene related substances according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise that the flow split ratio is 5-20: 1.
5. the method for detecting 2, 3-dimethyl bromobenzene related substances according to claim 1, wherein the capillary chromatographic column is Astec CHIRALDEX B-DA.
6. The method for detecting 2, 3-dimethylbromobenzene related substances according to claim 1, wherein the length of the capillary chromatographic column is 15-60 m, and the inner diameter is 0.25-0.53 mm.
7. The method for detecting 2, 3-dimethylbromobenzene related substances according to claim 1, wherein the thickness of a liquid film of a stationary phase coating of the capillary chromatographic column is 0.10-0.25 μm.
8. The method for detecting 2, 3-dimethylbromobenzene related substances according to claim 1, wherein the chromatographic conditions of the gas chromatography further comprise the sample amount of 0.9-1.1 μ L.
9. The method for detecting 2, 3-dimethylbromobenzene related substances according to claim 1, wherein the temperature of said hydrogen flame ionization detector is 200-300 ℃.
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