Method for detecting related substances of 4-chlorobenzoyl chloride

Abstract

The invention relates to the technical field of pharmaceutical analysis, and particularly discloses a method for detecting related substances of 4-chlorobenzoyl chloride. According to the method, a chromatographic column with 50% of phenyl and 50% of methylpolysiloxane as a stationary liquid is adopted to perform gas chromatographic analysis on a 4-chlorobenzoyl chloride sample, and accurate detection of four related substances, namely methyl parachlorobenzoate, ethyl parachlorobenzoate, o-chlorobenzoyl chloride and m-chlorobenzoyl chloride, in the 4-chlorobenzoyl chloride and the content of the four related substances is realized at the same time. The detection method is high in specificity, low in detection limit and quantitation limit, good in linear relation, high in recovery rate, good in repeatability, good in stability, good in durability, easy and rapid to operate, low in detection cost and accurate and reliable in detection result, and guarantees are provided for monitoring the quality stability and clinical medication safety of rebamipide.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting related substances of 4-chlorobenzoyl chloride. Background Art

[0002] Rebamipide is a gastric mucosal protectant, which has the effects of protecting and repairing the gastric mucosa, increasing the amount of gastric mucus, and promoting the regeneration of gastric mucosal cells. 4-Chlorobenzoyl chloride is one of the important raw materials in the synthesis of rebamipide. At present, the common synthesis process of 4-chlorobenzoyl chloride is as follows: adding chlorobenzene and an acylation reagent (such as thionyl chloride or acid anhydride, etc.) into a reaction kettle and stirring, and then heating to 80-100 °C for reaction. However, limited by the current production technology and control technology level, in the actual production process of 4-chlorobenzoyl chloride, related substances of 4-chlorobenzoyl chloride, such as methyl p-chlorobenzoate, ethyl p-chlorobenzoate, o-chlorobenzoyl chloride, and m-chlorobenzoyl chloride, will inevitably be mixed in the product. These related substances participate in the subsequent synthesis of rebamipide together with 4-chlorobenzoyl chloride, which will seriously affect the purity of the final product, thus seriously affecting the quality and efficacy of the drug and bringing impacts on the health of patients.

[0003] However, there is no relevant report on the quality evaluation method of 4-chlorobenzoyl chloride at present. In order to control the related substances in 4-chlorobenzoyl chloride, ensure the quality of rebamipide synthesized with 4-chlorobenzoyl chloride as a synthetic material, and further ensure the medication safety of patients, it is necessary to invent a detection method that can effectively determine the content of related substances in 4-chlorobenzoyl chloride, effectively control the purity in the finally synthesized rebamipide, ensure the efficacy, and inhibit side effects. Summary of the Invention

[0004] Aiming at the problem that the related substances of 4-chlorobenzoyl chloride cannot be effectively detected in the prior art, the present invention provides a method for detecting related substances of 4-chlorobenzoyl chloride.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] A method for detecting related substances of 4-chlorobenzoyl chloride, wherein the related substances of 4-chlorobenzoyl chloride include methyl p-chlorobenzoate, ethyl p-chlorobenzoate, o-chlorobenzoyl chloride, and m-chlorobenzoyl chloride, and gas chromatography is used for detection, which comprises the following steps:

[0007] Preparation of the test solution: dissolving a 4-chlorobenzoyl chloride sample in a solvent to obtain a test solution;

[0008] Preparation of the mixed reference solution: dissolving methyl p-chlorobenzoate reference substance, ethyl p-chlorobenzoate reference substance, o-chlorobenzoyl chloride reference substance, and m-chlorobenzoyl chloride reference substance in a solvent to obtain a mixed reference solution;

[0009] The mixed reference solution and the test solution are detected by gas chromatography. The chromatographic conditions of the gas chromatography include:

[0010] Chromatographic column: a chromatographic column using 50% phenyl - 50% methylpolysiloxane as the stationary liquid;

[0011] The temperature - rising program is as follows: the initial temperature is 68°C - 71°C, maintained for 8 min - 12 min, then heated at a rate of 4°C / min - 6°C / min to 108°C - 112°C, maintained for 10 - 12 min, and then heated at a rate of 28°C / min - 32°C / min to 258°C - 262°C, maintained for 4 min - 6 min;

[0012] The inlet temperature is 275 - 285°C;

[0013] The detector temperature is 275 - 285°C.

[0014] The detection method for impurities in 4 - chlorobenzoyl chloride provided by the present invention uses a chromatographic column with 50% phenyl - 50% methylpolysiloxane as the stationary liquid to perform gas chromatography analysis on 4 - chlorobenzoyl chloride samples, achieving accurate detection of four related substances, namely methyl 4 - chlorobenzoate, ethyl 4 - chlorobenzoate, 2 - chlorobenzoyl chloride, and 3 - chlorobenzoyl chloride, and their contents in 4 - chlorobenzoyl chloride. By limiting the temperature - rising program of gas chromatography and the temperatures of the inlet and detector, etc., the present invention improves the peak response intensity of the test solution and the mixed reference solution, thereby improving the detection accuracy. This detection method has strong specificity, low detection limit and quantification limit, good linear relationship, high recovery rate, good repeatability, good stability, good durability, and is simple and fast to operate, with low detection cost, and the detection results are accurate and reliable. It can provide data support for the effective control of the quality of 4 - chlorobenzoyl chloride during the production process, and provide guarantee for monitoring the quality stability of rebamipide and the safety of clinical medication.

[0015] Preferably, the solvent is acetonitrile.

[0016] Preferably, the concentration of 4 - chlorobenzoyl chloride in the test solution is 19 mg / mL - 21 mg / mL.

[0017] Preferably, the concentration of methyl 4 - chlorobenzoate in the mixed reference solution is 1 mg / mL - 2 mg / mL.

[0018] Preferably, the concentration of ethyl 4 - chlorobenzoate in the mixed reference solution is 1 mg / mL - 2 mg / mL.

[0019] Preferably, the concentration of 2 - chlorobenzoyl chloride in the mixed reference solution is 1 mg / mL - 2 mg / mL.

[0020] Preferably, the concentration of m-chlorobenzoyl chloride in the mixed reference solution is 1 mg / mL to 2 mg / mL.

[0021] Preferably, the chromatographic conditions of the gas chromatography further include: the detector is a flame ionization detector.

[0022] Preferably, the chromatographic conditions of the gas chromatography further include: the carrier gas is nitrogen, and the flow rate of the nitrogen is 2.8 mL / min to 3.2 mL / min.

[0023] Preferably, the chromatographic conditions of the gas chromatography further include: the injection volume is 0.8 μL to 1.2 μL.

[0024] Preferably, the chromatographic conditions of the gas chromatography further include: the split ratio is (5 - 15):1.

[0025] The chromatographic column is a DB-17 chromatographic column with a specification of 30 m × 0.32 mm and a packing diameter of 0.25 μm.

[0026] The detection method of the present invention using gas chromatography can accurately detect the related substances of 4-chlorobenzoyl chloride, and is applicable to the detection of methyl p-chlorobenzoate, ethyl p-chlorobenzoate, o-chlorobenzoyl chloride and m-chlorobenzoyl chloride in 4-chlorobenzoyl chloride, solving the problem that currently the methyl p-chlorobenzoate, ethyl p-chlorobenzoate, o-chlorobenzoyl chloride and m-chlorobenzoyl chloride in 4-chlorobenzoyl chloride cannot be effectively controlled. Moreover, this detection method is simple to operate and has high precision, and has the value of popularization and practical application. Description of the Drawings

[0027] Figure 1 It is the gas chromatogram of the blank solvent in Example 1;

[0028] Figure 2 It is the gas chromatogram of the mixed reference solution in Example 1;

[0029] Figure 3 It is the gas chromatogram of the spiked test solution in Example 4;

[0030] Figure 4 It is the gas chromatogram of the test solution in Example 1;

[0031] Figure 5 It is the gas chromatogram of the mixed solution in Comparative Example 1;

[0032] Among them, 1 is acetonitrile, 2 is m-chlorobenzoyl chloride, 3 is 4-chlorobenzoyl chloride, 4 is methyl p-chlorobenzoate, 5 is o-chlorobenzoyl chloride, and 6 is ethyl p-chlorobenzoate. Detailed Embodiments

[0033] The technical solution of the present invention will be described clearly and completely below. It should be understood that the specific embodiments described herein can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention within the scope of the described embodiments.

[0034] Example 1

[0035] This example provides a method for detecting related substances of 4-chlorobenzoyl chloride, which specifically includes the following steps:

[0036] (1) Solution preparation

[0037] Blank solvent: Acetonitrile;

[0038] Test solution: Accurately weigh 0.2 g of 4-chlorobenzoyl chloride sample, add acetonitrile to a 10 mL volumetric flask to make up the volume, and prepare a test solution of 4-chlorobenzoyl chloride with a concentration of 20 mg / mL;

[0039] Mixed reference solution: Accurately weigh 10 mg each of methyl 4-chlorobenzoate, ethyl 4-chlorobenzoate, o-chlorobenzoyl chloride, and m-chlorobenzoyl chloride, place them in the same 10 mL volumetric flask, add acetonitrile to make up the volume, and prepare a mixed reference solution; that is, in the mixed reference solution, the concentrations of methyl 4-chlorobenzoate, ethyl 4-chlorobenzoate, o-chlorobenzoyl chloride, and m-chlorobenzoyl chloride are all 1 mg / mL;

[0040] Reference stock solution: Accurately weigh 20 mg each of methyl 4-chlorobenzoate, ethyl 4-chlorobenzoate, o-chlorobenzoyl chloride, and m-chlorobenzoyl chloride, place them in a 20 mL volumetric flask, and prepare a mixed solution containing about 1 mg each in 1 mL with acetonitrile as the reference stock solution;

[0041] Spiked test solution: Take 0.2 g of 4-chlorobenzoyl chloride sample, place it in a 10 mL volumetric flask, add 1 mL of the reference stock solution, and make up the volume with acetonitrile.

[0042] (2) The chromatographic conditions of the specific gas chromatography method include:

[0043] Use a DB-17 chromatographic column (30 m × 0.32 mm, 0.25 μm);

[0044] The temperature programming of the gas chromatography is as follows: The initial temperature is 70 °C, maintained for 10 min, heated at a rate of 5 °C / min to 1100 °C, maintained for 10 min, and then heated at a rate of 30 °C / min to 260 °C, maintained for 5 min;

[0045] The detector is a flame ionization detector (FID), the injection port temperature is 280 °C, and the detector temperature is 280 °C;

[0046] The carrier gas is nitrogen, and the flow rate is 3 mL / min;

[0047] The injection volume is 1 μL;

[0048] The split ratio is 10:1.

[0049] Example 2

[0050] The above-mentioned blank solvent, test solution and mixed reference solution were detected by the above-mentioned gas chromatography method. Among them, the gas chromatogram results of the blank solvent, mixed reference solution and test solution are as Figures 1 - 3 shown. The resolution of each impurity in the spiked test solution was tested, and the test results are shown in Table 1. It can be seen from Figures 1 - 3 Table 1 that for the method for detecting impurities in 4-chlorobenzoyl chloride provided in this example, the blank solvent does not interfere with the detection of each component, the resolution between each component meets the requirements, and the method has good specificity.

[0051] Table 1

[0052] Component Retention time / min Resolution m - Chlorobenzoyl chloride 17.510 - 4 - Chlorobenzoyl chloride 18.080 2.116 Methyl 4 - chlorobenzoate 18.992 3.969 o - Chlorobenzoyl chloride 19.271 1.735 Ethyl 4 - chlorobenzoate 21.850 13.378

[0053] Example 3

[0054] Detection limit and quantitation limit:

[0055] Accurately weigh 4-chlorobenzoyl chloride, methyl p-chlorobenzoate, ethyl p-chlorobenzoate, o-chlorobenzoyl chloride and m-chlorobenzoyl chloride, and prepare the corresponding test solution and mixed reference solution according to the steps of solution preparation in Example 1, and detect according to the gas chromatography conditions in Example 1, record the chromatogram. When the peak height is 10 times the baseline noise, it is the quantitation limit, and when the peak height is 3 times the baseline noise, it is the detection limit. The test results of the quantitation limit and detection limit are shown in Table 2, and the test results of the repeatability of the quantitation limit are shown in Tables 2-7.

[0056] Test results of quantitation limit and detection limit:

[0057] The quantitation limit concentration of 4-chlorobenzoyl chloride is 0.1000 mg / mL, and the detection limit concentration is 0.0300 mg / mL; the quantitation limit concentration of methyl p-chlorobenzoate is 0.1014 mg / mL, and the detection limit concentration is 0.0304 mg / mL; the quantitation limit concentration of ethyl p-chlorobenzoate is 0.0978 mg / mL, and the detection limit concentration is 0.0293 mg / mL; the quantitation limit concentration of o-chlorobenzoyl chloride is 0.1022 mg / mL, and the detection limit concentration is 0.0307 mg / mL; the quantitation limit concentration of m-chlorobenzoyl chloride is 0.1023 mg / mL, and the detection limit concentration is 0.0307 mg / mL.

[0058] From the data in Table 2, it can be seen that the detection method provided by the present invention has low detection limit and quantitation limit for detecting related substances in 4-chlorobenzoyl chloride, and has the characteristics of high sensitivity for detecting related substances in 4-chlorobenzoyl chloride.

[0059] Table 2 Results of Repeatability Test for Peak Area at Quantitation Limit

[0060]

[0061] From the data in Table 2, it can be seen that the relative standard deviation (RSD) of the related substances of 4-chlorobenzoyl chloride determined by the detection method provided by the present invention is ≤10%, indicating that the quantitation limit has good repeatability.

[0062] Accurately weigh samples of 4-chlorobenzoyl chloride, methyl 4-chlorobenzoate, ethyl 4-chlorobenzoate, o-chlorobenzoyl chloride, and m-chlorobenzoyl chloride, and prepare sample solutions at 6 concentration levels respectively. Inject the above sample solutions under the above chromatographic conditions, measure the peak areas, use the concentration of the components in the sample solution as the abscissa and the peak area as the ordinate to plot the standard working curve and establish a linear equation. The final test results are shown in Tables 3 - 7.

[0063] Table 3 Results of Linearity Test for 4-Chlorobenzoyl Chloride

[0064]

[0065] Table 4 Results of Linearity Test for Methyl 4-Chlorobenzoate

[0066]

[0067] Table 5 Results of Linearity Test for Ethyl 4-Chlorobenzoate

[0068]

[0069] Table 6 Results of Linearity Test for o-Chlorobenzoyl Chloride

[0070]

[0071] Table 7 Results of Linearity Test for m-Chlorobenzoyl Chloride

[0072]

[0073]

[0074] From the data in Tables 3 - 7, it can be seen that the detection method provided by the present invention has a wide linear range, and there is a good linear relationship between the concentrations of 4-chlorobenzoyl chloride and its related substances and the peak areas measured by gas chromatography.

[0075] Example 4

[0076] Investigation of Recovery Rate:

[0077] Accurately weigh 20 mg each of methyl 4-chlorobenzoate, ethyl 4-chlorobenzoate, 2-chlorobenzoyl chloride, and 3-chlorobenzoyl chloride, place them in a 20 mL volumetric flask, and prepare a 1 mg / mL mixed solution with acetonitrile as the reference substance stock solution. Accurately weigh 0.2 g of the 4-chlorobenzoyl chloride test sample, place it in a 10 mL volumetric flask, prepare 9 portions in parallel, accurately add 0.5 mL, 1.0 mL, and 1.5 mL of the reference substance stock solution respectively, and make up to the scale line with acetonitrile to obtain the recovery spiked test sample solution. Use the detection method and chromatographic conditions in this protocol for detection. Each group of test sample solutions is detected in parallel 3 times. Finally, the recoveries of the related substances of 4-chlorobenzoyl chloride are shown in Tables 8 - 11. Among them, the chromatogram of the spiked test sample solution obtained by mixing 1.0 mL of the reference substance storage solution with the test sample is as Figure 3 shown:

[0078] Table 8 Detection Results of Recovery

[0079]

[0080]

[0081] Table 9 Detection Results of Recovery

[0082]

[0083] Table 10 Detection Results of Recovery

[0084]

[0085]

[0086] Table 11 Detection Results of Recovery

[0087]

[0088]

[0089] From the data in Tables 8 - 11, it can be seen that for the detection method provided by the present invention for the related substances of 4-chlorobenzoyl chloride at three different addition amounts, the spiked recoveries are 69.68% - 104.18%, and the relative standard deviation (RSD) ≤ 10%, indicating that the accuracy and repeatability of this method are good.

[0090] Example 5

[0091] Repeatability:

[0092] Take 6 batches of test samples of 4-chlorobenzoyl chloride from the same batch, prepare the test solution according to the method provided in Example 1, and inject the sample under the gas chromatography conditions provided in Example 1. Detect the contents of relevant substances in the test samples of 4-chlorobenzoyl chloride in different groups respectively. The final results are shown in Table 12:

[0093] Table 12 Repeatability Results

[0094]

[0095] From the data in Table 12, it can be seen that the detection results of the relevant substances in 4-chlorobenzoyl chloride of the same batch by the detection method provided by the present invention are basically the same, indicating good repeatability.

[0096] Example 6

[0097] Investigation on solution stability:

[0098] Precisely weigh 4-chlorobenzoyl chloride and related substances, prepare the test solution and the mixed reference substance solution according to the above preparation method, and detect them under the above chromatographic conditions after standing at room temperature for 0h, 4h, 8h, 12h, 16h, 20h, and 24h respectively. The stability results of the solution are shown in Table 13.

[0099] Table 13 Solution Stability Results

[0100]

[0101] It can be seen from Table 13 that the solution of the related substances of 4-chlorobenzoyl chloride prepared by this detection method is detected by the same method after standing at room temperature for 0h, 4h, 8h, 12h, 16h, 20h, and 24h, and the obtained results are basically the same, with a relative standard deviation (RSD) ≤ 10%, indicating that the solution prepared by this method has good stability.

[0102] Example 7

[0103] Robustness:

[0104] Precisely weigh each component of 4-chlorobenzoyl chloride and related substances, prepare the mixed reference substance solution according to the method provided in Example 1, change the initial temperature and the heating rate respectively, and keep other detection conditions unchanged. The resolution results of each substance are finally shown in Tables 14 - 15:

[0105] Table 14 Resolution at Different Initial Temperatures

[0106]

[0107]

[0108] Table 15 Resolution at Different Heating Rates

[0109]

[0110] As can be seen from the data in Tables 14 - 15, when changing the initial temperature of the chromatographic column and the heating rate, the resolution of the related substances of 4-chlorobenzoyl chloride is greater than 1.2, meeting the requirements for the resolution of impurities in the study of related substances, indicating that the durability of this method is good.

[0111] From Figures 1 - 3 As can be seen from the methodological investigations provided in Examples 1 - 7, the detection method provided by the present invention can rapidly and effectively separate and determine the related substances of 4-chlorobenzoyl chloride, thereby achieving an effective detection of the purity and the content of related substances of 4-chlorobenzoyl chloride.

[0112] Comparative Example 1

[0113] This comparative example provides a method for detecting the related substances of 4-chlorobenzoyl chloride, which specifically includes the following steps:

[0114] S1: Accurately weigh 10 mg each of 4-chlorobenzoyl chloride, methyl p-chlorobenzoate, ethyl p-chlorobenzoate, o-chlorobenzoyl chloride, and m-chlorobenzoyl chloride, respectively place them in 10 mL volumetric flasks, dilute to the mark with acetonitrile, take 1 mL of each of the above solutions and place them in the same 10 mL volumetric flask, dilute to the mark with acetonitrile to prepare a mixed solution containing 100 μg / mL of each impurity;

[0115] S2: Perform gas chromatography analysis using a capillary chromatographic column with 100% dimethylpolysiloxane as the stationary liquid, where:

[0116] Chromatographic column model: DB-1;

[0117] Chromatographic column specification: 50 m × 0.53 mm, 5 μm;

[0118] Detector: Flame ionization detector (FID);

[0119] Detector temperature: 250 °C;

[0120] Injector temperature: 250 °C;

[0121] Carrier gas and carrier gas flow rate: Nitrogen, 3.0 mL / min;

[0122] Split ratio: 10:1;

[0123] Injection volume: 1 μL;

[0124] Temperature programming: Initial temperature 100 °C, heat at a rate of 5 °C / min to 120 °C, hold for 20 min, heat at a rate of 2 °C / min to 660 °C, hold for 10 min, heat at a rate of 30 °C / min to 250 °C, hold for 10 min.

[0125] Perform a methodology verification on the chromatographic conditions of the detection method for the related substances of 4-chlorobenzoyl chloride as described above:

[0126] Accurately weigh 10 mg each of 4-chlorobenzoyl chloride, methyl 4-chlorobenzoate, ethyl 4-chlorobenzoate, 2-chlorobenzoyl chloride, and 3-chlorobenzoyl chloride respectively, place them in 10-mL volumetric flasks, dilute to the mark with acetonitrile. Take 1 mL of each of the above solutions and place them in the same 10-mL volumetric flask, dilute to the mark with acetonitrile to prepare a mixed solution containing 100 μg / mL of each impurity. Analyze the above solution according to the detection conditions, and the obtained chromatogram is as Figure 5 shown. It can be seen from the figure that when analyzing the related substances of 4-chlorobenzoyl chloride using a capillary chromatographic column with 100% dimethylpolysiloxane as the stationary liquid, the resolution between 4-chlorobenzoyl chloride and 3-chlorobenzoyl chloride does not meet the requirements, that is, the related substances of 4-chlorobenzoyl chloride cannot be separated using this chromatographic column, and this method does not have specificity.

[0127] Each of the above embodiments is only a preferred embodiment of the present invention and is not intended to limit the protection scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for detecting related substances of 4-chlorobenzoyl chloride, characterized in that, The 4-chlorobenzoyl chloride related substances include methyl p-chlorobenzoate, ethyl p-chlorobenzoate, o-chlorobenzoyl chloride and m-chlorobenzoyl chloride, and are detected by gas chromatography, comprising the following steps: Preparation of test solution: Dissolve 4-chlorobenzoyl chloride sample in solvent to obtain test solution; Preparation of mixed reference solution: dissolve methyl p-chlorobenzoate reference substance, ethyl p-chlorobenzoate reference substance, o-chlorobenzoyl chloride reference substance and m-chlorobenzoyl chloride reference substance in a solvent to obtain a mixed reference solution; The mixed reference solution and the test solution are detected by gas chromatography, and the chromatographic conditions of the gas chromatography include: Chromatographic column: A chromatographic column using 50% phenyl-50% methyl polysiloxane as the stationary liquid; The heating program is as follows: starting temperature 68°C-71°C, maintained for 8-12 min, heated to 108-112°C at a rate of 4-6°C / min, maintained for 10-12 min, heated to 258-262°C at a rate of 28-32°C / min, maintained for 4-6 min; The injection port temperature is 275-285°C; The detector temperature is 275-285°C.

2. The method for detecting related substances of 4-chlorobenzoyl chloride as claimed in claim 1, wherein The solvent is acetonitrile.

3. The method for detecting related substances of 4-chlorobenzoyl chloride as claimed in claim 1, characterized in that, The concentration of 4-chlorobenzoyl chloride in the test solution is 19 mg / mL to 21 mg / mL.

4. The method for detecting related substances of 4-chlorobenzoyl chloride as claimed in claim 1, wherein The concentration of methyl p-chlorobenzoate in the mixed reference solution is 1 mg / mL to 2 mg / mL; and / or The concentration of ethyl p-chlorobenzoate in the mixed reference solution is 1 mg / mL to 2 mg / mL.

5. The method for detecting related substances of 4-chlorobenzoyl chloride as claimed in claim 1, characterized in that, The concentration of o-chlorobenzoyl chloride in the mixed reference solution is 1 mg / mL to 2 mg / mL.

6. The method for detecting related substances of 4-chlorobenzoyl chloride as claimed in claim 1, characterized in that, The concentration of chlorobenzoyl chloride in the mixed reference solution is 1 mg / mL to 2 mg / mL.

7. The method for detecting related substances of 4-chlorobenzoyl chloride as claimed in claim 1, characterized in that, The chromatographic conditions of the gas chromatography also include: the detector is a hydrogen flame ionization detector.

8. The method for detecting related substances of 4-chlorobenzoyl chloride as claimed in claim 1, characterized in that, The chromatographic conditions of the gas chromatography method also include: the carrier gas is nitrogen, and the flow rate of the nitrogen is 2.8 mL / min to 3.2 mL / min.

9. The method for detecting related substances of 4-chlorobenzoyl chloride as claimed in claim 1, characterized in that, The chromatographic column is a DB-17 chromatographic column with a specification of 30m×0.32mm and a filler diameter of 0.25μm.

10. The method for detecting related substances of 4-chlorobenzoyl chloride according to claim 1, characterized in that: Preferably, the chromatographic conditions of the gas chromatography method also include: a split ratio of (5-15):1.

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