Gas chromatography detection method for residual quantity of 2-chloropyrrole in sunitinib intermediate 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid
By using headspace sampling and gas chromatography with a highly selective ECD detector, the problem of accurately detecting 2-chloropyrrole residues in sunitinib intermediates has been solved, achieving high-sensitivity and low-cost trace detection and ensuring the accuracy and repeatability of the detection results.
Patent Information
- Application Number
- CN202511858026.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-10
- Publication Date
- 2026-02-27
AI Technical Summary
Existing technologies have difficulty accurately detecting the residual amount of 2-chloropyrrole in the sunitinib intermediate 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, especially in low-concentration trace detection. Furthermore, conventional FID detectors have poor response, and high-boiling-point samples cannot be completely vaporized, leading to incomplete detection.
Headspace sampling combined with a high-sensitivity ECD detector was used. Gas chromatography was employed to prepare an antioxidant solution, separate and calculate the residual amount of 2-chloropyrrole through a chromatographic column to ensure effective separation of the peak from the solvent, and a highly selective ECD detector was used for detection.
It achieves accurate determination of 2-chloropyrrole residues with a limit of quantification of 0.125 ng/ml, equivalent to 0.004 ppm. The detection process is simple, low-cost, and highly reproducible, making it suitable for the detection of trace amounts of genotoxic impurities.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the detection technical field, and particularly to a gas chromatography detection method for residual amount of 2-chloropyrrole in 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, which is a intermediate of sunitinib. BACKGROUND
[0002] 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is an organic compound, which is a light yellow powder, and is mainly used as a key intermediate of anticancer drug sunitinib.
[0003] The main synthesis process of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is to use tert-butyl acetoacetate as a starting material, and to prepare it through 5-step reactions. In the reaction process, genotoxic impurities 2-chloropyrrole may be produced, and a small amount of 2-chloropyrrole may be left in the product. Sunitinib is a new type of multi-target oral drug for treating tumors, and the research on genotoxic impurities is an important content in the research work of this kind of new drug. Many pharmaceutical companies will prefer to choose pharmaceutical intermediates with genotoxic impurities within an acceptable range. Therefore, the residual amount of 2-chloropyrrole used in the synthesis process of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is an important content of quality control. On October 27, 2017, the International Agency for Research on Cancer of the World Health Organization announced the preliminary arrangement of the carcinogen list. The chloride ion and pyrrole ring in the structural formula of 2-chloropyrrole are both warning structures of genotoxic impurities, and may have mutagenic and teratogenic properties. It is a potential genotoxic impurity. According to ICH M7 guidelines and the conventional oral dose of sunitinib, the acceptable intake of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is 50ppm, which is calculated by TTC. In order to fully guarantee the quality and safety of the product, the present application develops a method for detecting the residual amount of 2-chloropyrrole according to the limit of 10ppm.
[0004] 2-chloropyrrole is a volatile halogenated hydrocarbon compound with a boiling point of about 145℃. It is preferable to use GC method for detection. The response of GC method using conventional FID detector is poor for detecting this kind of compound, and trace detection of 10ppm is not applicable. Therefore, high sensitivity and high selectivity ECD detector is used to solve this problem. The boiling point of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is 374.9±42.0℃ (Predicted), and the conventional liquid injection method cannot be used. Therefore, the headspace injection method is selected to collect and analyze 2-chloropyrrole in the sample. SUMMARY
[0005] Therefore, the application provides a gas chromatography detection method for the residual amount of 2-chloropyrrole in a sunitinib intermediate 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, which can accurately and simply determine the residual amount of 2-chloropyrrole.
[0006] The technical scheme of the application is achieved as follows: the application provides a gas chromatography detection method for the residual amount of 2-chloropyrrole in a sunitinib intermediate 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, which comprises the following steps: 1) preparing a 2-chloropyrrole control solution: weighing 2-chloropyrrole, placing it in a measuring flask, diluting it with N,N-dimethylformamide as a control solution, and the concentration of 2-chloropyrrole is 1-10 mg / ml; 2) preparing a 2-chloropyrrole control solution: measuring the control solution in the above step and placing it in a measuring flask, diluting it with N,N-dimethylformamide as a control solution, and the concentration of 2-chloropyrrole is 0.022-3 μg / ml; precisely measuring the control solution and placing it in a top empty bottle, adding an antioxidant, the addition amount of the antioxidant is 0.5 mg / ml-3 mg / ml, tightly closing the bottle, gently shaking to dissolve, and then obtaining the solution; and preparing six parallel samples; 3) preparing a test solution: precisely weighing 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, placing it in a top empty bottle, dissolving it with N,N-dimethylformamide, adding an antioxidant, the addition amount of the antioxidant is 0.5 mg / ml-3 mg / ml; tightly closing the bottle, gently shaking to mix the solution uniformly, and then obtaining the solution; and preparing two parallel samples; 4) detection: detecting the 2-chloropyrrole control solution and the test solution by gas chromatography, detecting by an ECD detector, recording the peak area, and calculating the content of 2-chloropyrrole according to an external standard method.
[0007] In the gas chromatography condition of the application, the chromatographic column is a 6% cyanopropyl benzene, 94% dimethylsiloxane capillary column, the injection port temperature is 250 DEG C, the detector temperature is 280 DEG C, the carrier gas is high-purity nitrogen with a purity of greater than or equal to 99.999%, the column flow rate is 2 ml / min, the constant flow mode, the split ratio is 5:1, the oven temperature is 140 DEG C, the equilibrium time is 20 min, and the GC cycle time is 45 min.
[0008] Further, in the gas chromatography condition, the programmed temperature condition is that the initial temperature is 120 DEG C, the holding time is 10 min, and the temperature is raised to 250 DEG C at a rate of 10 DEG C / min.
[0009] Further, the antioxidant is ascorbic acid or tea polyphenol.
[0010] Further, the chromatographic column is Agilent DB-624, and the specification of the chromatographic column is 30 m*0.45 mm*2.55 µm. The sample of the control solution and the sample of the test solution is injected after 30 min of equilibrium in the gas chromatograph.
[0011] The formula for calculating the residual amount of 2-chloropyrrole is: ; Wherein: A Spl The peak area of 2-chloropyrrole in the sample solution; A std The average value of the peak area of 2-chloropyrrole in the control solution; W std The sample weight of 2-chloropyrrole in the control stock solution, in mg; W spl The sample weight of the test sample, in mg.
[0012] The present application has the following beneficial effects relative to the prior art: The gas chromatographic detection method for the residual amount of 2-chloropyrrole in the intermediate 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid of sunitinib provided by the present application can effectively separate the 2-chloropyrrole peak from the solvent peak, and the separation degree is greater than 1.5. The problem of difficult vaporization of the test sample due to high boiling point is solved by adopting headspace sampling. The problem that the FID detector cannot detect trace amounts of genotoxic impurities with a residual amount of less than 10 ppm is solved by adopting the ECD detector with high sensitivity and selectivity. The limit of quantification of 2-chloropyrrole can reach 0.125 ng / ml, which is equivalent to 0.004 ppm. This method is accurate and simple, and can accurately determine the residual amount of 2-chloropyrrole. The instrument operation cost is low, the detection process is simple and convenient, and it has good repeatability. It can be used for detecting trace amounts of genotoxic impurities in products. BRIEF DESCRIPTION OF DRAWINGS
[0013] Figure 1 The gas chromatogram of the first injection of the 2-chloropyrrole control solution of Example 1 of the present application.
[0014] Figure 2 The gas chromatogram of the test sample solution 1 of Example 1 of the present application.
[0015] Figure 3 The linear regression graph obtained in Example 3 of the present application. DETAILED DESCRIPTION
[0016] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present application.
[0017] Gas chromatography (FID detector) is usually used to analyze the purity of compounds, but in some cases, it is difficult to accurately measure the residual amount of trace halogenated alkanes, especially when it comes to the detection of halogen-based genotoxic impurities in API or pharmaceutical intermediates, which are usually ppm level limits. The halogenated alkanes detected by the ordinary FID detector generally have the disadvantages of poor peak shape and low column efficiency, and low concentration trace detection often cannot accurately detect the peak. Therefore, the FID detector cannot be used to detect most halogen-based genotoxic impurities. 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid is a solid sample with a high boiling point. Preparing a solution for gas phase detection cannot be vaporized into the chromatographic column, which will cause the residual 2-chloropyrrole to be not completely detected. Therefore, the headspace sampling method is adopted. The residual 2-chloropyrrole in the test sample is vaporized from the test sample under certain temperature conditions, and then the gas is injected into the chromatographic column through the headspace sampler, so as to achieve the purpose of separation and detection, avoiding the problem that the test sample cannot be completely vaporized.
[0018] The pyrrole ring in 2-chloropyrrole is easy to be oxidized under high temperature conditions. Adding an appropriate amount of antioxidant to the reference solution and test sample solution can effectively avoid the problem that 2-chloropyrrole is easily oxidized at high temperature in the headspace heating furnace, resulting in inaccurate detection results.
[0019] In order to further illustrate the detection method of the present application, the following different examples and comparative examples are set.
[0020] In the following examples, the instruments, chemical reagents and gas chromatography analysis conditions are as follows: Instruments and chemical reagents used: gas chromatograph (Agilent8860, Agilent Corporation), electronic balance (BS124S, Sartorius Corporation), DB-624 chromatographic column (30m x 0.45mm x 2.55µm, Agilent Corporation), N, N-dimethylformamide for chromatographic purity, 2-chloropyrrole for analytical purity.
[0021] Gas chromatography analysis conditions: Chromatographic column: 6% cyanopropyl benzene, 94% dimethylsiloxane capillary column (30m x 0.45mm x 2.55µm) Injection port temperature: 250℃ Detector temperature: 280℃ Carrier gas: High purity nitrogen Flow rate: 2 ml / min (constant flow mode) Split ratio: 5:1 Oven temperature: 140°C Equilibration time: 20 min GC cycle time: 45 min Temperature program: Initial temperature 120°C, hold for 10 min, ramp to 250°C at 10°C / min. Example 1
[0022] A gas chromatography detection method for 2-chloropyrrole residues in 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid with high efficiency detection and high detection accuracy: Solution preparation: Diluent: N,N-dimethylformamide Blank: Accurately pipette 2 ml of N,N-dimethylformamide into a top empty bottle, add about 2 mg of ascorbic acid, tighten the bottle cap, and gently shake to dissolve, and obtain.
[0023] 2-chloropyrrole control solution: Accurately weigh 300 mg of 2-chloropyrrole, accurately measure, and place in a 100 ml volumetric flask. Dilute to the mark with N,N-dimethylformamide. Accurately pipette 1.0 ml of the above solution into a 100 ml volumetric flask, and dilute to the mark with N,N-dimethylformamide. As a control stock solution.
[0024] 2-chloropyrrole control solution: Accurately pipette 1.0 ml of the above control stock solution into a 100 ml volumetric flask, and dilute to the mark with N,N-dimethylformamide. As a control solution, the concentration of 2-chloropyrrole is about 0.3 μg / ml. Accurately pipette 2 ml of the control solution into a top empty bottle, add about 2 mg of ascorbic acid, tighten the bottle cap, and gently shake to dissolve, and obtain. Take 6 parallel samples.
[0025] Test sample solution: Accurately weigh about 60 mg of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid, accurately measure, and place in a 20 ml top empty bottle. Add about 2 mg of ascorbic acid, accurately pipette 2 ml of N,N-dimethylformamide into the top empty bottle, tighten the bottle cap, and gently shake to dissolve, and obtain. Prepare 2 parallel samples.
[0026] Determination: Inject the blank, control solution, and test sample solution into the gas chromatograph, and record the chromatogram. The injection sequence is as follows:
[0027] Record the chromatogram as shown in Figure 1 and Figure 2 Figure 1 The chromatogram of the first injection of the sample solution, Figure 2 The chromatogram of sample solution 1.
[0028] Wherein Figure 1 The peak area information is as follows:
[0029] Figure 2 The peak area information is as follows:
[0030] The content of 2-chloropyrrole was calculated by the external standard method using the peak area of 2-chloropyrrole in the reference solution and the sample solution. The test results are as follows: Example 2
[0031] This example is used to verify the limit of quantification of the analysis method Blank: accurately measure 2 ml of N, N-dimethylformamide into a top empty bottle, add about 2 mg of ascorbic acid, tighten the bottle cap, and gently shake to dissolve.
[0032] Limit of quantification solution: accurately transfer 1 ml of 2-chloropyrrole reference solution in Example 1 into a 100 ml volumetric flask, dilute to the calibration mark with N, N-dimethylformamide, shake well, accurately measure 2 ml into a top empty bottle, add about 2 mg of ascorbic acid, tighten the bottle cap, and gently shake to dissolve.
[0033] Determination: take the blank and the limit of quantification solution and inject them in the following order, record the chromatogram, and calculate the signal-to-noise ratio of the 2-chloropyrrole chromatographic peak. The injection order is as follows:
[0034] The results show that the signal-to-noise ratio (S / N) of this limit of quantification solution is 369:1, so further dilute it 25 times with N, N-dimethylformamide, accurately measure 2 ml into a top empty bottle, tighten the bottle cap, inject and analyze, record the chromatogram, and the results show that the signal-to-noise ratio of the 2-chloropyrrole chromatographic peak in the diluted solution is 13.29:1, which is about 10:1, so this concentration is the limit of quantification concentration, which is 0.12498 ng / ml.
[0035] Inject the limit of quantification solution of 0.12498 ng / ml continuously for 6 times, calculate the RSD of the peak area and the peak time, and the results are as follows:
[0036] The results show that the RSD of the peak area of the 6-needle quantitative solution is 2.43%, which is much smaller than 10%, and the RSD of the peak time is only 0.03%. The signal-to-noise ratio of the 6-needle injection is stable at 12:1-14:1. The method can accurately detect 0.12 ng / ml of 2-chloropyrrole solution, and the limit of the test sample is only 0.004 ppm. Example 3
[0037] This example is used to verify the linearity of 2-chloropyrrole.
[0038] 2-chloropyrrole control linear stock solution (3 μg / ml): precisely transfer 1 ml of the 2-chloropyrrole control stock solution in Example 1 into a 10 ml volumetric flask, dilute to the calibration mark with N,N-dimethylformamide, and shake well to obtain.
[0039] Precisely transfer 0.2 ml, 0.5 ml, 1.0 ml, 1.5 ml, 2.0 ml, and 3.0 ml of the 2-chloropyrrole control linear stock solution into different 10 ml volumetric flasks, respectively, and then dilute to the calibration mark with N,N-dimethylformamide, and shake well to obtain linear solutions with concentrations of 0.06 μg / ml (20%), 0.15 μg / ml (50%), 0.30 μg / ml (100%), 0.45 μg / ml (150%), 0.6 μg / ml (200%), and 0.90 μg / ml (300%).
[0040] Linear solution ① (0.125 ng / ml, 0.04%): take the quantitative limit solution in Example 2.
[0041] Linear solution ② (0.06 μg / ml, 20%): precisely transfer 0.2 ml of the 2-chloropyrrole control linear stock solution into a 10 ml volumetric flask, dilute to the calibration mark with N,N-dimethylformamide, and shake well to obtain.
[0042] Linear solution ③ (0.15 μg / ml, 50%): precisely transfer 0.5 ml of the 2-chloropyrrole control linear stock solution into a 10 ml volumetric flask, dilute to the calibration mark with N,N-dimethylformamide, and shake well to obtain.
[0043] Linear solution ④ (0.30 μg / ml, 100%): precisely transfer 1.0 ml of the 2-chloropyrrole control linear stock solution into a 10 ml volumetric flask, dilute to the calibration mark with N,N-dimethylformamide, and shake well to obtain.
[0044] Linear solution ⑤ (0.45 μg / ml, 150%): precisely transfer 1.5 ml of the 2-chloropyrrole control linear stock solution into a 10 ml volumetric flask, dilute to the calibration mark with N,N-dimethylformamide, and shake well to obtain.
[0045] Linear solution ⑥ (0.60 μg / ml, 200%): precisely pipette 2.0 ml of the 2-chloropyrryl control linear stock solution into a 10-ml volumetric flask, dilute to the mark with N,N-dimethylformamide, shake well, and you get it.
[0046] Linear solution ⑦ (0.90 μg / ml, 300%): precisely pipette 3.0 ml of the 2-chloropyrryl control linear stock solution into a 10-ml volumetric flask, dilute to the mark with N,N-dimethylformamide, shake well, and you get it.
[0047] Precisely pipette 2 ml of each of linear solution ① to linear solution ⑦ into different headspace bottles, take three parallel samples of each concentration of solution, add about 2 mg of ascorbic acid, tighten the bottle cap, gently shake to dissolve, and you get it. Take the above solutions for sample analysis, respectively, and record the chromatogram. Linear regression is performed with the concentration of 2-chloropyrryl in the linear solution and the average peak area of 2-chloropyrryl obtained from each concentration solution, and a standard curve graph is drawn.
[0048] The linear data is summarized in the following table:
[0049] The concentration (mg / ml) is taken as the abscissa, and the 2-chloropyrryl peak area is taken as the ordinate. Linear regression is performed, and the linear results and linear equation are shown in Table 1. Figure 3 The results show that the analysis method described in Example 1 is detected, and the 2-chloropyrryl has a good linear relationship in the concentration range of 0.000125 μg / ml to 0.9 μg / ml, and the linear equation is y = 26004x + 73.653, R 2 = 0.9998 (> 0.990). Example 4
[0050] This example aims to verify the precision of the chromatographic detection method of the present application.
[0051] 2-chloropyrryl control stock solution: weigh 300 mg of 2-chloropyrryl, accurately weigh, and place it in a 100-ml volumetric flask. Dilute to the mark with N,N-dimethylformamide. Precisely pipette 1.0 ml of the above solution into a 100-ml volumetric flask, dilute to the mark with N,N-dimethylformamide, and use it as the control stock solution.
[0052] 2-chloropyrryl control solution: precisely pipette 1.0 ml of the above control stock solution into a 100-ml volumetric flask, dilute to the mark with N,N-dimethylformamide, and use it as the control solution. The concentration of 2-chloropyrryl is about 0.3 μg / ml. Precisely pipette 2 ml of the control solution into a headspace bottle, add about 2 mg of ascorbic acid, tighten the bottle cap, and gently shake to dissolve, and you get it. Take six parallel samples.
[0053] Test solution: about 60 mg of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid was accurately weighed, placed in a 20 ml headspace bottle, 2 ml of N,N-dimethylformamide was accurately measured and placed in the headspace bottle, about 2 mg of ascorbic acid was added, the bottle cap was tightly closed, and dissolution was achieved by gently shaking. Six samples were prepared in parallel.
[0054] Determination After the instrument was balanced, 6 injections of the above-mentioned 2-chloropyrrole reference solution and test solution were made, respectively, the content of 2-chloropyrrole in the 6 test solutions was calculated, and the RSD was calculated. The specific results are shown in the table below:
[0055] As can be seen from the above table data, the content of 2-chloropyrrole in the 6 test solutions is about 0.4 ppm, and the RSD of the 6 injections is 3.0%, which is much smaller than 20%, and the repeatability of the injection is good.
[0056] Comparative Example 1 On the basis of Example 1, other conditions were kept unchanged, the constant temperature mode was used, and the temperature of the chromatographic column was increased to 280℃. The separation degree of 2-chloropyrrole and the solvent peak in the test solution and the reference solution of this comparative example was less than 1, and accurate determination of the residual amount of 2-chloropyrrole could not be performed.
[0057] Comparative Example 2 On the basis of Example 1, other conditions were kept unchanged, and ascorbic acid was not added to the reference solution and the test solution. The peak of 2-chloropyrrole did not appear in the reference solution and the test solution, and the residual amount of 2-chloropyrrole in the test solution could not be calculated.
[0058] Comparative Example 3 On the basis of Example 1, other conditions were kept unchanged, and the temperature of the headspace sampler was set to 100℃. The peak area of 2-chloropyrrole in the reference solution of this comparative example was only 325, and 2-chloropyrrole did not appear in the test solution. The response was poor, and accurate determination of the residual amount of 2-chloropyrrole could not be performed.
[0059] Comparative Example 4 On the basis of Example 1, other conditions were kept unchanged, and the difference was that the FID detector headspace sampling was used. The peak area of 2-chloropyrrole in the reference solution of this comparative example was only 209, and the tailing factor was 1.6. 2-chloropyrrole did not appear in the test solution. The response was poor, and accurate determination of the residual amount of 2-chloropyrrole could not be performed.
[0060] The above is only the preferred embodiment of the present application, and is not used to limit the present application. The concentration of 2-chloropyrrole in the stock solution of the control sample can be 1-10 mg / ml; the concentration of 2-chloropyrrole in the control sample solution is 0.022-3 μg / ml; the amount of antioxidant added in the control sample solution and the sample solution is 0.5 mg / ml-3 mg / ml. Ascorbic acid can be replaced by tea polyphenol. Within the above range, good test results are obtained.
[0061] Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.
Claims
1. A gas chromatography method for detecting the amount of 2-chloropyrrole remaining in a sunitinib intermediate, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid, characterized in that, It comprises the following steps: 1) Preparation of 2-chloropyrrole control solution: 2-chloropyrrole is weighed and placed in a volumetric flask, diluted with N, N-dimethylformamide as a control stock solution, and the concentration of 2-chloropyrrole is 1-10 mg / ml; 2) Preparation of 2-chloropyrrole control solution: The control stock solution is measured and placed in a volumetric flask, diluted with N, N-dimethylformamide as a control solution, and the concentration of 2-chloropyrrole is 0.022-3 μg / ml; The control solution is precisely measured and placed in a top empty bottle, and an antioxidant is added in an amount of 0.5 mg / ml-3 mg / ml, the bottle cap is tightly closed, and the solution is dissolved by gently shaking, and then 6 samples are taken in parallel; 3) Test solution: 5-formyl-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid is precisely weighed and placed in a top empty bottle, dissolved with N, N-dimethylformamide, and an antioxidant is added in an amount of 0.5 mg / ml-3 mg / ml; The bottle cap is tightly closed, and the solution is mixed uniformly by gently shaking, and then 2 samples are prepared in parallel; 4) Detection: The 2-chloropyrrole control solution and the test solution are detected by gas chromatography, and the peak area is recorded by ECD detector, and the content of 2-chloropyrrole is calculated according to the external standard method.
2. A gas chromatography method for detecting the residual amount of 2-chloropyrrole in a sunitinib intermediate, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid according to claim 1, characterized in that, In the gas chromatography conditions, the chromatographic column is a 6% cyanopropyl benzene, 94% dimethylsiloxane capillary column, the injection port temperature is 250℃, the detector temperature is 280℃, the carrier gas is pure nitrogen with a purity of ≥99.999%, the column flow rate is 2 ml / min, the constant flow mode, the split ratio is 5:1, the oven temperature is 140℃, the equilibrium time is 20 min, and the GC cycle time is 45 min.
3. A method for detecting the amount of 2-chloropyrrole in a sunitinib intermediate, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid, by gas chromatography according to claim 2, wherein the column is a DB-5 column. In the gas chromatography conditions, the temperature programming conditions are as follows: the initial temperature is 120℃, maintained for 10 min, and then increased to 250℃ at a rate of 10℃ / min.
4. A gas chromatography method for detecting the residual amount of 2-chloropyrrole in a sunitinib intermediate, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid according to claim 2, characterized in that, The antioxidant is ascorbic acid or tea polyphenol.
5. A method for detecting the amount of 2-chloropyrrole in a sunitinib intermediate, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid, by gas chromatography according to claim 2, wherein the column is a DB-5 column. The chromatographic column is Agilent DB-624, and the specification of the chromatographic column is 30 m x 0.45 mm x 2.55 µm.
6. A method for detecting the amount of 2-chloropyrrole in a sunitinib intermediate, 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid, by gas chromatography according to claim 3, wherein the column is a DB-5 column. The control solution and the test solution are injected after being equilibrated in the gas chromatograph for 30 min.
7. A method for detecting the residual amount of 2-chloropyrrole in a sunitinib intermediate 5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxylic acid according to any one of claims 1 to 6 by gas chromatography, characterized in that, The formula for calculating the residual amount of 2-chloropyrrole is: ； Where: A Spl — peak area of 2-chloropyrrole in the test solution; A std — average of the peak areas of 2-chloropyrrole in the reference solutions; W std — the weighed amount of 2-chloropyrrole in the reference stock solution, in mg; W spl — the weighed amount of the test sample, in mg.