Method for determining impurity content of fenerenone starting material 4-cyano-2-methoxybenzaldehyde

Abstract

The invention discloses a method for determining the impurity content of a fenerenone starting material 4-cyano-2-methoxybenzaldehyde, and belongs to the technical field of medical analysis. The method comprises the following steps: 1) preparing a test solution and a self-control solution; 2) setting high performance liquid detection conditions: adopting a chromatographic column taking octadecyl bonded silica gel as a filler, taking an anhydrous sodium carbonate buffer solution as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out gradient elution; and (3) respectively sucking the test solution and the self-contrast solution, injecting into a liquid chromatograph, recording a chromatogram, and quantifying by adopting a self-contrast method. According to the method, the contents of the three impurities in the 4-cyano-2-methoxybenzaldehyde can be rapidly, effectively, accurately and reliably detected, the product quality of a fenerenone raw material medicine is improved, and the medication safety of a patient is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical analysis, and in particular relates to a method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde, a starting material of finerenone. Background Art

[0002] Finerenone is a non-steroidal selective mineralocorticoid receptor antagonist that is widely used in the treatment of chronic kidney disease associated with type 2 diabetes. It can significantly reduce patients' urine albumin-to-creatinine ratio, reduce the risk of decreased renal function, renal failure, cardiovascular death, non-fatal heart attack and heart failure, and can delay the need for dialysis or kidney transplantation in the future.

[0003] In the process of drug synthesis, the detection of related substances in the starting materials is very important, which ensures the quality of the synthesis process and the purity of the final product. 4-Cyano-2-methoxybenzaldehyde is a key starting material for the synthesis of phenerenone, and it may produce more than one impurity. The detection method of 4-Cyano-2-methoxybenzaldehyde manufacturers has a low detection ability for impurities, and only controls the total impurities, and the control of each characteristic impurity is unclear.

[0004] Therefore, it is necessary to improve the inspection method for the impurity content of 4-cyano-2-methoxybenzaldehyde and establish a rapid and effective detection method, which is beneficial to improving the product quality of finerenone and improving the safety of patient medication. Summary of the invention

[0005] In order to solve the above technical problems, the present invention proposes a method for determining the impurity content in 4-cyano-2-methoxybenzaldehyde, a starting material of finerenone, by using HPLC, which can quickly, effectively, accurately and reliably separate and detect the impurity content in 4-cyano-2-methoxybenzaldehyde.

[0006] In order to solve the above problems, the technical solution adopted by the present invention is as follows:

[0007] 1. A method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde, a starting material of phenarezone, comprising the following steps:

[0008] (1) Prepare a test solution and a self-control solution of 4-cyano-2-methoxybenzaldehyde;

[0009] (2) Setting high performance liquid phase detection conditions, using octadecyl bonded silica gel as a chromatographic column filler, and gradient elution with mobile phase A and mobile phase B; the gradient elution program is: 0-8 min, the volume percentage of mobile phase A is 75%, and the volume percentage of mobile phase B is 25%; 8-20 min, the volume percentage of mobile phase A is 75%-60%, and the volume percentage of mobile phase B is 25%-40%; 20-40 min, the volume percentage of mobile phase A is 60%-30%, and the volume percentage of mobile phase B is 40%-70%; 40-70 min, the volume percentage of mobile phase A is 30%, and the volume percentage of mobile phase B is 70%;

[0010] (3) Aspirate the self-control solution and the test solution separately, inject them into the liquid chromatograph, record the chromatogram, and use the self-control method for quantification;

[0011] Among them, the names of the impurities 4-cyano-2-methoxybenzaldehyde detected in the starting material of phenaretin are: 3-methoxy-4-methylbenzonitrile, 4-dibromomethyl-3-methoxybenzonitrile and 3-hydroxy-4-methylbenzonitrile.

[0012] Furthermore, in the step 1), the method for preparing the test solution is: taking 4-cyano-2-methoxybenzaldehyde test sample, adding acetonitrile to dissolve and dilute to prepare a solution containing 0.5 mg of 4-cyano-2-methoxybenzaldehyde per 1 ml; the method for preparing the self-control solution is: taking 1 ml of the test solution, placing it in a 100 mL volumetric flask, diluting it to the scale with acetonitrile, and shaking it well to use as the self-control solution.

[0013] Furthermore, in step 2), the column temperature of the chromatographic column is 30-40°C.

[0014] Furthermore, in step 2), the mobile phase A is 0.01 mol / L anhydrous sodium carbonate, and phosphoric acid is added to adjust the pH to 9.0-10.0; and the mobile phase B is acetonitrile.

[0015] Furthermore, in step 2), the flow rate of the mobile phase is 0.9 to 1.1 mL / min.

[0016] Furthermore, in step 3), the detection wavelength of the liquid chromatograph is 250 nm.

[0017] Compared with the prior art, the advantages of the present invention are as follows:

[0018] (1) The present invention adopts a method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde by high performance liquid chromatography, and there is sufficient separation between the main component and the known impurities and other impurities, and the acetonitrile peak does not interfere with the determination of the main peak and each impurity.

[0019] (2) The degradation products produced under various destruction conditions of the present invention can be completely separated from the main peak, the degradation products do not interfere with the determination of known impurities, the reduction in the destruction of the main peak should be basically consistent with the decrease in its content, the purity of the main peak is not less than 990, the material balance, the specificity of related substance detection is good, and when the chromatographic condition parameters undergo slight changes, there is no effect on the impurity separation and inspection results, and the durability is good.

[0020] (3) The present invention can quickly, effectively, accurately and reliably detect the impurity content of 4-cyano-2-methoxybenzaldehyde, which is beneficial to improving the product quality of finerenone and improving the safety of patient medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is a test chromatogram under the chromatographic conditions of the present invention;

[0022] Figure 2 To test the undestroyed chromatogram in the destruction test;

[0023] Figure 3 It is the photodestruction chromatogram in the destruction test;

[0024] Figure 4 It is the high temperature destruction chromatogram in the destruction test;

[0025] Figure 5 It is the pyrolysis destruction chromatogram in the destruction test;

[0026] Figure 6 The acid destruction chromatogram in the destruction test;

[0027] Figure 7 It is the chromatogram of alkaline destruction in the destruction test;

[0028] Figure 8 It is the chromatogram of oxidation destruction in the destruction test;

[0029] Fig. 9 The main component linearity and range diagram of 4-cyano-2-methoxybenzaldehyde tested under the liquid chromatography conditions of the present invention;

[0030] Fig.10 Linearity and range diagram of 4-cyano-2-methoxybenzaldehyde impurity 1 tested under the liquid chromatography conditions of the present invention;

[0031] Fig.11 Linearity and range diagram of 4-cyano-2-methoxybenzaldehyde impurity 2 tested under the liquid chromatography conditions of the present invention;

[0032] Fig.12 Linearity and range diagram of 4-cyano-2-methoxybenzaldehyde impurity 3 tested under the liquid chromatography conditions of the present invention. DETAILED DESCRIPTION

[0033] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with specific embodiments.

[0034] The HPLC detection conditions used in the following examples are as follows: chromatographic column: YMC-Triart C18, size: 15 cm × 0.46 cm, 5 μm; flow rate: 1.0 mL / min; column temperature: 35 ° C; mobile phase: mobile phase A is 0.01 mol / L anhydrous sodium carbonate, phosphoric acid is added to adjust the pH to 9.50, and mobile phase B is acetonitrile; detection wavelength: 250 nm.

[0035] Example 1

[0036] A method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde by high performance liquid chromatography, the steps are as follows:

[0037] (1) Preparation of test solution and self-control solution: The test solution was prepared by taking an appropriate amount of 4-cyano-2-methoxybenzaldehyde test sample, dissolving it in acetonitrile and diluting it to make a solution containing about 0.5 mg of 4-cyano-2-methoxybenzaldehyde per 1 ml. The self-control solution was prepared by accurately pipetting 1 ml of the test solution into a 100-mL volumetric flask, diluting it to the mark with acetonitrile, and shaking it well to prepare the self-control solution.

[0038] (2) Setting the HPLC detection conditions: the chromatographic column is YMC-Triart C18 with a specification of 15 cm×0.46 cm, octadecyl bonded silica gel is used as the filler, the mobile phase A is 0.01 mol / L anhydrous sodium carbonate, phosphoric acid is added to adjust the pH to 9.50, the mobile phase B is acetonitrile, the flow rate is 1.0 mL / min for gradient elution, and the column temperature is 35°C; the detection wavelength is 250 nm, the gradient elution conditions are 0-8 min, the volume percentage of mobile phase A is 75%, and the volume percentage of mobile phase B is 25%; 8-20 min, the volume percentage of mobile phase A is 75%-60%, and the volume percentage of mobile phase B is 25%-40%; 20-40 min, the volume percentage of mobile phase A is 60%-30%, and the volume percentage of mobile phase B is 40%-70%; 40-70 min, the volume percentage of mobile phase A is 30%, and the volume percentage of mobile phase B is 70%.

[0039] (3) Accurately pipette 10 μL of the test solution and reference solution respectively, inject them into the liquid chromatograph, and record the chromatogram. The results are as follows: Figure 1 shown.

[0040] Figures 2 to 8This is a test chromatogram under the chromatographic conditions of the present invention. It can be seen from the figure that at a detection wavelength of 250nm, the main component, known impurities and unknown impurities can be well separated, and the acetonitrile peak does not interfere with the determination, which meets the standard.

[0041] Example 2

[0042] The detection method of Example 1 was validated from several aspects, including system applicability, destructive testing, limit of quantification, limit of detection, linear relationship, precision, repeatability, accuracy, solution stability, and durability.

[0043] 1. System suitability determination

[0044] Blank solution: acetonitrile

[0045] Impurity 1 localization solution: Take an appropriate amount of impurity 1 reference substance and add acetonitrile to prepare 1 ml of localization solution containing 10 μg of impurity 1.

[0046] Impurity 2 localization solution: Take an appropriate amount of impurity 2 reference substance and add acetonitrile to prepare 1 ml of localization solution containing 10 μg of impurity 2.

[0047] Impurity 3 localization solution: Take an appropriate amount of impurity 3 reference substance and add acetonitrile to prepare 1 ml of localization solution containing 10 μg of impurity 3.

[0048] Main component localization solution: Take an appropriate amount of 4-cyano-2-methoxybenzaldehyde reference substance and add acetonitrile to prepare 1 ml of localization solution containing 10 μg of 4-cyano-2-methoxybenzaldehyde.

[0049] Test solution: Accurately weigh an appropriate amount of the test sample and dissolve and dilute it with acetonitrile to make a solution containing approximately 0.5 mg of 4-cyano-2-methoxybenzaldehyde per 1 ml as the test solution.

[0050] System suitability solution: Accurately weigh an appropriate amount of the test sample, add an appropriate amount of impurity 1, impurity 2, and impurity 3 positioning solutions, dissolve and dilute with acetonitrile to make a mixed solution containing approximately 0.5 mg of 4-cyano-2-methoxybenzaldehyde test sample and 2.5 μg of impurity 1, impurity 2, and impurity 3 per 1 ml, as the system suitability solution.

[0051] 10 μl of each of the blank solution, test solution, system suitability solution and each impurity location solution was injected into the high performance liquid chromatograph, the detection wavelength was 250 nm, and the chromatogram was recorded to examine the separation of each component. The results are shown in Table 1 below.

[0052] Table 1 Impurity location and separation

[0053]

[0054] Table 1 is a table of impurity location and separation. It can be seen from the table that at a wavelength of 250nm, the main component, each known impurity and other impurities can be effectively separated, and the acetonitrile peak does not interfere with the determination of the main peak and each impurity.

[0055] 2. Destructive testing

[0056] Blank solution: acetonitrile.

[0057] Undestroyed solution: Take an appropriate amount of the test sample and dissolve and dilute it with acetonitrile to make a solution containing about 0.5 mg of 4-cyano-2-methoxybenzaldehyde per 1 ml, which is used as the undestroyed solution.

[0058] Acid destruction solution: Take an appropriate amount of the test sample, place it in a 20ml volumetric flask, add 1mL of 1mol / L hydrochloric acid solution, and destroy it at room temperature for 2h. Then add an equal amount of 1mol / L sodium hydroxide solution to neutralize it, add acetonitrile to dilute to the fixed volume, mix well, and use it as the acid destruction solution.

[0059] Alkali destruction solution: Take an appropriate amount of the test sample, place it in a 20ml volumetric flask, add 1mL of 1mol / L sodium hydroxide solution, and destroy it at room temperature for 4h. Then add an equal amount of 1mol / L hydrochloric acid solution to neutralize it, add acetonitrile to dilute to the fixed volume, mix well, and use it as the alkaline destruction solution.

[0060] Oxidative destruction solution: Take an appropriate amount of the test sample, place it in a 20ml volumetric flask, add 0.5mL of 0.2mmol / L potassium permanganate solution, and destroy it at room temperature for 1h. Then add acetonitrile to dilute to volume and mix well to prepare the oxidative destruction solution.

[0061] Photodestruction solution: Take an appropriate amount of the test sample, dissolve it in acetonitrile and dilute it to make a solution containing about 0.5 mg of 4-cyano-2-methoxybenzaldehyde per 1 ml, and photodestruct it under 365nm, 254nm and visible light for 4 hours to use as the photodestruction solution.

[0062] High temperature destruction solution: Take an appropriate amount of the test sample and place it in a 20 ml volumetric flask. Place it at 90°C for 2 hours, then add acetonitrile to dilute to volume and mix well. This is the high temperature destruction solution.

[0063] Pyrolysis destruction solution: Take an appropriate amount of the test sample, place it in a 20ml volumetric flask, add an appropriate amount of acetonitrile to dissolve it, place it at 80℃ for 1h, then add acetonitrile to dilute to volume and mix well to prepare the pyrolysis destruction solution.

[0064] Acid-base blank: Take 1 ml of 1 mol / L hydrochloric acid solution and 1 ml of 1 mol / L sodium hydroxide solution, place them in a 20 ml volumetric flask, add acetonitrile to dilute to volume, and mix well.

[0065] Oxidation blank: Take 0.5mL of 0.2mmol / L potassium permanganate solution and place it in a 20ml volumetric flask, add acetonitrile to dilute to volume, and mix well.

[0066] Take 10 μl of the system suitability solution and the above test solution and inject them into the chromatograph, record the chromatogram, and analyze the changes of each impurity. For the test solution under various destruction conditions, use diode array measurement to measure the peak purity or spectral similarity. The results are shown in Table 2 and attached. Figures 2 to 8 shown.

[0067] Table 2 Destruction investigation results

[0068] Before destruction Light damage High temperature damage Oxidative damage Acid damage Alkali damage Pyrolysis 100.00％ 99.90％ 97.45％ 98.79％ 101.09％ 98.67％ 102.50％

[0069] Figures 2 to 8 This is the test chromatogram in the destruction test. It can be seen from the figure that the degradation products produced under various destruction conditions should be completely separated from the main peak, and the degradation products do not interfere with the determination of known impurities. Table 2 is the destruction investigation result table. It can be seen from the table that the reduction in the destruction of the main peak of this product is basically consistent with the decrease in its normalized content. The total peak areas detected after the samples of the same concentration were destroyed under different conditions are basically similar, indicating that the chromatographic conditions can effectively detect the degradation impurities.

[0070] 3. Limit of Quantitation and Limit of Detection Experiments

[0071] Take appropriate amount of stock solution of main component, impurity 1, impurity 2 and impurity 3 under system suitability. Use stepwise dilution method to measure the limit of quantification (S / N≥10) and limit of detection (S / N≥3). The results are shown in Table 3 below.

[0072] Table 3 Detection limit and quantification limit

[0073]

[0074]

[0075] Table 3 is the detection limit and quantification limit results. It can be seen from the table that low concentrations of known impurities can be effectively detected under the chromatographic conditions.

[0076] 4. Injection precision

[0077] Take appropriate amount of stock solution of main component, impurity 1, impurity 2, and impurity 3 under system suitability as injection precision solution. Take 10 μL and inject into liquid chromatograph under the above chromatographic conditions, inject 6 times continuously, and record the peak area. The results are shown in Table 4 below.

[0078] Table 4 Injection precision results

[0079] Injection precision 4-Cyano-2-methoxybenzaldehyde Impurity 1 Impurity 2 Impurity 3 1 1.61225 0.96485 1.09836 1.24609 2 1.61009 0.96397 1.10187 1.26417 3 1.61224 0.96657 1.10035 1.24713 4 1.61795 0.96682 1.10475 1.26086 5 1.61450 0.96698 1.10795 1.26202 6 1.61316 0.96718 1.10742 1.25199 average 1.61336 0.96606 1.10345 1.25538 RSD% 0.17％ 0.14％ 0.35％ 0.63％

[0080] Table 4 is the injection precision result table. It can be seen from the table that the injection precision of the chromatographic conditions is good.

[0081] 5. Solution stability

[0082] Take appropriate amounts of the stock solutions of the main component, impurity 1, impurity 2, and impurity 3 to prepare reference solutions.

[0083] Take an appropriate amount of the test sample, dissolve and dilute it with acetonitrile to make a solution containing about 0.5 mg of 4-cyano-2-methoxybenzaldehyde per 1 ml, as the test sample solution.

[0084] Self-control solution: Take 1 ml of the test solution and place it in a 100 ml volumetric flask, add acetonitrile to dilute to volume, mix well, and use it as the self-control solution.

[0085] Under the above chromatographic conditions, samples were injected at 0 hours, 12 hours, 24 hours, 36 hours, 40 hours, 44 hours, 48 ​​hours, 52 hours, 56 hours and 60 hours to investigate its intraday stability.

[0086] The results are shown in Tables 5, 6 and 7 below.

[0087] Table 5 Stability results of reference solution

[0088]

[0089] Table 6 Stability results of test solution

[0090]

[0091] Table 7 Stability results of test solution

[0092]

[0093]

[0094] Table 5 is the stability result table of the reference solution, Table 6 is the stability result table of the test solution, and Table 7 is the stability result table of the self-control solution. It can be seen from Tables 5, 6 and 7 that the test solution and the reference solution have good stability within 60 hours.

[0095] 6. Linearity and range

[0096] Take appropriate amount of main component reference substance and impurity 1, 2, 3 reference substance, add acetonitrile to prepare a mixed solution containing about 5 μg of main component and impurity 1, 2, 3 in 1 ml as linear stock solution. Take the above solutions and dilute them with acetonitrile to prepare linear solutions of various concentrations according to the table below.

[0097] Table 8 Linear solution preparation table

[0098]

[0099] Under the above chromatographic conditions, linear solutions were prepared at 1.25%, 5%, 10%, 50%, 100%, and 200% limits. 10 μl of each of the above solutions was accurately measured and injected into the HPLC. The chromatogram was recorded, the peak area was determined, and linear regression was performed with the peak area A as the ordinate and the concentration C as the abscissa. The results are shown in Table 9 and Appendix Figures 9 to 12 shown.

[0100] Table 9 Linearity determination results

[0101]

[0102]

[0103] The slope K was measured based on the results of the standard curve plotted above and substituted into the following formula to calculate the relative correction factor. The results are shown in Table 10. Calculation formula:

[0104]

[0105] Where: K 主成分 : Slope of SM1 standard curve; K 杂质 : Impurity standard curve slope

[0106] Table 10 Correction factor determination results

[0107] Impurity Name Relative correction factor Impurity 1 1.73 Impurity 2 1.57 Impurity 3 1.39

[0108] Figures 9 to 12 Table 9 is the linear regression equation of the main components and known impurities of 4-cyano-2-methoxybenzaldehyde tested under the liquid chromatography conditions of the present invention. Figures 9 to 12 It can be seen that under the present chromatographic conditions, the linear results of the main component and each known impurity are good. Table 10 shows the results of the correction factor determination. The correction factors of each known impurity are all within the range of 0.2-5, and the content can be calculated by the self-control method.

[0109] 7. Repeatability

[0110] Accurately weigh the appropriate amount of the test sample, dissolve it in acetonitrile and dilute it to make a solution containing about 0.5 mg of 4-cyano-2-methoxybenzaldehyde per 1 ml as the test solution. Pipette 1 ml of the test solution and dilute it to 100 ml as the self-control solution. Repeat the measurement 6 times. The results are shown in Table 11.

[0111] Table 11 Repeatability test results

[0112]

[0113] Table 11 shows the repeatability test results. It can be seen from the table that the absolute deviation of each impurity and total impurity content of the 6 repeatability sample test results is ≤ 5% of the limit, and the repeatability is good.

[0114] 8. Accuracy

[0115] Recovery rate stock solution: Take appropriate amount of impurity 1, impurity 2, and impurity 3 reference substances, weigh accurately, add acetonitrile to dissolve and dilute to make a mixed solution containing approximately 25 μg of impurity 1, impurity 2, and impurity 3 per 1 ml.

[0116] Accurately pipette the above stock solution and dilute it according to Table 12 to prepare 50%, 100% and 200% stock solutions, and prepare 3 copies of each concentration in parallel.

[0117] Table 12 Recovery solution preparation table

[0118]

[0119]

[0120] Take 1 ml of the above recovery solution, place it in a 100 ml volumetric flask, and dilute it to the mark with acetonitrile as the control solution. Take 10 μl of each of the above samples for injection, record the peak area of ​​known impurities, and calculate the recovery rate and RSD of each known impurity. The results are shown in Table 13.

[0121] Table 13 Recovery rate experimental results

[0122]

[0123]

[0124] Table 13 shows the recovery rate experimental results. The results show that the recovery rates of impurities 1, 2, and 3 and the average recovery rate are all within the range of 92% to 105%, RSD≤10%, and the recovery rate is good.

[0125] 9. Intermediate precision

[0126] Different operators, at different times and using different instruments, conducted inspections of relevant substances on the same batch of samples using the repeatability test method. The results are shown in Table 14.

[0127] Table 14 Intermediate precision test results

[0128]

[0129] Table 14 shows the results of the intermediate precision experiment. The results show that different operators tested samples at different times and with different instruments. There was no significant change in the impurity and total impurity content of the 12 samples tested (absolute deviation ≤ 10% of the limit), and the intermediate precision was good.

[0130] 10. Durability inspection

[0131] The robustness of the method for the impurity content of cyano-2-methoxybenzaldehyde was verified mainly from five aspects: different initial proportions of mobile phase, different pH, different flow rates, different column temperatures and different chromatographic columns. The results are shown in Table 15.

[0132] Table 15 Durability conditions

[0133]

[0134] Table 16 Durability test results

[0135]

[0136] Table 16 shows the results of the durability experiment. The results show that when there are slight changes in column temperature, flow rate, initial proportion of mobile phase, and pH, and when the same model and type of chromatographic column are used, the main component and impurities 1, 2, and 3 can be effectively separated, and other impurities and blank acetonitrile do not interfere with the determination of impurities 1, 2, 3 and the main component. The test results do not change significantly. This method has good durability.

[0137] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. 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 determining the impurity content of 4-cyano-2-methoxybenzaldehyde, a starting material of finerenone, characterized in that: Here are the steps: (1) Prepare a test solution and a self-control solution of 4-cyano-2-methoxybenzaldehyde; (2) Setting high performance liquid chromatography detection conditions, using a chromatographic column with octadecyl bonded silica as a filler, and gradient elution with mobile phase A and mobile phase B; the gradient elution program is: 0-8 min, the volume percentage of mobile phase A is 75%, and the volume percentage of mobile phase B is 25%; 8-20 min, the volume percentage of mobile phase A is 75%-60%, and the volume percentage of mobile phase B is 25%-40%; 20-40min, the volume percentage of mobile phase A is 60%-30%, and the volume percentage of mobile phase B is 40%-70%; 40-70 min, the volume percentage of mobile phase A is 30%, and the volume percentage of mobile phase B is 70%; (3) Aspirate the self-control solution and the test solution separately, inject them into the liquid chromatograph, record the chromatogram, and use the self-control method for quantification; Among them, the names of the impurities 4-cyano-2-methoxybenzaldehyde detected in the starting material of phenaretin are: 3-methoxy-4-methylbenzonitrile, 4-dibromomethyl-3-methoxybenzonitrile and 3-hydroxy-4-methylbenzonitrile.

2. The method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde, a starting material of finerenone, according to claim 1, characterized in that: In the step 1), the method for preparing the test solution is: taking 4-cyano-2-methoxybenzaldehyde test sample, adding acetonitrile to dissolve and dilute to prepare a solution containing 0.5 mg of 4-cyano-2-methoxybenzaldehyde per 1 ml; the method for preparing the self-control solution is: taking 1 ml of the test solution, placing it in a 100 mL volumetric flask, diluting it to the scale with acetonitrile, and shaking it well to use as the self-control solution.

3. The method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde, a starting material of finerenone, according to claim 1, characterized in that: In step 2), the column temperature of the chromatographic column is 30-40°C.

4. The method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde, a starting material of finerenone, according to claim 1, characterized in that: In step 2), the mobile phase A is 0.01 mol / L anhydrous sodium carbonate, and phosphoric acid is added to adjust the pH to 9.0-10.0; the mobile phase B is acetonitrile.

5. The method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde, a starting material of finerenone, according to claim 1, characterized in that: In step 2), the flow rate of the mobile phase is 0.9-1.1 mL / min.

6. The method for determining the impurity content of 4-cyano-2-methoxybenzaldehyde, a starting material of finerenone, according to claim 1, characterized in that: In step 3), the detection wavelength of the liquid chromatograph is 250 nm.

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