Method for detecting related substance 3-chloropropionic acid in osimertinib starting material 3-chloropropionyl chloride

Abstract

The invention discloses a method for detecting a related substance 3-chloropropionic acid in osimertinib starting material 3-chloropropionyl chloride, which comprises the following steps: reacting a sample with C1-C6 alkyl primary amine to preferentially convert 3-chloropropionyl chloride into an amide derivative; then adding an acyl chloride reagent and an alcohol esterification reagent, so that 3-chloropropionic acid is subjected to esterification reaction; then adding organic alkali for neutralization to obtain a stable test solution; and finally analyzing and quantifying through gas chromatography. Through step-by-step derivatization design, the interference of the main component 3-chloropropionyl chloride is thoroughly eliminated by using the preferential reaction of C1-C6 alkyl primary amine, then 3-chloropropionic acid is subjected to esterification reaction, and hydrochloric acid generated in the reaction is completely neutralized by adding organic alkali, so that the hydrolysis of the target derivative methyl 3-chloropropionate is effectively inhibited, and the stability of the target derivative methyl 3-chloropropionate is ensured. The method has the advantages of strong anti-interference performance, high accuracy, high sensitivity (the limit of quantitation is less than or equal to 0.03%), simple operation and easy industrial application.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical analysis and detection, and particularly relates to a detection method of related substance 3-chloropropanoic acid in 3-chloropropanoyl chloride. BACKGROUND

[0002] Osimertinib is an important third-generation EGFR tyrosine kinase inhibitor. 3-chloropropanoyl chloride is a key starting material in the synthesis process of osimertinib, and its quality directly affects the purity and safety of the final product osimertinib. 3-chloropropanoyl chloride is active and easy to hydrolyze to generate related substance 3-chloropropanoic acid, so a precise quantitative detection method must be established to strictly control its quality.

[0003] The prior art CN113030288A discloses a gas chromatography analysis method for detecting 3-chloropropanoyl chloride and 3-chloropropanoic acid (GC-FID) by esterification with methanol, but in this method, due to the acidic conditions of HCl generated in the esterification reaction of 3-chloropropanoyl chloride and methanol, the esterification reaction of related substance 3-chloropropanoic acid and methanol is induced, the products after esterification of the two are the same, and the esterification products are prone to hydrolytic degradation, which leads to the inability to distinguish and accurately quantify the related substance 3-chloropropanoic acid on the chromatogram, and cannot meet the strict quality control requirements.

[0004] Therefore, there is an urgent need for a detection method that can completely eliminate the interference of the main component, has high accuracy, and ensures high stability of the related substance derivative. SUMMARY

[0005] The present application aims to provide an innovative derivatization method that can stably convert the related substance 3-chloropropanoic acid in the 3-chloropropanoyl chloride sample into a detectable stable derivative, while overcoming the problems of main component interference and related substance derivative degradation; based on the innovative derivatization method, further provide a detection method with strong anti-interference, high accuracy, high stability of related substance derivative, simple operation, and easy industrial application.

[0006] In order to achieve the above-mentioned purposes, the present application adopts the following technical solutions:

[0007] On the one hand, the present application provides a derivatization method for processing 3-chloropropanoyl chloride sample to make the related substance 3-chloropropanoic acid therein detectable, comprising the following steps:

[0008] (i) contacting the sample with a C1-C6 alkyl primary amine to react, so that the 3-chloropropanoyl chloride is preferentially converted into an amide derivative;

[0009] (ii) adding an acyl chloride reagent and an alcohol esterification reagent to the reaction system of step (i) to make the 3-chloropropanoic acid undergo esterification reaction to generate a 3-chloropropanoic acid derivative.

[0010] Preferably, the C1-C6 alkyl primary amine is a C4-C6 straight-chain alkyl primary amine, preferably n-butylamine;

[0011] Preferably, the acyl chloride reagent is acetyl chloride, propionyl chloride or benzoyl chloride, preferably acetyl chloride.

[0012] Preferably, the alcohol esterification reagent is methanol, ethanol or isopropanol, preferably methanol.

[0013] Preferably, in step (i), the sample is first dissolved in an aprotic organic solvent, preferably a halogenated hydrocarbon or nitrile solvent, more preferably dichloromethane or acetonitrile.

[0014] Preferably, in step (i), the concentration of the sample is 80-100 mg / mL (calculated as 3-chloropropionyl chloride).

[0015] Preferably, the derivatization method is carried out in an ice water bath (e.g. 0-5°C).

[0016] Preferably, the ratio of the amount of the C1-C6 alkyl primary amine: 3-chloropropionyl chloride sample is 1-3 mL: 0.9 g.

[0017] Preferably, the ratio of the amount of the acyl chloride reagent: 3-chloropropionyl chloride sample is 3-5 mL: 0.9 g.

[0018] Preferably, the ratio of the amount of the alcohol esterification reagent: 3-chloropropionyl chloride sample is 8-12 mL: 0.9 g.

[0019] The present application adopts a step-by-step derivatization reaction, and in the derivatization method, an aprotic organic solvent (such as dichloromethane, acetonitrile, preferably dichloromethane) is used to dissolve the sample, which specifically solves the problem of the easy hydrolysis of 3-chloropropionyl chloride, provides a strictly hydrophobic and chemically inert reaction environment, and thus fundamentally avoids the hydrolysis side reaction. This ensures that the step-by-step derivatization reaction of the related substance 3-chloropropionic acid with the C1-C6 alkyl primary amine, the acyl chloride reagent and the alcohol reagent can be carried out quantitatively, specifically and efficiently, which lays an indispensable foundation for the accurate and stable detection of trace 3-chloropropionic acid through gas chromatography.

[0020] In the derivatization method, the C1-C6 alkyl primary amine (such as n-butylamine) is added to the sample solution, which preferentially reacts with 3-chloropropionyl chloride to generate an inert amide derivative (such as ClCH2CH2CONHC4H9), completely eliminating the interference of 3-chloropropionyl chloride derivatization and improving the detection accuracy.

[0021] The acyl chloride reagent (such as acetyl chloride) is added in the derivatization method to consume the excess C1-C6 alkyl primary amine (such as n-butylamine) and provide an acidic environment, catalyzing the esterification reaction of 3-chloropropionic acid with the alcohol reagent (such as methanol) to generate 3-chloropropionic acid ester (such as ClCH2CH2COOCH3).

[0022] In another aspect, the present application provides a method for detecting 3-chloropropionic acid, a related substance of 3-chloropropionyl chloride, comprising the following steps:

[0023] a) Derivatizing the 3-chloropropionyl chloride sample by using any of the above-mentioned derivatization methods;

[0024] b) Adding an organic base to neutralize the reaction system to obtain a stable test solution;

[0025] c) Performing gas chromatography analysis on the test solution to determine the content of 3-chloropropionic acid.

[0026] Preferably, the organic base is pyridine or triethylamine, and more preferably pyridine.

[0027] Preferably, the concentration of the test solution is 15-20 mg / mL (based on the original 3-chloropropionyl chloride), and more preferably 18 mg / mL (based on the original 3-chloropropionyl chloride).

[0028] Preferably, the amount of the organic base: 3-chloropropionyl chloride sample is 4-7.5 mL: 0.9 g, and more preferably 5 mL: 0.9 g.

[0029] Preferably, the detection method comprises the following steps:

[0030] a) Contacting the 3-chloropropionyl chloride sample with n-butylamine to react, so that the 3-chloropropionyl chloride is preferentially converted into an amide derivative; adding acetyl chloride and methanol to the reaction system to make the 3-chloropropionic acid undergo esterification to generate 3-chloropropionic acid methyl ester;

[0031] b) Adding pyridine to neutralize the reaction system to obtain a stable test solution;

[0032] c) Performing gas chromatography analysis on the test solution to determine the content of 3-chloropropionic acid.

[0033] In step b), the organic base (such as pyridine) is added to completely neutralize the hydrochloric acid (HCl) generated in the derivatization method / step a), so that the 3-chloropropionic acid ester (such as ClCH2CH2COOCH3) is stable.

[0034] Preferably, in step c), the conditions of the gas chromatography analysis are as follows:

[0035] The gas chromatograph is Agilent 7890B GC-FID.

[0036] and / or, the chromatographic column is selected from a column with stationary phase comprising cyanopropyl phenyl polysiloxane; preferably DB-1701, further preferably, with specification of 30 m x 0.25 mm, 1.00 μm;

[0037] and / or, the injection port temperature is 260-300℃, preferably 280℃;

[0038] and / or, the gas chromatograph is programmed with a program of starting temperature 75-85℃ and maintaining for 4-6 minutes, then increasing the temperature to 210-230℃ at a rate of 15-25℃ per minute and maintaining for 15-25 minutes; preferably, starting temperature 80℃, maintaining for 5 minutes, increasing the temperature to 220℃ at a rate of 20℃ per minute, maintaining for 20 minutes;

[0039] and / or, the detector temperature is 280-320℃, preferably 300℃;

[0040] and / or, the split ratio of the gas chromatograph is 45:1 to 55:1, preferably 50:1;

[0041] and / or, the injection volume is 0.5-2 μL, preferably 1 μL.

[0042] Preferably, the content is calculated by external standard method in step c);

[0043] More preferably, step c) is: the test sample solution and the control solution of known concentration of 3-chloropropanoic acid are detected by gas chromatography, the content of 3-chloropropanoic acid is calculated by external standard method, and the calculation formula is:

[0044]

[0045] wherein,

[0046] A 样 is the peak area of 3-chloropropanoic acid in the chromatogram of the test sample solution;

[0047] A 对 is the peak area of 3-chloropropanoic acid in the chromatogram of the control solution;

[0048] C 对 is the concentration of 3-chloropropanoic acid in the control solution;

[0049] N is the volume of the test sample solution;

[0050] m is the weight of the 3-chloropropanoyl chloride sample.

[0051] More preferably, the limit of quantification of the detection method for 3-chloropropanoic acid is ≤0.03%.

[0052] In another aspect, the present application provides application of any of the above-mentioned derivatization methods or any of the above-mentioned detection methods in quality control of osimertinib or its analogues or its starting materials.

[0053] The target derivative and the 3-chloropropionic acid derivative described in the present application are both 3-chloropropionic acid esters (such as 3-chloropropionic acid methyl ester / ClCHCH2COOCH3).

[0054] Compared with the prior art, the detection method and the derivatization method contained therein provided by the present application have the following beneficial effects:

[0055] 1. Strong anti-interference and high accuracy: the present application first converts a large amount of 3-chloropropionyl chloride in the sample into an inert amide (such as the inert amide ClCH2CH2CONHC4H9 when the C1-C6 alkyl primary amine is n-butylamine) by using an innovative step-by-step derivatization reaction, thereby completely eliminating the interference of the 3-chloropropionyl chloride on the subsequent derivatization process of the related substance 3-chloropropionic acid, and finally achieving a recovery rate of 94.34% to 109.56% with high accuracy.

[0056] 2. High stability of the target derivative: after the derivatization is completed, a sufficient amount of organic base (such as pyridine) is added to completely neutralize the hydrochloric acid (HCl) generated in the reaction system, which effectively inhibits the acid-catalyzed hydrolysis of the target derivative trichloropropionic acid ester (such as 3-chloropropionic acid methyl ester) in the subsequent processing and analysis process. According to tests, the peak area changes by less than 5% after the derivatized test sample solution is placed at room temperature for 41 hours, showing excellent stability.

[0057] 3. High sensitivity: through systematic optimization of the gas chromatography conditions, especially by selecting a DB-1701 chromatographic column and using a low-temperature programmed heating strategy, the thermal decomposition of the target derivative in the injection port and the chromatographic column is significantly reduced, thereby improving the chromatographic peak response. The method has a high signal-to-noise ratio, and the limit of quantification can reach 0.03%, which can meet the precise detection requirements of trace 3-chloropropionic acid.

[0058] 4. Simple operation and easy industrial application: the detection method of the present application only needs to use an ice water bath (such as 0-5°C) and a conventional gas chromatograph and conditions, without the need for expensive low-temperature experiments or equipment or liquid chromatography-mass spectrometry (LC-MS / MS), which significantly reduces the detection cost and is simple to operate, and is particularly suitable for quality control and analysis in industrial production processes. BRIEF DESCRIPTION OF DRAWINGS

[0059] Figure 1 : Chromatogram of blank solution in specificity test of Example 1;

[0060] Figure 2: Example 1 specificity test chromatogram of the sample solution (where AXTN-SM4-ZZ1 is a 3-chloropropionic acid derivative ClCH2CH2COOCH3).

[0061] Figure 3 : Example 1 specificity test chromatogram of the sample solution (where AXTN-SM4-ZZ1 is a 3-chloropropionic acid derivative ClCH2CH2COOCH3). DETAILED DESCRIPTION

[0062] The method of the present application will be described below by means of specific examples, so that the technical solution of the present application is easier to understand and grasp, but the present application is not limited thereto. In the following examples, the experimental methods described are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0063] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the tables needed to be used in the embodiment or prior art description, and the tables described below are only examples of the present application and do not constitute a limitation on the technical solutions of the present application.

[0064] Example 1

[0065] Instrument: Agilent 7890B GC-FID gas chromatograph

[0066] Gas chromatography conditions:

[0067] Chromatographic column: DB-1701 (30 m x 0.25 mm, 1.00 μm); programmed temperature: initial temperature 80℃, maintain for 5 minutes, increase the temperature to 220℃ at a rate of 20℃ per minute, maintain for 20 minutes; injection port temperature: 280℃; detector (FID) temperature: 300℃; flow rate: 3 mL / min; split ratio: 50:1; injection volume: 1 μL

[0068] Solution preparation:

[0069] (1) Blank solution: take dichloromethane 10 mL, n-butylamine 2 mL, place in a 50 mL volumetric flask, add acetyl chloride 4 mL in an ice water bath, shake well, then add methanol 10 mL, shake well, then shake at room temperature at 300 rpm for 10 min, add pyridine 5 mL, and dilute to volume with methanol.

[0070] (2) Reference substance stock solution: take 3-chloropropionic acid 270 mg, accurately weigh, place in a 50 mL volumetric flask, dissolve and dilute to the mark with dichloromethane.

[0071] (3) Control solution: take 5 mL of control stock solution, 5 mL of dichloromethane, 2 mL of n-butylamine, and put them into a 50 mL volumetric flask. Add 4 mL of acetyl chloride in an ice water bath (0-5°C), shake well, then add 10 mL of methanol, mix well, shake at 300 rpm at room temperature for 10 min, add 5 mL of pyridine, and dilute with methanol.

[0072] (4) Test solution (including derivatization and neutralization steps): take about 900 mg of 3-chloropropionyl chloride sample, accurately weigh, put into a 50 mL volumetric flask, add 10 mL of dichloromethane, shake well, add 2 mL of n-butylamine in an ice water bath (0-5°C), shake well, then shake at 300 rpm at room temperature for 10 min, add 4 mL of acetyl chloride in an ice water bath (0-5°C), shake well, then add 10 mL of methanol, shake well, then shake at 300 rpm at room temperature for 10 min, add 5 mL of pyridine, and dilute with methanol.

[0073] Detection and calculation: accurately take 1 μL of the blank solution, the control solution, and the test solution, inject into the gas chromatograph, record the chromatogram, and calculate the concentration of the test solution and the content of the related substance 3-chloropropionic acid in the test solution by peak area according to the external standard method.

[0074] Calculation formula:

[0075]

[0076] A 样 is the peak area of 3-chloropropionic acid in the chromatogram of the test solution;

[0077] A 对 is the peak area of 3-chloropropionic acid in the chromatogram of the control solution;

[0078] C 对 is the concentration of 3-chloropropionic acid in the control solution;

[0079] C 供 is the concentration of 3-chloropropionic acid in the test solution;

[0080] N is the volume of the test solution;

[0081] m is the weight of the 3-chloropropionyl chloride sample.

[0082] Specificity test:

[0083] Accurately take 1 μL of the blank solution, the control solution, and the test solution, inject into the gas chromatograph, and record the chromatogram. The blank solution has no interference with the determination, and the control solution has no interference with the determination of the test solution. The chromatogram is shown in Figure 1. Figure 1The chromatogram of the test solution, wherein AXTN-SM4-ZZ1 is a 3-chloropropionic acid derivative (i.e. ClCH2CH2COOCH3), shows that the peak of the 3-chloropropionic acid derivative is separated from the matrix baseline, indicating that the method has good specificity.

[0084] Limit of quantification test:

[0085] An appropriate amount of the reference solution was diluted with methanol, and 1 μl was precisely taken and injected into the gas chromatograph, and the chromatogram was recorded. The limit of quantification was calculated when S / N≥10. The results showed that when the concentration of 3-chloropropionic acid was 5.77 μg / mL, S / N was 20.6, and the content of the related substance 3-chloropropionic acid in the 3-chloropropionyl chloride sample was 0.03%.

[0086] Accuracy test:

[0087] Accuracy solution: about 900 mg of the 3-chloropropionyl chloride sample (the content of 3-chloropropionic acid in the sample had been determined) was precisely weighed, and the weight was recorded. An appropriate amount of the reference stock solution was added (so that the added content was 0.3%, 3%, and 4.5%) to a 50 mL volumetric flask, which was shaken, 10 mL of dichloromethane was added, which was shaken, 2 mL of n-butylamine was added in an ice water bath, which was shaken, and then shaken at 300 rpm at room temperature for 10 min. 4 mL of acetyl chloride was added in an ice water bath, which was shaken, and then 10 mL of methanol was added, which was shaken, and then shaken at 300 rpm at room temperature for 10 min. 5 mL of pyridine was added, and the volume was adjusted with methanol.

[0088] Three portions were prepared for each concentration, 1 μL was precisely taken and injected into the gas chromatograph, the chromatogram was recorded, and the recovery rate was calculated. The results are shown in the table below.

[0089]

[0090] Note 1: The measured amount of the related substance is the actual measured weight of 3-chloropropionic acid;

[0091] Note 2: The amount of the related substance brought in is the weight of 3-chloropropionic acid contained in the 3-chloropropionyl chloride sample;

[0092] Note 3: The amount of the related substance added is the weight of the added 3-chloropropionic acid reference;

[0093] Note 4: Recovery rate = (measured amount - amount brought in) / added amount * 100%.

[0094] It can be seen that the recovery rate of each concentration is between 94.34% and 109.56% with RSD < 5%, indicating that the method has good recovery rate and high accuracy.

[0095] Testers A and B respectively according to the test sample solution configuration method parallel configuration of 6 test sample solutions, respectively, precision 1 μL, injected into the gas chromatograph, record 3-chloropropanoic acid peak area, the results of the following table:

[0096]

[0097] The results show that the RSD is less than 3%, the detection method is good precision.

[0098] Linear test:

[0099] Precision 1 μL, injected into the gas chromatograph, record chromatogram, the results are as follows.

[0100]

[0101] It can be seen that when the concentration of 3-chloropropanoic acid is 53.37 μg / mL-1067.31 μg / mL, the relative content of 3-chloropropanoic acid in the test sample is in the range of 0.3%-6%, the linear equation is y=0.1707x+0.0044, r=0.9999, and the detection method is linear.

[0102] Stability test:

[0103] The prepared control solution and test sample solution were placed at room temperature for 12 h or other time points, and were determined according to the above method, and the peak area was recorded. The results are as follows.

[0104] Time of placement (h) Control solution peak area Change (%) Time of placement (h) Test solution Change (%) 0 104.025 / 0 37.376 / 12 104.330 0.3 12 37.383 0.1 45 104.495 0.5 41 38.898 4.1

[0105] The control solution was placed at room temperature for 45 h, and the peak area changed by 0.5%. The test sample solution was placed at room temperature for 41 h, and the peak area changed by 4.1%. Both were less than 5%, indicating that the derivative of the test sample solution was stable.

[0106] Comparative Example 1

[0107] According to the method of Example 1, the n-butylamine of step (4) test sample solution (including the steps of derivatization and neutralization) was replaced with an equal molar amount of aniline. The results showed that the peak area of 3-chloropropanoic acid derivative (i.e. ClCH2CH2COOCH3) increased from 194.635 to 516.450 at room temperature for 1 hour, showing a significant growth trend, indicating that the derivative is extremely unstable when aniline (aromatic amine) is used.

[0108] Comparative Example 2

[0109] Following the procedure of Example 1, the amount of pyridine used in the preparation of the test sample solution (including derivatization and neutralization steps) was replaced with 3 mL. The results showed that the peak area of the 3-chloropropionic acid derivative (i.e., ClCH2CH2COOCH3) increased from 51.767 to 57.457 over 3 hours at room temperature, indicating that an insufficient amount of organic base (3 mL) can result in a decrease in the stability of the derivative.

Claims

1. A derivatization method for treating a 3-chloropropionyl chloride sample to make the related substance 3-chloropropionic acid detectable therein, characterized in that, Includes the following steps: (i) The sample is reacted with a C1-C6 alkyl primary amine to preferentially convert 3-chloropropionyl chloride into an amide derivative; (ii) Add an acyl chloride reagent and an alcohol esterification reagent to the reaction system of step (i) to cause the 3-chloropropionic acid to undergo an esterification reaction to generate a 3-chloropropionic acid derivative.

2. The derivatization method as described in claim 1, characterized in that: The C1-C6 alkyl primary amine is a C4-C6 straight-chain alkyl primary amine, preferably n-butylamine; And / or, the acyl chloride reagent is acetyl chloride, propionyl chloride or benzoyl chloride, preferably acetyl chloride; And / or, the alcohol esterification agent is methanol, ethanol or isopropanol, preferably methanol.

3. The derivatization method as described in claim 1 or 2, characterized in that: In step (i), the sample is first dissolved in an aprotic organic solvent, preferably a halogenated hydrocarbon or nitrile solvent, more preferably dichloromethane or acetonitrile; And / or, the concentration of the sample is 80-100 mg / mL (calculated as 3-chloropropionyl chloride).

4. The derivatization method according to any one of claims 1-3, characterized in that: The derivatization method is carried out in an ice-water bath (e.g., 0-5°C); And / or, the ratio of the C1-C6 alkyl primary amine to 3-chloropropionyl chloride sample is 1-3 mL: 0.9 g; And / or, the ratio of the acyl chloride reagent to the 3-chloropropionyl chloride sample is 3-5 mL: 0.9 g; And / or, the ratio of the alcohol esterification reagent to 3-chloropropionyl chloride sample is 8-12 mL: 0.9 g.

5. A method for detecting 3-chloropropionic acid, a related substance in 3-chloropropionyl chloride, characterized in that, Includes the following steps: a) Derivatize the sample using the method described in any one of claims 1-4; b) Add an organic base to the reaction system to neutralize it, and a stable test solution is obtained; c) Perform gas chromatography analysis on the test solution to determine the content of 3-chloropropionic acid.

6. The detection method as described in claim 5, characterized in that: The organic base is pyridine or triethylamine, preferably pyridine.

7. The detection method as described in claim 5 or 6, characterized in that: The concentration of the test solution is 15-20 mg / mL (based on the original 3-chloropropionyl chloride), and / or the ratio of the organic base to the 3-chloropropionyl chloride sample is 4-7.5 mL: 0.9 g.

8. The detection method according to any one of claims 5-7, characterized in that, In step c), the conditions for the gas chromatography analysis are as follows: The gas chromatograph is an Agilent 7890B GC-FID. And / or, the chromatographic column is selected from a column whose stationary phase contains cyanopropylphenyl polysiloxane; preferably DB-1701, more preferably, with dimensions of 30m × 0.25mm, 1.00μm; And / or, injection port temperature: 260-300℃; And / or, the gas chromatograph uses a programmed temperature rise, the program of which is: an initial temperature of 75-85°C and maintained for 4-6 minutes, then the temperature is increased to 210-230°C at a rate of 15-25°C per minute and maintained for 15-25 minutes; And / or, the detector temperature is 280-320℃; And / or, the split ratio of the gas chromatograph is 45:1-55:1; And / or, the injection volume is 0.5-2 μL.

9. The detection method according to any one of claims 5-8, characterized in that: In step c), the content is calculated using the external standard method; preferably, step c) involves: performing gas chromatography analysis on the test solution and a reference solution of 3-chloropropionic acid of known concentration, and calculating the content of 3-chloropropionic acid using the external standard method, with the following formula: in, A 样 The peak area of ​​3-chloropropionic acid in the chromatogram of the test solution; A 对 The peak area of ​​3-chloropropionic acid in the chromatogram of the control solution is shown. C 对 This represents the concentration of 3-chloropropionic acid in the reference solution; N is the volume of the test solution; m is the amount of 3-chloropropionyl chloride sample weighed. And / or, the detection method has a limit of quantification of ≤0.03% for 3-chloropropionic acid.

10. The application of the derivatization method according to any one of claims 1-4 and the detection method according to any one of claims 5-9 in the quality control of osimertinib or its analogues or their starting materials.

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