Liquid phase detection method for rapidly monitoring synthesis of 3-((allyloxy) methyl)-4-(2-(pyrrolidine-1-yl) ethyoxyl) aniline

Abstract

The invention relates to the technical field of analysis of medical intermediates, and particularly provides a liquid phase detection method for rapidly monitoring synthesis of 3-((allyloxy) methyl)-4-(2-(pyrrolidine-1-yl) ethyoxyl) aniline. High performance liquid chromatography is adopted for detection, an octadecyl bonded silica gel chromatographic column is adopted, and a mobile phase is a phosphate buffer-acetonitrile system; the detection method is simple to operate and high in sensitivity, the specificity, linearity, range and limit of quantitation all meet the requirements, the content of related impurities and non-specific impurities in 3-((allyloxy) methyl)-4-(2-(pyrrolidine-1-yl) ethyoxyl) aniline can be accurately controlled, and the detection method is suitable for large-scale popularization and application of 3-((allyloxy) methyl)-4-(2-(pyrrolidine-1-yl) ethyoxyl) aniline. Therefore, the quality of the 3-((allyloxy) methyl)-4-(2-(pyrrolidine-1-yl) ethyoxyl) aniline is effectively controlled, and the method has a good application prospect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediate analysis, and in particular to a liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline. Background Art

[0002] A pharmaceutical intermediate, chemical name: 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline, CAS number: 937273-33-1, structural formula is as follows:

[0003]

[0004] 3-((Allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline is a key intermediate in the API Pacritinib for the treatment of adult myelofibrosis and severe thrombocytopenia. Its quality will directly affect the quality of the API, especially its impurities are difficult to remove during the subsequent API synthesis process, which seriously affects the quality of the API Pacritinib. 3-((Allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline is a key intermediate in Pacritinib, and monitoring of the reaction conditions during its synthesis is crucial.

[0005] The synthetic route of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline is as follows:

[0006]

[0007] Because side reactions during the reaction process will seriously affect the quality of the product, 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine is the key raw material for the synthesis of the intermediate. Whether the raw material reaction is complete and the side reactions during the reaction process will seriously affect the quality of the paclitaxel raw material. At the same time, as an anti-tumor drug, paclitaxel has significant side effects while having significant efficacy, mainly causing adverse reactions such as diarrhea and nausea. It is well known that compounds containing nitro compounds are listed as alarm structures and have serious toxic adverse reactions. In order to reduce the adverse reactions of cancer patients during the period of taking paclitaxel and improve their quality of life, it is even more necessary to strictly control the amount of nitro compounds during the reaction process.

[0008] Therefore, it is crucial to develop a liquid phase detection method to monitor the reaction. Summary of the Invention

[0009] In view of this, the present invention proposes a detection method for rapidly monitoring the reaction process of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline. The method can monitor the progress of the reaction and stop the reaction in time, thereby better controlling the reaction at an extremely low level.

[0010] In some embodiments, the invention provides a liquid phase detection method for rapidly monitoring the reaction process of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline, wherein the chromatographic conditions of the liquid phase detection include:

[0011] The liquid chromatography column is an octadecyl bonded silica gel column;

[0012] Mobile phase A is an aqueous solution containing 0.2 wt% potassium dihydrogen phosphate;

[0013] Mobile phase B was acetonitrile;

[0014] The column temperature for liquid chromatography is 25-35°C;

[0015] A VWD UV detector was used with a detection wavelength of 205-230 nm;

[0016] The mobile phase flow rate was 1.0-1.5 mL / min;

[0017] Elution mode: gradient elution;

[0018] The injection volume is 10-20 μL;

[0019] The specific impurity is 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine.

[0020] In some embodiments, the gradient elution program is:

[0021] From 0 to 15 min, the volume ratio of mobile phase A to mobile phase B was linearly changed from (90-80):(10-20) to (40-60):(60-40);

[0022] During 15 to 20 minutes, the volume ratio of mobile phase A to mobile phase B was kept constant at (40-60):(60-40);

[0023] From 20 to 20.1 minutes, the volume ratio of mobile phase A to mobile phase B was linearly changed from (40-60): (60-40) to (90-80): (10-20);

[0024] From 20.1 to 25 minutes, the volume ratio of mobile phase A to mobile phase B remained constant at (90-80):(10-20).

[0025] In some embodiments, preferably, the gradient elution procedure is:

[0026] From 0 to 15 min, the volume ratio of mobile phase A to mobile phase B was linearly changed from 85:15 to 50:50;

[0027] The volume ratio of mobile phase A to mobile phase B was kept constant at 50:50 for 15 to 20 minutes;

[0028] From 20 to 20.1 min, the volume ratio of mobile phase A to mobile phase B was linearly changed from 50:50 to 85:15;

[0029] From 20.1 to 25 minutes, the volume ratio of mobile phase A to mobile phase B remained constant at 85:15.

[0030] In some embodiments, the chromatographic column is filled with octadecyl bonded silica gel, has a column length of 150 mm, a column inner diameter of 4.6 mm, an injection volume of 10 μL, a flow rate of 1.0 mL / min, a detection wavelength of 230 nm, and a column temperature of 30° C.

[0031] In some embodiments, solution preparation is further included, including the following preparation steps:

[0032] Diluent: mobile phase A: mobile phase B in a volume ratio of (85:15) mixed;

[0033] Impurity reference solution: Dissolve an appropriate amount of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine working standard in diluent and dilute to 1 μg / ml.

[0034] Test solution: Take 1 ml of the control reaction solution of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline, place it in a 10 ml volumetric flask, and add diluent to make up to volume.

[0035] In some embodiments, the relative retention time RT of the specific impurity 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine is 2.58.

[0036] In some embodiments, the detection method comprises:

[0037] Step 1. Prepare system suitability solution: Prepare a mixed solution of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline standard and 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine standard using diluent to prepare a solution containing 1 mg / mL of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline and 1 μg / mL of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine.

[0038] Step 2: Prepare the test solution: take 1 mL of the reaction solution and dilute it to 10 mL with diluent;

[0039] Step 3: Use the diluent as the blank solvent, and mix the blank solvent, system suitability solution, test solution, and reference solution separately; perform liquid chromatography under chromatographic conditions and record the chromatogram.

[0040] In some embodiments, the determination of a standard curve of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine and 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline is also included.

[0041] In some embodiments, the method of drawing a standard curve comprises:

[0042] S1. Accurately weigh 10 mg of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine working standard and 10 mg of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline working standard into a 100 ml volumetric flask. Dissolve in diluent and dilute to volume. Shake well to obtain a linear mixed stock solution.

[0043] S2. Accurately pipette 0.2 ml, 0.5 ml, 0.8 ml, 1.0 ml, 1.5 ml, and 2.0 ml of the linear stock solution into 100 ml volumetric flasks, add diluent to the mark, and shake well to obtain 0.2 μg / ml, 0.5 μg / ml, 0.8 μg / ml, 1.0 μg / ml, 1.5 μg / ml, and 2.0 μg / ml standard curve solutions;

[0044] S3. Take the standard curve solution and perform high performance liquid chromatography analysis. The chromatographic conditions are the above-mentioned chromatographic conditions. Draw a standard curve based on the relationship between the concentration μg / ml and the chromatographic peak area. The correction factor is 0.84.

[0045] In some embodiments, the specific impurity content is calculated using the area normalization method, and the reaction endpoint determination standard is: specific impurity content ≤ 0.05% (w / w)

[0046] Currently, there are no detection methods for this intermediate. Based on the structure of this intermediate and the raw materials, a high-performance liquid chromatography method has been developed. This method is simple and rapid to operate, completely avoiding overreactions and side reactions. It also offers excellent separation and high detection sensitivity, and has been methodologically validated. This method is fully compatible with monitoring the reaction process of the intermediate 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline.

[0047] The present invention has the following beneficial effects compared to the prior art:

[0048] (1) The instrument provided by the present invention has low operating cost, simple and convenient detection process, good repeatability, and can be used to evaluate product quality;

[0049] (2) The present invention meets the requirements in terms of system applicability and specificity, linearity and range;

[0050] (3) The detection method provided by the present invention can quickly and accurately control the amount of raw materials in the reaction process, effectively reduce the toxic and side effects of cancer patients taking paclitinib, and improve their quality of life. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0052] Figure 1 is a liquid chromatogram of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline;

[0053] Figure 2 is a liquid chromatogram of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine;

[0054] Figure 3 The hydrogen spectrum of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline;

[0055] Figure 4 The carbon spectrum of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline;

[0056] Figure 5 The hydrogen spectrum of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine;

[0057] Figure 6 This is the carbon spectrum of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine. DETAILED DESCRIPTION

[0058] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the present invention belong. If the definitions set forth in this section are contrary to or otherwise inconsistent with definitions set forth in the patents, patent applications, published patent applications, and other publications incorporated herein by reference, the definitions listed in this section take precedence over the definitions incorporated herein by reference.

[0060] Unless otherwise specified, the methods used in the following examples are conventional methods. The materials, reagents, and instruments used are conventional materials, reagents, and instruments in the art, and can be obtained commercially by those skilled in the art unless otherwise specified.

[0061] When an amount, concentration or other value or parameter is expressed as a range, a preferred range or a range defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper range limit or preferred value with any lower range limit or preferred value, regardless of whether the range is disclosed alone. For example, when a range "1 to 5" is disclosed, the described range should be interpreted as including the ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within the range. In the present specification and claims, range definitions may be combined and / or interchanged, and if not otherwise stated, such ranges include all subranges contained therein.

[0062] Example 1

[0063] A method for rapidly monitoring the reaction process of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline comprises the following steps:

[0064] (1) System suitability solution: Take 10 mg of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine working standard, accurately weigh it, transfer it to a 100 ml volumetric flask, add diluent to dissolve it and dilute it to the mark, shake well, take 100 mg of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline, accurately pipette 1.0 ml to the same 100 ml volumetric flask, add diluent to dissolve it and dilute it to the mark, shake well, and obtain 1 μg / ml 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine solution and 1 mg / ml test solution;

[0065] (2) Setting the liquid chromatograph parameters: Agilent 1260 liquid chromatograph, Openlab software, octadecyl bonded silica gel column (Waters XBridge C18 4.6×150mm 5μm), injection volume 10μL; flow rate 1.0ml / min; detection wavelength 230nm; column temperature 30℃; mobile phase A is phosphate buffer, mobile phase B is acetonitrile; gradient elution, the gradient program is as follows:

[0066]

[0067] (3) The system suitability solution was subjected to liquid chromatography under the conditions of step (2), and the chromatogram was recorded. The chromatogram was compared with the chromatogram of the test solution and the chromatogram of the reference solution to obtain the content of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine. At the same time, the chromatograms of the two substance peak positioning solutions were obtained respectively. The results were as follows: Figure 1 、 Figure 2 As shown, the hydrogen and carbon spectra of the two substances are shown in Figures 3 to 6 . .

[0068] (4) In the system suitability solution, the retention time of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine solution was 14.718 min, the retention time of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline was 5.700 min, and the separation degree was 6.78, which met the requirements.

[0069] Example 2

[0070] Specificity and system suitability

[0071] According to the chromatographic conditions of Example 1, the blank solution, system suitability solution, 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine solution, 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline solution, and the intermediate control reaction solution were injected for specificity testing. The results are shown in Table 1.

[0072] Table 1: Specificity test results

[0073]

[0074]

[0075] As shown in Table 1, the separation degree of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine and 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline is greater than 1.5, which meets the separation requirements.

[0076] Reference solution: Take an appropriate amount of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine working standard, dissolve it in diluent, dilute to the mark, and shake well to obtain a 1 μg / ml reference solution. Inject the reference solution into the liquid chromatograph and perform 6 consecutive injections. The test results are shown in Table 2.

[0077] Table 2 Test results of reference solution

[0078] Serial number Peak area Retention time 1 1330 14.711 2 1319 14.728 3 1344 14.718 4 1325 14.712 5 1331 14.713 6 1327 14.718 average value 1329 14.720 RSD% 0.63 0.04

[0079] As shown in Table 2, the reference solution was injected 6 times continuously, and the RSD of its peak area and retention time were both less than 2.0%.

[0080] Linearity and range

[0081] Preparation of linear stock solution: Take 10 mg of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine working standard and 10 mg of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline, accurately weigh them, transfer them to the same 100 ml volumetric flask, add diluent to dissolve and dilute to the scale, shake well, and obtain.

[0082] Preparation of 20% linear solution: Take 0.2 ml of linear stock solution and place it in a 100 ml volumetric flask, add diluent to the scale and shake well.

[0083] Preparation of 50% linear solution: Take 0.5 ml of linear stock solution and place it in a 100 ml volumetric flask, add diluent to the scale and shake well.

[0084] Preparation of 80% linear solution: Take 0.8 ml of linear stock solution and place it in a 100 ml volumetric flask, add diluent to the mark and shake well.

[0085] Preparation of 100% linear solution: Take 1.0 ml of linear stock solution and place it in a 100 ml volumetric flask, add diluent to the mark and shake well.

[0086] Preparation of 150% linear solution: Take 1.5 ml of linear stock solution and place it in a 100 ml volumetric flask, add diluent to the scale and shake well.

[0087] Preparation of 200% linear solution: Take 2.0 ml of linear stock solution and place it in a 100 ml volumetric flask, add diluent to the scale and shake well.

[0088] 10 μL of each of the above solutions was taken and injected into a liquid chromatograph. The chromatogram was recorded, and a standard curve was plotted with the concentration as the abscissa x and the peak area as the ordinate Y. The regression equation and correlation coefficient r were calculated, and the correction factors for 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine and 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline were calculated. The linearity results for 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine are shown in Table 3, and the linearity results for 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline are shown in Table 4.

[0089] Table 3 Linearity results of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine

[0090]

[0091]

[0092] Table 4 Linearity results of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline

[0093]

[0094] The table above shows that the correction factor F for 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine and 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline is 0.84, indicating that the main peak slope / impurity slope is 1115.9106 / 1324.6136. Therefore, the area normalization method can be used to detect the 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine impurity during the reaction monitoring of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline. Because a correction factor of 0.84 overestimates the impurity content, a limit of 0.1% is sufficient to meet the impurity control requirements of intermediates and subsequent APIs.

[0095] Limit of quantification

[0096] Quantitation limit solution: Take 3 ml of 20% linear solution, place it in a 10 ml volumetric flask, add diluent to the scale, shake well, and obtain.

[0097] Take 10 μL of the quantitation limit solution and inject it into the liquid chromatograph. Repeat six injections, record the chromatogram, and calculate the signal-to-noise ratio (S / N). The quantitation limit results are shown in Tables 5 and 6.

[0098] Table 5 Quantitation limit test results of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine

[0099]

[0100] Table 6 Quantitation limit test results of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline

[0101]

[0102] As shown in Tables 5 and 6, the method of the present invention has high detection sensitivity and can accurately determine the content of each impurity in 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline.

[0103] Example 3

[0104] A liquid phase assay for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline. The assay for the reaction liquid of the intermediate 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline produced by our company specifically includes the following steps:

[0105] 0.1 ml of each batch reaction solution was taken, 0.9 ml of diluent was added, and the mixture was mixed uniformly. The blank solvent, system suitability solution, and reaction solution were injected according to the chromatographic conditions described in Example 1. The chromatogram was recorded, and the purity of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline and the impurity content of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine were calculated according to area normalization. The results are shown in Table 7.

[0106] Table 7 Test results of each batch of in-process control reaction solution

[0107] batch purity% Impurity content% 2404010301 99.58 0.02 2404010302 99.47 0.04 2404010303 99.53 0.03 2405020401 99.62 Not detected

[0108] As can be seen from the above table, the differences between batches are small, and this method can accurately monitor the reaction and meet the experimental needs.

[0109] The above results demonstrate that this method can rapidly and accurately monitor the evolution of raw materials during the reaction of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline. Methodological validation demonstrates that the quantitative control of the content of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine in the reaction solution using area normalization provides accurate and reliable results. This method can rapidly and accurately monitor the progress of the 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline reaction, strictly control the amount of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine impurities, reduce adverse reactions in cancer patients taking Pacritinib, and improve their quality of life.

[0110] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline, characterized in that: Liquid chromatography conditions included: The liquid chromatography column is an octadecyl bonded silica gel column; Mobile phase A is an aqueous solution containing 0.2 wt% potassium dihydrogen phosphate; Mobile phase B was acetonitrile; The column temperature for liquid chromatography is 25-35°C; A VWD UV detector was used with a detection wavelength of 205-230 nm; The mobile phase flow rate was 1.0-1.5 mL / min; Elution mode: gradient elution; The injection volume is 10-20 μL; The specific impurity is 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine.

2. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 1, characterized in that: The gradient elution program was: From 0 to 15 min, the volume ratio of mobile phase A to mobile phase B was linearly changed from (90-80):(10-20) to (40-60):(60-40); During 15 to 20 minutes, the volume ratio of mobile phase A to mobile phase B was kept constant at (40-60):(60-40); From 20 to 20.1 minutes, the volume ratio of mobile phase A to mobile phase B was linearly changed from (40-60): (60-40) to (90-80): (10-20); From 20.1 to 25 minutes, the volume ratio of mobile phase A to mobile phase B remained constant at (90-80):(10-20).

3. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 1, characterized in that: The gradient elution program was: From 0 to 15 min, the volume ratio of mobile phase A to mobile phase B was linearly changed from 85:15 to 50:50; The volume ratio of mobile phase A to mobile phase B was kept constant at 50:50 for 15 to 20 minutes; From 20 to 20.1 min, the volume ratio of mobile phase A to mobile phase B was linearly changed from 50:50 to 85:15; From 20.1 to 25 minutes, the volume ratio of mobile phase A to mobile phase B remained constant at 85:

15.

4. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 1, characterized in that: The chromatographic column is filled with octadecyl bonded silica gel, has a column length of 150 mm, a column inner diameter of 4.6 mm, an injection volume of 10 μL, a flow rate of 1.0 mL / min, a detection wavelength of 230 nm, and a column temperature of 30° C.

5. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 1, characterized in that: It also includes solution preparation, including the following preparation steps: Diluent: mobile phase A: mobile phase B in a volume ratio of (85:15) mixed; Impurity reference solution: Dissolve an appropriate amount of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine working standard in diluent and dilute to 1 μg / ml. Test solution: Take 1 ml of the control reaction solution of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline, place it in a 10 ml volumetric flask, and add diluent to make up to volume.

6. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 1, characterized in that: The relative retention time RT of the specific impurity 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine is 2.

58.

7. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 1, characterized in that: The detection method comprises: Step 1. Prepare system suitability solution: Prepare a mixed solution of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline standard and 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine standard using diluent to prepare a solution containing 1 mg / mL of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline and 1 μg / mL of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine. Step 2: Prepare the test solution: take 1 mL of the reaction solution and dilute it to 10 mL with diluent; Step 3: Use the diluent as the blank solvent, and mix the blank solvent, system suitability solution, test solution, and reference solution separately; perform liquid chromatography under chromatographic conditions and record the chromatogram.

8. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 7, characterized in that: Also included are the determination of standard curves for 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine and 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline.

9. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 8, characterized in that: Standard curve drawing methods include: S1. Accurately weigh 10 mg of 1-(2-(2-((allyloxy)methyl)-4-nitrophenoxy)ethyl)pyrrolidine working standard and 10 mg of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline working standard into a 100 ml volumetric flask. Dissolve in diluent and dilute to volume. Shake well to obtain a linear mixed stock solution. S2. Accurately pipette 0.2 ml, 0.5 ml, 0.8 ml, 1.0 ml, 1.5 ml, and 2.0 ml of the linear stock solution into 100 ml volumetric flasks, add diluent to the mark, and shake well to obtain 0.2 μg / ml, 0.5 μg / ml, 0.8 μg / ml, 1.0 μg / ml, 1.5 μg / ml, and 2.0 μg / ml standard curve solutions; S3. Take the standard curve solution and perform high performance liquid chromatography analysis. The chromatographic conditions are the chromatographic conditions described in claim 1. Draw a standard curve based on the relationship between the concentration μg / ml and the chromatographic peak area. The correction factor is 0.

84.

10. The liquid phase detection method for rapidly monitoring the synthesis of 3-((allyloxy)methyl)-4-(2-(pyrrolidin-1-yl)ethoxy)aniline according to claim 9, characterized in that: The specific impurity content was calculated using the area normalization method.

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