A high performance liquid chromatography separation method for various substances in the reaction process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt

Abstract

A high-performance liquid chromatography separation method for various substances in a bis-(N-bis(dimethylamino)methylene)-immonium chloride salt comprises the following steps: during the preparation of the bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, an aniline solution is added, and the remaining amount of intermediates and raw materials and the generated amount of target products in each step can be accurately analyzed by a high-performance liquid chromatograph; the reaction end point can be more accurately determined by the amount of each substance, the reaction time is saved, the reaction yield is improved, and the method makes up for the lack of an analytical method for monitoring the reaction progress in the synthesis process of the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt. The method has important guiding significance for the optimization of experimental conditions and provides technical support for laboratory research and development and industrial production.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals, and in particular relates to a high performance liquid chromatography separation method for various substances in the reaction process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt. Background Art

[0002] Fluorinated aromatic compounds have unique physical and chemical properties and biological activity. They are one of the fastest growing chemicals in the field of fine chemicals. They are widely used in medicine, pesticides, light industry, materials, electronics and other fields. They have broad development prospects and strong vitality. The synthesis and application of aromatic fluorides have become the focus of research and development of research institutions and enterprises in various countries. There are many methods for the synthesis of aromatic fluorides. Among them, the halogen exchange method through the Halex reaction is the main industrial synthesis method. Due to the characteristics of its reaction, it is often necessary to add an appropriate phase transfer catalyst to the Halex reaction system to effectively promote the fluorination reaction, make the reaction milder and faster, and obtain higher selectivity and yield of aromatic fluorides. Commonly used phase transfer catalysts include quaternary ammonium salts, quaternary phosphonium salts and ethers. N-alkyl conjugated quaternary ammonium salts are a novel phase transfer catalyst that is resistant to high temperatures and highly active. It can obtain high yields of aromatic fluorides at lower reaction temperatures and shorter reaction times. It has received widespread attention and application in recent years.

[0003] In the document "Chemical World" (Yang Weiling, Song Fen, Su Xiaoli, Chem. World, 2018, 59(9), 576-580), the synthesis of N-alkyl conjugated ionic quaternary ammonium salt catalysts and their application in phase transfer catalysis Halex reaction were studied, but no literature reports on methods for monitoring the progress of the reaction during the catalyst synthesis process were found.

[0004] In the synthesis of catalysts, the endpoint of chlorination reaction is determined by whether bubbles are generated in the reaction system when diphosgene is added; the endpoint of condensation reaction is determined by whether the reaction solution turns brown. There are too many uncertainties in judging the progress of the reaction based on traditional experimental phenomena. If you want a shorter reaction time, lower production cost, higher catalyst purity and synthesis yield, you need to develop a routine laboratory detection method to monitor the reaction process, which is very necessary for laboratory research and development and enterprise production. Summary of the invention

[0005] The object of the present invention is to provide a high performance liquid chromatography separation method for various substances in the reaction process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, which can accurately and efficiently detect bis-(N-bis(dimethylamino)methylene)-immonium chloride salt and impurity content, monitor the reaction process of preparing bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, shorten the reaction time, reduce the production cost, and improve the product purity and yield.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] A high performance liquid chromatography separation method for various substances in a bis-(N-bis(dimethylamino)methylene)-immonium chloride reaction process comprises the following steps:

[0008] 1) taking the chlorination reaction solution in the preparation process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, adding aniline solution and stirring until the reaction is complete, then adding 40-90% by volume acetonitrile aqueous solution, shaking well to obtain sample solution 1, and setting aside;

[0009] 2) taking the condensation reaction liquid in the preparation process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, adding aniline solution and stirring until the reaction is complete, then adding 40-90% by volume acetonitrile aqueous solution, shaking well to obtain sample solution 2, and setting aside;

[0010] 3) The sample solution 1 and the sample solution 2 obtained in step 1) and step 2) are separated by a high performance liquid chromatograph, using a chromatographic column with octadecylsilane bonded silica gel as a filler, acetonitrile and buffer as mobile phases, and the following chromatographic separation conditions:

[0011] Detection wavelength: 220nm~240nm;

[0012] Mobile phase flow rate: 0.8mL / min~1.0mL / min;

[0013] Gradient elution was performed, and the gradient elution program was as follows: 0-5 min: acetonitrile volume fraction was 1%; 5-25 min: acetonitrile volume fraction increased uniformly from 1% to 100%; 25-30 min: acetonitrile volume fraction was 100%.

[0014] Furthermore, it is characterized in that the high performance liquid chromatography method uses an ultraviolet detector to detect bis-(N-bis(dimethylamino)methylene)-immonium chloride salt and impurities, and the detection wavelength is 220nm to 240nm.

[0015] Furthermore, the column temperature is 35-45°C.

[0016] Furthermore, the injection volume is 5 to 10 μL.

[0017] Preferably, the buffer solution is water, a 0.05% by volume phosphoric acid aqueous solution, or a 0.1% by volume phosphoric acid aqueous solution.

[0018] Preferably, the chromatographic column is one of the following chromatographic columns:

[0019] Brand: SHIMADZU-GL WondaCract ODS-2, specification: 4.6*250mm*5μm;

[0020] Brand: Agilent ZORBAX Eclipse XDB-C18, specification: 4.6*150mm*5μm;

[0021] Brand: GL Sciences Inertsil ODS-3, specification: 4.6*250mm*5μm.

[0022] Further, the preparation method of the bis-(N-bis(dimethylamino)methylene)-immonium chloride salt comprises the following steps:

[0023] 1) Tetramethylurea and ethylene dichloride were added into a reaction apparatus, and diphosgene was slowly added dropwise at 20-30° C. After the addition was completed, the temperature was maintained at 20-30° C. and stirring was continued to carry out chlorination reaction;

[0024] 2) After the chlorination reaction is completed, the temperature is controlled at 20-40° C., tetramethylguanidine is added dropwise to the solution, and after the addition is completed, the temperature is maintained at 20-40° C. and the condensation reaction is continued by stirring. After the reaction is completed, the solvent dichloroethane is evaporated to obtain the catalyst bis-[N-bis(dimethylamino)methylene]-chloroimide salt.

[0025] Preferably, the added amount of the aniline solution is 5 to 20 times the mass fraction of tetramethylurea.

[0026] In actual applications, the R&D personnel of our laboratory found that the intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride produced during the reaction of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt cannot be vaporized and produce a peak in GC because it exists in the form of chloride salt. In addition, due to its high activity, it immediately generates the raw material tetramethylurea when it comes into contact with water, so it cannot be directly monitored using HPLC.

[0027] When using HPLC separation method to separate bis-(N-bis(dimethylamino)methylene)-immonium chloride and related substances, the active intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride has high activity and will generate tetramethylurea immediately when it meets water. It cannot be directly detected by HPLC. The reaction is as follows:

[0028]

[0029] Therefore, bis-(N-bis(dimethylamino)methylene)-immonium chloride and related substances cannot be directly detected by high performance liquid chromatography separation method.

[0030] In the preparation process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, a derivatization reagent aniline is added, wherein the active intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride positive ion and aniline undergo a derivatization reaction as follows:

[0031]

[0032] In the preparation process of the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, aniline is added to the chlorination reaction solution in the first step, and high performance liquid chromatography separation can detect the raw material tetramethyl urea and the generated active intermediate N-(dimethylamino-chloro)methylene-dimethylamino ammonium chloride.

[0033] In the second step, aniline is added to the condensation reaction solution, and high performance liquid chromatography separation can detect the product bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, the raw material tetramethylguanidine hydrochloride, the active intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride generated by the first step chlorination reaction, and the raw material tetramethylurea.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] By monitoring the remaining amount of raw materials and the amount of target product generated during the reaction process with a high performance liquid chromatograph, the reaction endpoint can be determined more accurately, reaction time can be saved, and the reaction yield can be improved. This fills the gap in the lack of an analytical method to monitor the reaction process during the synthesis of the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, has important guiding significance for the optimization of experimental conditions, and provides technical support for laboratory research and development and industrial production.

[0036] The high performance liquid chromatography separation method provided by the invention can effectively detect bis-(N-bis(dimethylamino)methylene)-immonium chloride salt and various impurity peaks, and has good separation effect, good precision, high accuracy, simple operation and small sampling amount. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 is the HPLC spectrum of the blank solvent sample 1 in Example 3;

[0038] Figure 2 is the HPLC spectrum of the blank solvent sample 2 in Example 3;

[0039] Figure 3is the HPLC spectrum of the system suitability solvent sample 3 in Example 3;

[0040] Figure 4 is the HPLC spectrum of the system suitability solvent sample 4 in Example 3;

[0041] Figure 5 This is the HPLC spectrum of sample 4 during the precision test.

[0042] Figure 6 This is the HPLC spectrum of the test solvent sample 5.

[0043] Figure 7 is the HPLC spectrum of the test solvent sample 6; DETAILED DESCRIPTION

[0044] The present invention is further described below in conjunction with specific embodiments.

[0045] Solution configuration:

[0046] (1) Preparation of blank solution:

[0047] Sample 1: 80% (40-90%) acetonitrile aqueous solution by volume.

[0048] Sample 2: Weigh 0.2 g (0.0845 g to 0.4584 g) of aniline solution into a 50 mL volumetric flask, add 80% (40 to 90%) acetonitrile aqueous solution to the mark, shake well and set aside.

[0049] (2) Preparation of system adaptability solution:

[0050] Sample 3: Weigh 0.1 g of the above chlorination reaction solution into a 50 mL volumetric flask, add 5 to 20 times the mass fraction of tetramethyl urea as the raw material in the system (i.e., 0.0845 g to 0.338 g of aniline solution), shake to promote complete reaction of the active intermediate, then add 80% (40% to 90%) acetonitrile aqueous solution to the scale, shake well and set aside.

[0051] Sample 4: Weigh 0.1 g of the above condensation reaction solution into a 50 mL volumetric flask, add 5 to 20 times the mass fraction of tetramethylguanidine as the raw material in the system (i.e., 0.1146 g to 0.4584 g of aniline solution), shake to promote complete reaction of the active intermediate, then add 80% (40% to 90%) acetonitrile aqueous solution to the scale, shake well and set aside.

[0052] (3) Preparation of test solution:

[0053] Sample 5: Accurately weigh 0.1250 g (accurate to 0.0001 g) of the pure catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt into a 100 mL volumetric flask, add 80% (40% to 90%) acetonitrile aqueous solution to the scale, and shake to obtain a test solution of the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt with a concentration of 1.25 mg / mL.

[0054] Sample 6: Accurately weigh 0.0248 g of impurity A and 0.0212 g of impurity D in a 50 mL volumetric flask, add 80% (40% to 90%) acetonitrile aqueous solution to the scale, and shake to obtain a test solution with an impurity concentration of 0.496 mg / mL and an impurity D concentration of 0.424 mg / mL.

[0055] (4) Preparation of comparative solution

[0056] Sample 7: Weigh 0.1 g of the above chlorination reaction solution into a 50 mL volumetric flask, add 80% (40% to 90%) acetonitrile aqueous solution to the mark, shake well and set aside.

[0057] Sample 8: Weigh 0.1 g of the above condensation reaction solution into a 50 mL volumetric flask, add 80% (40% to 90%) acetonitrile aqueous solution to the mark, shake well and set aside.

[0058] Example 1

[0059] Instrument and chromatographic conditions: Agilent 1260 high performance liquid chromatography system was used;

[0060] The chromatographic column is SHIMADZU-GL WondaCract ODS-2 4.6*250mm*5μm;

[0061] Mobile phase A: 0.05% phosphoric acid aqueous solution;

[0062] Mobile phase B: acetonitrile;

[0063] Detection wavelength: 230nm;

[0064] Flow rate: 0.8 mL / min;

[0065] Injection volume 5 μL;

[0066] Column temperature: 35°C.

[0067] The gradient elution program is shown in Table 1:

[0068] Table 1

[0069]

[0070] Take the system suitability solution sample 3 and sample 4, and inject them into the high performance liquid chromatograph to record the chromatogram according to the above chromatographic conditions. From the chromatogram, it can be seen that the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, the active intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride and the raw material tetramethylguanidine hydrochloride and the raw material tetramethylurea can be detected under this condition.

[0071] Example 2

[0072] Instrument and chromatographic conditions: Agilent 1260 high performance liquid chromatography system was used;

[0073] The chromatographic column is Agilent ZORBAX Eclipse XDB-C18 4.6*150mm*5μm;

[0074] Mobile phase A: water;

[0075] Mobile phase B: acetonitrile;

[0076] Detection wavelength: 240nm;

[0077] Flow rate: 1.0 mL / min;

[0078] Injection volume 5 μL;

[0079] Column temperature: 45°C.

[0080] The gradient elution program is shown in Table 2:

[0081] Table 2

[0082]

[0083] Take the system suitability solution sample 3 and sample 4, and inject them into the high performance liquid chromatograph to record the chromatogram according to the above chromatographic conditions. From the chromatogram under this condition, it can be seen that the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, the active intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride and the raw material tetramethylguanidine hydrochloride and the raw material tetramethylurea can be detected.

[0084] Example 3

[0085] Instrument and chromatographic conditions: Agilent 1260 high performance liquid chromatography system was used;

[0086] The chromatographic column is GL Sciences Inertsil ODS-3 4.6*250mm*5μm;

[0087] Mobile phase A: 0.1% phosphoric acid aqueous solution;

[0088] Mobile phase B: acetonitrile;

[0089] Detection wavelength: 220nm;

[0090] Flow rate: 0.8 mL / min;

[0091] Injection volume 5 μL;

[0092] Column temperature: 40℃.

[0093] The gradient elution program is shown in Table 3:

[0094] Table 3

[0095]

[0096]

[0097] Take system blank solution samples 1 and 2, adaptive solution samples 3 and 4, and comparative solution samples 7 and 8, and inject them into a high performance liquid chromatograph to record chromatograms according to the above chromatographic conditions. Under this condition, the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride, the active intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride, and the raw material tetramethylguanidine hydrochloride and the raw material tetramethylurea can be detected. And under this condition, the chromatographic peaks are symmetrical and the separation is the best, that is, the chromatographic conditions are the optimal chromatographic conditions.

[0098] Figure 1 This is the HPLC spectrum of the blank solvent sample 1 of Example 3, which shows the baseline and noise of the instrument.

[0099] Figure 2 This is the HPLC spectrum of the blank solvent sample 2 of Example 3. It can be seen from the figure that 5.59min is the chromatographic peak of aniline.

[0100] Figure 3 The chromatographic peaks of the system suitability solution 3 in the HPLC spectrum are assigned to each other. For specific data, see Table 4.

[0101] Table 4

[0102]

[0103] Figure 3 The HPLC spectrum of the system suitability solvent sample 3 of Example 3 reflects the chromatographic peaks of the first step of the chlorination reaction liquid in the preparation process of the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, 5.66min for aniline, 12.53min for the intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride, and 13.90min for tetramethyl urea;

[0104] Figure 4 The HPLC spectrum of the system suitability solvent sample 4 of Example 3 reflects the chromatographic peaks of the second step condensation reaction liquid in the preparation process of the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, 5.60min for aniline, 10.90min for tetramethylguanidine hydrochloride, 10.58min for the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, 12.46min for the intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride, and 13.81min for tetramethylurea;

[0105] Figure 4 The chromatographic peaks of the medium system suitability solution 4 in the HPLC spectrum are assigned to each other. For specific data, see Table 5.

[0106] Table 5

[0107]

[0108] In the chromatogram, when the separation degree R>1.5, it can be said that the two substances can be completely separated.

[0109] The chromatographic conditions of this comparative example are exactly the same as those of Example 3, except that the sample solution is treated differently, and no aniline solution is added during the reaction. It can be seen from the chromatogram under this condition that in the chromatogram of sample 7, there is only the chromatographic peak of the raw material tetramethyl urea, and the chromatographic peak of the intermediate intermediate N-(dimethylamino-chloro)methylene-dimethylamino ammonium chloride cannot be detected; in the chromatogram of sample 8, there are only the chromatographic peaks of the catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, the raw material tetramethylguanidine hydrochloride and the raw material tetramethyl urea, and the chromatographic peak of the intermediate N-(dimethylamino-chloro)methylene-dimethylamino ammonium chloride cannot be detected.

[0110] Therefore, without adding aniline, it is impossible to distinguish the intermediate N-(dimethylamino-chloro)methylene-dimethylaminoammonium chloride from bis-(N-bis(dimethylamino)methylene)-immonium chloride salt and impurities.

[0111] The method of the present invention can monitor the remaining amount of raw materials and the generated amount of target products in the reaction process, can more accurately determine the reaction endpoint, save reaction time, and improve the reaction yield, making up for the lack of an analytical method for monitoring the reaction process during the synthesis of the current catalyst bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, has important guiding significance for the optimization of experimental conditions, and provides technical support for laboratory research and development and industrial production.

[0112] Precision experiment:

[0113] The prepared sample 4 was injected 6 times continuously under the experimental conditions of Example 3, and the precision was calculated by retention time and peak area respectively. The precision calculated by retention time t (in min) is shown in Table 6, and the precision calculated by peak area A (in 1) of the chromatographic peak is shown in Table 7.

[0114] Table 6

[0115]

[0116] Table 7

[0117]

[0118] According to the 2020 edition of the Chinese Pharmacopoeia, Part IV: 9101 Analytical Method Validation Guidelines, since the content of impurity A, intermediate C, and impurity D is between 0.1% and 10%, it can be seen that the acceptable range of precision of impurity A, intermediate C, and impurity D is RSD < 1.5%; since the content of catalyst B is > 90%, it can be seen that the acceptable range of density of catalyst B is RSD < 1.0%. The results in Tables 6 and 7 show that this method has good precision.

[0119] Figure 5 This is the HPLC spectrum of sample 4 under the conditions of Example 3 during the precision test.

[0120] Accuracy test

[0121] Prepare the solution:

[0122] Sample 1: Use a pipette to transfer 5 mL of the test solution sample 6 and 20 mL of the test solution sample 5 into a 50 mL volumetric flask, add 95% acetonitrile aqueous solution to the scale and shake well to obtain a sample 1 solution with an impurity A concentration of 49.60 mg / L and an impurity D concentration of 42.40 mg / L.

[0123] Sample 2: Use a pipette to transfer 10 mL of the test solution sample 6 and 20 mL of the test solution sample 5 into a 50 mL volumetric flask, add 95% acetonitrile aqueous solution to the scale and shake well to obtain a sample 2 solution with an impurity A concentration of 99.20 mg / L and an impurity D concentration of 84.80 mg / L.

[0124] Sample 3: Use a pipette to transfer 25 mL of the test solution sample 6 and 20 mL of the test solution sample 5 into a 50 mL volumetric flask, add 95% acetonitrile aqueous solution to the scale and shake well to obtain a sample 3 solution with an impurity A concentration of 248.00 mg / L and an impurity D concentration of 212.00 mg / L.

[0125] The results were determined according to the conditions of Example 3, as shown in Tables 9 and 10.

[0126] Table 9 shows the accuracy of the determination of impurity A.

[0127] Table 9

[0128]

[0129]

[0130] Table 10 shows the accuracy of the determination of impurity D.

[0131] Table 10

[0132]

[0133] According to the 2020 edition of the "Chinese Pharmacopoeia" Part IV: 9101 Analytical Method Validation Guidelines, since the content of impurity A and impurity D is between 5% and 30%, it can be seen that the recovery limit of impurity A and impurity D is between 98% and 101%, and the acceptable range of precision is RSD <2.0%; it can be seen from the data in Tables 8 and 9 that this method has high accuracy.

[0134] Figure 6 This is the HPLC spectrum of the test solvent sample 5 of Example 3. It can be seen from the figure that the pure catalyst is relatively clean and free of impurities.

[0135] Figure 7 This is the HPLC spectrum of the test solvent sample 6 of Example 3. It can be seen from the figure that the impurities tetramethylguanidine hydrochloride and tetramethylurea are at 10.22min and 13.87min respectively.

Claims

1. A high performance liquid chromatography separation method for various substances in the reaction process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, comprising the following steps: 1) taking the chlorination reaction solution in the preparation process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, adding aniline solution and stirring until the reaction is complete, then adding 40-90% by volume acetonitrile aqueous solution, shaking well to obtain sample solution 1, and setting aside; 2) taking the condensation reaction liquid in the preparation process of bis-(N-bis(dimethylamino)methylene)-immonium chloride salt, adding aniline solution and stirring until the reaction is complete, then adding 40-90% by volume acetonitrile aqueous solution, shaking well to obtain sample solution 2, and setting aside; 3) The sample solution 1 and the sample solution 2 obtained in step 1) and step 2) are separated by a high performance liquid chromatograph, using a chromatographic column with octadecylsilane bonded silica gel as a filler, acetonitrile and buffer as mobile phases, and the following chromatographic separation conditions: Detection wavelength: 220nm~240nm; Mobile phase flow rate: 0.8mL / min~1.0mL / min; Gradient elution was performed, and the gradient elution program was as follows: 0-5min: acetonitrile volume fraction was 1%; 5-25min: the volume fraction of acetonitrile increases uniformly from 1% to 100%; 25-30min: the volume fraction of acetonitrile is 100%.

2. The high performance liquid chromatography separation method of each substance in the bis-(N-bis(dimethylamino)methylene)-immonium chloride reaction process according to claim 1, characterized in that: The high performance liquid chromatography separation method adopts an ultraviolet detector to detect bis-(N-bis(dimethylamino)methylene)-immonium chloride salt and impurities, and the detection wavelength is 220nm-240nm.

3. The high performance liquid chromatography separation method of each substance in the bis-(N-bis(dimethylamino)methylene)-immonium chloride reaction process according to claim 1, characterized in that: The column temperature is 35-45°C.

4. The high performance liquid chromatography separation method of each substance in the bis-(N-bis(dimethylamino)methylene)-immonium chloride reaction process according to claim 1, characterized in that: The injection volume is 5-10 μL.

5. The high performance liquid chromatography separation method of each substance in the bis-(N-bis(dimethylamino)methylene)-immonium chloride reaction process according to claim 1, characterized in that: The buffer solution is water, a 0.05% by volume phosphoric acid aqueous solution or a 0.1% by volume phosphoric acid aqueous solution.

6. The high performance liquid chromatography separation method of each substance in the bis-(N-bis(dimethylamino)methylene)-immonium chloride reaction process according to claim 1, characterized in that: The chromatographic column is one of the following chromatographic columns: Brand: SHIMADZU-GL WondaCract ODS-2, specification: 4.6*250mm*5μm; Brand: Agilent ZORBAX Eclipse XDB-C18, specification: 4.6*150mm*5μm; brand: GLSciencesInertsilODS-3, specification: 4.6*250mm*5μm.

7. The high performance liquid chromatography separation method of various substances in the bis-(N-bis(dimethylamino)methylene)-immonium chloride reaction process according to claim 1, characterized in that: The preparation method of the bis-(N-bis(dimethylamino)methylene)-immonium chloride salt comprises the following steps: 1) Add tetramethyl urea and ethylene dichloride into a reaction apparatus, slowly drop diphosgene at 20-30° C., and after the dropwise addition is completed, maintain the temperature at 20-30° C. and continue stirring to carry out chlorination reaction; 2) After the chlorination reaction is completed, the temperature is controlled at 20-40° C., tetramethylguanidine is added dropwise to the solution, and after the addition is completed, the temperature is maintained at 20-40° C. and the condensation reaction is continued by stirring. After the reaction is completed, the solvent dichloroethane is evaporated to obtain the catalyst bis-[N-bis(dimethylamino)methylene]-chloroimide salt.

8. The high performance liquid chromatography separation method of various substances in the bis-(N-bis(dimethylamino)methylene)-immonium chloride reaction process according to claim 7, characterized in that: The added amount of the aniline solution is 5 to 20 times the mass fraction of tetramethylurea.

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