Method for detecting impurities in trifluoromethanesulfonate

Abstract

The invention belongs to the field of drug mutagenesis impurity detection and analysis, and relates to a method for detecting impurities of trifluoromethanesulfonate, in particular to a method for detecting impurities of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate. Specifically, according to the detection method disclosed by the invention, tetrabutylammonium bromide is used as a derivatization reagent to derivatize trifluoromethanesulfonate, a corresponding derivative halogenated alkane is detected by GC-MS (Gas Chromatography-Mass Spectrometer), and then the content of trifluoromethanesulfonate is determined. The method provided by the invention solves the problem that the detection result may have false negative in the prior art, and has the advantages of high sensitivity, low detection limit, good repeatability and high accuracy, and all substances can be well separated.

Description

Technical Field

[0001] The invention relates to the field of drug mutagenic impurity detection and analysis, and in particular to a method for detecting trifluoromethanesulfonate impurities, in particular to a method for detecting methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate impurities. Background Art

[0002] Trifluoromethanesulfonic acid is an acid radical reagent commonly used in the process of drug synthesis, and lower alcohols (methanol, ethanol, isopropanol, etc.) are widely used as solvents or recrystallization solvents in the reaction process. Among them, trifluoromethanesulfonic acid can easily react with lower alcohols to generate corresponding trifluoromethanesulfonate impurities such as methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate. Trifluoromethanesulfonates such as methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate are genotoxic impurities with carcinogenicity. Therefore, their content needs to be strictly controlled during drug research and development.

[0003] Prior art discloses a method for adopting sodium iodide derivatization, and the amount of methyl methanesulfonate, ethyl methanesulfonate and isopropyl methanesulfonate is determined by quantitatively detecting derivatives iodomethane, iodoethane and 2-iodopropane, but this method is not suitable for the detection of trifluoromethanesulfonate. CN112730642A and CN112782303A report the method for detecting methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate, and its detection method mainly uses lower alcohol (n-butyl alcohol, isopropanol, etc.) as diluent and derivatization reagent at the same time, and detects its corresponding ether derivative product. The inventor finds that the defect of this sample preparation method directly using derivatization reagent as diluent is that when the content of trifluoromethanesulfonate in the test sample is at ppm level, trifluoromethanesulfonate cannot react with alcohol derivatization reagent, thereby making the detection result of trifluoromethanesulfonate in the test sample false negative, and the quality control of potential mutagenic impurities cannot be guaranteed.

[0004] Therefore, there is an urgent need for a method for detecting trifluoromethanesulfonate impurities that is simple to operate, has high sensitivity, low detection limit, good repeatability, and high accuracy. Summary of the invention

[0005] In order to solve the above problems, the present invention discloses a derivatization headspace GC-MS detection method, which utilizes the property of trifluoromethanesulfonate as a strong alkylating agent to react with tetrabutylammonium bromide or tetrabutylammonium iodide to generate halogenated alkanes such as methyl halides and ethyl halides with strong volatility and high GC-MS response, and quantitatively detects trifluoromethanesulfonate by measuring the content of halogenated alkanes such as methyl halides and ethyl halides. The present invention uses a capillary column (DB-624 or other equivalent chromatographic columns) with a stationary phase of 6% cyanopropylphenyl-94% dimethylpolysiloxane as a chromatographic column for gas phase separation. The method of the present invention solves the problem of false negatives in the detection results in the prior art. The method has high sensitivity, a detection limit as low as 5.0ppm, good repeatability, high accuracy, and all substances can be well separated. The method of the present invention effectively avoids the interference of the drug matrix and can accurately detect trifluoromethanesulfonate with extremely low concentration in the drug, for example, the content of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate can be detected simultaneously.

[0006] The present invention relates to a method for detecting trifluoromethanesulfonate impurities, comprising:

[0007] Step 1) preparing a test solution: weighing an appropriate amount of a test sample, then adding a diluent and a derivatization reagent to obtain a test solution, wherein the derivatization reagent is a tetrabutylammonium bromide solution;

[0008] Step 2) preparing a reference solution: preparing a triflate stock solution with a diluent, adding a derivatization reagent to obtain a reference solution, wherein the derivatization reagent is a tetrabutylammonium bromide solution or a tetrabutylammonium iodide solution;

[0009] Step 3) Detection: Use headspace gas chromatography-mass spectrometry to detect the test solution and the reference solution respectively.

[0010] In some embodiments, in step 2), the concentration of the trifluoromethanesulfonate stock solution relative to the test sample is 26 ppm (ie, the concentration of the trifluoromethanesulfonate stock solution is equivalent to 26 parts per million of the test sample concentration), or other limits.

[0011] In some embodiments, in step 1) and step 2), the diluent is an aprotic solvent, preferably n-heptane, n-hexane or acetonitrile.

[0012] In some embodiments, in step 1) and step 2), the tetrabutylammonium bromide solution and the tetrabutylammonium iodide solution are each prepared using acetonitrile as a solvent, that is, in step 1) and step 2), the tetrabutylammonium bromide solution is an acetonitrile solution of tetrabutylammonium bromide, and the tetrabutylammonium iodide solution is an acetonitrile solution of tetrabutylammonium iodide.

[0013] In some embodiments, the concentration of tetrabutylammonium bromide solution in the derivatization reagent is 0.5-20 mg / mL.

[0014] In some embodiments, the trifluoromethanesulfonate of the present invention is methyl trifluoromethanesulfonate, ethyl trifluoromethanesulfonate, or a combination of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate.

[0015] In some embodiments, methyl trifluoromethanesulfonate reacts in tetrabutylammonium bromide solution to generate methyl bromide; ethyl trifluoromethanesulfonate reacts in tetrabutylammonium bromide solution to generate ethyl bromide. In some embodiments, the diluent in step 2) is an aprotic solvent, preferably n-heptane, n-hexane or acetonitrile.

[0016] In some embodiments, the gas chromatography-mass spectrometry conditions in step 3) include performing programmed temperature separation using DB-624 as a chromatographic column.

[0017] In some embodiments, the specifications of the chromatographic column in step 3) are 30m*0.32mm, 1.8μm.

[0018] In some embodiments, the gas chromatography-mass spectrometry conditions in step 3) further include an inlet temperature of 180°C-220°C.

[0019] In some embodiments, the gas chromatography-mass spectrometry conditions in step 3) further include an inlet temperature of 180°C;

[0020] In some embodiments, the gas chromatography-mass spectrometry conditions in step 3) include a split ratio of 10:1-30:1. In some embodiments, the gas chromatography-mass spectrometry conditions in step 3) include a split ratio of 20:1-30:1. In some embodiments, the gas chromatography-mass spectrometry conditions in step 3) include a split ratio of 20:1 or 30:1.

[0021] In some embodiments, the gas chromatography-mass spectrometry conditions in step 3) further include:

[0022] Carrier gas: helium;

[0023] Flow rate mode: constant flow;

[0024] Column flow rate: 1.3 mL / min-1.7 mL / min, preferably 1.5 mL / min;

[0025] Injector: headspace injector;

[0026] Headspace conditions: bottle temperature 70-80°C; sampling needle temperature (90°C); transfer line temperature (100°C); holding time (30 min); GC cycle time (32 min); injection time (0.5 min);

[0027] Injection volume: 1.0mL;

[0028] Heating program:

[0029]

[0030] In some embodiments, the detector used in step 3) is: MS detector; the detection conditions are as follows:

[0031] Ion source: electron bombardment ion source (EI source);

[0032] Ion source temperature: 230°C;

[0033] Mass analyzer: single quadrupole;

[0034] Quadrupole temperature: 150℃;

[0035] MS transfer line temperature: 280°C;

[0036] Gain factor: 1.0;

[0037] Solvent delay: 0min;

[0038] MS scanning mode: SIM, m / z: 93.9 (methyl bromide); m / z: 107.9 (ethyl bromide).

[0039] In some embodiments, the method for detecting triflate impurities of the present invention further comprises calculating the content of triflate in the test sample, which is calculated by an external standard method.

[0040] In some embodiments, the content of trifluoromethanesulfonate in the test sample is calculated as follows:

[0041]

[0042] A T is the peak area of ​​the impurity to be detected in the test solution;

[0043] A S The average value of the peak area of ​​the impurity to be tested by three consecutive injections of the reference solution;

[0044] W T is the sample amount of the test solution, mg;

[0045] W S The mass of the impurity to be tested weighed to prepare the reference solution, mg;

[0046] D T is the dilution factor of the test solution;

[0047] D Sis the dilution multiple of the reference solution;

[0048] P is the content of the reference substance, %.

[0049] Terminology

[0050] In the description of the present invention, “plurality” means two or more than two, unless otherwise clearly and specifically defined.

[0051] The term "room temperature" means ambient temperature, referring to a temperature between about 10°C and about 30°C, or between about 20°C and 30°C, or about 25°C.

[0052] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0053] The term "ppm" means parts per million.

[0054] The term "v / v" means volume ratio.

[0055] The term "% vol" means volume percentage.

[0056] In the following, all numbers disclosed herein are approximate, regardless of whether the word "about" or "approximately" is used. The value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number with a value of N is disclosed, any number with a value of N+ / -1%, N+ / -2%, N+ / -3%, N+ / -5%, N+ / -7%, N+ / -8%, N+ / -10%, N+ / -15% or N+ / -20% will be explicitly disclosed, where "+ / -" means plus or minus. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] Figure 1 This is the gas phase-mass spectrum of the blank solution of Example 7;

[0058] Figure 2 This is the gas phase-mass spectrum of the detection limit solution of Example 7;

[0059] Figure 3This is the gas phase-mass spectrum of the reference solution of Example 7;

[0060] Figure 4 This is the gas phase-mass spectrum of the spiked solution of the test sample in Example 7;

[0061] Figure 5 This is the gas phase-mass spectrum of the test solution in Example 7;

[0062] Figure 6 This is the gas phase-mass spectrum of the reference solution of Comparative Example 1;

[0063] Figure 7 This is the gas phase-mass spectrometry of the reference solution of Comparative Example 2;

[0064] Figure 8 This is the gas phase-mass spectrum of the reference solution of Comparative Example 3. DETAILED DESCRIPTION

[0065] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

[0066] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0067] The instrument used in the specific embodiment of the present invention is:

[0068] Detector: headspace GC-MS (Agilent Technologies, Inc., USA); electronic balance (Mettler); chromatographic column DB-624 (30m*0.32mm, 1.8μm, Agilent Technologies, Inc., USA). The chromatographic column used for the validation method is: DB-624 (30m*0.32mm, 1.8μm). Carrier gas: helium; flow rate mode: constant flow; column flow rate: 1.5ml / min; injector: headspace injector;

[0069] The heating program is:

[0070]

[0071] In the weighing process of the following examples, an error within 10% of the theoretical weight is an acceptable error. For example, when weighing about 50 mg of tetrabutylammonium bromide, an error of no more than 10% is acceptable in the actual weighing.

[0072] Example 1

[0073] 1. Chromatographic conditions:

[0074] Chromatographic column: DB-624 (30m*0.32mm, 1.8μm)

[0075] Inlet temperature: 180°C;

[0076] Split ratio: 30:1;

[0077] Carrier gas: helium;

[0078] Flow rate mode: constant flow;

[0079] Column flow rate: 1.5 mL / min;

[0080] Injector: headspace injector;

[0081] Headspace conditions: bottle temperature (60°C); sampling needle temperature (80°C); transfer line temperature (100°C); holding time (30 min); GC cycle time (32 min); injection time (0.5 min);

[0082] Injection volume: 1.0mL;

[0083] Heating program:

[0084]

[0085] Detector: MS detector;

[0086] Ion source: electron bombardment ion source (EI source);

[0087] Ion source temperature: 230°C;

[0088] Mass analyzer: single quadrupole;

[0089] Quadrupole temperature: 150℃;

[0090] MS transfer line temperature: 280°C;

[0091] Gain factor: 1.0;

[0092] Solvent delay: 0min;

[0093] MS scanning mode: SIM, m / z: 93.9 (methyl bromide); m / z: 107.9 (ethyl bromide);

[0094] 2. Solution preparation:

[0095] Diluent: acetonitrile;

[0096] Derivatization reagent: Take about 50 mg of tetrabutylammonium bromide in a 100 mL volumetric flask, dissolve it in acetonitrile and make up to volume to obtain the derivatization reagent, with a concentration of 0.5 mg / mL;

[0097] Reference substance stock solution 1: Weigh about 32 mg of methyl trifluoromethanesulfonate and about 32 mg of ethyl trifluoromethanesulfonate, accurately weigh, put into a 25 mL volumetric flask, dissolve and make up to volume with a diluent, shake well, and obtain;

[0098] Reference substance stock solution 2: Pipette 1.0 mL of reference substance stock solution 1 into a 25 mL volumetric flask, dilute to volume with diluent, and shake well;

[0099] Reference substance stock solution 3: Pipette 1.0 mL of reference substance stock solution 2 into a 100 mL volumetric flask, dilute to volume with diluent, and shake well;

[0100] Reference substance solution: Pipette 1.0 mL of reference substance stock solution 3 + 1.0 mL of derivatization reagent into a 20 mL headspace bottle and seal with a press cap;

[0101] The reference solution was taken for GC-MS analysis. The experimental results are shown in Table a below. The experimental results show that this method has a high signal-to-noise ratio (S / N) and good separation of the detected objects.

[0102] Table a

[0103] Derivative product name Peak area S / N Separation Methyl bromide 133.376 33.7 19.1 Ethyl bromide 366.421 84.7 20.1

[0104] Embodiment 2:

[0105] The derivatization reagent is prepared as follows: about 100 mg of tetrabutylammonium bromide is taken into a 100 mL volumetric flask, dissolved in acetonitrile and fixed to volume, and the concentration is 1 mg / mL. The chromatographic conditions and other experimental methods and solution preparation are exactly the same as those in Example 1. The experimental results are shown in Table b below. The experimental results show that the method has a high signal-to-noise ratio (S / N) and good separation of the detected objects.

[0106] Table b

[0107] Derivative product name Peak area S / N Separation Methyl bromide 236.256 64.8 13.4 Ethyl bromide 461.671 102.4 20.8

[0108] Embodiment 3:

[0109] The derivatization reagent of tetrabutylammonium bromide with a concentration of 2 mg / mL was prepared by referring to the method of Example 1. The chromatographic conditions, other experimental methods and solution preparation were exactly the same as those of Example 1. The experimental results are shown in Table c below. The experimental results show that the method has a high signal-to-noise ratio and good separation of the detected objects.

[0110] Table c

[0111] Derivative product name Peak area S / N Separation Methyl bromide 228.231 107.1 21.5 Ethyl bromide 473.637 180.1 21.5

[0112] Embodiment 4:

[0113] The split ratio in the chromatographic conditions was 20:1, the diluent was n-heptane, the headspace bottle temperature was changed to 70°C, the concentration of the derivatization reagent of tetrabutylammonium bromide was 1 mg / mL, and the other chromatographic conditions and other experimental methods and solution preparation were exactly the same as those in Example 1. The experimental results are shown in Table d below, and the experimental results show that the method has a high signal-to-noise ratio and good separation of the detected objects.

[0114] Table D

[0115] Derivative product name Peak area S / N Separation Methyl bromide 1602.755 372.6 19.0 Ethyl bromide 876.078 188.4 19.7

[0116] Embodiment 5:

[0117] The split ratio in the chromatographic conditions was 20:1, the diluent was n-heptane, the headspace bottle temperature was changed to 70°C, the concentration of the derivatization reagent of tetrabutylammonium bromide was 5 mg / mL, and the other chromatographic conditions and other experimental methods and solution preparation were exactly the same as those in Example 1. The experimental results are shown in Table e below, which show that the method has a high signal-to-noise ratio and good separation of the detected objects.

[0118] Table E

[0119] Derivative product name Peak area S / N Separation Methyl bromide 1570.253 347.3 18.9 Ethyl bromide 846.646 176.1 19.5

[0120] Embodiment 6:

[0121] The split ratio in the chromatographic conditions was 20:1, the diluent was n-heptane, the headspace bottle temperature was changed to 70°C, the concentration of the derivatization reagent of tetrabutylammonium bromide was 20 mg / mL, and the other chromatographic conditions and other experimental methods and solution preparation were exactly the same as those in Example 1. The experimental results are shown in Table f below, which show that the method has a high signal-to-noise ratio and good separation of the detected objects.

[0122] Table f

[0123] Derivative product name Peak area S / N Separation Methyl bromide 1576.111 385.0 18.3 Ethyl bromide 889.243 196.4 19.2

[0124] Example 7: Methodology Validation

[0125] 1. Chromatographic conditions:

[0126] Chromatographic column: DB-624 (30m*0.32mm, 1.8μm)

[0127] Inlet temperature: 180°C;

[0128] Split ratio: 20:1;

[0129] Carrier gas: helium;

[0130] Flow rate mode: constant flow;

[0131] Column flow rate: 1.5 mL / min;

[0132] Injector: headspace injector;

[0133] Headspace conditions: bottle temperature (80°C); sampling needle temperature (90°C); transfer line temperature (100°C); holding time (30 min); GC cycle time (32 min); injection time (0.5 min);

[0134] Injection volume: 1.0mL;

[0135] Heating program:

[0136]

[0137] Detector: MS detector;

[0138] Ion source: electron bombardment ion source (EI source);

[0139] Ion source temperature: 230°C;

[0140] Mass analyzer: single quadrupole;

[0141] Quadrupole temperature: 150℃;

[0142] MS transfer line temperature: 280°C;

[0143] Gain factor: 1.0;

[0144] Solvent delay: 0min;

[0145] MS scanning mode: SIM, m / z: 93.9 (methyl bromide); 107.9 (ethyl bromide);

[0146] 2. Solution preparation:

[0147] Diluent: n-heptane;

[0148] Derivatization reagent: Take about 100 mg of tetrabutylammonium bromide in a 100 mL volumetric flask, dissolve it in acetonitrile and make up to volume;

[0149] Blank solution: Pipette 1.0 mL of n-heptane + 2.0 mL of derivatization reagent into a 20 mL headspace bottle and seal it with a cap;

[0150] Reference substance stock solution 1: Weigh about 32 mg of methyl trifluoromethanesulfonate and about 32 mg of ethyl trifluoromethanesulfonate, accurately weigh, put into a 25 mL volumetric flask, dissolve and make up to volume with a diluent, shake well, and obtain;

[0151] Reference substance stock solution 2: Pipette 1.0 mL of reference substance stock solution 1 into a 25 mL volumetric flask, dilute to volume with diluent, and shake well;

[0152] Reference substance stock solution 3: Pipette 1.0 mL of reference substance stock solution 2 into a 100 mL volumetric flask, dilute to volume with diluent, and shake well;

[0153] Reference solution: Pipette 1.0 mL of reference stock solution 3 + 2.0 mL of derivatization reagent into a 20 mL headspace bottle, seal with a press cap, and prepare three portions in parallel, namely, reference solution 1, reference solution 2, and reference solution 3.

[0154] Detection limit stock solution: Pipette 2.0 mL of reference stock solution into a 10 mL volumetric flask, make up to volume with diluent, and shake well;

[0155] Detection limit solution: Pipette 1.0 mL of detection limit stock solution + 2.0 mL of derivatization reagent into a 20 mL headspace bottle and seal it with a cap;

[0156] Test solution: weigh about 20 mg of the test sample into a 20 mL headspace bottle, pipette 1.0 mL of n-heptane + 2.0 mL of derivatization reagent, and seal the bottle with a cap;

[0157] Test sample spike solution: weigh about 20 mg of the test sample into a 20 mL headspace bottle, transfer 1.0 mL of reference sample stock solution 3 + 2.0 mL of derivatization reagent, seal with a cap, and prepare three portions in parallel, namely, test sample spike solution 1, test sample spike solution 2, and test sample spike solution 3;

[0158] According to the test solution and injection needle number in Table A below, and the above chromatographic conditions, GC-MS analysis was performed and the chromatogram was recorded (wherein the main spectrum is as follows Figure 1-5 Specific experimental results are shown in Tables 1-5.

[0159] Table A: Test solutions and injection numbers

[0160]

[0161]

[0162] Calculate the spike recovery R value, the average value of the R value and its relative standard deviation RSD value. The calculation formula of the R value is as follows:

[0163]

[0164] Where: A T+S is the peak area of ​​each impurity in the test sample spiked solution;

[0165] A T is the peak area of ​​each impurity in the test solution;

[0166] A S is the average of the peak areas of each impurity in 3 reference solutions;

[0167] W T is the weight of the test sample in the test solution, mg;

[0168] W T+S is the weight of the test sample in the test sample spike solution, mg.

[0169] According to the measured peak response value, the content of the impurity to be tested in the test sample is calculated according to the following formula:

[0170]

[0171] Where: A T is the peak area of ​​the impurity to be detected in the test solution;

[0172] A S The average value of the peak area of ​​the impurity to be tested by three consecutive injections of the reference solution;

[0173] W T is the sample amount of the test solution, mg;

[0174] W S The mass of the impurity to be tested weighed to prepare the reference solution, mg;

[0175] D T is the dilution factor of the test solution;

[0176] D S is the dilution multiple of the reference solution;

[0177] P is the content of the reference substance, %.

[0178] Experiments show that the system applicability, specificity, accuracy (detectability), detection limit and solution stability of the method of the present invention all meet the detection requirements.

[0179] Table 1 System suitability results

[0180]

[0181]

[0182] Conclusion: The experimental results show that 1) the signal-to-noise ratio (S / N) of the impurities methyl bromide and ethyl bromide in the detection limit solution is 81.5 and 47.7 respectively (acceptable standard ≥3); 2) the RSD of the peak area of ​​the impurities methyl bromide and ethyl bromide after three consecutive injections is 1.55% and 0.60% respectively (acceptable standard ≤15.0%). Therefore, the system suitability meets the detection requirements.

[0183] Table 2 Specificity results

[0184]

[0185] N / A means None

[0186] Conclusion: The specificity experimental results show that 1) the blank solution has no interference (should have no interference) with the detection of methyl bromide and ethyl bromide in the reference solution and the test solution; 2) methyl bromide and ethyl bromide were not detected in the test solution, and the methyl bromide and ethyl bromide peaks in the reference solution and the test solution were baseline separated from the adjacent chromatographic peaks; 3) the retention time of methyl bromide and ethyl bromide peaks in the test solution was consistent with that in the reference solution; 4) compared with the test solution, the peak area of ​​methyl bromide and ethyl bromide in the test solution was significantly increased. Therefore, the specificity of the test method of the present invention is good.

[0187] Table 3 Detectability results

[0188]

[0189]

[0190] N / A means no or not involved in the calculation

[0191] Conclusion: The detectability results show that: 1) the R values ​​of methyl bromide and ethyl bromide in the test sample spiked solution ranged from 84.9% to 88.6% and 97.7% to 98.6% (the acceptable standard is between 80.0% and 120.0%); 2) the RSD (n=3) values ​​of the R values ​​of methyl bromide and ethyl bromide in the test sample spiked solution were 2.17% and 0.46% (the acceptable standard is ≤15.0%). Therefore, the method of the present invention has high accuracy and good detectability.

[0192] Table 4 Detection limit results

[0193]

[0194] Conclusion: The detection limit results show that the signal-to-noise ratio of methyl bromide and ethyl bromide after three consecutive injections of the detection limit solution is above 33.2, and can reach up to 71 (acceptable standard ≥3). The detection limit concentration levels of methyl bromide and ethyl bromide are both 5.0ppm. Therefore, the test method of the present invention has a high signal-to-noise ratio, a low detection limit, and high sensitivity.

[0195] Table 5 Solution stability results

[0196]

[0197] Conclusion: The solution stability results show that the ratio of the methyl bromide and ethyl bromide areas to the peak area at 0 h in the reference solution and the test solution within 7.4 h and 4.2 h, respectively, are between 0.97 and 1.00 (the acceptable standard is between 0.70 and 1.30). This indicates that the reference solution and the test solution are stable at room temperature within 7.4 h and 4.2 h, respectively.

[0198] Comparative Example 1: Sodium iodide solution as a derivatization reagent

[0199] Solution preparation

[0200] Derivatization reagent: Take about 54g sodium iodide + about 50mg ascorbic acid (VC) in a 200mL beaker, dissolve with 100mL ultrapure water, shake well, and obtain;

[0201] Reference substance stock solution 1: Weigh about 32 mg of methyl trifluoromethanesulfonate and about 32 mg of ethyl trifluoromethanesulfonate, accurately weigh, put into a 25 mL volumetric flask, dissolve and make up to volume with DMF, shake well, and obtain;

[0202] Reference substance stock solution 2: Pipette 1.0 mL of reference substance stock solution 1 into a 25 mL volumetric flask, dilute to volume with DMF, and shake well;

[0203] Reference substance stock solution 3: Pipette 1.0 mL of reference substance stock solution 2 into a 100 mL volumetric flask, dilute to volume with DMF, and shake well;

[0204] Reference solution: Pipette 1.0 mL of reference stock solution 3 + 1.0 mL of ultrapure water into a 20 mL headspace bottle, shake well, add 1.0 mL of derivatization reagent, and seal with a cap. The derivatized products are CH3I and CH3CH2I.

[0205] GC-MS conditions

[0206]

[0207] The reference solution was subjected to GC-MS analysis. The results of Spectrum 6 showed that when sodium iodide + ascorbic acid was used as the derivatization reagent, the responses of the derivative products CH3I and CH3CH2I were very small and could not meet the detection requirements.

[0208] Comparative Example 2: Sodium iodide acetonitrile solution as a derivatization reagent

[0209] Acetonitrile was used as solvent, and sodium iodide derivatization reagent was prepared with reference to Comparative Example 1. The preparation of other solutions and detection conditions were the same as those in Comparative Example 1. The reference solution was subjected to GC-MS analysis. The results of Spectrum 7 showed that the response of the derivative product methyl iodide could meet the detection requirements, but the response of ethyl iodide was very small and did not meet the detection requirements.

[0210] Comparative Example 3: Potassium bromide acetonitrile solution as a derivatization reagent

[0211] Solution preparation

[0212] Derivatization reagent: Prepare saturated potassium bromide solution with acetonitrile;

[0213] Reference substance stock solution 1: Weigh about 32 mg of methyl trifluoromethanesulfonate and about 32 mg of ethyl trifluoromethanesulfonate, accurately weigh, put into a 25 mL volumetric flask, dissolve and make up to volume with acetonitrile, shake well, and obtain;

[0214] Reference substance stock solution 2: Pipette 1.0 mL of reference substance stock solution 1 into a 25 mL volumetric flask, dilute to volume with acetonitrile, and shake well;

[0215] Reference substance stock solution 3: Pipette 1.0 mL of reference substance stock solution 2 into a 100 mL volumetric flask, dilute to volume with acetonitrile, and shake well;

[0216] Reference solution: Pipette 1.0 mL of reference stock solution 3 + 1.0 mL of saturated potassium bromide into a 20 mL headspace bottle, shake well, and seal with a cap. The derivative products are methyl bromide (CH3Br) and ethyl bromide (CH3CH2Br).

[0217] GC-MS conditions

[0218]

[0219] The reference solution was subjected to GC-MS analysis. The results of Figure 8 show that when potassium bromide is used as a derivatization reagent, the response of the derivative product ethyl bromide (CH3CH2Br) meets the detection requirements, while the response of methyl bromide (CH3Br) is too small to meet the detection requirements.

[0220] Comparative Example 4: n-Butanol as a derivatization agent

[0221] Methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate were detected by the isobutanol or n-butanol derivatization method described in CN112730642A and CN112782303A. The concentration of the reference solution described in the present application (512 ng / mL, relative to the test sample concentration of 26 ppm) was prepared for GC-MS analysis. The experimental results showed that the expected methyl isobutyl ether and ethyl isobutyl ether (derivative products) or the expected methyl n-butyl ether and ethyl n-butyl ether (derivative products) could not be detected. The expected derivative products could not be detected even when different solvents (such as DMSO, DMA, etc.) or the chromatographic column DB-624 (30 m*0.32 mm, 1.8 μm) used in the present application were used.

[0222] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the parameters of the analytical method. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for detecting trifluoromethanesulfonate impurities, comprising: Step 1) Prepare the test solution: weigh an appropriate amount of the test sample, then add a diluent and a derivatization reagent to obtain a test solution; Step 2) preparing a reference solution: preparing a triflate stock solution with a diluent, adding a derivatization reagent, and obtaining a reference solution; Step 3) Detection: Use headspace gas chromatography-mass spectrometry to detect the test solution and the reference solution respectively; Wherein, the derivatization reagent in step 1) and step 2) is tetrabutylammonium bromide solution or tetrabutylammonium iodide solution.

2. The detection method according to claim 1, wherein the trifluoromethanesulfonate stock solution in step 2) has a concentration of 26 ppm relative to the test sample.

3. The detection method according to claim 1, wherein the diluent in step 1 and step 2) is an aprotic solvent, preferably n-heptane, n-hexane or acetonitrile; optionally, the tetrabutylammonium bromide solution and the tetrabutylammonium iodide solution are each prepared using acetonitrile as a solvent.

4. The detection method according to any one of claims 1 to 3, wherein the trifluoromethanesulfonate is methyl trifluoromethanesulfonate, ethyl trifluoromethanesulfonate, or a combination of methyl trifluoromethanesulfonate and ethyl trifluoromethanesulfonate.

5. The detection method according to any one of claims 1 to 4, wherein the gas chromatography-mass spectrometry conditions in step 3) include temperature separation using DB-624 as a chromatographic column.

6. The detection method according to claim 5, wherein: The specifications of the chromatographic column are 30m*0.32mm, 1.8μm.

7. The detection method according to any one of claims 1 to 6, wherein the gas chromatography-mass spectrometry conditions in step 3) further include an injection port temperature of 180°C-220°C, preferably 180°C.

8. According to the detection method according to any of claims 1-7, the gas chromatography-mass spectrometry conditions in step 3) include a split ratio of 10:1-30:1, preferably 20:1-30:1, more preferably 20:1 or 30:

1.

9. According to any of claims 1 to 8, the gas chromatography-mass spectrometry conditions in step 3) further include: Carrier gas: helium; Flow rate mode: constant flow; Column flow rate: 1.3 mL / min-1.7 mL / min, preferably 1.5 mL / min; Injector: headspace injector; Headspace conditions: bottle temperature 60-80°C; sampling needle temperature (90°C); transfer line temperature (100°C); holding time (30 min); GC cycle time (32 min); injection time (0.5 min); Injection volume: 1.0mL; Heating program:

10. The detection method according to any of claims 1 to 9, wherein in step 3), the detection is performed using a MS detector under the following conditions: Ion source: electron bombardment ion source; Ion source temperature: 230°C; Mass analyzer: single quadrupole; Quadrupole temperature: 150℃; MS transfer line temperature: 280°C; Gain factor: 1.0; Solvent delay: 0min; MS scanning mode: SIM, m / z: 93.9; m / z: 107.9.

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