Analysis method for measuring content of chloride ions in 3, 3-difluorocyclobutylamine hydrochloride and application thereof

Abstract

The invention provides an analysis method for determining the content of chloride ions in 3, 3-difluorocyclobutylamine hydrochloride and application thereof, and the analysis method comprises the following steps: (1) mixing an external standard substance with a reagent to obtain an external standard substance detection liquid; (2) mixing a to-be-detected sample with a reagent to obtain a to-be-detected sample detection solution; and (3) respectively carrying out 35Cl nuclear magnetic resonance testing on the external standard substance detection solution and the to-be-detected sample detection solution, and calculating the chloride ion content in the to-be-detected sample according to the test result. The analysis method provided by the invention can accurately and effectively detect the content of chloride ions in the 3, 3-difluorocyclobutylamine hydrochloride, is high in precision, good in repeatability and good in stability, and can guide and optimize the synthesis process of the 3, 3-difluorocyclobutylamine hydrochloride.

Description

Technical Field

[0001] The invention belongs to the field of instrumental analysis, and specifically relates to an analytical method for determining the chloride ion content in 3,3-difluorocyclobutanamine hydrochloride and an application thereof, and in particular relates to an analytical method for determining the chloride ion content in 3,3-difluorocyclobutanamine hydrochloride with high accuracy and an application thereof. Background Art

[0002] 3,3-Difluorocyclobutaneamine hydrochloride, the molecular formula is C4H7NF2·HCl, the molecular weight is 143.56, and its structural formula is as follows:

[0003]

[0004] 3,3-Difluorocyclobutane hydrochloride is an important drug synthesis intermediate, which can be used to synthesize some organic small molecules with pharmaceutical activity, such as isocitrate dehydrogenase-1 (IDH1) inhibitors (ivosidenib) for the treatment of acute myeloid leukemia, Pim kinase inhibitors, 5-HT1A and 5-HT1B receptor modulators for the treatment of cognitive diseases, etc. The chloride ion is the salt-forming group of 3,3-difluorocyclobutane hydrochloride, and its accurate determination is crucial to guide the optimization of API process and effectively serve the production of preparations.

[0005] Common methods for determining the chloride ion content in hydrochloride compounds include ion chromatography (IC) and high performance liquid chromatography equipped with ELSD or CAD detectors. However, these methods have some limitations, such as: (1) method development, including specific chromatographic conditions, is required for each new compound; (2) ion components are usually sensitive to some organic modifiers, which are used to increase the solubility of the analyte; (3) detectors based on the aerosol principle may show durability problems, which may be caused by non-volatile impurities in the HPLC eluent or as system contaminants. In addition, there are silver nitrate titration (AgNO3), ICP-OES and ICP-MS methods. However, for different compounds, these methods all show specificity problems and are difficult to be used in the detection of chloride ion content in 3,3-difluorocyclobutanamine hydrochloride. Therefore, how to provide an accurate and effective method for detecting the chloride ion content in 3,3-difluorocyclobutanamine hydrochloride has become an urgent problem to be solved. Summary of the invention

[0006] In view of the deficiencies in the prior art, the object of the present invention is to provide an analytical method for determining the chloride ion content in 3,3-difluorocyclobutylamine hydrochloride and its application, and in particular to provide an analytical method for determining the chloride ion content in 3,3-difluorocyclobutylamine hydrochloride with high accuracy and its application. The analytical method provided by the present invention can accurately and effectively detect the content of chloride ions in 3,3-difluorocyclobutylamine hydrochloride, has high precision, good repeatability, good stability, and can guide the optimization of the synthesis process of 3,3-difluorocyclobutylamine hydrochloride.

[0007] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0008] In one aspect, the present invention provides an analytical method for determining the chloride ion content in 3,3-difluorocyclobutaneamine hydrochloride, the analytical method comprising the following steps:

[0009] (1) mixing an external standard with a reagent to obtain an external standard detection solution;

[0010] (2) mixing the sample to be tested with the reagent to obtain a test solution of the sample to be tested;

[0011] (3) The external standard test solution and the sample test solution are respectively 35 Cl NMR test, calculate the chloride ion content in the sample to be tested based on the test results.

[0012] There is no order distinction between steps (1) and (2).

[0013] The quantitative nuclear magnetic resonance technology used in this application is a powerful technology compared to other analytical methods. It can be used in the pharmaceutical industry for reaction monitoring, impurity and degradation product measurement, counterion and residual solvent determination, and drug and formulation product testing. Chlorine has two magnetic nuclei. 35 Cl and 37 Cl, where 35 The natural abundance of Cl is 75.78%, relative 1 The signal sensitivity of H is 3.58×10 -3 ,Compare 37 Cl is one order of magnitude higher and is a more suitable nucleus for NMR detection. The spin quantum number of the chlorine nucleus is 3 / 2, which has a serious fourth-order moment effect and will produce a relatively broad signal peak. However, for highly symmetrical compounds, such as Cl - , CCl4 and ClO4 - , a relatively sharp peak can be observed, so the present invention adopts 35Cl NMR is a very effective method for quantitatively detecting the content of chloride ions in hydrochloride. Conventional chlorides such as sodium chloride are common inorganic ion compounds that are easily soluble in water, highly stable and inexpensive. As an external standard for determining the content of chloride ions, it has high advantages and convenience.

[0014] The analytical method provided by the invention can quickly and accurately determine the chloride ion content in 3,3-difluorocyclobutylamine hydrochloride. The method is simple to operate and has high accuracy, and does not require the addition of an internal standard substance. A new method is provided for determining the chloride ion content in 3,3-difluorocyclobutylamine hydrochloride, and an experimental basis is provided for its quality control research.

[0015] Preferably, the reagent is a combination of heavy water and water or heavy water, preferably a combination of heavy water and water.

[0016] Preferably, the volume ratio of heavy water to water is (50-99):(1-50), preferably (50-60):(40-50). In the volume ratio, the number of heavy water can be 50, 55, 60, 65, 70, 75, 80, 85, 90 or 99, and the number of water can be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50, etc., but are not limited to the values ​​listed above. Other values ​​not listed within the above numerical range are also applicable.

[0017] Preferably, the external standard comprises any one of sodium chloride, ammonium chloride, potassium chloride or magnesium chloride, preferably sodium chloride.

[0018] Preferably, the 35 The Cl NMR test uses a zg pulse sequence, and the test temperature is 296-300K, such as 296K, 297K, 298K, 299K or 300K, etc. However, it is not limited to the values ​​listed above, and other values ​​not listed within the above range are also applicable.

[0019] Preferably, the 35 The pulse width of the Cl NMR test is 15 to 18 μs, preferably 17 μs.

[0020] Preferably, the 35 The number of scans for the Cl NMR test is 155 to 180, preferably 158 to 170.

[0021] Preferably, the 35 The relaxation time of the Cl NMR test is 0.2 to 1.0 s, preferably 0.4 to 0.6 s.

[0022] Preferably, the 35The number of empty scans for the Cl NMR test is 2 to 6 times, preferably 3 to 5 times.

[0023] Preferably, the 35 The number of sampling points for the Cl NMR test is 16-64k, preferably 24-36k.

[0024] Preferably, the 35 The spectrum width of the Cl nuclear magnetic resonance test is 350 to 550 ppm, preferably 450 to 550 ppm.

[0025] Preferably, the 35 The radio frequency center frequency of the Cl nuclear magnetic resonance test is -5 to 5 ppm, preferably -2 to 2 ppm.

[0026] Among them, the pulse width can be 15μs, 16μs, 17μs or 18μs, etc., the number of scans can be 155 times, 160 times, 165 times, 170 times, 175 times or 180 times, etc., the relaxation time can be 0.2s, 0.3s, 0.4s, 0.5s, 0.6s, 0.7s, 0.8s, 0.9s or 1s, etc., the number of empty scans can be 2 times, 3 times, 4 times, 5 times or 6 times, etc., and the number of sampling points can be 16k, 20k, 24k, 28k, 32k, 36k , 40k, 44k, 48k, 52k, 56k, 60k or 64k, etc., the spectrum width can be 350ppm, 400ppm, 450ppm, 500ppm or 550ppm, etc., the RF center frequency can be -5ppm, -4ppm, -3ppm, -2ppm, -1ppm, 0ppm, 1ppm, 2ppm, 3ppm, 4ppm or 5ppm, etc., but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0027] The above-mentioned specific parameter control can effectively improve the accuracy of detection.

[0028] Preferably, the 35 The Cl NMR measurements were performed using a Bruker AVANCE NEO 400 MHz instrument equipped with a BBO probe.

[0029] Preferably, the calculation formula of the chloride ion content is as follows:

[0030] Chloride ion content (%) = (M Cl / M 外标 )×(A x / C x )×(C R / A R )×100%;

[0031] Where M Clis the relative atomic mass of the chlorine atom, M 外标 is the relative molecular mass of the external standard, A x is the peak area of ​​chloride ion in 3,3-difluorocyclobutaneamine hydrochloride, A R is the peak area of ​​chloride ion in the external standard, C x is the concentration of 3,3-difluorocyclobutane hydrochloride, C R is the concentration of the external standard.

[0032] On the other hand, the present invention also provides the use of the above analytical method in the preparation of 3,3-difluorocyclobutaneamine hydrochloride.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] The invention provides an analytical method for determining the chloride ion content in 3,3-difluorocyclobutylamine hydrochloride. The method can quickly and accurately determine the chloride ion content in the 3,3-difluorocyclobutylamine hydrochloride. The method is simple to operate and has high accuracy, and does not require the addition of an internal standard substance. A new method is provided for determining the chloride ion content in the 3,3-difluorocyclobutylamine hydrochloride, and an experimental basis is provided for quality control research thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 is the external standard NaCl in Example 1 35 Cl NMR spectrum;

[0036] Figure 2 is the sample 3,3-difluorocyclobutylamine hydrochloride in Example 1 35 Cl NMR spectrum;

[0037] Figure 3 This is the result graph of the regression equation in the linear test. DETAILED DESCRIPTION

[0038] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0039] In the following examples and tests, the sources of reagents, drugs and instruments are as follows:

[0040] 3,3-difluorocyclobutylamine hydrochloride (Nanjing Yaoshi Technology Co., Ltd., batch number: FR1106766-001-01), in the following specific embodiments, the 3,3-difluorocyclobutylamine hydrochloride is also referred to as the "test sample";

[0041] NaCl (Shanghai MacLean Biochemical Technology Co., Ltd., batch number: C14963327, content 99.8%);

[0042] Heavy water (Shanghai Titan Technology Co., Ltd., batch number: P2334825);

[0043] H2O (Milli-Q);

[0044] Balance (Mettler Toledo XSR205DU / A)

[0045] 400MHz AVANCE NEO NMR spectrometer (Bruker, Switzerland).

[0046] Example 1

[0047] This embodiment provides an analytical method for determining the chloride ion content in 3,3-difluorocyclobutaneamine hydrochloride, and the specific steps are as follows:

[0048] Accurately weigh 200 mg of sodium chloride and place it in a 10 mL volumetric flask, add heavy water-water (50:50) to dissolve and dilute to the scale to obtain an external standard test solution; place 300 mg of 3,3-difluorocyclobutylamine hydrochloride to be tested in a 10 mL volumetric flask, add heavy water-water (50:50) to dissolve and dilute to the scale to obtain a test sample test solution; then, the external standard test solution and the test sample test solution were mixed. 35 Cl NMR test, calculate the chloride ion content in the sample based on the results.

[0049] The instrument parameters are as follows:

[0050] NMR spectrometer: Bruker AVANCE NEO 400MHz, equipped with BBO probe;

[0051] Pulse sequence: zg;

[0052] 90° pulse width: 17μs;

[0053] Detection temperature: 298K;

[0054] Scan times: 160 times;

[0055] Relaxation delay time: 0.5s;

[0056] Number of empty sweeps: 4 times;

[0057] Number of sampling points: 32k;

[0058] Spectral width: 500ppm;

[0059] Center frequency: 0ppm.

[0060] The calculation formula is as follows:

[0061] Chloride ion content (%) = (M Cl / MNaCl )×(A x / C x )×(C R / A R )×100%;

[0062] Where: M Cl : relative atomic mass of Cl, M Cl =35.5 g·mol -1 ;

[0063] M Cl : Relative molecular weight of external standard NaCl, M NaCl =58.5 g·mol -1 ;

[0064] A x : Peak area of ​​chloride ion in 3,3-difluorocyclobutaneamine hydrochloride;

[0065] A R : Peak area of ​​chloride ion in external standard NaCl;

[0066] C x : Concentration of 3,3-difluorocyclobutane hydrochloride (mg / mL);

[0067] C R : The concentration of external standard NaCl (mg / mL).

[0068] The external standard NaCl 35 The Cl NMR spectrum is shown in Figure 1 As shown, the sample 3,3-difluorocyclobutylamine hydrochloride 35 The Cl NMR spectrum is shown in Figure 2 shown.

[0069] The following methodological tests were all performed based on the method of Example 1.

[0070] Linear:

[0071] Weigh 1000.14 mg of sodium chloride accurately into a 20 mL volumetric flask, add weighted water-water (50:50) to dissolve and dilute to the mark, shake well, and use as a stock solution; accurately measure the stock solution and dilute it to obtain linear chloride ion solutions with mass concentrations of 6.06 mg / mL (50%), 9.08 mg / mL (75%), 12.11 mg / mL (100%), 15.14 mg / mL (125%), and 18.17 mg / mL (150%), respectively. Accurately transfer 0.5 mL of each concentration into a nuclear magnetic tube and perform the following steps according to Example 1. 35Cl NMR detection. Linear regression was performed with the mass concentration of the prepared chloride ion as the horizontal axis and the peak area as the vertical axis. The results are as follows (the regression equation is as follows Figure 3 shown):

[0072] Table 1. Chloride ion linearity test results

[0073]

[0074]

[0075] According to the test data in Table 1, the correlation coefficient of the chloride ion in this method is 1 within the concentration range of 6.06 mg / mL to 18.17 mg / mL, and the linear relationship is good.

[0076] System precision:

[0077] Based on the method of Example 1, select the 100% sodium chloride linear solution in the linear test, accurately pipette 0.5 mL into the NMR tube, and perform 35 The Cl NMR test was repeated 6 times, and the results are as follows:

[0078] Table 2. System precision test results

[0079] Sampling times Peak area 1 1223973702912 2 1212425164288 3 1221034861056 4 1227299771392 5 1214561250560 6 1223503358464 average value 1220466351445 RSD 0.48

[0080] According to the test data in Table 2, the RSD value of the chloride ion peak area in sodium chloride obtained from 6 repeated experiments was 0.48%, indicating that the system precision of this method is relatively high.

[0081] Method precision (repeatability):

[0082] Six test solutions were prepared using the method of Example 1, and the samples were injected separately. The average content and relative standard deviation of the six samples were calculated. The results are as follows:

[0083] Table 3. Method precision (repeatability) test results

[0084]

[0085]

[0086] According to the test data in Table 3, the RSD of the chloride ion content determination results in the 6 samples is 0.60%, indicating that the precision of this method is relatively high.

[0087] Solution stability:

[0088] External standard solution: Accurately weigh 100.02 mg of sodium chloride, place in a 5 mL volumetric flask, add heavy water-water (50:50) to dissolve and dilute to the scale, shake well, and use as the external standard solution.

[0089] Test solution: Accurately weigh 150.86 mg of 3,3-difluorocyclobutylamine hydrochloride, place in a 5 mL volumetric flask, add heavy water-water (50:50) to dissolve and dilute to the scale, shake well, and use as the test solution.

[0090] Take the same sample solution, and according to the sampling parameters of Example 1, measure the peak area of ​​the quantitative signal of the external standard and the test sample at each time point at 0, 2, 4, 8, 12, 24, and 48 hours, respectively, investigate the stability of the external standard and the test sample solution at 20°C, and calculate the RSD value. The results are as follows:

[0091] Table 4. Solution stability test results

[0092] Time / Hour Chloride ion peak area of ​​external standard solution Chloride ion peak area of ​​the test solution 0 1230228190976 755776506624 2 1222390987008 751134574464 4 1214410905344 753284127232 8 1234733229824 768675509376 12 1222272013312 754158332032 24 1229968658688 758537586048 48 1225450575872 757535668096 RSD(%) 0.55 0.76

[0093] According to the test data in Table 4, the RSDs of the chloride ion peak areas of the external standard solution and the test solution were 0.55% and 0.76%, respectively, indicating good stability within 48 hours.

[0094] Method accuracy:

[0095] Calculation of chloride ion content in blank samples: Using the method precision result, the original chloride ion content (mg) in each sample was calculated as 24.52%.

[0096] External standard stock solution: Accurately weigh 1250.83 mg of sodium chloride, place in a 25 mL volumetric flask, add weighted water-water (50:50) to dissolve and dilute to the scale, shake well, and use as the external standard stock solution.

[0097] 80% recovery solution: Accurately weigh about 100 mg of 3,3-difluorocyclobutylamine hydrochloride, place in a 5 mL volumetric flask, add 0.8 mL of external standard stock solution, dissolve and dilute to scale with heavy water-water (50:50), shake well. Prepare 3 portions in the same way.

[0098] 100% recovery solution: Accurately weigh about 100 mg of 3,3-difluorocyclobutylamine hydrochloride, place in a 5 mL volumetric flask, add 1 mL of external standard stock solution, dissolve and dilute to scale with heavy water-water (50:50), shake well. Prepare 3 portions in the same way.

[0099] 120% recovery solution: Accurately weigh about 100 mg of 3,3-difluorocyclobutylamine hydrochloride, place in a 5 mL volumetric flask, add 1.2 mL of external standard stock solution, dissolve and dilute to scale with heavy water-water (50:50), shake well. Prepare 3 portions in the same way.

[0100] Accurately measure 0.5 mL of each of the above solutions into NMR tubes and perform 35 The results of the Cl NMR test are as follows:

[0101] Table 5. Method accuracy test results

[0102]

[0103]

[0104] According to the test data in Table 5, the recovery rate of this method is between 99.4% and 104.0%, and the RSD is 1.9%, indicating that this method has a high accuracy.

[0105] Limit of Detection (LOD) and Limit of Quantitation (LOQ):

[0106] Test solution: Accurately weigh about 40.09 mg of 3,3-difluorocyclobutylamine hydrochloride, place in a 5 mL volumetric flask, add heavy water-water (50:50) to dissolve and dilute to the scale, shake well, and use as the test solution.

[0107] Take the above test solution and dilute it with heavy water-water (50:50) for detection. The mass concentration corresponding to the signal-to-noise ratio (S / N) of 3 is taken as the detection limit, and the mass concentration corresponding to the signal-to-noise ratio (S / N) of 100 is taken as the quantification limit. The results are as follows:

[0108] Table 6. Limit of detection (LOD) and limit of quantification (LOQ) test results

[0109] Detection items Chloride ion concentration (mg / mL) Limit of Detection (LOD) 0.098 Limit of Quantitation (LOQ) 3.712

[0110] According to the test data in Table 6, when the method is used to determine the chloride ion content in 3,3-difluorocyclobutaneamine hydrochloride, the detection limit is 0.098 mg / mL and the quantification limit is 3.712 mg / mL, with high sensitivity.

[0111] Method Durability:

[0112] External standard solution: Accurately weigh 101.23 mg of sodium chloride, place in a 5 mL volumetric flask, add heavy water-water (50:50) to dissolve and dilute to the scale, shake well, and use as the external standard solution.

[0113] Test solution: Accurately weigh 150.79 mg of 3,3-difluorocyclobutylamine hydrochloride, place in a 5 mL volumetric flask, add heavy water-water (50:50) to dissolve and dilute to the scale, shake well, and use as the test solution.

[0114] Accurately measure 0.5 mL of each of the above solutions into NMR tubes and perform 35 Cl NMR detection, the detection parameters are as follows:

[0115] NMR spectrometer: Bruker AVANCE NEO 400MHz, equipped with BBO probe;

[0116] Reagent: D2O:H2O=50:50;

[0117] Pulse sequence: zg;

[0118] Detection temperature: 298K

[0119] Scan times: 160 times;

[0120] Number of empty sweeps: 4 times;

[0121] Number of sampling points: 32k;

[0122] Spectral width: 500ppm;

[0123] Center frequency: 0ppm.

[0124] The results are as follows:

[0125] Table 7. Method robustness test results

[0126]

[0127] According to the test data in Table 7, by changing the relevant sampling parameters, the recovery rate of the chloride ion content in the test sample and the chloride ion content determined under the original conditions is about 100.2%, indicating that the method has high durability.

[0128] Method application comparison:

[0129] The two batches of samples were tested using the method of Example 1 and the existing silver nitrate titration method (GB 11896-89), and the results are as follows:

[0130] Table 8. Test results of chloride ion content in 3,3-difluorocyclobutane hydrochloride

[0131]

[0132] According to the test data in Table 8, the results of chloride ion content in two batches of products determined by this method are close to those detected by silver nitrate titration, indicating that this method is accurate and reliable.

[0133] In summary, the method of the present invention can realize the rapid and accurate detection of chloride ions in 3,3-difluorocyclobutylamine hydrochloride, and the operation is simple, stable and reproducible, which provides a reliable basis for the optimization of the synthesis process and the formulation of quality standards of 3,3-difluorocyclobutylamine hydrochloride.

[0134] Comparison and verification:

[0135] Based on the durability test of the above method, based on the method of Example 1, the pulse width was changed to 14 μs and the number of scans was changed to 150 times, and the other parameters were kept unchanged for testing. The results are as follows:

[0136] Table 9. Comparative verification test results

[0137]

[0138] According to the test data in Table 8, this method effectively improves the accuracy of the method by controlling specific parameters.

[0139] The applicant declares that the present invention illustrates the analytical method for determining the chloride ion content in 3,3-difluorocyclobutylamine hydrochloride and its application through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0140] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0141] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. An analytical method for determining the chloride ion content in 3,3-difluorocyclobutaneamine hydrochloride, characterized in that: The analytical method comprises the following steps: (1) mixing an external standard with a reagent to obtain an external standard detection solution; (2) mixing the sample to be tested with the reagent to obtain a test solution of the sample to be tested; (3) The external standard test solution and the sample test solution are respectively 35 Cl NMR test, calculate the chloride ion content in the sample to be tested based on the test results; There is no order distinction between steps (1) and (2).

2. The analysis method according to claim 1, characterized in that The reagent is a combination of heavy water and water or heavy water, preferably a combination of heavy water and water.

3. The analysis method according to claim 2, characterized in that The volume ratio of the heavy water to water is (50-99):(1-50), preferably (50-60):(40-50).

4. The analysis method according to any one of claims 1 to 3, characterized in that The external standard includes any one of sodium chloride, ammonium chloride, potassium chloride or magnesium chloride, preferably sodium chloride.

5. The analysis method according to any one of claims 1 to 4, characterized in that Said 35 The Cl NMR test uses a zg pulse sequence and the test temperature is 296~300K.

6. The analysis method according to any one of claims 1 to 5, characterized in that Said 35 The pulse width of the Cl NMR test is 15 to 18 μs, preferably 17 μs; Preferably, the 35 The number of scans for the Cl NMR test is 155 to 180, preferably 158 to 170; Preferably, the 35 The relaxation time of the Cl NMR test is 0.2 to 1.0 s, preferably 0.4 to 0.6 s; Preferably, the 35 The number of empty scans for Cl NMR testing is 2 to 6, preferably 3 to 5; Preferably, the 35 The number of sampling points for the Cl NMR test is 16-64k, preferably 24-36k.

7. The analysis method according to any one of claims 1 to 6, characterized in that Said 35 The spectrum width of the Cl NMR test is 350 to 550 ppm, preferably 450 to 550 ppm; Preferably, the 35 The radio frequency center frequency of the Cl nuclear magnetic resonance test is -5 to 5 ppm, preferably -2 to 2 ppm.

8. The analysis method according to any one of claims 1 to 7, characterized in that Said 35 The Cl NMR measurements were performed using a Bruker AVANCE NEO 400 MHz instrument equipped with a BBO probe.

9. The analysis method according to any one of claims 1 to 8, characterized in that The calculation formula of the chloride ion content is as follows: Chloride ion content (%) = (M Cl / M 外标 )×(A x / C x )×(C R / A R )×100%; Where M Cl is the relative atomic mass of the chlorine atom, M 外标 is the relative molecular mass of the external standard, A x is the peak area of ​​chloride ion in 3,3-difluorocyclobutaneamine hydrochloride, A R is the peak area of ​​chloride ion in the external standard, C x is the concentration of 3,3-difluorocyclobutane hydrochloride, C R is the concentration of the external standard.

10. Use of the analytical method according to any one of claims 1 to 9 in the preparation of 3,3-difluorocyclobutaneamine hydrochloride.

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