Detection method of ziprasidone synthesis intermediate 3-(1-piperazine)-1,2-benzisothiazole hydrochloride

Abstract

The invention provides a detection method for ziprasidone synthesis intermediate 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, belonging to the technical field of drug quality analysis and detection. The invention selects acetonitrile and triethylamine-containing aqueous solution in a certain proportion as mobile phases, performs programmed gradient elution in coordination, and improves separation degree and analytical sensitivity; a diode array detector is adopted, and the 2008-2022Shimadzu Corporation LabSolutions software / similar software carried by the diode array detector is used to confirm the relative quantification of main impurities in the main product 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride; and the method provided by the invention has short analysis time, simple analysis operation and good repeatability and adaptability.

Description

Technical Field

[0001] The present invention relates to the technical field of drug quality analysis and detection, and in particular to a method for detecting ziprasidone synthesis intermediate 3-(1-piperazine)-1,2-benzisothiazole hydrochloride. Background Art

[0002] Ziprasidone hydrochloride is a new type of antipsychotic drug, which is prepared by condensation reaction of 5-chloroethyl-6-chloroindol-2-one and 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride. The structural formula of Ziprasidone hydrochloride is shown below.

[0003]

[0004] Ziprasidone hydrochloride has strict quality standards, such as: United States Pharmacopoeia, USP-NF Ziprasidone Hydrochloride, 31 / 10 / 2020, 1-8,; European Pharmacopoeia, EUROPEAN PHARMACOPOEIA 10.0, Ziprasidone Hydrochloride monohydrate General Notices (1) apply to all other texts, 04 / 2016: 2649, 4257-4247; Chinese Pharmacopoeia, etc.

[0005] In the prior art, the analysis of the intermediate 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride and its related substances used in the synthesis of ziprasidone does not confirm whether the main peak of the main product 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride contains impurities, the maximum absorption wavelength of each substance and the main impurity, and the relative quantification of the main impurities and total impurities. If 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride is not strictly controlled in terms of quality, the post-processing cost of purifying the ziprasidone product synthesized therefrom will be greatly increased. Therefore, in order to make the synthesized ziprasidone original drug meet the requirements of the pharmacopoeia quality standards, it is of great significance to establish a high-performance liquid chromatography separation and analysis method for the intermediate 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride with good separation, relative quantification method for determining main impurities, high analytical sensitivity, simple operation and good adaptability. Summary of the invention

[0006] The purpose of the present invention is to provide a detection method for 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, an intermediate for the synthesis of ziprasidone. The detection method provided by the present invention has good separation, can determine the relative quantitative method of the main impurities, has high analytical sensitivity, is simple to operate and has good adaptability.

[0007] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0008] The present invention provides a method for detecting 3-(1-piperazine)-1,2-benzisothiazole hydrochloride, an intermediate for synthesizing ziprasidone, comprising the following steps:

[0009] Prepare a solution of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested;

[0010] The solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is subjected to high performance liquid chromatography analysis to obtain a chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested;

[0011] According to the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the content of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride is obtained;

[0012] According to the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the relative quantification of the main impurities in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is obtained in cooperation with the diode array detector and its accompanying data software;

[0013] The conditions of the HPLC analysis include:

[0014] Mobile phase: comprising mobile phase A and mobile phase B, wherein the mobile phase A is a triethylamine aqueous solution with a pH value of 8.0±0.2, and the mobile phase B is acetonitrile; gradient elution program: 0.01-5 min, 68v%-72v% mobile phase A; 5-40 min, mobile phase A decreases from 68v%-72v% to 28v%-32v%; 40-41 min, mobile phase A increases from 28v%-32v% to 68v%-72v%; 41-50 min, mobile phase A is maintained at 68v%-72v%.

[0015] Preferably, the detection wavelength of the HPLC analysis is 315-317 nm.

[0016] Preferably, the filler in the chromatographic column used for the high performance liquid chromatography analysis is octaalkylsilane bonded silica gel, and the particle size of the filler is 5 μm; the specification of the chromatographic column is 4.6 mm×150 mm.

[0017] Preferably, the column temperature of the HPLC analysis is 30-40°C.

[0018] Preferably, the injector temperature of the HPLC analysis is room temperature. Preferably, the mobile phase flow rate of the HPLC analysis is 0.8-1.0 mL / min.

[0019] Preferably, the injection volume of the HPLC analysis is 10 to 20 μL.

[0020] Preferably, the preparation method of the solution of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested comprises:

[0021] After mixing acetonitrile and water, ultrasonic degassing is performed to obtain a diluent;

[0022] The 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride sample to be tested and the diluent are mixed, and then ultrasonicated and filtered in sequence to obtain a solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested.

[0023] Preferably, the volume ratio of acetonitrile to water is (40-60): (40-60).

[0024] Preferably, the method for detecting and obtaining the relative quantification of the main impurity in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested comprises the following steps:

[0025] Using a diode array detector and 2008-2022 Shimadzu Corporation Lab Solutions software / similar software provided by the diode array detector, ultraviolet-visible light scanning is performed on each impurity in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be measured to obtain an ultraviolet-visible absorption curve and a maximum absorption wavelength of each impurity;

[0026] At the respective maximum absorption wavelengths of the impurities, the area normalization method is used to compare the area normalization results at the respective maximum wavelengths to confirm that the impurity with the highest percentage content is the main impurity;

[0027] Using the 2008-2022 Shimadzu Corporation LabSolutions software / similar software, analyze and detect various parameters of the main peak of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, including the minimum peak purity similarity, the minimum peak purity threshold, and the separation between the main peak and the adjacent peaks, to confirm whether the main peak contains unseparated impurity components.

[0028] The invention provides a detection method for 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, an intermediate for synthesizing ziprasidone. A certain proportion of acetonitrile and an aqueous solution containing triethylamine are selected as mobile phases, and programmed gradient elution is performed in coordination to improve separation and analytical sensitivity. A diode array detector is adopted, and the 2008-2022 Shimadzu Corporation Lab Solutions software / similar software carried by the detector is used to confirm the relative quantification of main impurities in the main product 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride. The method provided by the invention has short analysis time, simple analysis operation, and good repeatability and adaptability. The detection method provided by the invention can be used to control the main content and impurity content level of the intermediate 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride for synthesizing ziprasidone, which will greatly reduce the post-processing cost of purifying the synthesized ziprasidone product, and is of great significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the HPLC spectrum of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested in Example 1 of the present invention;

[0030] Figure 2 The above figure is the absorption spectrum of the main component of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested in Example 1 of the present invention, wherein Figure 2 The lower figure in the middle is the absorption spectrum of the main impurity;

[0031] Figure 3 is a specific spectrum of the main peak of the HPLC spectrum of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested in Example 2 of the present invention, wherein Figure 3 The figure below is the peak purity detection spectrum;

[0032] Figure 4 This is the HPLC spectrum of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested in Example 2 of the present invention measured at the maximum absorption wavelength of the main impurity. DETAILED DESCRIPTION

[0033] The present invention provides a method for detecting 3-(1-piperazine)-1,2-benzisothiazole hydrochloride, an intermediate for synthesizing ziprasidone, comprising the following steps:

[0034] Prepare a solution of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested;

[0035] The solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is subjected to high performance liquid chromatography analysis to obtain a chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested;

[0036] According to the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the content of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride is obtained;

[0037] According to the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the relative quantification of the main impurities in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is obtained in cooperation with the diode array detector and its accompanying data software;

[0038] The conditions of the HPLC analysis include:

[0039] Mobile phase: comprising mobile phase A and mobile phase B, wherein the mobile phase A is a triethylamine aqueous solution with a pH value of 8.0±0.2, and the mobile phase B is acetonitrile; gradient elution program: 0.01-5 min, 68v%-72v% mobile phase A; 5-40 min, mobile phase A decreases from 68v%-72v% to 28v%-32v%; 40-41 min, mobile phase A increases from 28v%-32v% to 68v%-72v%; 41-50 min, mobile phase A is maintained at 68v%-72v%.

[0040] In the present invention, unless otherwise specified, the raw materials used are conventional commercially available products in the art.

[0041] The present invention prepares a solution of 3-(1-piperazine)-1,2-benzisothiazole hydrochloride to be tested.

[0042] In the present invention, the preparation method of the solution of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested preferably comprises:

[0043] After mixing acetonitrile and water, ultrasonic degassing is performed to obtain a diluent;

[0044] After the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride sample to be tested and the diluent are mixed, ultrasonication and filtration are performed in sequence to obtain a solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested.

[0045] In the present invention, the volume ratio of acetonitrile and water is preferably (40-60): (40-60). The present invention has no special restrictions on the ultrasonic degassing method, and a well-known technical solution can be used. The present invention has no special restrictions on the ultrasonic method, and a well-known technical solution can be used to achieve complete dissolution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride sample to be tested. In the present invention, the pore size of the filter membrane used for filtration is preferably ≤0.45μm. The present invention removes undissolved solid particles by filtration, which is beneficial to subsequent improvement of the accuracy and sensitivity of subsequent test results. In the present invention, the concentration of the solution of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is preferably 0.1-0.5mg / mL.

[0046] After obtaining the solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the present invention performs high performance liquid chromatography analysis on the solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested to obtain a chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested.

[0047] In the present invention, the conditions for the HPLC analysis include:

[0048] Mobile phase: comprising mobile phase A and mobile phase B, wherein the mobile phase A is a triethylamine aqueous solution with a pH value of 8.0±0.2, and the mobile phase B is acetonitrile; gradient elution program: 0.01-5 min, 68v%-72v% mobile phase A; 5-40 min, mobile phase A decreases from 68v%-72v% to 28v%-32v%; 40-41 min, mobile phase A increases from 28v%-32v% to 68v%-72v%; 41-50 min, mobile phase A is maintained at 68v%-72v%.

[0049] In the present invention, the preparation of the triethylamine aqueous solution with a pH of 8.0±0.2 preferably comprises: adding 1.8 to 2.2 mL of triethylamine to 1000 mL of water, and then filtering with a filter membrane with a pore size of ≤0.45 μm.

[0050] In the present invention, the conditions of the high performance liquid chromatography analysis preferably also include: the detection wavelength of the detector used is preferably 315-317nm; the filler in the chromatographic column used is preferably octaalkylsilane bonded silica gel, and the particle size of the filler is preferably 5μm; the specification of the chromatographic column is preferably 4.6mm×150mm; the column temperature is preferably 30-40℃, more preferably 32-37℃; the injector temperature is preferably room temperature; the mobile phase flow rate is preferably 0.8-1.0mL / min; the injection volume is preferably 10-20μL. The present invention selects octaalkylsilane bonded silica gel adapted to high alkalinity and high water content as the stationary phase, i.e., the filler, selects a certain proportion of acetonitrile and triethylamine-containing aqueous solution as the mobile phase, performs programmed gradient elution in coordination, and controls the column temperature, injector temperature, mobile phase flow rate and injection volume of the high performance liquid chromatography analysis, thereby improving the separation degree and analytical sensitivity of the detection method, and can effectively separate the main product 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride from each impurity.

[0051] After obtaining the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the present invention obtains the content of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride according to the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested.

[0052] According to the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the relative quantification of the main impurities in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is obtained in cooperation with a diode array detector and its accompanying data software.

[0053] In the present invention, the method for detecting and obtaining the relative quantification of the main impurity in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested preferably comprises the following steps:

[0054] Using a diode array detector and 2008-2022 Shimadzu Corporation Lab Solutions software / similar software provided by the diode array detector, ultraviolet-visible light scanning is performed on each impurity in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be measured to obtain an ultraviolet-visible absorption curve and a maximum absorption wavelength of each impurity;

[0055] At the respective maximum absorption wavelengths of the impurities, the area normalization method is used to compare the area normalization results at the respective maximum wavelengths to confirm that the impurity with the highest percentage content is the main impurity;

[0056] Using the 2008-2022 Shimadzu Corporation Lab Solutions software / similar software, analyze and detect the various parameters of the main peak of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, including the minimum peak purity similarity, the minimum peak purity threshold, and the separation between the main peak and the adjacent peaks, to confirm whether the main peak contains unseparated impurity components.

[0057] The present invention adopts a diode array detector and utilizes the 2008-2022 Shimadzu Corporation Lab Solutions software / similar software to detect various parameters of the main peak, including whether the main peak contains impurities, the minimum peak purity similarity, the minimum peak purity threshold, and the separation degree between the main peak and the adjacent peaks, etc., to confirm whether the main peak of the sample contains impurities and whether other components are completely separated; the software is used to test the maximum absorption wavelength of each peak, analyze at each maximum absorption wavelength, quantify by area normalization method, compare the percentage content results analyzed at each maximum absorption wavelength, the main impurity has the highest percentage content, and perform sample analysis at the maximum absorption wavelength of the main impurity, calculate the relative area percentage content of each substance by area normalization method, obtain the percentage content of the main product, the main impurity and the total impurity, formulate product quality indicators, and guide industrial production.

[0058] The detection method provided by the present invention can be used for the quality control of the intermediate 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, has the characteristics of good separation, can effectively separate the main product from various impurities, can confirm that the main peak of the main product does not contain impurities, can determine the relative percentage content of the main impurities and the total impurities, has high analytical sensitivity, short analysis time, simple operation, good repeatability and adaptability, and is stable and reliable.

[0059] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0060] All chemical reagents in the following examples are commercially available, except for methanol and acetonitrile which are chromatographically pure, all others are analytically pure; water is Yibao purified water; the intermediate 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride is produced by Hunan Kaiyuan Biotechnology Co., Ltd.

[0061] The 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride sample to be tested in Example 1 and Example 2 of the present invention is the same sample.

[0062] Example 1

[0063] The detection method of ziprasidone synthesis intermediate 3-(1-piperazine)-1,2-benzisothiazole hydrochloride, the steps are as follows:

[0064] After mixing acetonitrile and water in a volume ratio of 50:50, ultrasonic degassing was performed to obtain a diluent;

[0065] Weigh 15 mg of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride sample to be tested into a 50 mL volumetric flask, add 30 mL of the diluent, dissolve by ultrasonication, and then make up to volume with the diluent, and then filter with a filter membrane with a pore size of ≤0.45 μm to obtain a solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested with a concentration of 0.3 mg / mL;

[0066] The solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is subjected to high performance liquid chromatography analysis under the following conditions to obtain an HPLC spectrum of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested by the area normalization method at the maximum absorption wavelength of the main component, as shown in FIG. Figure 1 As shown;

[0067] The conditions of the HPLC analysis are:

[0068] High performance liquid chromatograph: Shimadzu LC-20A, diode array detector, the detection wavelength of the detector used is 230nm; the filler in the chromatographic column used is octaalkylsilane bonded silica gel, the particle size of the filler is 5μm; the specification of the chromatographic column is Ultimate XB C18 (150mm×Φ4.6mm, 5μm); the column temperature is 35℃; the injector temperature is room temperature; the mobile phase flow rate is 1.0mL / min; the injection volume is 20μL

[0069] Mobile phase: including mobile phase A and mobile phase B, wherein mobile phase A is triethylamine aqueous solution with a pH value of 8.0±0.2, and mobile phase B is acetonitrile; in terms of volume percentage, the gradient elution program is shown in Table 1.

[0070] Table 1 Gradient elution program

[0071]

[0072] On the HPLC spectrum of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, a diode array detector is used in conjunction with the 2008-2022 Shimadzu Corporation LabSolutions software to perform ultraviolet-visible light scanning on each peak of each impurity in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, to obtain the maximum absorption wavelength of the various impurities, and the analysis is performed at each maximum absorption wavelength, and the area normalization method is used for quantitative analysis, and the results of the area normalization method at each maximum wavelength are compared to confirm that the impurity with the highest percentage content is the main impurity;

[0073] Figure 1 is the HPLC spectrum of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, Figure 1 The peak table of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is shown in Table 2.

[0074] Table 2 Peak table

[0075]

[0076]

[0077] It can be seen from Table 2 that the retention time of the largest impurity measured at the maximum absorption wavelength of the main component at 230 nm is 15.754.

[0078] The liquid phase diode array detector is used to continuously detect the above main impurities at all wavelengths of the ultraviolet spectrum, and the maximum absorption wavelength of the main impurity (retention time of 15.754 min) in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested in Example 1 is 316 nm, and the absorption spectrum is as shown in FIG. Figure 2 shown.

[0079] Example 2

[0080] The detection method of ziprasidone synthesis intermediate 3-(1-piperazine)-1,2-benzisothiazole hydrochloride, the steps are as follows:

[0081] After mixing acetonitrile and water in a volume ratio of 50:50, ultrasonic degassing was performed to obtain a diluent;

[0082] Weigh 15 mg of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride sample to be tested into a 50 mL volumetric flask, add 30 mL of the diluent, dissolve by ultrasonication, and then make up to volume with the diluent, and then filter with a filter membrane with a pore size of ≤0.45 μm to obtain a solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested with a concentration of 0.3 mg / mL;

[0083] The solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is subjected to high performance liquid chromatography analysis under the following conditions to obtain an HPLC spectrum of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested by the area normalization method at the maximum absorption wavelength of the main impurity, as shown in FIG. Figure 1 As shown;

[0084] The conditions of the HPLC analysis are:

[0085] High performance liquid chromatograph: Shimadzu LC-20A, diode array detector, the detection wavelength of the detector used is 316 nm; the filler in the chromatographic column used is octaalkylsilane bonded silica gel, and the particle size of the filler is 5 μm; the specification of the chromatographic column is Ultimate XB C18 (150 mm×Φ4.6 mm, 5 μm); the column temperature is 35°C; the injector temperature is room temperature; the mobile phase flow rate is 1.0 mL / min; the injection volume is 20 μL;

[0086] The HPLC spectrum of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested at the maximum absorption wavelength (316 nm) of the main impurity is as follows: Figure 4 As shown by Figure 4 The peak table obtained is shown in Table 3.

[0087] Table 3 Peak table

[0088]

[0089] It can be seen from Table 3 that after the maximum absorption wavelength of the main component was changed to the maximum absorption wavelength of the main impurity, the purity of the main component decreased from 99.788% to 99.715%.

[0090] In the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested ( Figure 4 ), using the 2008-2022Shimadzu Corporation LabSolutions software / similar software, analyze and detect the various parameters of the main peak of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, determine whether the main peak contains impurities, the minimum peak purity similarity, and the minimum peak purity threshold, and obtain the specificity spectrum of the main peak of the HPLC spectrum of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested in Example 2, as shown in Figure 3 As shown by Figure 3It can be seen that no impurities were detected in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the minimum peak purity similarity was 1.000000, the minimum peak purity threshold was 0.999994, the minimum peak purity index was 5, the separation between the main peak and the adjacent peaks was greater than 2.0, and the total analysis time was within 50 min.

[0091] In order to test the repeatability of the solution of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested (hereinafter referred to as the test sample solution) prepared in Example 2 of the detection method provided by the present invention on different instruments, the stability of the test sample solution and the durability of the analysis method, the following experiments were carried out respectively:

[0092] 1. Repeatability experiment

[0093] According to the same detection method as in Example 2, the same type of HPLC and the same HPLC analysis conditions, different people tested the same sample 5 times in a row on different instruments (test subject A on HPLC No. 1, test subject B on HPLC No. 2) (i.e., each person tested the same sample five times), and calculated the area normalization percentage of the main component (3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride), main impurities and total impurities according to the peak area normalization method, and obtained the repeatability experimental results as shown in Table 4.

[0094] Table 4 Repeatability test results

[0095]

[0096] As shown in Table 4, the RSDs of the main components were 0.003% and 0.004% (less than 2.0%), the RSDs of the main impurity contents were 2.80% and 2.62% (less than 5.0%), and the RSDs of the total impurities were 0.88% and 1.15% (less than 5.0%). The method provided by the present invention has good repeatability, and the repeatability test meets the requirements.

[0097] 2. Stability test of sample solution

[0098] According to the same detection method and the same HPLC analysis conditions as in Example 2, the same sample solution to be tested was sampled and analyzed at different times, and the peak areas of the main components, main impurities and total impurities were calculated. The results of the sample solution stability experiment are shown in Table 5.

[0099] Table 5 Test results of stability of sample solutions

[0100]

[0101] As shown in Table 5, the RSD of the peak area of ​​the main component is 0.32% (less than 2%), the RSD of the peak area of ​​the main impurity is 2.90% (less than 20%), and the RSD of the peak area of ​​the total impurity is 1.01% (less than 20%). The test sample solution prepared by the method provided by the present invention has good stability and is stable within 3 days.

[0102] 3. Durability test of analytical method

[0103] According to the same detection method as in Example 2, for the same sample solution to be tested, one of the parameters (mobile phase flow rate, column temperature or mobile phase ratio) was changed for sample analysis, and the peak area percentages of the main component, main impurity and total impurities were calculated according to the peak area normalization method. The results of the durability experiment of the analytical method are shown in Table 6.

[0104] Table 6 Analysis method durability test results

[0105]

[0106]

[0107] As can be seen from Table 6, the results obtained by slightly changing the analytical conditions are within the allowable range (main component RSD≤2.0%, main impurity RSD≤20%, total impurity RSD≤20%), indicating that the method provided by the present invention has high durability.

[0108] In summary, the detection method of the intermediate 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride for the synthesis of ziprasidone provided by the present invention can effectively separate the main product 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride from various impurities, has good repeatability, good stability of the sample solution to be tested, high durability, and is stable and feasible after methodological verification.

[0109] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for detecting 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, an intermediate for the synthesis of ziprasidone, characterized in that: The following steps are involved: Prepare a solution of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested; The solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is subjected to high performance liquid chromatography analysis to obtain a chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested; According to the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the content of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride is obtained; According to the chromatogram of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested, the relative quantification of the main impurities in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested is obtained in cooperation with the diode array detector and its accompanying data software; The conditions of the HPLC analysis include: Mobile phase: including mobile phase A and mobile phase B, wherein the mobile phase A is a triethylamine aqueous solution with a pH value of 8.0±0.2, and the mobile phase B is acetonitrile; gradient elution program: 0.01-5 min, 68v%-72v% mobile phase A; 5-40 min, mobile phase A decreases from 68v%-72v% to 28v%-32v%; 40-41 min, mobile phase A increases from 28v%-32v% to 68v%-72v%; 41-50 min, mobile phase A is maintained at 68v%-72v%; The filler in the chromatographic column used for high performance liquid chromatography analysis is octaalkylsilane bonded silica gel, and the particle size of the filler is 5 μm; the specification of the chromatographic column is 4.6 mm×150 mm.

2. The detection method according to claim 1, characterized in that: The detection wavelength of the high performance liquid chromatography analysis is 315-317 nm.

3. The detection method according to claim 1, characterized in that: The column temperature of the HPLC analysis is 30-40°C.

4. The detection method according to claim 1, characterized in that: The injector temperature of the HPLC analysis is room temperature.

5. The detection method according to claim 1, characterized in that: The mobile phase flow rate of the high performance liquid chromatography analysis is 0.8-1.0 mL / min.

6. The detection method according to claim 1, characterized in that: The injection volume of the high performance liquid chromatography analysis is 10-20 μL.

7. The detection method according to claim 1, characterized in that: The preparation method of the solution of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested comprises: After mixing acetonitrile and water, ultrasonic degassing is performed to obtain a diluent; The 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride sample to be tested and the diluent are mixed, and then ultrasonicated and filtered in sequence to obtain a solution of the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested.

8. The detection method according to claim 7, characterized in that: The volume ratio of acetonitrile to water is (40-60): (40-60).

9. The detection method according to claim 1, characterized in that: The method for detecting and obtaining relative quantification of the main impurity in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested comprises the following steps: Using a diode array detector and the 2008-2022 Shimadzu Corporation Lab Solutions software provided with the diode array detector, ultraviolet-visible light scanning is performed on each impurity in the 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride to be tested to obtain the ultraviolet-visible absorption curve and maximum absorption wavelength of each impurity; At the respective maximum absorption wavelengths of the impurities, the area normalization method is used to compare the area normalization results at the respective maximum wavelengths to confirm that the impurity with the highest percentage content is the main impurity; The 2008-2022 Shimadzu Corporation LabSolutions software was used to analyze and detect various parameters of the main peak of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, including the minimum peak purity similarity, the minimum peak purity threshold, and the separation between the main peak and the adjacent peaks to confirm whether the main peak contains unseparated impurity components.

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