Detection method of intermediate 5-chloroethyl-6-chloroindole-2-ketone for ziprasidone synthesis

Abstract

The invention provides a detection method of an intermediate 5-chloroethyl-6-chloroindole-2-ketone for ziprasidone synthesis, and belongs to the technical field of drug quality analysis and detection. According to the method, a cyano silane bonded silica gel chromatographic column is selected, acetonitrile in a certain proportion and a phosphate-triethylamine buffer solution with the pH value of 5.0 + / -0.2 are adopted as mobile phases, program gradient elution is cooperatively carried out, a main product can be effectively separated from impurities, and high separation degree and analysis sensitivity are achieved; according to the method, a diode array detector is adopted, and 2008-2022 Shimadzu Corporation LabSolutions software / similar software carried by the diode array detector is used for confirming the maximum absorption wavelength and the relative percentage content of main impurities in the main product 5-chloroethyl-6-chloroindole-2-ketone. The method provided by the invention is short in analysis time, simple in analysis operation, capable of determining whether the main product contains impurities or not, and relatively good in repeatability and adaptability.

Description

Technical Field

[0001] The invention relates to the technical field of drug quality analysis and detection, and in particular to a detection method for 5-chloroethyl-6-chloroindole-2-one, an intermediate for synthesizing ziprasidone. 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 5-chloroethyl-6-chloroindol-2-one. 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 reported literature, the intermediate 5-chloroethyl-6-chloroindol-2-one is evaluated for quality by melting point mp, hydrogen spectrum 1HNMR and infrared spectrum IR analysis, or is identified by liquid chromatography-mass spectrometry, but there is no clear liquid chromatography analysis condition. The quality control method suitable for liquid chromatography analysis of the intermediate 5-chloroethyl-6-chloroindol-2-one product has not been reported. In addition, the main content level of the intermediate 5-chloroethyl-6-chloroindol-2-one used in the synthesis of ziprasidone, the existence and relative percentage of impurities, whether each component is completely separated, and especially whether the main product contains impurities (such as its isomers, etc.) will directly affect the product quality of the synthesized ziprasidone hydrochloride. It is necessary to establish an analytical method and determine the product quality standard. Other impurities mainly include reduced intermediates, over-reduced and dihalogenated substances. The existence and amount of these impurities, if they are not strictly controlled for quality, will greatly increase the post-processing cost of purifying the synthesized ziprasidone product. In order to make the synthesized ziprasidone technical meet the pharmacopoeia quality standard requirements, reduce post-processing costs and improve economic benefits, it is of great significance to establish a high performance liquid chromatography separation and analysis method for 5-chloroethyl-6-chloroindol-2-one intermediate with good separation, 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 5-chloroethyl-6-chloroindol-2-one, an intermediate for synthesizing ziprasidone. The detection method provided by the present invention has high separation degree, can determine the relative quantitative method of main products, main impurities and total impurities, has high analytical sensitivity, short analysis time, simple analytical operation, and good repeatability and 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 5-chloroethyl-6-chloroindol-2-one, an intermediate for synthesizing ziprasidone, comprising the following steps:

[0009] Prepare a solution of 5-chloroethyl-6-chloroindol-2-one to be tested;

[0010] The solution of the 5-chloroethyl-6-chloroindol-2-one to be tested is subjected to high performance liquid chromatography analysis to obtain a chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested;

[0011] According to the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested, the relative percentage content of 5-chloroethyl-6-chloroindol-2-one is obtained;

[0012] According to the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested, the relative percentage content of the main impurities and the total impurities in the 5-chloroethyl-6-chloroindol-2-one to be tested is detected 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 phosphate-triethylamine buffer with a pH value of 5.0±0.2, and the mobile phase B is acetonitrile; gradient elution program: 0.01-10 min, 65v%-75v% mobile phase A; 10-35 min, mobile phase A decreases from 65v%-75v% to 25v%-35v%; 35-40 min, mobile phase A increases from 25v%-35v% to 65v%-75v%; 40-50 min, mobile phase A is maintained at 65v%-75v%.

[0015] Preferably, the detection wavelength of the HPLC analysis is 255-257 nm.

[0016] Preferably, the filler in the chromatographic column used for the high performance liquid chromatography analysis is cyanosilane bonded silica gel, and the particle size of the filler is 5 μm; the specification of the chromatographic column is 4.6 mm×250 mm.

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

[0018] Preferably, the mobile phase flow rate of the HPLC analysis is 1.2 to 1.5 mL / min.

[0019] Preferably, the injection volume of the HPLC analysis is 8 to 20 μL.

[0020] Preferably, the method for preparing the solution of 5-chloroethyl-6-chloroindol-2-one to be tested comprises:

[0021] After mixing acetonitrile and phosphate-triethylamine buffer, ultrasonic degassing is performed to obtain a diluent;

[0022] A certain amount of the 5-chloroethyl-6-chloroindol-2-one sample to be tested and the diluent are mixed, and then ultrasonicated and filtered in sequence to obtain a solution of the 5-chloroethyl-6-chloroindol-2-one to be tested with a concentration of 0.1-0.2 mg / mL.

[0023] Preferably, the volume ratio of acetonitrile to phosphate-triethylamine buffer in the diluent is (30-70): (30-70).

[0024] Preferably, the method for detecting and obtaining the quantitative relative percentage content of the main impurity in the 5-chloroethyl-6-chloroindol-2-one to be detected 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 5-chloroethyl-6-chloroindol-2-one 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] The 2008-2022 Shimadzu Corporation LabSolutions software / similar software is used to analyze and detect various parameters of the main peak of 5-chloroethyl-6-chloroindol-2-one, 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 5-chloroethyl-6-chloroindol-2-one, an intermediate for synthesizing ziprasidone. A cyanosilane bonded silica gel column is selected, acetonitrile in a certain proportion and a phosphate-triethylamine buffer with a pH value of 5.0±0.2 are used as mobile phases, and programmed gradient elution is performed in coordination, so that a main product can be effectively separated from various impurities, and separation degree and analytical sensitivity are improved; a diode array detector is adopted, and the 2008-2022Shimadzu CorporationLabSolutions software / similar software carried by the detector is used to confirm the relative percentage content of the main impurities in the main product 5-chloroethyl-6-chloroindol-2-one. The method provided by the invention has short analysis time and simple analysis operation, and can confirm whether the main product contains impurities, and has good repeatability and adaptability. The detection method provided by the invention can be used to control the main content, main impurity and total impurity content levels of 5-chloroethyl-6-chloroindol-2-one, an intermediate for synthesizing ziprasidone, and will greatly reduce the post-processing cost of purifying the synthesized ziprasidone product, which is of great significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is the HPLC spectrum of the 5-chloroethyl-6-chloroindol-2-one sample solution in Example 1 of the present invention;

[0030] Figure 2 The absorption spectrum of the main impurity in the 5-chloroethyl-6-chloroindol-2-one sample in Example 1 of the present invention, wherein the upper portion is a liquid chromatogram and the lower portion is an absorption spectrum of the main impurity;

[0031] Figure 3 This is a specificity spectrum of the main peak of the HPLC spectrum of the 5-chloroethyl-6-chloroindol-2-one sample solution in Example 1 of the present invention, wherein the upper part is a liquid chromatogram and the lower part is a main peak purity detection spectrum. DETAILED DESCRIPTION

[0032] The present invention provides a method for detecting 5-chloroethyl-6-chloroindol-2-one, an intermediate for synthesizing ziprasidone, comprising the following steps:

[0033] Prepare a solution of a certain concentration of 5-chloroethyl-6-chloroindol-2-one to be tested;

[0034] The solution of the 5-chloroethyl-6-chloroindol-2-one to be tested is subjected to high performance liquid chromatography analysis to obtain a chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested;

[0035] According to the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested, the relative percentage content of 5-chloroethyl-6-chloroindol-2-one is obtained;

[0036] According to the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested, the relative percentage content of the main impurities and the total impurities in the 5-chloroethyl-6-chloroindol-2-one to be tested is detected in cooperation with the diode array detector and its accompanying data software;

[0037] The conditions of the HPLC analysis include:

[0038] Mobile phase: comprising mobile phase A and mobile phase B, wherein the mobile phase A is a phosphate-triethylamine buffer with a pH value of 5.0±0.2, and the mobile phase B is acetonitrile; gradient elution program: 0.01-10 min, 65v%-75v% mobile phase A; 10-35 min, mobile phase A decreases from 65v%-75v% to 25v%-35v%; 35-40 min, mobile phase A increases from 25v%-35v% to 65v%-75v%; 40-50 min, mobile phase A is maintained at 65v%-75v%.

[0039] In the present invention, unless otherwise specified, the raw materials used are conventional commercial products in the art.

[0040] The invention prepares a solution of 5-chloroethyl-6-chloroindol-2-one to be tested.

[0041] In the present invention, the preparation method of the solution of 5-chloroethyl-6-chloroindol-2-one to be tested preferably comprises:

[0042] After mixing acetonitrile and phosphate-triethylamine buffer, ultrasonic degassing is performed to obtain a diluent;

[0043] After the 5-chloroethyl-6-chloroindol-2-one sample to be tested is dissolved in a diluent, ultrasonication and filtration are performed in sequence to obtain a solution of the 5-chloroethyl-6-chloroindol-2-one to be tested with a concentration of 0.1 to 0.2 mg / mL.

[0044] In the present invention, the pH value of the phosphate-triethylamine buffer is preferably 5.0±0.2.

[0045] In the present invention, the volume ratio of acetonitrile to phosphate-triethylamine buffer in the diluent is preferably (30-70):(30-70), more preferably 40-60.

[0046] 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 5-chloroethyl-6-chloroindol-2-one 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 protecting the chromatographic column and subsequently improving the accuracy and sensitivity of the test results. In the present invention, the concentration of the solution of 5-chloroethyl-6-chloroindol-2-one to be tested is preferably 0.1 ～ 0.2 mg / mL, more preferably 0.1 mg / mL.

[0047] After obtaining the solution of 5-chloroethyl-6-chloroindol-2-one to be tested, the present invention performs high performance liquid chromatography analysis on the solution of 5-chloroethyl-6-chloroindol-2-one to be tested to obtain a chromatogram of 5-chloroethyl-6-chloroindol-2-one to be tested.

[0048] In the present invention, the conditions of the HPLC analysis include:

[0049] Mobile phase: comprising mobile phase A and mobile phase B, wherein the mobile phase A is a phosphate-triethylamine buffer with a pH value of 5.0±0.2, and the mobile phase B is acetonitrile; the gradient elution program is: 0.01-10 min, 65v%-75v% mobile phase A; 10-35 min, mobile phase A is reduced from 65v%-75v% to 25v%-35v%; 35-40 min, mobile phase A is increased from 25v%-35v% to 65v%-75v%; 40-50 min, mobile phase A is maintained at 65v%-75v%, and more preferably: 0.01-10 min, 70v% mobile phase A; 10-35 min, mobile phase A is reduced from 70v% to 30v%; 35-40 min, mobile phase A is increased from 30v% to 70v%; 40-50 min, mobile phase A is maintained at 70v%.

[0050] In the present invention, the preparation of the phosphate-triethylamine buffer with a pH value of 5.0±0.2 preferably includes: dissolving potassium dihydrogen phosphate in water, adding triethylamine, adjusting the pH value to 5.0±0.2 with phosphoric acid, and filtering with a filter membrane with a pore size of ≤0.45 μm.

[0051] 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 255-257nm, more preferably 256nm; the filler in the chromatographic column used is preferably cyanosilane bonded silica gel; the particle size of the filler is preferably 5μm; the specifications of the chromatographic column are preferably 4.6mm×250mm, the column temperature is preferably 30-40°C, more preferably 35°C; the mobile phase flow rate is preferably 1.2-1.5mL / min, more preferably 1.3mL / min; the injection volume is preferably 8-20μL, more preferably 10μL. The present invention selects low-carbon-content cyanosilane bonded silica gel suitable for high buffer salt concentration and high water content as a stationary phase, i.e., a filler, selects a certain proportion of acetonitrile and a phosphate-triethylamine buffer with a pH value of 5.0±0.2 as a mobile phase, performs programmed gradient elution in coordination, and controls the column temperature, mobile phase flow rate, and injection volume of high performance liquid chromatography analysis, thereby improving the separation degree and analytical sensitivity of the detection method, and can effectively separate the main product 5-chloroethyl-6-chloroindole-2-one from various impurities.

[0052] After obtaining the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested, the present invention obtains the relative percentage content of 5-chloroethyl-6-chloroindol-2-one according to the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested.

[0053] According to the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested, the relative percentage contents of the main impurities and the total impurities in the 5-chloroethyl-6-chloroindol-2-one to be tested are obtained in cooperation with the diode array detector and its data software.

[0054] In the present invention, the method for detecting and obtaining the relative percentage content of the main impurity in the 5-chloroethyl-6-chloroindol-2-one to be tested comprises the following steps:

[0055] 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 5-chloroethyl-6-chloroindol-2-one to be measured to obtain an ultraviolet-visible absorption curve and a maximum absorption wavelength of each impurity;

[0056] 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 relative percentage content is the main impurity;

[0057] The 2008-2022 Shimadzu Corporation LabSolutions software / similar software is used to analyze and detect various parameters of the main peak of 5-chloroethyl-6-chloroindol-2-one, 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.

[0058] 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 the respective 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 the sample is analyzed at the maximum absorption wavelength of the main impurity, and the relative area percentage content of each substance is calculated by area normalization method to obtain the percentage content of the main product, the main impurity and the total impurity, formulate product quality indicators, and guide industrial production.

[0059] The detection method provided by the invention can be used for the quality control of the intermediate 5-chloroethyl-6-chloroindol-2-one, has the characteristics of good separation, being able to effectively separate the main product from various impurities, being able to confirm that the main peak of the main product does not contain impurities, determining the relative percentage content of the main impurities and the total impurities, high analytical sensitivity, short analysis time, simple operation, good repeatability and adaptability, and being stable and reliable.

[0060] 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.

[0061] Example 1

[0062] The detection method of 5-chloroethyl-6-chloroindol-2-one, an intermediate used in the synthesis of ziprasidone, comprises the following steps:

[0063] After mixing acetonitrile and phosphate-triethylamine buffer with a volume ratio of 40:60 and performing ultrasonic degassing, a diluent is obtained;

[0064] The preparation steps of the phosphate-triethylamine buffer with a pH value of 5.0±0.05 are as follows: 2.72 g of potassium dihydrogen phosphate is weighed and dissolved in 1000 mL of water, 2 mL of triethylamine is added, the pH value is adjusted to 5.0±0.2 with phosphoric acid, and filtered with a filter membrane with a pore size of ≤0.45 μm to obtain a phosphate-triethylamine buffer with a pH value of 5.0±0.05;

[0065] Weigh 10 mg of the 5-chloroethyl-6-chloroindol-2-one sample to be tested into a 100 mL volumetric flask, add 50 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 5-chloroethyl-6-chloroindol-2-one to be tested with a concentration of 0.1 mg / mL;

[0066] The solution of the 5-chloroethyl-6-chloroindol-2-one to be tested is subjected to high performance liquid chromatography analysis under the following conditions to obtain an HPLC spectrum of the 5-chloroethyl-6-chloroindol-2-one 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;

[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 256 nm; the filler in the chromatographic column used is cyanosilane bonded silica gel, and the particle size of the filler is 5 μm; the specification of the chromatographic column is Agilgent Zorbax SB-CN (250 mm×Φ4.6 mm, 5 μm); the column temperature is 35°C; the mobile phase flow rate is 1.3 mL / min; the injection volume is 10 μL.

[0069] Mobile phase: including mobile phase A and mobile phase B, wherein mobile phase A is phosphate-triethylamine buffer with a pH value of 5.0±0.05, 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 5-chloroethyl-6-chloroindol-2-one to be tested, a diode array detector is used in conjunction with the 2008-2022 Shimadzu Corporation Lab Solutions software to perform ultraviolet-visible light scanning on each peak of each impurity in the 5-chloroethyl-6-chloroindol-2-one to be tested, to obtain the maximum absorption wavelength of the various impurities, and the impurities are analyzed at their respective maximum absorption wavelengths, and the area normalization method is used for quantitative analysis. The results of the area normalization method at each maximum wavelength are compared to confirm that the impurity with the highest percentage is the main impurity.

[0073] Figure 1 is the HPLC spectrum of 5-chloroethyl-6-chloroindol-2-one to be tested, Figure 1 The peak table of 5-chloroethyl-6-chloroindol-2-one to be tested is obtained, as shown in Table 2.

[0074] Table 2 Peak table of the HPLC spectrum of 5-chloroethyl-6-chloroindol-2-one to be tested

[0075]

[0076]

[0077] As shown in Table 2, the main peak separation degree is 3.832, the separation is very complete, the analysis time is within 45 minutes, the relative percentage content of the main component by area normalization method is 99.544%, the relative content of the main impurity is 0.112%, and the relative content of the total impurity is 0.456%.

[0078] The software is used to perform ultraviolet visible light scanning on the main impurity to obtain the absorption spectrum of the main impurity in the 5-chloroethyl-6-chloroindole-2-one to be tested in Example 1 as shown in FIG. Figure 2 As shown, the upper part is the liquid chromatography diagram, and the lower part is the absorption spectrum diagram of the main impurity. Figure 2 It can be seen that the maximum absorption wavelength of the main impurity is 256.21nm. It can be confirmed that when analyzed at a wavelength of 256nm, the absorption of the main impurity is the largest and the sensitivity is the highest at this absorption wavelength.

[0079] In the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested ( Figure 1 ), using the 2008-2022Shimadzu Corporation LabSolutions software / similar software, analyze and detect the various parameters of the main peak of 5-chloroethyl-6-chloroindol-2-one, 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 5-chloroethyl-6-chloroindol-2-one to be tested in Example 1, such as Figure 3 As shown by Figure 3It can be seen that no impurities were detected in the main peak of 5-chloroethyl-6-chloroindol-2-one to be tested, the minimum peak purity similarity was 1.000000, the minimum peak purity threshold was 0.999820, the minimum peak purity index was 180, the separation between the main peak and the adjacent peaks was greater than 2.0, and the total analysis time was within 45 min.

[0080] In order to test the repeatability of the solution of 5-chloroethyl-6-chloroindol-2-one to be tested (hereinafter referred to as the test sample solution) prepared in Example 1 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:

[0081] 1. Repeatability experiment

[0082] According to the same detection method as in Example 1, 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 (5-chloroethyl-6-chloroindol-2-one), main impurities and total impurities according to the peak area normalization method, and the repeatability experimental results are shown in Table 3.

[0083] Table 3 Repeatability test results

[0084]

[0085] As shown in Table 3, the RSDs of the main components were 0.007% and 0.00638% (less than 2.0%), the RSDs of the main impurity contents were 1.183% and 1.878% (less than 5.0%), and the RSDs of the total impurities were 1.481% and 1.394% (less than 5.0%). The method provided by the present invention has good repeatability, and the repeatability test meets the requirements.

[0086] 2. Stability test of sample solution

[0087] According to the same detection method and the same HPLC analysis conditions as in Example 1, 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 4.

[0088] Table 4 Test results of stability of sample solutions

[0089]

[0090] As shown in Table 4, the RSD of the peak area of ​​the main component is 0.490% (less than 2%), the RSD of the peak area of ​​the main impurity is 4.25% (less than 20%), and the RSD of the peak area of ​​the total impurity is 5.124% (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.

[0091] 3. Durability test of analytical method

[0092] According to the same detection method as in Example 1, 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 5.

[0093] Table 5 Analysis method durability test results

[0094]

[0095]

[0096] As can be seen from Table 5, 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.

[0097] In summary, the detection method of the intermediate 5-chloroethyl-6-chloroindol-2-one for the synthesis of ziprasidone provided by the present invention can effectively separate the main product 5-chloroethyl-6-chloroindol-2-one 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.

[0098] 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 5-chloroethyl-6-chloroindol-2-one, an intermediate for the synthesis of ziprasidone, characterized in that: The following steps are involved: Prepare a solution of 5-chloroethyl-6-chloroindol-2-one to be tested; The solution of the 5-chloroethyl-6-chloroindol-2-one to be tested is subjected to high performance liquid chromatography analysis to obtain a chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested; According to the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested, the relative percentage content of 5-chloroethyl-6-chloroindol-2-one is obtained; According to the chromatogram of the 5-chloroethyl-6-chloroindol-2-one to be tested, the relative percentage content of the main impurities and the total impurities in the 5-chloroethyl-6-chloroindol-2-one to be tested is detected in cooperation with the diode array detector and its accompanying data software; The conditions of the HPLC analysis include: Mobile phase: comprising mobile phase A and mobile phase B, wherein the mobile phase A is a phosphate-triethylamine buffer with a pH value of 5.0±0.2, and the mobile phase B is acetonitrile; gradient elution program: 0.01-10 min, 65v%-75v% mobile phase A; 10-35 min, mobile phase A decreases from 65v%-75v% to 25v%-35v%; 35-40 min, mobile phase A increases from 25v%-35v% to 65v%-75v%; 40-50 min, mobile phase A is maintained at 65v%-75v%.

2. The detection method according to claim 1, characterized in that: The detection wavelength of the high performance liquid chromatography analysis is 255-257 nm.

3. The detection method according to claim 1, characterized in that: The filler in the chromatographic column used for high performance liquid chromatography analysis is cyanosilane bonded silica gel, and the particle size of the filler is 5 μm; the specification of the chromatographic column is 4.6 mm×250 mm.

4. The detection method according to claim 1, characterized in that: The column temperature of the high performance liquid chromatography analysis is 30-40°C.

5. The detection method according to claim 1, characterized in that: The mobile phase flow rate of the high performance liquid chromatography analysis is 1.2 to 1.5 mL / min.

6. The detection method according to claim 1, characterized in that: The injection volume of the high performance liquid chromatography analysis is 8 to 20 μL.

7. The detection method according to claim 1, characterized in that: The preparation method of the solution of 5-chloroethyl-6-chloroindole-2-one to be tested comprises: After mixing acetonitrile and phosphate-triethylamine buffer, ultrasonic degassing is performed to obtain a diluent; A certain amount of the 5-chloroethyl-6-chloroindol-2-one sample to be tested is dissolved in a diluent, and then ultrasonicated and filtered in sequence to obtain a solution of the 5-chloroethyl-6-chloroindol-2-one to be tested with a concentration of 0.1 to 0.2 mg / mL.

8. The detection method according to claim 7, characterized in that: The volume ratio of acetonitrile to phosphate-triethylamine buffer in the diluent is (30-70): (30-70).

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 5-chloroethyl-6-chloroindol-2-one to be detected comprises the following steps: 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 5-chloroethyl-6-chloroindol-2-one to be measured to obtain an ultraviolet-visible absorption curve and a 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 / similar software is used to analyze and detect various parameters of the main peak of 5-chloroethyl-6-chloroindol-2-one, 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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