Method for analyzing and detecting lafutidine raw material and related substances thereof through high performance liquid chromatography

Abstract

The invention provides a method for analyzing and detecting a lafutidine raw material and related substances thereof through high performance liquid chromatography, and the lafutidine raw material is (2Z)-4-[[4-(1-piperidyl methyl)-2-pyridyl] oxy]-2-butene-1-ol and related substances and other related substances thereof. The detection method comprises the following steps: detecting a to-be-detected sample by using high performance liquid chromatography, and determining the content of (2Z)-4-[[4-(1-piperidyl methyl)-2-pyridyl] oxy]-2-butene-1-ol and the related substances thereof in the to-be-detected sample based on a detection result. The method can be used for accurately detecting the contents of the lafutidine raw material and the related substances thereof, has the advantages of simplicity in operation, high practical reliability, better stability, strong data reproducibility, high sensitivity and the like, and provides an effective technical basis for accurately determining or separating the related substances.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine. Specifically, the present invention relates to a method for analyzing and detecting raw materials of Lafutidine and its isomers by high performance liquid chromatography (HPLC). More specifically, the present invention relates to a method for analyzing and detecting (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances by high performance liquid chromatography (HPLC). Background Art

[0002] Lafutidine tablets are a new generation of histamine H 2 receptor blockers, which can continuously inhibit the basal secretion, nocturnal secretion of gastric acid and pepsin, and the gastric acid secretion induced by stimulating factors such as tetrapeptide gastrin, bethanechol, and gastric distension. Lafutidine acts on the capsaicin-sensitive afferent nerves of the digestive tract mucosa, mediates the release of calcitonin gene-related peptide and nitric oxide, increases mucosal blood flow, promotes mucus secretion, and promotes mucosal epithelial regeneration, thereby playing a role in protecting the digestive tract mucosa, resisting the damage of mucosal by stimulating factors such as gastric acid, alcohol, and bile, promoting ulcer healing, and preventing ulcer recurrence.

[0003] In the synthesis process of Lafutidine, it is necessary to effectively analyze and detect the quality of its raw material (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. The possible impurity components are as follows:

[0004]

[0005] At present, there is no relatively mature report on the analysis and detection of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances by high performance liquid chromatography (HPLC).

[0006] Therefore, it is urgent to develop a method using high performance liquid chromatography to analyze and detect Lafutidine raw materials and their related substances in order to effectively monitor the quality of Lafutidine raw materials. Summary of the Invention

[0007] The present invention aims to solve at least one of the technical problems existing in the prior art to some extent. For this purpose, the present invention has developed a method using high performance liquid chromatography (HPLC) to analyze the purity of Lafutidine raw material (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol, and can effectively separate (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances at the same time, so as to realize the quality control of raw materials in the production of Lafutidine.

[0008] In the first aspect of the present invention, a method for detecting (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances is proposed. According to an embodiment of the present invention, the method includes: detecting a sample to be tested by high performance liquid chromatography, and based on the detection result, determining the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the sample to be tested. The high performance liquid chromatography analysis method provided by the present invention for detecting the raw material of lafutidine, (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances has the advantages of simple operation, high practical reliability, good stability, strong data reproducibility, high sensitivity, etc., and has a good resolution between (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances, providing an effective technical basis for accurately determining or separating related substances, thereby realizing the quality control of raw materials in the production of lafutidine.

[0009] According to an embodiment of the present invention, the method for detecting (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances may further include at least one of the following additional technical features:

[0010] According to an embodiment of the present invention, the mobile phase used in the high performance liquid chromatography is selected from a mixed solution of ammonium bicarbonate and acetonitrile. The inventors found that the traditional detection method cannot completely separate the peaks of the raw material of lafutidine, (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances, resulting in the inability to effectively separate (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol from some impurities, or the situation where some related substances are not detected. For this reason, through a large number of experiments, the inventors found that when the mobile phase is selected from a mixed solution of ammonium bicarbonate and acetonitrile, the peaks of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and other impurities can be better separated, so that the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and other related substances can be accurately detected respectively, and each chromatographic peak can be effectively separated, having the advantages of strong specificity, high accuracy, good reproducibility, high sensitivity, etc.

[0011] According to an embodiment of the present invention, the ammonium bicarbonate exists in the form of a solution, that is, ammonium bicarbonate solution.

[0012] According to an embodiment of the present invention, the concentration of the ammonium bicarbonate solution is 45 mM to 55 mM. For example, 45 mM, 46 mM, 47 mM, 48 mM, 49 mM, 50 mM, 51 mM, 52 mM, 53 mM, 54 mM, 55 mM.

[0013] According to an embodiment of the present invention, the pH value of the ammonium bicarbonate solution is 10.0 to 11.0. Therefore, the peaks of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and other impurities can be well separated, so that the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and other related substances can be accurately detected respectively, and each chromatographic peak can be effectively separated, having the advantages of strong specificity, high accuracy, good reproducibility, high sensitivity, etc.

[0014] According to an embodiment of the present invention, the volume ratio of the ammonium bicarbonate solution to acetonitrile is (65 - 75):(25 - 35). Therefore, the peaks of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and other impurities can be well separated, so that the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and other related substances can be accurately detected respectively, and each chromatographic peak can be effectively separated, having the advantages of strong specificity, high accuracy, good reproducibility, high sensitivity, etc.

[0015] According to an embodiment of the present invention, the related substances are selected from at least one of the following:

[0016]

[0017] According to an embodiment of the present invention, the high performance liquid chromatography uses isocratic elution.

[0018] The inventor obtained the above isocratic elution conditions through a large number of experiments. Thus, the resolution between (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and other related substances can be improved, the peak shapes of each component are good, and the peak emergence time is appropriate.

[0019] According to an embodiment of the present invention, the chromatographic column of the high performance liquid chromatography is selected from Waters XBridge Shield RP18 3.5 μm or an equivalent chromatographic column, and the equivalent chromatographic column mainly refers to a C18 chromatographic column with a chimeric polar group. The inventors obtained the above chromatographic column through a large number of experiments. Thus, the accuracy and resolution of the detection results of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and other related substances can be further improved, the peak shapes of each component are good, and the peak emergence time is appropriate.

[0020] According to an embodiment of the present invention, the flow rate of the mobile phase in the high performance liquid chromatography detection is 0.5 - 1.5 mL / min. The inventors obtained the above flow rate through a large number of experiments. Thus, the resolution between each component can be improved, the peak shapes of each component are good, and the peak emergence time is appropriate, so as to further effectively separate (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol.

[0021] According to an embodiment of the present invention, the detection wavelength used in the high performance liquid chromatography detection is 260 - 290 nm. The inventors obtained the above detection wavelength through a large number of experiments. Thus, the absorption intensity is relatively large, the detection sensitivity is relatively high, and the effect is relatively good.

[0022] According to an embodiment of the present invention, the column temperature used in the high performance liquid chromatography detection is 15 - 35 °C. The inventors comprehensively considered various factors such as the stationary phase, the mobile phase, and the detection effect, and finally selected the above column temperature. Within this temperature range, the resolution, peak shapes such as the half-peak width, peak height, etc. are all relatively good.

[0023] In the second aspect of the present invention, the present invention provides a method for detecting (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances. According to an embodiment of the present invention, the method uses high performance liquid chromatography to detect a sample to be tested, and based on the detection results, determines the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the sample to be tested; wherein, the mobile phase used in the high performance liquid chromatography includes ammonium bicarbonate and acetonitrile, and the pH value of the ammonium bicarbonate solution is 10.0 - 11.0; the related substances are selected from at least one of the following: The high performance liquid chromatography (HPLC) uses isocratic elution; the chromatographic column of the HPLC is selected from Waters XBridge Shield RP18 3.5 μm or an equivalent chromatographic column, and the equivalent chromatographic column mainly refers to a C18 chromatographic column with embedded polar groups; the flow rate of the mobile phase in the HPLC detection is 0.8 - 1.2 mL / min; the detection wavelength used in the HPLC detection is 263 - 283 nm; the column temperature used in the HPLC detection is 20 - 30 °C.

[0024] The HPLC analysis method provided by the present invention for detecting (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material of Lafutidine has the advantages of simple operation, high practical reliability, good stability, strong data reproducibility, high sensitivity, etc., and the resolution between (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances is good, providing an effective technical basis for accurately determining or separating the related substances, thereby realizing the quality control of the raw materials in the production of Lafutidine.

[0025] In the third aspect of the present invention, the present invention proposes a quality control method for the raw material sample of Lafutidine. According to the embodiments of the present invention, the method includes detecting the raw material sample of Lafutidine by the method described in the first aspect or the second aspect to obtain the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances; based on the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances, determining whether the quality of the raw material sample of Lafutidine meets the standard. As described above, by using the method of the present invention, the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material sample of Lafutidine can be accurately determined, and the measurement results are compared and analyzed with the respective corresponding thresholds, thereby realizing the quality control of the raw material sample of Lafutidine.

[0026] According to the embodiments of the present invention, the purity of the raw material of Lafutidine (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is greater than 95.0%, which is an indication that the quality of the raw material sample of Lafutidine is qualified, and its detection limit is 0.01 μg / mL.

[0027] The additional aspects and advantages of the present invention will be given in part in the following description, become apparent in part from the following description, or be understood through the practice of the present invention. Description of the Drawings

[0028] The above and / or additional aspects and advantages of the present invention will become apparent and be readily understood from the following description of embodiments in conjunction with the accompanying drawings, wherein:

[0029] Figure 1 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 1 of the present invention;

[0030] Figure 2 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 2 of the present invention;

[0031] Figure 3 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 3 of the present invention;

[0032] Figure 4 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 4 of the present invention;

[0033] Figure 5 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 5 of the present invention;

[0034] Figure 6 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 6 of the present invention;

[0035] Figure 7 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 7 of the present invention;

[0036] Figure 8 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 8 of the present invention;

[0037] Figure 9 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 9 of the present invention;

[0038] Figure 10 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 10 of the present invention;

[0039] Figure 11 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Embodiment 11 of the present invention;

[0040] Figure 12 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Comparative Example 1 of the present invention;

[0041] Figure 13 Shows the high-performance liquid chromatography (HPLC) chromatogram of the obtained sample according to Comparative Example 2 of the present invention. Detailed implementation manners

[0042] Embodiments of the present invention will be described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as limiting the present invention. For those not specified in the embodiments regarding specific technologies or conditions, they shall be carried out according to the technologies or conditions described in the literature in the art or according to the product specifications. For reagents or instruments not specified by the manufacturer, they are all conventional products that can be obtained through commercial purchase.

[0043] Example 1

[0044] In this embodiment, the content of the raw material of lafutidine (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances was quantitatively analyzed by HPLC method as follows:

[0045] (1) The chromatographic conditions are as follows:

[0046] High performance liquid chromatograph: Dionex: UltiMate3000;

[0047] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0048] Mobile phase: 50 mM ammonium bicarbonate (adjusted to pH 10.5 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0049] Flow rate: 1.0 mL / min;

[0050] Detection wavelength: 273 nm;

[0051] Column temperature: 25°C;

[0052] Injection volume: 20 μL;

[0053] Diluent: 30% acetonitrile;

[0054] (2) Take 10 mg of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and place it in a 20 ml volumetric flask. Dissolve it with 30% acetonitrile and dilute to the mark, shake well, and use it as the sample solution;

[0055] (3) Take 20 μL of the sample solution and perform high performance liquid chromatography analysis under the conditions in step (1), and record the chromatogram.

[0056] The chromatogram is as Figure 1 shown, Figure 1Peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, and the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5). Moreover, the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol appears at about 17.433 min.

[0057]

[0058] Example 2

[0059] The content of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material of lafutidine was detected according to the method of Example 1. Among them, the chromatographic conditions are as follows:

[0060] High performance liquid chromatograph: Dionex: UltiMate3000;

[0061] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0062] Mobile phase: 50 mM ammonium bicarbonate (pH adjusted to 10.5 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0063] Flow rate: 0.8 mL / min;

[0064] Detection wavelength: 278 nm;

[0065] Column temperature: 25°C;

[0066] Injection volume: 20 μL;

[0067] Diluent: 30% acetonitrile;

[0068] The chromatogram is as Figure 2 shown. Figure 2Peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under these conditions, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol appears at about 20.110 min.

[0069] Example 3

[0070] Determine the content of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material of Lafutidine according to the method of Example 1. Among them, the chromatographic conditions are as follows:

[0071] High performance liquid chromatograph: Dionex: UltiMate3000;

[0072] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0073] Mobile phase: 50 mM ammonium bicarbonate (adjusted to pH 10.5 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0074] Flow rate: 1.2 mL / min;

[0075] Detection wavelength: 278 nm;

[0076] Column temperature: 25°C;

[0077] Injection volume: 20 μL;

[0078] Diluent: 30% acetonitrile;

[0079] The chromatogram is as Figure 3 shown, Figure 3 Peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under these conditions, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol appears at about 15.462 min.

[0080] Example 4

[0081] The content of the raw material of Lafutidine, (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol, and its related substances was detected according to the method of Example 1. Among them, the chromatographic conditions were as follows:

[0082] High performance liquid chromatograph: Dionex: UltiMate3000;

[0083] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0084] Mobile phase: 50 mM ammonium bicarbonate (pH adjusted to 10.5 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0085] Flow rate: 1.0 mL / min;

[0086] Detection wavelength: 278 nm;

[0087] Column temperature: 20 °C;

[0088] Injection volume: 20 μL;

[0089] Diluent: 30% acetonitrile;

[0090] The chromatogram is as Figure 4 shown. Figure 4 In the figure, peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, and the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is at about 17.713 min.

[0091] Example 5

[0092] The content of the raw material of Lafutidine, (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol, and its related substances was detected according to the method of Example 1. Among them, the chromatographic conditions were as follows:

[0093] High performance liquid chromatograph: Dionex: UltiMate3000;

[0094] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0095] Mobile phase: 50 mM ammonium bicarbonate (pH adjusted to 10.5 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0096] Flow rate: 1.0 mL / min;

[0097] Detection wavelength: 278 nm;

[0098] Column temperature: 30 °C;

[0099] Sample injection volume: 20 μL;

[0100] Diluent: 30% acetonitrile;

[0101] The chromatogram is as Figure 5 shown, Figure 5 in which peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is at about 17.110 min.

[0102] Example 6

[0103] The content of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material of lfamotidine was detected according to the method of Example 1, and the chromatographic conditions were as follows:

[0104] High performance liquid chromatograph: Dionex: UltiMate3000;

[0105] Chromatographic column: Waters XBridge Shield RP18 3.5 μm;

[0106] Mobile phase: 50 mM ammonium bicarbonate (pH adjusted to 10.5 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0107] Flow rate: 1.0 mL / min;

[0108] Detection wavelength: 263 nm;

[0109] Column temperature: 25 °C;

[0110] Sample injection volume: 20 μL;

[0111] Diluent: 30% acetonitrile;

[0112] The chromatogram is as Figure 6 shown, Figure 6 in which peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is at about 17.407 min.

[0113] Example 7

[0114] The content of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material of lafutidine was detected according to the method of Example 1, and the chromatographic conditions were as follows:

[0115] High performance liquid chromatograph: Dionex: UltiMate3000;

[0116] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0117] Mobile phase: 50 mM ammonium bicarbonate (adjusted to pH 10.5 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0118] Flow rate: 1.0 mL / min;

[0119] Detection wavelength: 283 nm;

[0120] Column temperature: 25°C;

[0121] Injection volume: 20 μL;

[0122] Diluent: 30% acetonitrile;

[0123] The chromatogram is as Figure 7 shown, Figure 7Peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under these conditions, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is at about 17.410 min.

[0124] Example 8

[0125] Determine the content of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material of Lafutidine according to the method of Example 1. Among them, the chromatographic conditions are as follows:

[0126] High performance liquid chromatograph: Dionex: UltiMate3000;

[0127] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0128] Mobile phase: 50 mM ammonium bicarbonate (pH adjusted to 10.5 with ammonia water): acetonitrile = 65:35 (volume ratio);

[0129] Flow rate: 1.0 mL / min;

[0130] Detection wavelength: 273 nm;

[0131] Column temperature: 25°C;

[0132] Injection volume: 20 μL;

[0133] Diluent: 30% acetonitrile;

[0134] The chromatogram is as Figure 8 shown, Figure 8 Peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under these conditions, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is at about 14.357 min.

[0135] Example 9

[0136] The content of the raw material of Lafutidine, (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances was detected according to the method of Example 1. Among them, the chromatographic conditions were as follows:

[0137] High performance liquid chromatograph: Dionex: UltiMate3000;

[0138] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0139] Mobile phase: 50 mM ammonium bicarbonate (adjusted to pH 10.5 with ammonia water): acetonitrile = 75:25 (volume ratio);

[0140] Flow rate: 1.0 mL / min;

[0141] Detection wavelength: 273 nm;

[0142] Column temperature: 25°C;

[0143] Injection volume: 20 μL;

[0144] Diluent: 30% acetonitrile;

[0145] The chromatogram is as Figure 9 shown. The peak No. 1 in Figure 9 is impurity A, the peak No. 2 is impurity B, the peak No. 3 is impurity C, and the peak No. 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is at about 10.890 min.

[0146] Example 10

[0147] The content of the raw material of Lafutidine, (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances was detected according to the method of Example 1. Among them, the chromatographic conditions were as follows:

[0148] High performance liquid chromatograph: Dionex: UltiMate3000;

[0149] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0150] Mobile phase: 50 mM ammonium bicarbonate (pH adjusted to 10.0 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0151] Flow rate: 1.0 mL / min;

[0152] Detection wavelength: 273 nm;

[0153] Column temperature: 25 °C;

[0154] Sample injection volume: 20 μL;

[0155] Diluent: 30% acetonitrile;

[0156] The chromatogram is as shown Figure 10 in Figure 10 which peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, and the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is at about 16.597 min.

[0157] Example 11

[0158] The content of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material of Lafutidine was detected according to the method of Example 1, and the chromatographic conditions were as follows:

[0159] High performance liquid chromatograph: Dionex: UltiMate 3000;

[0160] Chromatographic column: Waters XBridge Shield RP18 3.5 μm;

[0161] Mobile phase: 50 mM ammonium bicarbonate (pH adjusted to 11.0 with ammonia water): acetonitrile = 70:30 (volume ratio);

[0162] Flow rate: 1.0 mL / min;

[0163] Detection wavelength: 273 nm;

[0164] Column temperature: 25 °C;

[0165] Sample injection volume: 20 μL;

[0166] Diluent: 30% acetonitrile;

[0167] The chromatogram is as Figure 11 shown, Figure 11 in which peak 1 is impurity A, peak 2 is impurity B, peak 3 is impurity C, and peak 5 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, the peak shape of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is good, the main peak can be well separated from the impurities, the resolution between each chromatographic peak can meet the requirements (resolution ≥ 1.5), and the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol is at about 17.553 min.

[0168] Comparative Example 1

[0169] The contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the raw material of lafutidine were detected according to the method of Example 1. Among them, the chromatographic conditions were as follows:

[0170] High performance liquid chromatograph: Dionex: UltiMate3000;

[0171] Chromatographic column: Waters Symmetry C18 4.6 mm × 250 mm, 5 μm;

[0172] Mobile phase: 50 mM sodium dihydrogen phosphate (pH adjusted to 3.0 with phosphoric acid): acetonitrile = 70:30 (volume ratio);

[0173] Flow rate: 1.0 mL / min;

[0174] Detection wavelength: 273 nm;

[0175] Column temperature: 25 °C;

[0176] Injection volume: 20 μL;

[0177] Diluent: 30% acetonitrile;

[0178] The chromatogram is as Figure 12 shown, Figure 12The peak No. 1 in the figure is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol has no retention on the stationary phase, the resolution between it and its impurities is less than 1.5, and complete separation is not achieved. Moreover, the peak of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol appears at about 1.663 min.

[0179] Comparative Example 2

[0180] The contents of the raw material of Lafutidine (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances were detected according to the method of Example 1. Among them, the chromatographic conditions were as follows:

[0181] High performance liquid chromatograph: Dionex: UltiMate3000;

[0182] Chromatographic column: Waters XBridge Shield RP18 3.5μm;

[0183] Mobile phase: 50 mM ammonium bicarbonate (adjusted to pH 10.5 with ammonia water): acetonitrile = 55:45 (volume ratio);

[0184] Flow rate: 1.0 mL / min;

[0185] Detection wavelength: 273 nm;

[0186] Column temperature: 25°C;

[0187] Injection volume: 20 μL;

[0188] Diluent: 30% acetonitrile

[0189] The chromatogram is as Figure 13 shown. Figure 13 The peak No. 1 in the figure is impurity C, and the peak No. 3 is (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol. It can be seen that under this condition, impurity A and impurity B are not detected.

[0190] In the description of this specification, the description with reference to terms such as "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" means that the specific features, structures, materials, or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, without contradiction, those skilled in the art can combine and combine the different embodiments or examples described in this specification and the features of different embodiments or examples.

[0191] Although the embodiments of the present invention have been shown and described above, it can be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those of ordinary skill in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for detecting (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances, characterized in that, it includes: detecting a sample to be tested by high performance liquid chromatography, and based on the detection result, determining the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the sample to be tested.

2. The method according to claim 1, characterized in that, the mobile phase of the high performance liquid chromatography is selected from a mixed solution of ammonium bicarbonate and acetonitrile; optionally, the ammonium bicarbonate exists in the form of a solution; optionally, the concentration of the ammonium bicarbonate solution is 45 mM to 55 mM; optionally, the pH value of the ammonium bicarbonate solution is 10.0 to 11.0; optionally, the volume ratio of the ammonium bicarbonate solution to acetonitrile is (65 - 75):(25 - 35).

3. The method according to claim 1, characterized in that, the related substances are selected from at least one of the following:

4. The method according to claim 1, characterized in that, the high performance liquid chromatography uses isocratic elution.

5. The method according to claim 1, characterized in that, the chromatographic column of the high performance liquid chromatography is selected from Waters XBridge Shield RP18 3.5 μm or an equivalent chromatographic column.

6. The method according to claim 1, characterized in that, the flow rate of the mobile phase in the high performance liquid chromatography detection is 0.5 to 1.5 mL / min; optionally, the detection wavelength used in the high performance liquid chromatography detection is 260 to 290 nm.

7. The method according to claim 1, characterized in that, the column temperature used in the high performance liquid chromatography detection is 15 to 35 °C.

8. A method for detecting (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances, characterized in that, detecting a sample to be tested by high performance liquid chromatography, and based on the detection result, determining the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances in the sample to be tested; wherein, ammonium bicarbonate and acetonitrile are used as the mobile phase in the high performance liquid chromatography; the pH value in the ammonium bicarbonate solution is 10.0 to 11.0; the related substances are selected from at least one of the following: the high performance liquid chromatography uses isocratic elution; the chromatographic column of the high performance liquid chromatography is selected from Waters XBridge Shield RP18 3.5 μm or an equivalent chromatographic column; the flow rate of the mobile phase in the high performance liquid chromatography detection is 0.8 to 1.2 mL / min; the detection wavelength used in the high performance liquid chromatography detection is 263 to 283 nm; the column temperature used in the high performance liquid chromatography detection is 20 to 30 °C.

9. A quality control method for a raw material sample of lfamotidine, characterized in that, it includes: The raw material sample of lafutidine is detected by the method according to any one of claims 1 to 8, and the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances are obtained; Based on the contents of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol and its related substances, it is determined whether the quality of the raw material sample of lafutidine meets the standard.

10. According to the quality control method described in claim 9, it is characterized in that the purity of (2Z)-4-[[4-(1-piperidinylmethyl)-2-pyridinyl]oxy]-2-buten-1-ol in the raw material of lafutidine being greater than 95.0% is an indication that the quality of the raw material sample of lafutidine is qualified; Optionally, the related substances are selected from at least one of the following:

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