Method for detecting related substances of vortioxetine intermediate impurities

Abstract

The invention provides a method for detecting related substances of vortioxetine impurities, which is characterized in that separation and detection are carried out by adopting a high performance liquid chromatography method, taking a silica gel bonded octadecylsilane column as a chromatographic column, taking a certain proportion of inorganic salt buffer solution-organic phase as a mobile phase and adopting a gradient elution mode. The method for detecting the related substances of the vortioxetine intermediate impurities is good in separation degree, high in specificity, high in precision and good in repeatability, and lays a solid foundation for quality research of vortioxetine.

Description

Technical Field

[0001] The invention relates to the technical field of chemical drug analysis, and in particular to an analytical detection method for analyzing and determining related substances of vortioxetine intermediate 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene by liquid chromatography. Background Art

[0002] Major depressive disorder (MDD) is a mental illness characterized by mood changes, weight changes, loss of appetite, insomnia or hypersomnia (excessive sleep), restlessness, increased fatigue, increased guilt or inferiority, slow thinking or lack of concentration, which seriously affects people's work and life. The onset of depression often accompanies a person's life, causing great pain to individuals and families. Current research data shows that vortioxetine has a definite effect and few side effects. Vortioxetine is expected to become the most successful new drug among antidepressants.

[0003] The chemical name of the vortioxetine intermediate is: 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene, and its molecular formula is C 14 H 13 BrS, molecular weight is 293.22.

[0004] The structural formula of 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene is:

[0005] In the process of synthesizing vortioxetine lactate, the control of intermediate purity is crucial to reduce the occurrence of side reactions and the generation of impurities, thereby improving the yield and purity of the final product, which has important practical significance in the quality control of the vortioxetine lactate synthesis process. Summary of the invention

[0006] The present invention provides a method for detecting impurity-related substances of a vortioxetine intermediate, thereby being able to quickly, effectively and accurately monitor the purity of the vortioxetine intermediate and achieve quality control of the final product raw material drug thereof.

[0007] The invention provides a method for detecting impurity-related substances of a vortioxetine intermediate, which adopts a high performance liquid chromatography method, uses a chromatographic column as a silica gel-bonded octadecylsilane column, uses a certain proportion of an inorganic salt buffer solution as a mobile phase A and an organic phase as a mobile phase B, and performs gradient elution.

[0008] The present invention provides a method for detecting impurity-related substances in a vortioxetine intermediate, wherein the isocratic elution procedure is: Time (min) A% B% 0.00 63 37 3.00 63 37 4.00 45 55 17.00 40 60 18.00 10 90 30.00 10 90 30.01 63 37 37.00 63 37 .

[0009] Preferably, the inorganic salt buffer solution is phosphate, specifically dipotassium hydrogen phosphate, with a concentration of 0.02 mol / L and a pH value of 7.45.

[0010] Preferably, the organic phase is methanol.

[0011] Preferably, the chromatographic column provided is YMC-Triart-C18 (4.6 mm×150 mm, 5 µm).

[0012] The separation and determination method of the present invention can be implemented according to the following method: (1) Take an appropriate amount of 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene sample and dissolve the sample in methanol to prepare a sample solution containing 0.4 mg of 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene per 1 ml; (2) Set the mobile phase flow rate to 0.5-1.5 mL / min, preferably 1.0 mL / min, the detection wavelength to 210-260 nm, the optimal detection wavelength to 220 nm, the column oven temperature to 20-50 °C, and the optimal column oven temperature to 40 °C; (3) Take 10-50 μl of the sample solution in 1) above and inject it into a liquid chromatograph to separate and determine vortioxetine and related substances. Wherein: High performance liquid chromatograph: Agilent 1260 InfinityII; Chromatographic column: YMC-Triart-C18 (4.6 mm × 150 mm, 5 µm); Mobile phase A: 0.02 mol / L potassium dihydrogen phosphate buffer solution (weigh 4.56 g potassium dihydrogen phosphate, dissolve in water and dilute to 1000 ml, adjust pH to 7.45 with phosphoric acid); mobile phase B: methanol; elution according to the following gradient: Time (min) A% B% 0.00 63 37 3.00 63 37 4.00 45 55 17.00 40 60 18.00 10 90 30.00 10 90 30.01 63 37 37.00 63 37 Flow rate: 1.0 mL / min; column temperature: 40°C; detection wavelength: 220 nm; injection volume: 10 μl.

[0013] The invention adopts a chromatographic column of a silica gel-bonded octadecylsilane column, which can effectively separate 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene from various impurities. The invention solves the problem of separation and determination of 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene and various impurities, thereby reducing the occurrence of side reactions, improving the yield and purity of the product, and ensuring the controllable quality of vortioxetine lactate. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the blank solvent HPLC chart for Example 1.

[0015] Figure 2 HPLC chart of the intermediate and its related substances in Example 1. DETAILED DESCRIPTION

[0016] The following examples are used to further understand the present invention, but are not intended to limit the scope of this embodiment. Example

[0017] Instruments and conditions High performance liquid chromatograph: Agilent 1260 InfinityII; Chromatographic column: YMC-Triart-C18 (4.6 mm × 150 mm, 5 µm); Mobile phase A: 0.02 mol / L potassium dihydrogen phosphate buffer solution (weigh 4.56 g potassium dihydrogen phosphate, dissolve in water and dilute to 1000 ml, adjust pH to 7.45 with phosphoric acid); mobile phase B: methanol; elution according to the following gradient: Time (min) A% B% 0.00 63 37 3.00 63 37 4.00 45 55 17.00 40 60 18.00 10 90 30.00 10 90 30.01 63 37 37.00 63 37 Flow rate: 1.0 mL / min; column temperature: 40°C; detection wavelength: 254 nm; injection volume: 10 μl; Take appropriate amount of 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene and its impurities, dissolve the sample in methanol, and prepare a sample solution containing 0.4 mg / mL of 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene and about 100 µg / mL of its impurities. Perform HPLC analysis under the above conditions and record the chromatogram. The results are shown in the attached Figure 1 , Figure 1 The chromatographic peak with a retention time of 3.440 min is 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene, and the other chromatographic peaks are the chromatographic peaks of various impurities.

[0018] from Figure 1 - Figure 2 It is shown that the method of the present invention can separate 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene from its impurities and can accurately perform quantitative detection, thereby effectively controlling the product quality of vortioxetine.

Claims

1. A method for analyzing and detecting impurity-related substances in vortioxetine intermediates, using high performance liquid chromatography, a chromatographic column is a silica gel bonded octadecylsilane column, a certain proportion of inorganic salt buffer solution-organic phase as the mobile phase, and gradient elution, which can separate the intermediates and impurities.

2. According to the analytical detection method of claim 1, the organic phase is selected from one of the following compounds: methanol, acetonitrile, tetrahydrofuran.

3. According to the analytical detection method described in claim 1, the inorganic salt buffer solution is selected from one of the following inorganic salts: phosphate, perchlorate, and formate.

4. The analytical detection method according to claim 1, wherein the elution gradient process is:

5. According to the analytical detection method of claim 1, the chromatographic column preferably has a length of 150 mm, a diameter of 4.6 mm, and a filler particle size of 5 µm.

6. According to the analytical detection method described in claims 1 and 3, the inorganic salt buffer solution is preferably dipotassium hydrogen phosphate, the optimal concentration of which is 0.02 mol / L and the pH value is 7.

45.

7. According to the analytical detection method according to claims 1 and 2, the organic phase is preferably methanol.

8. The analytical detection method according to claim 1 comprises the following steps: ① setting the flow rate to 0.5-1.5 ml / min; ② setting the detection wavelength to 210-260 nm; ③ setting the column temperature to 20-50°C; ④ setting the injection volume to 5-20 µl.

9. According to the analytical detection method of claim 8, the chromatographic conditions are as follows: ① the flow rate is preferably 1.0 ml / min; ② the wavelength is preferably 220 nm; ③ the column temperature is preferably 40°C; ④ the injection volume is preferably 10 µl.

10. The analytical detection method according to claim 1, wherein the impurities are:

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