Veltioxetine boron trifluoride complex impurity and preparation method thereof

Abstract

The invention provides a vothioxetine boron trifluoride complex impurity and a preparation method thereof, and the vothioxetine boron trifluoride complex impurity is obtained by separation and purification through liquid chromatography by taking an octadecyl bonded silica gel chromatographic column as a stationary phase and taking an acetonitrile-ammonium formate buffer solution as a mobile phase. The impurity provided by the invention is of great significance to quality control of a vothioxetine raw material medicine and a vothioxetine preparation.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to vortioxetine boron trifluoride complex impurities and a preparation method thereof. Background Art

[0002] Vortioxetine was approved for marketing by the US FDA in 2013 and was approved for marketing in China by the National Medical Products Administration in November 2017 for the treatment of depression in adults. The drug exerts its antidepressant effect by inhibiting 5-HT reuptake mediated by the 5-HT transporter and regulating the activity of multiple 5-HT receptors. In vitro and animal studies have shown that in addition to increasing the concentration of 5-HT in the brain, vortioxetine can also enhance dopamine, norepinephrine, acetylcholine, histamine, and glutamate neurotransmission in certain areas of the brain, and reduce γ-aminobutyric acid neurotransmission. Clinical studies have shown that vortioxetine can simultaneously improve the symptoms and cognitive function of patients with depression and promote the recovery of their social function.

[0003] The inventors discovered a new impurity with a relatively high content during the study of vortioxetine impurities. The impurity was confirmed to be a vortioxetine boron trifluoride complex impurity that has not been reported in the literature through structural confirmation. The impurity content is relatively high, and studying the impurity is conducive to better controlling the quality of vortioxetine. Therefore, determining the structure of the impurity and establishing a preparation method to obtain a reference substance of the impurity are of great significance for the quality control of vortioxetine raw materials and preparations. Summary of the invention

[0004] The object of the present invention is to provide a new vortioxetine boron trifluoride complex impurity and a preparation method thereof.

[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following solution.

[0006] The present invention provides a vortioxetine boron trifluoride complex impurity, the structural formula of which is shown in formula (I): .

[0007] The invention also provides a method for preparing the impurities of the vortioxetine boron trifluoride complex.

[0008] In one embodiment, the method for preparing a vortioxetine boron trifluoride complex impurity of the present invention is characterized by: using liquid chromatography to separate and purify the vortioxetine intermediate solution to obtain the impurity.

[0009] In the preparation method of the present invention, the liquid chromatography column is an octadecyl bonded silica gel column, and the mobile phase is composed of acetonitrile-ammonium formate buffer.

[0010] Furthermore, in the preparation method of the present invention, the chromatographic column is XDB C18 (9.4*250 mm, 5 μm).

[0011] In the preparation method of the present invention, the acetonitrile in the mobile phase is 50% to 90% v / v.

[0012] In the preparation method of the present invention, the elution procedure is gradient elution, 0-30min, and the proportion of acetonitrile increases from 60% to 100%.

[0013] In the preparation method of the present invention, the mobile phase flow rate is 6-10 ml / min, the detection wavelength is 210-250 nm, and the column temperature is 25-35° C.

[0014] Preferably, in the preparation method of the present invention, the flow rate of the mobile phase is 8 ml / min, the detection wavelength is 226 nm, and the column temperature is 30°C.

[0015] Furthermore, the preparation method of the present invention comprises collecting the eluate prepared by chromatographic separation, desalting, and then freeze-drying with a freeze dryer to obtain the vortioxetine boron trifluoride complex impurity.

[0016] In a specific embodiment, a method for preparing a vortioxetine boron trifluoride complex impurity of the present invention comprises the following steps: a) Take the vortioxetine intermediate solution and filter it with a 0.45um organic filter membrane to obtain the test solution; b) Separate and purify the aqueous solution obtained in step a) by gradient elution using C18 as the stationary phase (9.4×250 mm, 5 μm) and acetonitrile-ammonium formate buffer as the mobile phase, and receive the target eluate (such as Figure 1 The RT is 8.236min); c) The eluate obtained in step b) is placed under nitrogen to blow off the organic phase, and all the eluate is desalted and then freeze-dried in a freeze dryer to obtain the vortioxetine boron trifluoride complex.

[0017] Beneficial technical effects of the present invention: The invention provides a vortioxetine boron trifluoride complex impurity with a completely new structure and a preparation method thereof, which can be used for quality research of vortioxetine raw materials and preparations thereof, improve the quality standard of vortioxetine, and is of great significance for quality control of vortioxetine raw materials and preparations thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Typical diagram of the separation and purification of impurities of vortioxetine boron trifluoride complex; Figure 2 Vortioxetine boron trifluoride complex impurity pure product purity; Figure 3Mass spectrometry of vortioxetine boron trifluoride complex impurity; Figure 4 Vortioxetine Boron Trifluoride Complex Impurity 1 H-NMR spectrum; Figure 5 Vortioxetine Boron Trifluoride Complex Impurity 1 H- 1 H COSY spectrum; Figure 6 Vortioxetine Boron Trifluoride Complex Impurity 13 C-NMR spectrum; Figure 7 HSQC spectrum of vortioxetine boron trifluoride complex impurity; Figure 8 HMBC spectrum of vortioxetine boron trifluoride complex impurity; Fig. 9 F-NMR spectrum of vortioxetine boron trifluoride complex impurity. DETAILED DESCRIPTION

[0019] The following examples are used to further illustrate and understand the spirit of the present invention, but are not intended to limit the scope of the present invention in any way.

[0020] Example 1 Instruments and conditions Agilent 1260 liquid chromatograph and Instrument workstation; manual injection; Instrument: Agilent 1260 High Performance Liquid Chromatograph Chromatographic column: XDB C18, 9.4*250mm, 5μm; Flow rate: 8ml / min; Detection wavelength: 226nm; Column temperature: 30°C; Mobile phase A: 3.15 g / L ammonium formate buffer; Mobile phase B: 90% acetonitrile; Gradient: 0-30 min, the proportion of mobile phase B increased from 60% to 100%.

[0021] Experimental steps: Sample solution: Take the vortioxetine intermediate solution and filter it with a 0.45um organic filter membrane to obtain the test solution.

[0022] Column purification and separation: Preparative separation was performed according to the above chromatographic conditions, see Figure 1 As shown in the figure, the target fraction (RT is 8.236 min) is received, the organic phase is blown off under nitrogen, and then after desalting treatment, the organic phase is freeze-dried in a freeze dryer to obtain a powdered solid.

[0023] The purity of the impurity pure product of vortioxetine boron trifluoride complex was tested according to the following method, and the purity was 100%, see Figure 2 .

[0024] Instruments and conditions Agilent 1200 liquid chromatograph and Instrument workstation from the United States; manual injection; Instrument: Agilent 1200 High Performance Liquid Chromatograph Chromatographic column: XDB C18, 4.6*250mm, 5μm; Flow rate: 1ml / min; Detection wavelength: 226nm; Column temperature: 30°C; Mobile phase A: 3.15 g / L ammonium formate buffer; Mobile phase B: 90% acetonitrile; Gradient: 0-30 min, the proportion of mobile phase B increased from 50% to 100%.

[0025] The spectral data of the impurity of the vortioxetine boron trifluoride complex prepared by the above method are as follows: ESI-MS: base peaks m / z 365.1474 and m / z 731.3019 are [MH] - and [2M-H] - Quasi-molecular ion peak, m / z 365.1474 and C 18 H 21 BF3N2S - The abundance ratio of m / z365.1474 and isotope peak m / z364.1511 is 100:24.8, indicating that this molecule contains a boron atom, which is consistent with the target molecule. Figure 3 ; NMR spectrum see Figure 4~Figure 9 The attribution of NMR signals is shown in Tables 1 to 3.

[0026]

[0027] Table 1 Impurities of vortioxetine boron trifluoride complex 1 H-NMR measurement data

[0028] Conclusion: From the test sample 1 From the integrated area of ​​the H-NMR spectrum, it can be seen that, in addition to the CDCl3 residual proton peak (7.255ppm) and the water peak (2.036ppm), a total of 23 H atoms were observed, which is consistent with the number of H atoms in the target molecule. 1The H-NMR spectrum showed that the H16 and H17 peaks disappeared, indicating active H. The chemical shifts and characteristics of all resonance peaks were consistent with the structural characteristics of the target molecule.

[0029] Table 2 Impurities of vortioxetine boron trifluoride complex 13 C-NMR measurement data

[0030] Conclusion: From the test sample 13 From the C-NMR spectrum, it can be seen that, in addition to the CDCl3 residual carbon atom peak (76.789-77.212 ppm), a total of 18 Cs were observed, which is consistent with the number of C atoms in the target molecule. The chemical shifts and characteristics of all resonance peaks are consistent with the structural characteristics of the target molecule.

[0031] Table 3 F-NMR spectrum test data of impurities of vortioxetine boron trifluoride complex

[0032] Conclusion: From the F-NMR spectrum of the test sample, it can be seen that two types of F were observed, which are consistent with the F atomic species of the target molecule. All resonance peak chemical shifts and characteristics are consistent with the structural characteristics of the target molecule.

Claims

1. A vortioxetine boron trifluoride complex impurity compound, the structural formula of which is shown in formula (I): 。 2. A method for preparing the vortioxetine boron trifluoride complex impurity compound according to claim 1, characterized in that: The vortioxetine intermediate solution is separated and purified by liquid chromatography.

3. The preparation method according to claim 2, wherein the liquid chromatography has a chromatographic column that is an octadecyl bonded silica gel chromatographic column and a mobile phase that is composed of an acetonitrile-ammonium formate buffer.

4. The preparation method according to claim 3, wherein the chromatographic column is XDB C18 (9.4*250 mm, 5 μm).

5. according to the preparation method according to claim 3, in the described mobile phase, acetonitrile is 50~90%v / v.

6. The preparation method according to claim 3, wherein the mobile phase flow rate is 6-10 ml / min, the detection wavelength is 210-250 nm, and the column temperature is 25-35°C.

7. The preparation method according to claim 6, wherein the flow rate of the mobile phase is 8 ml / min, the detection wavelength is 226 nm, and the column temperature is 30°C.

8. The preparation method according to claim 3, wherein the elution procedure is gradient elution, 0-30 min, and the acetonitrile ratio is increased from 60% to 100%.

9. The preparation method according to any one of claims 2 to 8, further comprising collecting the eluate prepared by chromatographic separation, desalting, and freeze-drying with a freeze dryer to obtain the vortioxetine boron trifluoride complex impurity.

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