Preparation method of vortioxetine hydrobromide alpha crystal form

Abstract

The invention relates to a preparation method of a hydrobromic acid vortioxetine alpha crystal form, which comprises the following steps: mixing hydrobromic acid vortioxetine shown in a formula I with a solvent A to obtain the hydrobromic acid vortioxetine alpha crystal form, wherein the solvent A is selected from at least two of n-butyl alcohol, isopropanol and sec-butyl alcohol. The alpha crystal form product obtained by the preparation method is high in purity, good in yield, appropriate in crystal particle size, good in fluidity, better in stability, simple and convenient in steps, low in cost, environment-friendly and suitable for industrial large-scale production.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a method for preparing vortioxetine hydrobromide α-crystal. Background Art

[0002] Vortioxetine hydrobromide, chemically known as 1-[2-(2,4-dimethylphenylmercapto)-phenyl]-piperazine hydrobromide, was approved for marketing by the U.S. Food and Drug Administration (FDA) in September 2013. This drug is a new antidepressant jointly developed by Takeda Pharmaceutical Company Limited of Japan and Lundbeck Pharma Ltd. of Denmark. The structural formula of vortioxetine hydrobromide is shown below:

[0003]

[0004] According to relevant research reports, vortioxetine hydrobromide not only selectively inhibits serotonin (5-HT) reuptake but also acts as a 5-HT3, 5-HT7, and 5-HT1D receptor antagonist, a 5-HT1A receptor agonist, a 5-HT1B receptor partial agonist, and a 5-HT transporter inhibitor. This drug can increase levels of serotonin neurotransmitters, norepinephrine, dopamine, acetylcholine, and histamine in specific brain regions, making it useful for treating major depressive disorder in adults. Based on its multimodal, multi-target mechanism of action, vortioxetine hydrobromide offers advantages over traditional tricyclic psychotropic drugs, including significant efficacy, good tolerability, and a favorable safety profile.

[0005] Drug solubility is a primary concern in the development of many dosage forms and a key factor in the effective absorption of a formulation. Therefore, for polymorphic compounds, it is crucial to proactively select a crystalline form with higher solubility during formulation development. Currently, multiple crystalline forms of vortioxetine hydrobromide have been reported, including α, β, and γ forms. The β form is the pharmaceutically acceptable crystalline form of vortioxetine hydrobromide worldwide. However, the solubility of the β form of vortioxetine hydrobromide in water is only 1.0 mg / mL, significantly lower than its solubility in other organic solvents. Furthermore, the US FDA-approved instructions for vortioxetine hydrobromide tablets indicate an absolute oral bioavailability of approximately 75% for the β form, which requires further improvement. Compared to the β form, the α form of vortioxetine hydrobromide has a solubility of 2.1 mg / mL, which is more conducive to its absorption in the human body. Therefore, it is crucial to rationally and effectively obtain the more soluble α form of vortioxetine hydrobromide.

[0006] The original patent CN102317272B discloses the purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine. The method involves dissolving the 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine-HBr salt in a solvent containing more than 65% isopropanol to precipitate an isopropanol solvate, which is then dissolved in a solvent that does not form a stable solvate. Cooling and distillation steps are performed to reduce impurities and improve yield, ultimately resulting in the precipitation of the β-crystalline form of vortioxetine. Patent CN106632145A discloses a new method for preparing the α-crystalline form of vortioxetine hydrobromide. This method involves dissolving vortioxetine hydrobromide in a good solvent (such as chloroform, dichloromethane, etc.), then adding the solution dropwise to a poor solvent at low temperature for crystallization to obtain the α-crystalline form. However, the good solvents used in this method, such as chloroform and dichloromethane, are Class II solvents and are highly toxic, which may pose safety and environmental challenges in industrial production. Furthermore, when repeating the examples, the resulting product powder suffered from severe static electricity and poor fluidity due to issues with particle size and growth orientation. Patent CN105367515B discloses a method for preparing an α-crystalline form of vortioxetine hydrobromide. The method primarily comprises: mixing vortioxetine hydrobromide with sec-butanol, heating to dissolve, and then cooling to crystallize to obtain a vortioxetine hydrobromide-sec-butanol complex; and removing the sec-butanol by heating to obtain an α-crystalline form of vortioxetine hydrobromide. However, this method only produces a solvate by low-temperature drying, while high-temperature desolvation and crystallization are time-consuming and energy-intensive. Patent CN110372635B discloses a method for preparing an α-crystalline form of vortioxetine hydrobromide. This method uses isopropyl acetate as a solvent and produces the α-crystalline form of vortioxetine hydrobromide by direct salification from a free base. However, this method is sensitive to the purity of the free base and requires it to be a high-purity free base; if a low-purity free base is used and no purification step is performed after salt formation, there is a risk that the purity of the obtained product will be substandard.

[0007] Therefore, there is an urgent need to provide a method for preparing vortioxetine hydrobromide α-crystalline form with simple steps, low cost, environmental friendliness, and suitability for industrial scale-up production, wherein the obtained vortioxetine hydrobromide α-crystalline form product has high purity, good yield, suitable crystal particle size, good fluidity, and good stability. Summary of the Invention

[0008] In view of this, the present invention provides a method for preparing vortioxetine hydrobromide α-crystalline form in order to solve at least one problem existing in the background technology.

[0009] To achieve the above object, the technical solution adopted by the present invention is:

[0010] The present invention provides a method for preparing an α-crystalline form of vortioxetine hydrobromide, which comprises the following steps:

[0011] Mixing vortioxetine hydrobromide represented by Formula I with solvent A to obtain the vortioxetine hydrobromide α-crystalline form; wherein the solvent A is selected from at least two of n-butanol, isopropanol, and sec-butanol;

[0012]

[0013] Preferably, the ratio of the volume (mL) of the solvent A to the mass (g) of vortioxetine hydrobromide is (10-40):1, preferably (15-35):1, and more preferably (20-30):1.

[0014] Preferably, after the mixing step, a heating step is further included.

[0015] More preferably, the heating temperature is 80°C to 120°C, preferably 85°C to 115°C, and more preferably 90°C to 110°C.

[0016] More preferably, after the heating step, a cooling and crystallization step is also included.

[0017] More preferably, the temperature of the cooling crystallization is room temperature.

[0018] Preferably, the preparation method comprises the following steps:

[0019] Mixing vortioxetine hydrobromide represented by Formula I with a mixed solvent of n-butanol and isopropanol to obtain the vortioxetine hydrobromide α-crystalline form;

[0020]

[0021] More preferably, the volume ratio of n-butanol to isopropanol is (1-5):1, preferably (2-4):1, and more preferably 3:1.

[0022] Further preferably, the ratio of the volume (mL) of the mixed solvent of n-butanol and isopropanol to the mass (g) of vortioxetine hydrobromide is 30:1.

[0023] More preferably, the heating temperature is 95°C to 110°C, preferably 100°C to 110°C, and more preferably 105°C to 110°C.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. The preparation method of the vortioxetine hydrobromide α-crystalline form provided by the present invention has a simple synthetic route, cheap and readily available raw materials, low cost, simple operation, mild reaction conditions, high product purity, high yield, and is environmentally friendly and suitable for industrial scale-up production.

[0026] 2. The vortioxetine hydrobromide α-crystalline form prepared by the present invention has an appropriate crystal particle size, good fluidity, and excellent stability; the particle size distribution spectrum shows a small particle size, with D10 of approximately 0.91 μm, D50 of approximately 9.82 μm, and D90 of approximately 33.2 μm, and the volume density is concentrated in the range of 1 to 100 μm (accounting for more than 95%). Its particle size range can directly meet the requirements of the formulation process, eliminating the micronization step, shortening the production cycle, and reducing energy consumption costs.

[0027] 3. The present invention uses a mixed solvent for crystallization, eliminating the need for high-temperature crystallization and allowing the α-form to be obtained through low-temperature drying. Furthermore, within the constraints of GMP production, which prohibit solvent recycling, the mixed solvent employed in the present invention offers both economical efficiency and safety.

[0028] 4. The purity of the vortioxetine prepared by the present invention is not limited to the free base form, and the selectivity of the α-crystal form reaches 100%. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the X-ray powder diffraction pattern of the α-crystalline form of vortioxetine hydrobromide obtained in Example 1.

[0030] Figure 2 This is the X-ray powder diffraction pattern of the α-crystalline form of vortioxetine hydrobromide obtained in Example 2.

[0031] Figure 3 This is the X-ray powder diffraction pattern of the α-crystalline form of vortioxetine hydrobromide obtained in Example 3.

[0032] Figure 4 This is the X-ray powder diffraction pattern of the β-crystalline form of vortioxetine hydrobromide obtained in Comparative Example 1.

[0033] Figure 5 This is the X-ray powder diffraction pattern of the β-crystalline form of vortioxetine hydrobromide obtained in Comparative Example 2.

[0034] Figure 6 This is the X-ray powder diffraction pattern of the β-crystalline form of vortioxetine hydrobromide obtained in Comparative Example 3.

[0035] Figure 7 This is the X-ray powder diffraction pattern of the β-crystalline form of vortioxetine hydrobromide obtained in Comparative Example 4.

[0036] Figure 8 This is the X-ray powder diffraction pattern of the β-crystalline form of vortioxetine hydrobromide obtained in Comparative Example 5.

[0037] Figure 9 This is the X-ray powder diffraction pattern of the β-crystalline form of vortioxetine hydrobromide obtained in Comparative Example 6.

[0038] Figure 10The vortioxetine hydrobromide α-crystalline form obtained in Example 1 1 H-NMR spectrum.

[0039] Figure 11 The vortioxetine hydrobromide α-crystalline form obtained in Example 1 13 C-NMR spectrum.

[0040] Figure 12 This is the particle size distribution spectrum of the vortioxetine hydrobromide α-crystalline form obtained in Example 1. DETAILED DESCRIPTION

[0041] To make the technical solutions and beneficial effects of the present invention more clearly understood, the following detailed description is given by way of specific embodiments. The accompanying drawings are not necessarily drawn to scale, and local features may be enlarged or reduced to more clearly illustrate the details of the local features. Unless otherwise defined, the technical and scientific terms used herein have the same meanings as those in the technical field to which this application belongs.

[0042] The present invention provides a method for preparing an α-crystalline form of vortioxetine hydrobromide, which comprises the following steps:

[0043] Mixing vortioxetine hydrobromide represented by Formula I with solvent A to obtain the vortioxetine hydrobromide α-crystalline form; wherein the solvent A is selected from at least two of n-butanol, isopropanol, and sec-butanol;

[0044]

[0045] In certain embodiments, the ratio of the volume (mL) of the solvent A to the mass (g) of vortioxetine hydrobromide is (10-40):1.

[0046] In certain embodiments, the ratio of the volume (mL) of the solvent A to the mass (g) of vortioxetine hydrobromide is (15-35):1.

[0047] In certain embodiments, the ratio of the volume (mL) of the solvent A to the mass (g) of vortioxetine hydrobromide is (20-30):1.

[0048] In certain embodiments, the mixing step further includes a heating step.

[0049] In certain embodiments, the heating temperature is 80°C to 120°C.

[0050] In certain embodiments, the heating temperature is 85°C to 115°C.

[0051] In certain embodiments, the heating temperature is 90°C to 110°C.

[0052] In certain embodiments, after the heating step, a cooling and crystallization step is further included.

[0053] In certain embodiments, the temperature of the cooling crystallization is room temperature.

[0054] In certain embodiments, after the step of cooling and crystallizing, the steps of filtering and washing are further included.

[0055] In certain embodiments, the washing solvent is solvent A.

[0056] In certain embodiments, in the washing step, the ratio of the volume (mL) of the solvent A to the mass (g) of vortioxetine hydrobromide is 1:1.

[0057] In certain embodiments, after the washing step, a drying step is further included.

[0058] In certain embodiments, the drying temperature is 30-80°C.

[0059] In certain embodiments, the drying temperature is 50-80°C.

[0060] In certain embodiments, the drying time is 8 to 36 hours.

[0061] The present invention provides a method for preparing an α-crystalline form of vortioxetine hydrobromide, which comprises the following steps:

[0062] Mixing vortioxetine hydrobromide represented by Formula I with a mixed solvent of n-butanol and isopropanol to obtain the vortioxetine hydrobromide α-crystalline form;

[0063]

[0064] In certain embodiments, the volume ratio of n-butanol to isopropanol is (1-5):1.

[0065] In certain embodiments, the volume ratio of n-butanol to isopropanol is (2-4):1.

[0066] In certain embodiments, the volume ratio of n-butanol to isopropanol is 3:1.

[0067] In certain embodiments, the ratio of the volume (mL) of the mixed solvent of n-butanol and isopropanol to the mass (g) of vortioxetine hydrobromide is (20-40):1.

[0068] In certain embodiments, the ratio of the volume (mL) of the mixed solvent of n-butanol and isopropanol to the mass (g) of vortioxetine hydrobromide is (25-35):1.

[0069] In certain embodiments, the ratio of the volume (mL) of the mixed solvent of n-butanol and isopropanol to the mass (g) of vortioxetine hydrobromide is 30:1.

[0070] In certain embodiments, the mixing step further includes a heating step.

[0071] In certain embodiments, the heating temperature is 95°C to 120°C.

[0072] In certain embodiments, the heating temperature is 100°C to 115°C.

[0073] In certain embodiments, the heating temperature is 105°C to 110°C.

[0074] In certain embodiments, after the heating step, a cooling and crystallization step is further included.

[0075] In certain embodiments, the temperature of the cooling crystallization is room temperature.

[0076] In certain embodiments, between the steps of heating and cooling for crystallization, a step of stirring until the solution is clear is also included.

[0077] In certain embodiments, after the step of cooling and crystallizing, the steps of filtering and washing are further included.

[0078] In certain embodiments, the washing solvent is a mixed solvent of n-butanol and isopropanol.

[0079] In certain embodiments, in the washing step, the ratio of the volume (mL) of the mixed solvent of n-butanol and isopropanol to the mass (g) of vortioxetine hydrobromide is 1:1.

[0080] In certain embodiments, after the washing step, a drying step is further included.

[0081] In certain embodiments, the drying temperature is 30-80°C.

[0082] In certain embodiments, the drying temperature is 50-80°C.

[0083] In certain embodiments, the drying time is 8 to 36 hours.

[0084] In the present invention, the synthesis of vortioxetine hydrobromide comprises the following steps:

[0085]

[0086] S1: Compounds SM01 and SM02 react under the action of a base to obtain compound S01.

[0087] In certain embodiments, in step S1, the base is selected from one or more of potassium carbonate, sodium carbonate, ammonium carbonate, lithium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide.

[0088] In certain embodiments, in step S1, the base is selected from potassium carbonate.

[0089] In the present invention, the synthesis of vortioxetine hydrobromide comprises the following steps:

[0090]

[0091] S2: Compound S01 reacts with a reducing agent to obtain compound S02.

[0092] In certain embodiments, in step S2, the reducing agent is selected from one or more of Raney nickel, palladium on carbon, Pd(OAc)2, Pd-BaSO4, Pd-CaCO3, Pd(OH)2, Pd(NO3)2, Pd(But)2, bis(cyclohexylphosphine)palladium, Pd(CF3CO2)2, palladium / alumina, Pd(CN)2, Pd(PPh3)4, Pd2(dba)3, Pd(dba)2, Pd(PPh3)Cl2, Pd(PPh3)2Cl2, PdCl2, PdCl2(dppf), PdCl2(CH3CN)2, PdI2, Pd[(P(O-Tol)3]2Cl2, Pd(Amphos)2Cl2 and PtO2.

[0093] In certain embodiments, in step S2, the reducing agent is selected from Raney nickel.

[0094] In the present invention, the synthesis of vortioxetine hydrobromide comprises the following steps:

[0095]

[0096] S3: Compound S02 reacts with a piperazine ring-forming agent to obtain compound S03.

[0097] In certain embodiments, in step S3, the piperazine ring-forming agent is selected from one or more of bis(2-chloroethyl)amine or a salt thereof, diethanolamine, and morpholine.

[0098] In certain embodiments, in step S3, the piperazine ring-forming agent is selected from bis(2-chloroethyl)amine.

[0099] In the present invention, the synthesis of vortioxetine hydrobromide comprises the following steps:

[0100]

[0101] S4: Compound S03 reacts with a base to obtain compound S04.

[0102] In certain embodiments, in step S4, the base is selected from one or more of potassium carbonate, sodium carbonate, ammonium carbonate, lithium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide.

[0103] In certain embodiments, in step S4, the base is selected from sodium hydroxide.

[0104] In the present invention, the synthesis of vortioxetine hydrobromide comprises the following steps:

[0105]

[0106] S5: Compound S04 reacts with hydrobromic acid to obtain vortioxetine hydrobromide as shown in Formula I.

[0107] The method of the present invention is described below by means of specific examples. It should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following examples. The implementation conditions adopted in the examples can be further adjusted according to specific requirements. The implementation conditions not specified are generally the conditions in routine experiments.

[0108] Example 1

[0109] Add 10g of crude vortioxetine hydrobromide to 300mL of a mixed solvent (n-butanol / isopropanol = 3:1), heat to 105-110°C, reflux with stirring to dissolve, keep warm for 30min, cool to room temperature for 4-5h to crystallize, then ice-bath for 1h, filter, wash the filter cake with 10mL of a mixed solvent (n-butanol / isopropanol = 3:1), and dry the filter cake in a vacuum oven at 55°C for 8h to obtain the product. Figure 1 The obtained product is vortioxetine hydrobromide α-crystalline with a yield of 89% and a purity of 99.5%.

[0110] Example 2

[0111] Add 10 g of crude vortioxetine hydrobromide to 200 mL of a mixed solvent (sec-butanol / n-butanol = 3:1), heat to 100-105°C, reflux with stirring to dissolve, keep warm for 30 minutes, cool to room temperature for 4-5 hours to crystallize, then ice-bath for 1 hour, filter, wash the filter cake with 10 mL of a mixed solvent (sec-butanol / n-butanol = 3:1), and dry the filter cake in a vacuum oven at 80°C for 36 hours to obtain the product. The X-ray diffraction pattern (e.g. Figure 2 The obtained product is vortioxetine hydrobromide α-crystalline with a yield of 80.5% and a purity of 99.6%.

[0112] Example 3

[0113] Add 10 g of crude vortioxetine hydrobromide to 200 mL of a mixed solvent (sec-butyl alcohol / isopropyl alcohol = 3:1), heat to 90-96°C, reflux with stirring to dissolve, keep warm for 30 minutes, cool to room temperature for 4-5 hours to crystallize, then ice-bath for 1 hour, filter, wash the filter cake with 10 mL of a mixed solvent (sec-butyl alcohol / isopropyl alcohol = 3:1), and dry the filter cake in a vacuum oven at 75°C for 24 hours to obtain the product. The X-ray diffraction pattern (e.g. Figure 3 The obtained product was vortioxetine hydrobromide α-crystalline with a yield of 83.6% and a purity of 99.8%.

[0114] Comparative Example 1

[0115] Add 10g of crude vortioxetine hydrobromide to 70mL of methanol, heat to 65-70℃, reflux with stirring to dissolve, keep warm for 30min, concentrate to 30mL of methanol at normal pressure, cool to room temperature for 3-4h to crystallize, then ice bath for 1h, filter, wash the filter cake with 7mL of methanol, and dry the filter cake to obtain the product. Figure 4 The obtained product is vortioxetine hydrobromide β-crystalline with a yield of 75% and a purity of 99.9%.

[0116] Comparative Example 2

[0117] Add 10g of crude vortioxetine hydrobromide to 400mL of ethanol, heat to 70-80℃, reflux with stirring to dissolve, keep warm for 30min, cool to room temperature for 4-5h to crystallize, then ice bath for crystallization for 1h, filter, wash the filter cake with 10mL of ethanol, and dry the filter cake to obtain the product. Figure 5 The obtained product is vortioxetine hydrobromide β-crystalline with a yield of 85% and a purity of 99.8%.

[0118] Comparative Example 3

[0119] Add 10g of crude vortioxetine hydrobromide to 300mL of acetone, heat to 55-60℃, reflux with stirring to dissolve, keep warm for 30min, cool to room temperature for 2-3h to crystallize, then ice bath for 1h, filter, wash the filter cake with 10mL of acetone, and dry the filter cake to obtain the product. Figure 6 The obtained product is vortioxetine hydrobromide β-crystalline with a yield of 83% and a purity of 99.5%.

[0120] Comparative Example 4

[0121] Add 10g of crude vortioxetine hydrobromide to 150mL of ethyl acetate, heat to 60-70℃, reflux with stirring to dissolve, keep warm for 30min, cool to room temperature for 2-3h to crystallize, then ice bath for 1h, filter, wash the filter cake with 10mL of ethyl acetate, and dry the filter cake to obtain the product. Figure 7 The obtained product is vortioxetine hydrobromide β-crystalline with a yield of 78% and a purity of 99.6%.

[0122] Comparative Example 5

[0123] Add 10g of crude vortioxetine hydrobromide to 100mL of water, heat to 98-102℃, reflux with stirring to dissolve, keep warm for 30min, cool to room temperature for 4-5h to crystallize, then ice bath for 1h, filter, wash the filter cake with 10mL of water, and dry the filter cake to obtain the product. Figure 8 The obtained product is vortioxetine hydrobromide β-crystalline with a yield of 76% and a purity of 99.3%.

[0124] Comparative Example 6

[0125] Add 10g of crude vortioxetine hydrobromide to 140mL of a mixture (methanol / water = 1:1), heat to 70-80°C, reflux with stirring to dissolve, keep warm for 30min, cool to room temperature for 2-3h to crystallize, then ice bath for crystallization for 1h, filter, wash the filter cake with 10mL of the mixture, and dry the filter cake to obtain the product. Figure 9 The obtained product is vortioxetine hydrobromide β-crystalline with a yield of 90% and a purity of 99.2%.

[0126] It should be understood that the above embodiments are exemplary and are not intended to encompass all possible implementations of the claims. Various modifications and variations may be made to the above embodiments without departing from the scope of this disclosure. Similarly, the various technical features of the above embodiments may be arbitrarily combined to form additional embodiments of the present invention that may not be explicitly described. Therefore, the above embodiments merely illustrate several implementations of the present invention and do not limit the scope of protection of the patent of this invention.

Claims

1. A method for preparing vortioxetine hydrobromide α-crystalline form, characterized in that: It includes the following steps: Mixing vortioxetine hydrobromide represented by Formula I with solvent A to obtain the vortioxetine hydrobromide α-crystalline form; wherein the solvent A is selected from at least two of n-butanol, isopropanol, and sec-butanol; 2. The preparation method according to claim 1, characterized in that The ratio of the volume (mL) of the solvent A to the mass (g) of vortioxetine hydrobromide is (10-40):1, preferably (15-35):1, and more preferably (20-30):

1.

3. The preparation method according to claim 1, characterized in that After the mixing step, a heating step is also included.

4. The preparation method according to claim 3, characterized in that The heating temperature is 80°C to 120°C, preferably 85°C to 115°C, and more preferably 90°C to 110°C.

5. The preparation method according to claim 3, characterized in that After the heating step, the method further includes a cooling and crystallization step.

6. The preparation method according to claim 5, characterized in that The temperature of the cooling crystallization is room temperature.

7. The preparation method according to any one of claims 1 to 6, characterized in that It includes the following steps: Mixing vortioxetine hydrobromide represented by Formula I with a mixed solvent of n-butanol and isopropanol to obtain the vortioxetine hydrobromide α-crystalline form; 8. The preparation method according to claim 7, characterized in that The volume ratio of n-butanol to isopropanol is (1-5):1, preferably (2-4):1, and more preferably 3:

1.

9. The preparation method according to claim 7, characterized in that The ratio of the volume (mL) of the mixed solvent of n-butanol and isopropanol to the mass (g) of vortioxetine hydrobromide is 30:

1.

10. The preparation method according to claim 7, characterized in that The heating temperature is 95°C to 110°C, preferably 100°C to 110°C, and more preferably 105°C to 110°C.

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