Process for the preparation of vortioxetine HBr salt form alpha

Abstract

A method of preparing vortioxetine HBr salt Form a is provided.

Description

Technical Field

[0001] This invention relates to a method for preparing specific polymorphs of vortioxetine HBr salt. Background Technology

[0002] International patent applications, including WO 03 / 029232 and WO 2007 / 144005, disclose the compound 1-[2-(2,4-dimethyl-phenylthioalkyl)-phenyl]-piperazine and its pharmaceutically acceptable salts. The WHO has previously published vortioxetine as the recommended International Nonproprietary Name (INN) for 1-[2-(2,4-dimethyl-phenylthioalkyl)-phenyl]-piperazine. Vortioxetine was previously known in the literature as Lu AA21004. In September and December 2013, the FDA and EMA, among numerous registration agencies worldwide, respectively, granted the first approval under the name Brintellix. TM Or Trintellix TM Vortioxetine, sold under the brand name in the United States and Canada, is used to treat depression / depressive episodes.

[0003] Vortioxetine contains 5-HT3, 5-HT7 and 5-HT 1D The receptor antagonist is 5-HT. 1A receptor agonists and 5-HT 1BIt is a partial agonist of the receptor and an inhibitor of the serotonin transporter. Furthermore, vortioxetine has been shown to enhance the levels of the neurotransmitters serotonin, norepinephrine, dopamine, acetylcholine, and histamine in specific brain regions. These activities are considered clinically relevant and may be involved in the compound's mechanism of action [J. Med. Chem., 54, 3206-3221, 2011; Eur. Neuropshycopharmacol., 18(Supplement 4), S321, 2008; Eur. Neuropshycopharmacol., 21(Supplement 4), S407-408, 2011; Int. J. Psychiatry Clin Pract., 5, 47, 2012]. These pharmacological properties give reason to believe that vortioxetine may have cognitive-enhancing effects. This view appears to be supported by clinical evidence, which has shown that vortioxetine has a direct beneficial effect on cognition independent of its antidepressant effect [Int. Clin. Psychopharm. 27, 215-227, 2012; Int J neuropharmacopharm 17, 1557-1567, 2014; Neuropsychopharm 40, 2025-2037, 2015].

[0004] Vortioxetine is commercially available as film-coated tablets and as oral drops, the tablets containing 5, 10, 15, and 20 mg of vortioxetine in the form of HBr salt, and the drops containing 20 mg / ml of vortioxetine in the form of DL lactate.

[0005] As initially disclosed in WO 2007 / 144005 and later confirmed in WO 2014 / 044721 and EP2975032, vortioxetine HBr salts exist in several crystalline forms. As the FDA label for vortioxetine indicates, the commercially available polymorph Trintellix is... TM It is the β-type of vortioxetine HBr salt. This application adheres to the nomenclature of polymorphs as defined in WO2007 / 144005.

[0006] Chinese patent applications CN 105367515, CN 106316986, and CN 104910099 disclose methods for preparing the α-form of vortioxetine HBr salt. These methods are characterized by several features that may limit their industrial applicability. Using ethyl acetate as a solvent in a strongly acidic environment (after adding an aqueous HBr solution) can lead to acid hydrolysis of the solvent. Other methods utilize an alcohol solvate as an intermediate, evaporating the alcohol from the solvate to obtain the α-form of vortioxetine HBr salt. Such methods require significant time and effort. Other methods involve the continuous use of several solvents and lengthy processing times, increasing the overall complexity of the process.

[0007] It is desirable to obtain different polymorphs of drug compounds because the choice of polymorph can be used to control factors such as solubility and bioavailability, which can again affect clinical outcomes or suitability in various formulation technologies.

[0008] This invention provides a simple method for preparing vortioxetine HBr salt α-form, which has high yield and is easily scalable. Summary of the Invention

[0009] In one embodiment, the present invention provides a method for preparing vortioxetine HBr salt α-crystal form (α-type), characterized by XRPD reflections of vortioxetine HBr salt crystals at 5.85, 9.30, 17.49, and 18.58 (°2θ) (±0.1°), the method comprising the following steps

[0010] a) Obtain a solution of vortioxetine in substantially pure toluene.

[0011] b) At a temperature above 10°C, the solution obtained in step a) is mixed with HBr and C1-C3 carboxylic acid to obtain a mixture b).

[0012] c) Collect the precipitate obtained in step b). Attached Figure Description

[0013] Figure 1 XRPD diffraction pattern of the product obtained in Example 1. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0014] Figure 2 XRPD diffraction pattern of the product obtained in Example 2. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0015] Figure 3 XRPD diffraction pattern of the product obtained in Example 3. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0016] Figure 4aXRPD diffraction pattern of the product obtained in Example 4 after drying overnight at RT. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0017] Figure 4b XRPD diffraction pattern of the product obtained in Example 4 after drying at 50°C overnight. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0018] Figure 4c XRPD diffraction pattern of the product obtained in Example 4 after drying at 80°C overnight. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0019] Figure 5 XRPD diffraction pattern of the product obtained in Example 5. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0020] Figure 6a XRPD diffraction pattern of the product obtained in Example 6 after drying overnight at RT. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0021] Figure 6b XRPD diffraction pattern of the product obtained in Example 6 after drying at 80°C overnight. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0022] Figure 7 XRPD diffraction pattern of the product obtained in Example 7. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0023] Figure 8 XRPD diffraction pattern of the product obtained in Example 8. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0024] Figure 9 XRPD diffraction pattern of the product obtained in Example 9. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0025] Figure 10 XRPD diffraction pattern of the product obtained in Example 10. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0026] Figure 11 XRPD diffraction pattern of the product obtained in Example 11. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0027] Figure 12 XRPD diffraction pattern of the product obtained in Example 12. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0028] Figure 13 XRPD diffraction pattern of the product obtained in Example 13. The x-axis represents the angle °2θ, and the y-axis represents the intensity count.

[0029] Figure 14 XRPD diffraction pattern of the product obtained in Example 14. The x-axis represents the angle °2θ, and the y-axis represents the intensity count. Detailed Implementation

[0030] This invention provides a method for preparing the α-type vortioxetine HBr salt. This crystal form is defined in Examples 4a and 4b of WO2007 / 144005 as a vortioxetine HBr salt crystal characterized by XRPD reflection at 5.85, 9.30, 17.49, and 18.58 (°2θ) (±0.1°). Similarly, the β-type vortioxetine HBr salt is defined in Examples 4c and 4d of WO 2007 / 144005 as a vortioxetine HBr salt crystal characterized by XRPD reflection at 6.89, 9.73, 13.78, and 14.62 (°2θ) (±0.1°). Similarly, vortioxetine HBr salt γ-type is defined in Examples 4e and 4f of WO 2007 / 144005 as vortioxetine HBr salt crystals characterized by XRPD reflections at 11.82, 16.01, 17.22, and 18.84 (°2θ) (±0.1°). X-ray powder diffraction (XRPD) patterns were obtained using a Panalytical X'Pert PRO X-ray diffractometer with CuK... α1 Radiation was measured. These samples were measured in reflection mode using an X'celerator detector within a 2θ-angle range of 5–40°.

[0031] In this article, "RT" is intended to represent room temperature, that is, a temperature between 19°C and 25°C.

[0032] The solution obtained in step a) is a free base of vortioxetine in substantially pure toluene. In this document, it may include a suspension of vortioxetine, i.e., a vortioxetine solution containing undissolved vortioxetine. For convenience, solutions in which all vortioxetine is dissolved, as well as solutions containing undissolved vortioxetine, are referred to herein as solutions. Any indication of vortioxetine concentration or amount will refer to the total amount of vortioxetine, i.e., the concentration or amount of dissolved and undissolved vortioxetine.

[0033] In step a) of the present invention, a vortioxetine solution in substantially pure toluene is obtained. In one embodiment, the concentration of vortioxetine in the solution is 10 g / L-500 g / L, such as 40 g / L-200 g / L, such as 50 g / L-200 g / L, such as 50 g / L-150 g / L, such as 100 g / L.

[0034] In step a) of this invention, a vortioxetine solution in substantially pure toluene is obtained. In one embodiment, "substantially pure" means toluene with a purity greater than 90%, such as greater than 95%, such as greater than 98%. The balance may include water (i.e., using non-dried toluene) or other solvents or solvent impurities, such as benzene, xylene, alkanes, or alkenes. In this document, "greater than XX% purity" means that the solvent contains greater than XX% toluene based on weight / weight.

[0035] The temperature of the solution obtained in step a) is not considered critical, but it can affect how much and how quickly vortioxetine can be brought into the solution. In one embodiment, the temperature is between 0°C and reflux temperature, such as between 5°C and 50°C, such as between 10°C and 30°C, such as about 20°C. In another embodiment, the temperature is between 25°C and 40°C. The temperature in step a) is considered to be within a specified range; for example, "between 0°C and reflux" means that the temperature of the solution obtained in step a) is within the specified range (at least at one point in time). In one embodiment, "at least at one point in time" means at least 1 minute, such as at least 5 minutes, such as at least 10 minutes.

[0036] In step b) of this invention, the solution obtained in step a) is mixed with HBr and C1-C3 carboxylic acids. The three components mixed in step b) (i.e., vortioxetine, HBr, and C1-C3 carboxylic acids) 1- C3 carboxylic acids can be mixed in any order. For example, the solution obtained in step a) can be added to HBr and C 1- In C3 carboxylic acids, or by combining HBr and C 1- C3 carboxylic acid is added to the solution obtained in step a).

[0037] The amount of HBr applied in step b) should be at least similar (on a molar basis) to the amount of vortioxetine in the solution obtained in step a) to optimize the yield. If necessary, the mixing in step b) can be performed in more than one step, wherein less than the total amount of the solution or HBr and C obtained in step a) is added in a single step. 1- C3 carboxylic acid. In one embodiment, the amount of HBr applied in step b) is between 0.9 and 10 molar equivalents relative to the amount of vortioxetine present in the solution obtained in step a), such as between 0.9 and 5 molar equivalents, between 0.9 and 2 molar equivalents, between 0.9 and 1.3 molar equivalents, or between 0.9 and 1.1 molar equivalents relative to the amount of vortioxetine present in the solution obtained in step a).

[0038] The temperature in step b) is above 10°C, which means that the solution obtained in step a) is reacted with HBr and C 1-When C3 carboxylic acids are mixed to obtain mixture b), the temperature is above 10°C. In one embodiment, the temperature in step b) is 40°C or lower, such as 25°C or lower. After obtaining mixture b), the temperature can be conveniently lowered to reduce solubility, thereby increasing the yield of vortioxetine HBr salt α-form. In one embodiment, the temperature is between -20°C and 30°C, such as between 0°C and 20°C, or such as between 0°C and 10°C.

[0039] In one embodiment, in step b) of the present invention, HBr:C 1- The molar ratio of C3 carboxylic acids is 1:1 to 1:10, such as 1:2 to 1:4, such as 1:2.9, or such as 1:7.7.

[0040] In this document, C1-C3 carboxylic acids refer to methyl methacrylate, acetic acid, or propionic acid, or mixtures thereof. In one embodiment, C1-C3 carboxylic acids refer to acetic acid, wherein 33% (w / w) of HBr in commercially available acetic acid is used in step b). In one embodiment, C1-C3 carboxylic acids refer to propionic acid.

[0041] In one embodiment, the present invention provides a method for preparing the α-crystal form of vortioxetine HBr salt, the method comprising the following steps:

[0042] a) Obtain a vortioxetine solution in substantially pure toluene, wherein the solution contains 10 g / L to 500 g / L of vortioxetine, wherein the substantially pure toluene contains more than 90% (w / w) toluene, and wherein the temperature of the solution is between 5°C and reflux.

[0043] b) The solution obtained in step a) is mixed with HBr and a C1-C3 carboxylic acid (such as acetic acid or propionic acid) to obtain mixture b), wherein the amount of HBr is 0.9-10 molar equivalents relative to the amount of vortioxetine in the solution obtained in step a), wherein the molar ratio of HBr to C1-C3 carboxylic acid is 1:1-1:10, and wherein the temperature of mixture b) is above 10°C; and

[0044] c) Collect the precipitate obtained in step b).

[0045] In one embodiment, the present invention provides a method for preparing the α-crystal form of vortioxetine HBr salt, the method comprising the following steps:

[0046] a) Obtain a vortioxetine solution in substantially pure toluene, wherein the solution contains 40 g / L to 200 g / L, such as 50 g / L to 200 g / L, of vortioxetine, and wherein the substantially pure toluene contains more than 95% (w / w) toluene, and wherein the temperature of the solution is between 10°C and 30°C, or between 25°C and 40°C.

[0047] b) The solution obtained in step a) is mixed with HBr and a C1-C3 carboxylic acid (such as acetic acid or propionic acid) to obtain mixture b), wherein the amount of HBr is 0.9-5 molar equivalents relative to the amount of vortioxetine in the solution obtained in step a), wherein the molar ratio of HBr to C1-C3 carboxylic acid is 1:1-1:8, such as 1:1-1:4, and wherein the temperature of mixture b) is above 10°C and at most 40°C, such as 25°C or lower; and

[0048] c) Collect the precipitate obtained in step b).

[0049] In one embodiment, the present invention provides a method for preparing the α-crystal form of vortioxetine HBr salt, the method comprising the following steps:

[0050] a) Obtain a vortioxetine solution in substantially pure toluene, wherein the solution contains 40 g / L to 200 g / L, such as 50 g / L to 150 g / L of vortioxetine, and wherein the substantially pure toluene contains more than 98% (w / w) of toluene, and wherein the temperature of the solution is between 20°C and 25°C, or between 25°C and 40°C.

[0051] b) The solution obtained in step a) is mixed with HBr and a C1-C3 carboxylic acid (such as acetic acid or propionic acid) to obtain mixture b), wherein the amount of HBr is 0.9 to 1.3 molar equivalents relative to the amount of vortioxetine in the solution obtained in step a), wherein the molar ratio of HBr to C1-C3 carboxylic acid is 1:1 to 1:8, such as 1:1 to 1:4, or more specifically 1:3, and wherein the temperature of mixture b) is above 10°C and below 40°C, such as below 25°C; and

[0052] c) Collect the precipitate obtained in step b).

[0053] In one embodiment, the present invention provides a method for preparing the α-crystal form of vortioxetine HBr salt, the method comprising the following steps:

[0054] a) Obtain a vortioxetine solution in substantially pure toluene, wherein the solution contains 100 g / L of vortioxetine, and wherein the substantially pure toluene contains more than 98% (w / w) of toluene, and wherein the temperature of the solution is between 25°C and 40°C, such as between 20°C and 25°C.

[0055] b) The solution obtained in step a) is mixed with HBr and a C1-C3 carboxylic acid (such as acetic acid or propionic acid) to obtain mixture b), wherein the amount of HBr is 0.9 to 1.1 molar equivalents relative to the amount of vortioxetine in the solution obtained in step a), wherein the molar ratio of HBr to C1-C3 carboxylic acid is 1:1 to 1:3, and wherein the temperature of mixture b) is above 10°C and at most 40°C, such as 25°C or lower; and

[0056] c) Collect the precipitate obtained in step b).

[0057] The experiments reported in Examples 1-5, 11, and 14 showed that vortioxetine HBr salts precipitated from toluene under a range of conditions did not provide the desired α-form. A range of vortioxetine concentrations (50 g / L–160 g / L), solvent variations (pure toluene and 95% aqueous toluene solution), and different temperatures (-15°C–50°C) were investigated. Finally, the use of pre-formed vortioxetine HBr salts and the formation of vortioxetine HBr salts by adding liquid and gaseous HBr were investigated. In addition to the conclusion that the investigated process conditions did not appear to provide the desired α-form, the results of Examples 1–5 also showed that seemingly minor variations in process conditions can cause differences in the precipitated crystal form.

[0058] In contrast, the experiments shown in Examples 6-10, 12 and 13 define the process conditions for producing the desired vortioxetine HBr salt α form in a robust and high-yield method.

[0059] In one embodiment, the present invention provides a method for obtaining the α-crystal form of vortioxetine HBr salt by the method of the present invention.

[0060] In one embodiment, the present invention provides a pharmaceutical composition comprising the vortioxetine HBr salt α crystal form obtained by the method of the present invention and a pharmaceutically acceptable excipient.

[0061] experiment

[0062] X-ray powder diffraction (XRPD) was obtained by using CuKα1 radiation on a PANalyticalX'Pert PRO X-ray diffractometer. To measure, these samples are measured in reflection mode using an X'celerator detector within a 2θ angle of 3-40°.

[0063] Example 1 (Reference)

[0064] Toluene (600 mL) and vortioxetine (100 g, 0.335 mol) were added to a 2 L three-necked flask equipped with a mechanical stirrer, thermometer, and reflux condenser. The mixture was heated to 65 °C with a heating mantle and water (27 mL, 1.5 mol) was added to obtain a clear solution. The heating mantle was removed, and an aqueous HBr solution (48%, 39.8 mL (59.3 g), 0.352 mol) was added. The flask was immediately cooled on ice / water. After a few minutes, precipitation began at 50-55 °C. Stirring was continued, and the mixture was cooled to 5 °C over the next 20 min. Stirring was continued for another 20 min. The precipitate was separated by filtration, washed on the filter with toluene (3 x 40 mL), and dried under vacuum overnight at 40 °C. Yield: 126.0 g. NMR showed the presence of very small amounts of toluene. XRPD showed that the separated product was a mixture of α- and β-forms of vortioxetine HBr salt. The obtained XRPDs are as follows. Figure 1 As shown.

[0065] Example 2 (Reference)

[0066] An attempt was made to dissolve vortioxetine HBr salt (1.0 g, 2.64 mmol) in toluene (6.0 mL) and water (0.27 mL) by heating the mixture under reflux for 5 min; however, no clear solution was obtained. More toluene (12 mL) and water (0.54 mL) were added. The clear mixture was quenched over an ice / NaCl mixture and stirred for 30 min. The precipitate was separated by filtration, washed on the filter with toluene (3 x 1 mL), and dried under vacuum overnight at room temperature. Yield: 1.1 g. XRPD showed that pure vortioxetine HBr salt β-form was obtained. The obtained XRPD is as follows: Figure 2 As shown.

[0067] Example 3 (Reference)

[0068] Vortioxetine (1.0 g, 3.35 mmol) was dissolved in toluene (6.0 mL) and water (0.27 mL) by heating the mixture to 65 °C. An aqueous HBr solution (48%, 0.4 mL (0.59 g), 3.52 mmol) was added, and the mixture was quenched on an ice / NaCl mixture for 10 min (to -15 °C) and stirred for 30 min. The precipitate was separated by filtration, washed on the filter with toluene (3 x 2 mL), and dried under vacuum overnight at room temperature. Yield: 1.16 g. XRPD showed that the obtained product was a mixture of vortioxetine HBr salt α-form, vortioxetine HBr salt hydrate, and unidentified components. Furthermore, XRPD indicated low crystallinity. The obtained XRPD is as follows: Figure 3 As shown.

[0069] Example 4 (Reference)

[0070] Toluene (200 mL) and vortioxetine (20.0 g, 67.0 mmol) were added to a 500 mL three-necked flask equipped with a mechanical stirrer, thermometer, and reflux condenser. The mixture was stirred overnight at RT to obtain a clear solution. An aqueous HBr solution (48%, 7.96 mL (11.9 g), 70.4 mmol) was rapidly added, and the reaction mixture was immediately cooled on an ice / water bath. Stirring was continued for 10 minutes under cooling. The precipitate was separated by filtration, washed with toluene (2 × 30 mL) on the filter, and dried under vacuum overnight at RT, 50 °C, and 80 °C. Yield: 24.57 g. NMR showed no presence of toluene. XRPD showed that the product obtained after drying the precipitate overnight at RT and 50 °C was a mixture of vortioxetine HBr salt α-form and vortioxetine HBr hydrate, and drying overnight at 80 °C reduced the amount of vortioxetine HBr hydrate, possibly due to the removal of water of crystallization. The XRPDs obtained after drying at RT, 50℃, and 80℃ are as follows: Figure 4a , 4b And 4c display.

[0071] Example 5 (Reference)

[0072] Toluene (80 mL) and vortioxetine (4.0 g, 13.4 mmol) were added to a 250 mL three-necked flask equipped with a magnetic stirrer, thermometer, and reflux condenser. The mixture was stirred to obtain a clear solution. Hydrogen bromide (gas) (approximately 1.1 g, 13.5 mmol) was carefully added from a valve bottle. Precipitation began immediately, and stirring was continued at RT for one hour after pH measurement (approximately pH = 1). The precipitate was separated by filtration and washed on the filter with toluene (2 x 10 mL). The product was filtered very slowly and dried under vacuum at 40 °C to constant weight. Yield: 5.97 g. XRPD showed that the separated product could not be identified as the α-type of vortioxetine HBr salt. NMR also showed that the obtained product contained a large amount of toluene. TGA showed a loss of approximately 13% weight between 50 and 110 °C. Continued drying at 130 °C decomposed the separated product into brown to black substances. The obtained XRPD is as follows: Figure 5 As shown.

[0073] Example 6

[0074] Toluene (200 mL) and vortioxetine (20.0 g, 67.0 mmol) were added to a 500 mL three-necked flask equipped with a mechanical stirrer, thermometer, and reflux condenser. The mixture was stirred at RT for 30 min to obtain a clear solution. HBr (33%, 12.32 mL (17.25 g), 70.4 mmol) in acetic acid was added rapidly, and the reaction mixture was immediately cooled on an ice / water bath. Cooling was continued with stirring for 10 min. The precipitated product was separated by filtration, washed with toluene (2 × 30 mL) on the filter, and dried under vacuum at RT and 80 °C overnight. Yield: 23.77 g. XRPD showed that the separated product was pure vortioxetine HBr salt α-form, regardless of drying conditions. The XRPD obtained after drying at RT and 80 °C are shown below. Figure 6a and 6b show.

[0075] Example 7

[0076] Toluene (3000 mL) and vortioxetine (300 g, 1.005 mmol) were added to a 4 L three-necked flask equipped with a mechanical stirrer, thermometer, and reflux condenser. The mixture was stirred at RT for 30 min to obtain a clear solution. The clear solution was cooled to 10 °C. After 5 min, HBr in acetic acid (33%, 185 mL (259 g), 1.055 mol) was added from a pressure equalization funnel. This addition raised the temperature to 23 °C. Precipitation began shortly after the addition of the HBr mixture in acetic acid and was quite severe until about half of the HBr mixture in acetic acid was added. At this point, most of the precipitate redissolved, and precipitation began again when the HBr mixture in acetic acid was continued to be added. Stirring was continued for 45 min while the temperature was lowered to 5 °C. The precipitate was separated by filtration, washed on the filter with toluene (3 x 100 mL), and dried under vacuum at RT overnight. Yield: 375.4 g. XRPD showed that the isolated product was pure vortioxetine HBr salt α-form. The obtained XRPR is as follows Figure 7 As shown.

[0077] Example 8

[0078] Toluene (50 ml) and vortioxetine (2.0 g, 6.7 mmol) were added to a 100 ml flask equipped with a magnetic stirrer. The mixture was stirred at RT for 30 min. HBr (33%, 1.23 ml, 1.73 g, 7.04 mmol) in acetic acid was added rapidly, and the reaction mixture was immediately cooled on an ice / water bath. Stirring was continued for 10 min. The precipitated product was separated by filtration, washed with toluene (2 x 5 ml) on the filter, and dried under vacuum at RT overnight. Yield: 2.41 g. XRPD showed that the separated product was pure vortioxetine HBr salt α-form. The obtained XRPD is as follows: Figure 8As shown.

[0079] Example 9

[0080] Toluene (10 ml) and vortioxetine (2.0 g, 6.7 mmol) were added to a 50 ml flask equipped with a magnetic stirrer. The mixture was stirred at RT for 30 min. To obtain a clear solution, the temperature was raised to 40 °C. HBr (33%, 1.23 ml, 1.73 g, 7.04 mmol) in acetic acid was added rapidly, and the reaction mixture was immediately cooled on an ice / water bath. Stirring was continued for 2 min, and then additional toluene (5.5 ml) was added to allow continued stirring (10 min). The precipitated product was separated by filtration, washed on the filter with toluene (2 x 5 ml), and dried under vacuum at RT overnight. Yield: 2.44 g. XRPD showed that the separated product was pure vortioxetine HBr salt α-form. The obtained XRPD was as follows: Figure 9 As shown.

[0081] Example 10

[0082] Toluene (20 ml) and vortioxetine (2.0 g, 6.7 mmol) were added to a 50 ml flask equipped with a magnetic stirrer. The mixture was stirred at 40 °C for 30 min. HBr (33%, 1.23 ml, 1.73 g, 7.04 mmol) in acetic acid was added rapidly, and the reaction mixture was immediately cooled on an ice / water bath. Precipitation hindered stirring; additional toluene (5.5 ml) was added to allow stirring to continue (10 min). The precipitate was separated by filtration, washed with toluene (2 x 5 ml) on the filter, and dried under vacuum at RT overnight. Yield: 2.30 g. XRPD showed that the separated product was pure vortioxetine HBr salt α-form. The obtained XRPD is as follows: Figure 10 As shown.

[0083] Example 11 (Reference)

[0084] Toluene (10 mL) and vortioxetine (2.0 g, 6.7 mmol) were added to a 50 mL flask equipped with a magnetic stirrer. The mixture was stirred at RT for 10 min, then at 10 °C for 10 min. HBr (33%, 1.23 mL, 1.73 g, 7.04 mmol) in acetic acid was added rapidly, and the reaction mixture was immediately cooled on an ice / water bath. Stirring was continued for 10 min. The precipitated product was separated by filtration, washed with toluene (2 x 5 mL) on the filter, and dried under vacuum at RT overnight. Yield: 2.43 g. XRPD showed that the separated product was pure vortioxetine HBr salt β-form. The obtained XRPD is as follows: Figure 11 As shown.

[0085] Example 12

[0086] Toluene (20 ml) and vortioxetine (2.0 g, 6.7 mmol) were added to a 50 ml flask equipped with a magnetic stirrer. The mixture was stirred at RT for 30 min. Acetic acid (2.00 ml, 2.10 g, 34.9 mmol) and HBr in acetic acid (33%, 1.23 ml, 1.73 g, 7.04 mmol) were rapidly added, and the reaction mixture was stirred for 20 min, then cooled on an ice / water bath. As the precipitation hindered stirring, additional toluene (5.5 ml) was added to allow stirring to continue (10 min). The precipitated product was separated by filtration, washed on the filter with toluene (2 x 5 ml), and dried under vacuum at RT overnight. Yield: 2.15 g. XRPD showed that the separated product was pure vortioxetine HBr salt α-form. The obtained XRPD is as follows: Figure 12 As shown.

[0087] Example 13

[0088] Toluene (20 ml) and vortioxetine (2.0 g, 6.7 mmol) were added to a 50 ml flask equipped with a magnetic stirrer. The mixture was stirred at RT for 30 min. HBr in propionic acid (33%, 1.23 ml, 1.73 g, 7.04 mmol) was rapidly added, and the reaction mixture was cooled on an ice / water bath. A solution of HBr in propionic acid was obtained by bubbling HBr gas through the propionic acid until the desired weight increase was achieved. Stirring was continued for 20 min. The precipitated product was separated by filtration, washed with toluene (2 × 5 ml) on the filter, and dried under vacuum at RT for 4 days. Yield: 1.91 g. XRPD showed that the separated product was pure vortioxetine HBr salt α-form. The obtained XRPD was as follows: Figure 13 As shown.

[0089] Example 14 (Reference)

[0090] Toluene (20 ml) and vortioxetine (2.0 g, 6.7 mmol) were added to a 50 ml flask equipped with a magnetic stirrer. The mixture was stirred at RT for 10 min, then at 10 °C for another 10 min. HBr (33%, 1.23 ml, 1.73 g, 7.04 mmol) in acetic acid was rapidly added, and the reaction mixture was then cooled on an ice / water bath and stirred for another 10 min. The precipitated product was separated by filtration, washed with toluene (2 x 5 ml) on the filter, and dried under vacuum at RT overnight. Yield: 2.46 g. XRPD showed that the separated product was vortioxetine HBr salt α-form, which also contained γ-form vortioxetine HBr salt. The obtained XRPD is as follows: Figure 14 As shown.

Claims

1. A method for preparing the α-form of vortioxetine HBr salt with characteristic XRPD reflection at 5.85, 9.30, 17.49, and 18.58 (°2θ) (±0.1°), the method comprising the following steps a) Obtain a vortioxetine solution in toluene, wherein the toluene has a purity greater than 90%; b) At a temperature above 10°C, the solution obtained in step a) is mixed with HBr and C1-C3 carboxylic acids to obtain mixture b); and c) Collect the precipitate obtained in step b).

2. The method according to claim 1, wherein the concentration of vortioxetine obtained in step a) is between 10 g / L toluene and 500 g / L toluene.

3. The method according to claim 2, wherein the concentration of vortioxetine obtained in step a) is between 40 g / L toluene and 200 g / L toluene.

4. The method of claim 1, wherein the toluene contains more than 95 w / w% toluene.

5. The method according to claim 1, wherein the temperature of the solution obtained in step a) is between 0°C and the reflux temperature.

6. The method of claim 5, wherein the temperature of the solution obtained in step a) is between 25°C and 40°C.

7. The method of claim 5, wherein the temperature of the solution obtained in step a) is between 10°C and 30°C.

8. The method according to claim 7, wherein the temperature of the solution obtained in step a) is 20°C.

9. The method of claim 1, wherein the amount of HBr in step b) is between 0.9 and 2 molar equivalents relative to the amount of vortioxetine present in the solution obtained in step a).

10. The method of claim 9, wherein the amount of HBr in step b) is between 1 and 1.3 molar equivalents relative to the amount of vortioxetine present in the solution obtained in step a).

11. The method according to claim 1, wherein the molar ratio of HBr to C1-C3 carboxylic acid in step b) is 1:1 to 1:

10.

12. The method according to claim 11, wherein in step b), the molar ratio of HBr to C1-C3 carboxylic acid is 1:2 to 1:4, and the C1-C3 carboxylic acid is acetic acid.

13. The method of claim 1, wherein the temperature of mixture b) is above 10°C and at most 40°C.

14. The method according to claim 1, wherein the C1-C3 carboxylic acid is acetic acid.

15. The method according to claim 1, wherein the C1-C3 carboxylic acid is propionic acid.

16. The method according to any one of claims 1-12, wherein the HBr and the C1-C3 carboxylic acid together form 33% w / w HBr dissolved in acetic acid.

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