AN IMPROVED PROCESS FOR THE PREPARATION OF VORTIOXETINE AND SALTS THEREOF

Abstract

The present invention relates to a novel crystalline polymorphic form of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride; commonly known as vortioxetine hydrochloride (hereafter referred to as the compound (Ia) and process for its preparation comprising of treating the compound (Ia) (as described herein) with a ketone solvent or mixture of ketone solvent with other solvents. The present invention also relates to an improved process for the preparation of vortioxetine hydrobromide (Ia), comprising reacting the compound (I) (as described herein) with hydrogen bromide solution in acetic acid.

Claims

1) An improved process for the preparation of vortioxetine hydrobromide (Ia), comprising: a) optionally dissolving the vortioxetine (I) in an organic solvent; and/or b) treating the resulting solution with hydrogen bromide solution in acetic acid.

2) The process as claimed in claim 1, wherein solvent used in step (a) is selected from ketones such as methyl ethyl ketone, acetone, methyl isobutyl ketone (MIBK): aprotic solvents such as acetonitrile and proprionitrile; aromatic solvent such as toluene, xylene and benzene.

3) Crystalline vortioxetine hydrochloride Form-P characterized by an x-ray diffraction pattern (XRD) as shown in FIG. 1

4) Crystalline vorioxetine hydrochloride Form-P as claimed in claim 3, having characteristic X-ray powder diffraction with peaks at about 3.82, 7.66, 11.48, 19.20, 20.23 and 23.10 2 degrees two-theta.

5) Crystalline vortioxetine hydrochloride Form-P as claimed in claim 3, having characteristic X-ray powder diffraction pattern with reflections corresponding to the d-spacing values 23.10, 11.53, 7.70, 4.62, 4.39 and 3.85.

6) A process for the preparation of vortioxetine hydrochloride (Ia) crystalline Form-P, comprises the steps of: a) suspending the vortioxetine hydrochloride (Ia) in a ketone solvent or mixture of ketone solvent with other solvents; and b) optionally stirring the reaction mixture of step (a); c) isolating the product vortioxetine hydrochloride crystalline Form-P.

7) The process as claimed in claim 4, wherein solvent used in step (a) is selected from ketones such as methyl ethyl ketone, acetone, methyl isobutyl ketone (MIBK).

8) The process as claimed in claim 4, wherein other solvent used in step (a) is selected from water.

Description

DESCRIPTION OF THE FIGURES

[0020] FIG. 1: X-ray Powder Diffraction (XRPD) pattern of the vortioxetine hydrochloride Form-P.

DETAILED DESCRIPTION OF THE INVENTION

[0021] Accordingly, the present invention relates to an improved process for the preparation of vortioxetine hydrobromide (Ia), represented by the following formula,

##STR00002##

comprising reacting the vortioxetine (the compound (I) represented by the following formula;

##STR00003##

[0022] with hydrogen bromide solution in acetic acid.

[0023] Accordingly, there is provided an improved process for the preparation of vortioxetine hydrobromide (Ia), represented by the following formula,

##STR00004##

comprising the step of. [0024] (a) optionally, dissolving the vortioxetine (D represented by the following formula; in an organic solvent;

##STR00005## [0025] (b) treating the reaction mixture containing vortioxetine (D of stage (a) with hydrogen bromide solution in acetic acid.

[0026] In the context of the present invention, the term optionally when used in reference to any element; including a process step e.g. dissolving the compound in organic solvent; it is intended to mean that the subject element that is organic solvent is used, or alternatively, is not used in the reaction. Both alternatives are intended to be within the scope of the present invention.

[0027] In an embodiment, the organic solvent is selected from the group consisting of the halogenated solvent such as dichloromethane, 4-bromotoluene, di-iodomethane, carbon tetrachloride, chlorobenzene and chloroform; alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; a ketone selected from methyl ethyl ketone, acetone, methyl isobutyl ketone (MIBK); an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; acetone; or a mixture thereof.

[0028] In a specific embodiment, the process for the preparation of vortioxetine hydrobromide (Ia), comprises the steps of: [0029] (1) dissolving the vortioxetine (I) in an organic solvent; [0030] (2) adding the hydrogen bromide solution in acetic acid to the reaction mixture of step (1); [0031] (3) heating the reaction mixture of the above step (2) at higher temperature of about 40-100 C.; [0032] (4) cooling the reaction mixture of the above step (3) at temperature of about 30 C.; [0033] (5) isolating the product vortioxetine hydrobromide (Ia).

[0034] The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme-1.

##STR00006##

[0035] In an embodiment, the reaction is performed at a temperature ranging between 40100 C., preferably 50-80 C.,

[0036] The organic solvent used in the step-(1) of the above process (as depicted in the Scheme-I) is selected from the group consisting of the halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; a ketone selected from methyl ethyl ketone, acetone, methyl isobutyl ketone (MIBK); an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; acetone; or a mixture thereof.

[0037] The term higher temperature of about 40-100 C. referred to in the step (3) of the above process (as depicted in the Scheme-I) can range from 45 C. to 90 C., preferably 50-80 C.

[0038] The term temperature of about 30 C. referred to in the step (4) of the above process (as depicted in the Scheme-I) can range from 25 C. to 35 C.

[0039] The term isolating the product referred to in the step (5) corresponds to the steps involving separation of organic phase, filtration, evaporation of solvent, washing and drying; precipitation, filtration of precipitated product.

[0040] The process of the present invention as illustrated in the above Scheme-I comprise treating vortioxetine hydrochloride (a) with sodium hydroxide solution (NaOH) to obtain vortioxetine (I) freebase crude. Vortioxetine (I) free base was dissolved in acetone followed by the addition of HBr in acetic acid solution into the reaction mass. The reaction mixture was stirred for 1 h at about 50 C. temperature; to provide the desired product % yield-about 85-90% and more than 99% HPLC purity.

[0041] It is evident from the processes reported in the prior art that the vortioxetine hydrobromide was obtained with low yield of about 80%; whereas the process of the present invention provided the pure vortioxetine in a yield of about 85-90% and purity of more than about 99% (HPLC). It is further evident that the prior art process refers the use of harsh reaction conditions, prolonged reaction time and requires repeated purification or multiple crystallization steps; which are avoided in the currently presented improved process. This amounts to a significant advantage over the processes reported in the prior art.

[0042] Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.

[0043] In an embodiment, there is provided a novel crystalline Form-P of vortioxetine hydrochloride (Ia).

[0044] In another embodiment, there is provided a novel crystalline Form-P of vortioxetine hydrochloride (Ia) having characteristic X-ray powder diffraction ( 2) angle 3.82, 7.66, 11.48, 19.20, 20.23 and 23.1.

[0045] In a yet another embodiment, there is provided a novel crystalline Form-P of vortioxetine hydrochloride (Ia) having characteristic X-ray powder diffraction (d spacing) 23.10, 11.53, 7.70, 4.62, 4.39 and 3.85.

[0046] In an embodiment, the crystalline Form-P of the vortioxetine hydrochloride (Ia) is further characterized by the X-ray powder diffraction graph having d-spacing and 2-theta values as per Table1.

[0047] The X-ray powder diffraction spectrum of vortioxetine hydrochloride (Ia) was measured under the following experimental conditions;

[0048] Instrument X-Ray Diffractometer. Bruker D8 Advance

[0049] X-Ray: Cu/40 kv/40 mA

[0050] Diverging 0.3

[0051] Counter Lynx Eye

[0052] Scan Mode Continuous

[0053] Scan Axes: Two Theta/Theta

[0054] Scan Range: 3 to 40

[0055] Generator power: 40 kV 40 mA

[0056] Scan range 3-40 2

[0057] Step size 0.02

[0058] Step time: 0.25 se

[0059] Sample rotation: 15 rpm

[0060] Detector Lynx-Eye

TABLE-US-00001 TABLE 1 summarizes the d-spacing values in A, and the corresponding 2 values of the crystalline Form-P of the vortioxetine hydrochloride (Ia). Angle d value 2-Theta Angstrom Intensity % 3.82 23.10 100.00 7.66 11.53 45.80 11.48 7.70 34.00 13.36 6.62 1.70 13.78 6.42 7.20 14.41 6.14 1.00 14.91 5.94 1.10 15.32 5.78 9.20 15.93 5.56 1.00 16.35 5.42 2.20 17.02 5.21 3.10 17.60 5.03 8.40 18.30 4.84 5.80 18.84 4.71 3.60 19.20 4.62 49.90 20.23 4.39 19.50 21.40 4.15 3.40 21.81 4.07 4.10 22.85 3.89 3.80 23.10 3.85 59.50 23.38 3.80 4.10 24.02 3.70 1.90 24.35 3.65 4.90 25.02 3.56 4.50 25.50 3.49 2.40 26.69 3.34 2.70 26.99 3.30 3.80 27.55 3.23 11.90 27.99 3.19 1.30 28.55 3.12 9.80 29.24 3.05 2.60 30.00 2.98 1.50 30.17 2.96 2.60 30.93 2.89 3.10 31.87 2.81 4.40 32.70 2.74 3.00 33.59 2.67 3.00 34.08 2.63 1.10 34.97 2.56 10.50 35.22 2.55 1.70 35.57 2.52 2.10 36.27 2.48 1.20 37.16 2.42 1.50 37.51 2.40 1.80 38.16 2.36 3.00 38.35 2.35 2.20 38.98 2.31 4.80 39.83 2.26 2.00

[0061] In another embodiment, the present invention relates to a process for the preparation of vortioxetine hydrochloride (Ia) crystalline Form-P, comprising treating the compound (Ia) (as described herein) with a ketone solvent or mixture of ketone solvent in other solvents.

[0062] Accordingly, the present invention relates to an improved process for the preparation of vortioxetine hydrochloride (a) crystalline Form-P, represented by the following formula,

##STR00007##

[0063] comprising treating vortioxetine hydrochloride (Ia) with a ketone solvent or mixture of ketone solvent with other solvents.

[0064] In a specific embodiment, the process for the preparation of vortioxetine hydrochloride (Ia) crystalline Form-P, comprises the steps of: [0065] (i) suspending the vortioxetine hydrochloride (Ia) in a ketone solvent or mixture of ketone solvent with other solvents; [0066] (ii) stirring the reaction mixture of step (i); [0067] (iii) isolating the product vortioxetine hydrochloride crystalline Form-P.

[0068] The ketone solvent used in the step-(i) of the above process is selected from the group consisting of methyl ethyl ketone, acetone, methyl isobutyl ketone (MIBK) and the like.

[0069] The other solvent used in the step-(i) of the above process is selected from the group consisting of the halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene and chloroform; alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; an ether solvent such as tetrahydrofuran, cyclopentyl methyl ether, 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; a ketone selected from methyl ethyl ketone, acetone, methyl isobutyl ketone (MIBK); an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrolidone (NMP); an aromatic solvent such as toluene, xylene and benzene; acetone; water or a mixture thereof.

[0070] The term isolating the product referred to in the step (iii) corresponds to the one or more is steps involving separation of organic phase, filtration, evaporation of solvent, precipitation, filtration of precipitated product, washing and drying.

[0071] There are several prior art documents that disclosed the methods for preparation of vortioxetine (I) fee base such as U.S. Pat. Nos. 7,144,884; 9,493,409; Published PCT application WO 2016/004908 A1 and other. The process in general comprises reaction of 2-((24-dimethylphenyl)thio)aniline with bis(2-chloroethyl)amine or its salt in varying solvent and reaction conditions to obtain vortioxetine free base. Any of the prior art method can be adopted for the purpose of preparation of vortioxetine (I) free base.

[0072] The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example-1: Preparation of Vortioxetine Hydrochloride (Form-P) [Ia]

[0073] Charged 750 mL of N-methyl-2-pyrrolidone (NMP) in a flask followed by the addition of 2-((2,4-dimethylphenyl)thio)aniline (250 g), Bis(2-chloroethyl)amine hydrochloride (779.5 g) and catalytic amount of potassium iodide. The reaction mixture was heated at a temperature of 110-120 C. for 2 days. The reaction mixture was cooled to the temperature of 25-30 C. followed by the addition of water (3 L) and Toluene (750 mL). The reaction mixture was cooled to 0-5 C. temperature and the obtained solid was filtered. The wet cake was suspended in acetone (1105 ml) and water (220 mL). The solid obtained was filtered and dried under vacuum as Vortioxetine Hydrochloride (Form-P) [yield: 1.75 g (47.8%): Purity: 99.8% (HPLC)].

Example-2: Preparation of Vortioxetine hydrochloride (Form-P) [Ia]

[0074] Charged 360 mL of N-Methyl-2-pyrrolidone (NMP) in a flask followed by the addition of 2-((2,4-dimethylphenyl)thio)aniline (120 g), Bis(2-chloroethyl)amine hydrochloride (374 g) and catalytic amount of potassium iodide. The reaction mixture was heated at a temperature of is 110-120 C. for 2 days. The reaction mixture was cooled to the temperature of 25-30 C., followed by the addition of water (1440 mL) and Toluene (360 mL). The reaction mixture was cooled to 0-5 C. temperature and the obtained solid was filtered. The wet cake was suspended in acetone (1200 mL). The solid obtained was filtered and dried under vacuum as Vortioxetine Hydrochloride (Form-P) [Yield: 103 g (58.77%); Purity: 99.7% (HPLC)].

Example-3: Preparation of Vortioxetine Hydrobromide [Ia]

[0075] Charged 10 mL of dichloromethane in a flask followed by the addition of Vortioxetine Hydrochloride (2 g), 10 mL of water and sodium hydroxide (0.36 g). The reaction mixture was stirred at a temperature of 25-30 C. and the separate organic layer was distilled out under vacuum. To the residue was added 20 mL of acetone and hydrobromic acid (1.6 g) solution in acetic acid; and the reaction mixture was heated at 50 C. temperature for 1 h. The reaction mixture was cooled to 25-30 C. temperature and the solid obtained was filtered to provide Vortioxetine Hydrobromide [Yield: 1.5 g (66%); Purity: 99.6% (HPLC)].

Example-4: Preparation of Vortioxetine Hydrobromide [Ia]

[0076] Charged 10 ml of dichloromethane in a flask followed by the addition of Vortioxetine Hydrochloride (2 g), 10 mL of water and sodium hydroxide (0.36 g). The reaction mixture was stirred at a temperature of 25-30 C. and the separate organic layer was distilled out under vacuum. To the residue was added 20 mL of acetonitrile and hydrobromic acid (1.6 g) solution in acetic acid; and the reaction mixture was heated at 50 C. temperature for 1 h. The reaction mixture was cooled to 25-30 C. temperature and the solid obtained was filtered to provide Vortioxetine Hydrobromide [Yield: 1.7 g (75%); Purity: 99.9% (HPLC)].

Example-5: Preparation of Vortioxetine Hydrobromide [Ia]

[0077] Charged 10 mL of dichloromethane in a flask followed by the addition of Vortioxeine Hydrochloride (2 g), 10 mL of water and sodium hydroxide (0.36 g). The reaction mixture was stirred at a temperature of 25-30 C. and the separate organic layer was distilled out under vacuum. To the residue was added 20 mL of methyl isobutyl ketone (M3K) and hydrobromic acid (1.6 g) solution in acetic acid; and the reaction mixture was heated at 50 C. temperature for 1 h. The reaction mixture was cooled to 25-30 C. temperature and the solid obtained was filtered to provide Vortioxetine Hydrobromide [Yield: 1.7 g (75%); Purity: 99.88% (HPLC)].

Example-6: Preparation of Vortioxetine Hydrobromide [Ia]

[0078] Charged 10 mL of dichloromethane in a flask followed by the addition of Vortioxetine Hydrochloride (2 g), 10 mL of water and sodium hydroxide (0.36 g). The reaction mixture was stirred at a temperature of 25-30 C. and the separate organic layer was distilled out under vacuum. To the residue was added 20 mL of toluene and hydrobromic acid (1.6 g) solution in acetic acid; and the reaction mixture was heated at 80 C. temperature for 1 h. The reaction mixture was cooled to 25-30 C. temperature and the solid obtained was filtered to provide Vortioxetine Hydrobromide [Yield: 1.5 g (66%); Purity: 99.9% (HPLC)].