Process for the preparation of vortioxetine and salts thereof

Abstract

The present invention provides an improved process for preparation of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine; commonly known as vortioxetine (referred to as the compound (I)) and pharmaceutically acceptable salts thereof; wherein the process comprises reaction of 2-((2,4-dimethylphenyl)thio)aniline (II) with bis(2-alkyl)amine (IIIa) or its salt in the presence of a cyclic amide solvent.

Claims

1. A process for the preparation of vortioxetine (I) or a salt thereof of formula, ##STR00013## consisting of the steps of reacting 2-((2,4-dimethylphenyl)thio)aniline (II) of the following formula; ##STR00014## with bis(2-alkyl)amine (IIIa) or its salt of the following formula; ##STR00015## wherein, X is a leaving group and R is H or a protecting group in a cyclic amide solvent, either providing compound (I) directly if R is H; or providing compound (Ia) if R is a protecting group, ##STR00016## which on deprotection provides compound (I).

2. The process according to the claim 1, wherein the cyclic amide solvent is selected from the group consisting of N-methyl-2-pyrrolidone (NMP), caprolactam, 2-piperidinone, azetidin-2-one, N-methyl caprolactame, 1-methylpiperidin-2-one, 1-methylazetidin-2-one; and a mixture thereof.

3. The process according to the claim 1, wherein the reaction is performed at temperature ranging between 80-180 C.

4. The process according to the claim 1, wherein the product vortioxetine (I) or a salt thereof is obtained in a yield of about 70%.

5. The process according to the claim 1, wherein the product vortioxetine (I) or a salt thereof is obtained with in a purity of at least 99% (HPLC).

6. The process according to the claim 1, wherein the product vortioxetine (I) or a salt thereof is further transformed into another acid addition salt of vortioxetine.

7. A process for the preparation of vortioxetine (I) or a salt thereof of formula, ##STR00017## comprising the steps of, reacting 2-((2,4-dimethylphenyl)thio)aniline (II) of formula; ##STR00018## with bis(2-alkyl)amine hydrochloride (III) of formula; ##STR00019## in N-methyl-2-pyrrolidone (NMP) solvent, at temperature ranging between 80-180 C.; and optionally transforming vortioxetine (I) or a salt thereof into its another acid addition salt.

8. A compound Vortioxetine (I) hydrobromide having particle size distribution range of d(10) between about 5 m to about 12 m, or d(50) between about 35 m to about 40 m or d(90) between about 80 m to about 180 m; or any combination thereof.

9. A compound Vortioxetine (I) hydrobromide having specific surface area value of at least 1 m.sup.2/g and not more than 2 m.sup.2/g.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Accordingly, the present invention relates to an improved process for the preparation of vortioxetine (the compound (I)) or its salt represented by the following formula,

(2) ##STR00003##
comprising; reacting 2-((2,4-dimethylphenyl)thio)aniline (the compound (II)) represented by the following formula;

(3) ##STR00004##
with bis(2-alkyl)amine (the compound (IIIa)) or its salt represented by the following formula;

(4) ##STR00005## wherein, X is a leaving group and R is H or a protecting group
in a cyclic amide solvent, either providing compound (I) directly if R is H; or providing compound (Ia) if R is a protecting group,

(5) ##STR00006##
which on deprotection provides compound (I).

(6) Accordingly, there is provided an improved process for the preparation of vortioxetine (the compound (I)) or its salt represented by the following formula,

(7) ##STR00007##
comprising; reacting 2-((2,4-dimethylphenyl)thio)aniline (the compound (II)) represented by the following formula;

(8) ##STR00008##
with bis(2-alkyl)amine (the compound (Ma)) or its salt represented by the following formula;

(9) ##STR00009## wherein, X is a leaving group and R is H or a protecting group
in a cyclic amide solvent at temperature ranging between 80-180 C.; either providing compound (I) directly if R is H; or providing compound (Ia) if R is a protecting group,

(10) ##STR00010##
which on deprotection provides compound (I);
and optionally transforming vortioxetine or its salt into its another acid salt.

(11) In the context of the present invention, the term optionally when used in reference to any element; including a process step e.g. conversion of a compound; it is intended to mean that the subject element is subsequently converted, or alternatively, is not converted to a further compound. Both alternatives are intended to be within the scope of the present invention.

(12) In an embodiment, the cyclic amide solvent is selected from the group consisting of N-methyl-2-pyrrolidone, caprolactam, 2-piperidinone, azetidin-2-one, N-methyl caprolactame, 1-methylpiperidin-2-one and 1-methylazetidin-2-one; or a mixture thereof.

(13) In an embodiment, the cyclic amide solvent is N-methyl-2-pyrrolidone (NMP).

(14) In an embodiment, the acid addition salts of vortioxetine are selected from hydrochloride, hydrobromide, hydrogen sulfate, phosphate, nitrate, acetate, ascorbate, benzoate, besylate, mesylate, succinate, oxalate, citrate, formate, fumarate, lactate, malonate, maleate, malate, palmitate, tartrate, and trifluoroacetate.

(15) In a specific embodiment, the process for the preparation of vortioxetine (I) or its salt comprises the steps of:

(16) (1) dissolving the compound (II) in an cyclic amide solvent;

(17) (2) adding the compound (IIIa) or its salt to the reaction mixture of step (1);

(18) (3) heating the reaction mixture of the above step (2) at temperature ranging between 80-180 C.;

(19) (4) cooling the reaction mixture of the above step (3) at temperature of about 30 C.;

(20) (5) isolating the product vortioxetine (I) or its salt.

(21) The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme-I,

(22) ##STR00011##

(23) In the compound bis(2-alkyl)amine (Ma) of the above process (as depicted in the Scheme-I) wherein, X is a leaving group selected from halogen such as Cl, Br, I or O-Mesyl (OMs), O-tosyl (OTs); and R is H or a protecting group selected from carbonyl, acyl, sulfonyl, sulfenyl, silyl, benzyl, butyloxycarbonyl (Boc) or ethoxycarbonyl.

(24) In an embodiment, the reaction is performed at a temperature ranging between 80-180 C., preferably 100-150 C.

(25) The cyclic amide solvent used in the step-(1) of the above process (as depicted in the Scheme-I) is selected from the group consisting of N-methyl-2-pyrrolidone, caprolactam, 2-piperidinone, azetidin-2-one, N-methyl caprolactame, 1-methylpiperidin-2-one and 1-methylazetidin-2-one; or a mixture thereof.

(26) In an embodiment, the amide solvent used in step-(1) of the above process (as depicted in the Scheme-I) is N-methyl-2-pyrrolidone (NMP).

(27) 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.

(28) 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.

(29) In an embodiment, the term deprotection refers to the process step involving removal of N-protecting group. In general, the deprotection is achieved by the treatment of the N-protected compound with an acid or other deprotecting agent. For instance, when the protecting group is butyloxycarbonyl (Boc); the deprotection is achieved at the step involving formation of acid addition salt.

(30) Similarly, the process of the present invention as per the specific embodiment described above is illustrated in the following Scheme-II,

(31) ##STR00012##

(32) The process of the present invention as illustrated in the above Scheme-II comprises reaction of 2-((2,4-dimethylphenyl)thio)aniline the compound (II) with bis(2-chloroethyl)amine hydrochloride the compound (III) in a cyclic amide solvent such as N-methyl-2-pyrrolidone (NMP) at a temperature of 120-130 C., to provide vortioxetine hydrochloride with about 70% yield and a purity of at least 99% HPLC purity.

(33) The term about in reference to the yield means a range of +5% of the specified yield.

(34) It is evident from the processes reported in the prior art that the vortioxetine was obtained with low yield of about 53%; whereas the process of the present invention provided the pure vortioxetine in a yield of about 70% and purity of at least 99% (HPLC). It is further evident that the prior art process refers the use of various reagents and coupling agents such as acid binding agent, metal catalyst or a phosphine ligand; which are avoided in the currently presented improved process. This amounts to a significant advantage over the processes reported in the prior art.

(35) Advantageously, the above identified elements of the process of the instant invention effectively contribute to the reduction of overall cost of the process.

(36) In another aspect, there is provided Vortioxetine (I) hydrobromide having particle size distribution range of d (10) of about less than 12 m, d (50) of about less than 40 m or d (90) of about less than 180 m; or any combination thereof.

(37) In another aspect, there is provided Vortioxetine (I) hydrobromide having particle size distribution range of d (10) of between about 5 m to about 12 m.

(38) In another aspect, there is provided Vortioxetine (I) hydrobromide having particle size distribution range of d (50) of between about 30 m to about 40 m.

(39) In another aspect, there is provided Vortioxetine (I) hydrobromide having particle size distribution range of d (90) of between about 80 m to about 180 m.

(40) The term about in reference to the particle size distribution range means a range of +5 m of the specified d(10), d(50) or d(90) particle size.

(41) The following Table-1 indicates the particle size range of Vortioxetine (I) hydrobromide as observed by the inventors:

(42) TABLE-US-00001 TABLE 1 Batch .No D(10) m D(50) m D(90) m A 10 36 100 B 9 33 109 C 11 35 176

(43) The above particle size ranges were observed when measured by Malvern Mastersizer particle size analyzer equipped with a 30 mm lens Mastersizer 3000, hydroSM. In general, the particle size distribution may be achieved by the process of the present invention or alternatively by any one of the known methods reported in the art like milling, micronization, grinding or sieving, which may reduce the particle.

(44) In another aspect, there is provided Vortioxetine (I) hydrobromide having particle size distribution range of d(10) between about 5 m to about 12 m, d(50) between about 30 m to about 40 m or d(90) between about 80 m to about 180 m; or any combination thereof.

(45) In another aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of Vortioxetine (I) hydrobromide having particle size distribution range of d (10) of about less than 12 m, d (50) of about less than 40 m or d (90) of about less than 180 m; or any combination thereof.

(46) In another aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of Vortioxetine (I) hydrobromide having particle size distribution range of d(10) between about 5 m to about 12 m, d(50) between about 30 m to about 40 m or d(90) between about 80 m to about 180 m; or any combination thereof.

(47) In another aspect, there is provided Vortioxetine (I) hydrobromide having specific surface area value from 0.05 to 2 m.sup.2/g.

(48) In another aspect, there is provided Vortioxetine (I) hydrobromide having specific surface area value from 0.1 to 1 m.sup.2/g.

(49) 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 [the Compound (I).HCl]

(50) Charged 30 mL of N-methyl-2-pyrrolidone (NMP) in a flask followed by the addition of 2-((2,4-dimethylphenyl)thio)aniline (II) (10 g) and Bis(2-chloroethyl)amine hydrochloride (III) (15.6 g). The reaction mixture was heated at a temperature of 120-130 C. for 2 days. The reaction mixture was cooled to the temperature of 25-30 C., followed by the addition of water (100 mL). The obtained solid was filtered and dried under vacuum as Vortioxetine Hydrochloride [Yield 70%; Purity: 99.5% (HPLC)].

Example-2: Preparation of Vortioxetine Hydrobromide [the Compound (I).HBr]

(51) Charged 50 mL of dichloromethane in a flask followed by the addition of Vortioxetine Hydrochloride (10 g) and 50 mL of 4% sodium hydroxide solution in water. 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 110 mL of isopropyl acetate and Hydrobromic acid (5.65 g) solution in water. The reaction mixture was stirred and filtered to provide Vortioxetine Hydrobromide [Yield 88%; Purity: 99.9% (HPLC)].