PROCESS FOR THE SYNTHESIS OF VORTIOXETINE

Abstract

The present invention relates to a process for the synthesis of Vortioxetine (I) or a pharmaceutically acceptable salt thereof. This process is accomplished by using a catalytic system consisting of a copper salt and an organic ligand, which can promote the formation of both C—N and C—S bond in one-pot, giving rise to an efficient, simple and industrially viable synthetic route for Vortioxetine.

Claims

1. A catalyst system, which comprises a copper catalyst and a ligand, and the ligand is selected from a compound of formula (II), ##STR00022## Wherein R is selected from any alkyl and substituted/unsubstituted aryl groups. Preferably, R is selected from methyl, ethyl, propyl, isopropyl, tertbutyl; and substituted/unsubstituted anthracenyl, fluorenyl, indanyl, indenyl, naphthyl, and phenyl groups.

2. The catalyst system of claim 1, wherein the copper catalyst is selected from CuI, CuCl, CuBr, Cu.sub.2O, Cu(acac).sub.2 CuCl.sub.2, CuBr.sub.2, CuI.sub.2, Cu(OAc).sub.2, Cu(OTf).sub.2, Cu(ClO.sub.4).sub.2, and CuSO.sub.4.

3. The catalyst system of claim 1, wherein the ligand is selected from the following structures (L1-L10): ##STR00023## ##STR00024##

4. A method for manufacturing Vortioxetine (I), ##STR00025## which comprises the reaction of 1,2-dihalobenzene, 2,4-dimethylbenzenethiol and piperazine in the presence of a base, a copper catalyst and a ligand according to claim 1 ##STR00026## wherein X and Y are selected from the group consisting of —Cl, —Br, and —I.

5. The method of claim 4, wherein the base is selected from any organic and inorganic base such as TEA, DBU, DIPEA, KOH, K.sub.2CO.sub.3, NaOH, Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3, CsOH, K.sub.3PO.sub.4, K.sub.2HPO.sub.4, Na.sub.3PO.sub.4, and Na.sub.2HPO.sub.4.

6. The method of claim 4, wherein all the reactions are carried out in one-pot.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present application is based on the discovery of a novel, alternative approach to synthesizing Vortioxetine. The synthesis described herein allows for the cost-effective preparation of Vortioxetine by reducing production time and cost.

##STR00006##

[0016] This approach provides a step-economical method for the low cost production of Vortioxetine. In order to realize a strategy based on cheap, readily available chemical inputs, step economy, and overall efficiency, novel copper catalytic system are relied on to promote the formation of both C—S and C—N bonds in one-pot reaction.

[0017] In one aspect, a synthetic method is provided as outlined below:

##STR00007##

[0018] The synthesis is accomplished by the coupling of 1,2-dihalobenzene, 2,4-dimethylbenzenethiol and piperazine in the presence of a base, a copper catalyst and a ligand to form Vortioxetine in one-pot reaction.

[0019] For the structure of 1,2-dihalobenzene, X and Y are selected from the group consisting of —CI, —Br, and —I.

[0020] The base herein is selected from any organic and inorganic base such as TEA, DBU, DIPEA, KOH, K.sub.2CO.sub.3, NaOH, Na.sub.2CO.sub.3, Cs.sub.2CO.sub.3, CsOH, K.sub.3PO.sub.4, K.sub.2HPO.sub.4, Na.sub.3PO.sub.4, and Na.sub.2HPO.sub.4. Example copper catalysts include CuI, CuCl, CuBr, Cu.sub.2O, Cu(acac).sub.2 CuCl.sub.2, CuBr.sub.2, Cult, Cu(OAc).sub.2, Cu(OTf).sub.2, Cu(ClO.sub.4).sub.2, and CuSO.sub.4. The ligand is selected from compound of formula (II),

##STR00008##

Wherein R is selected from any alkyl and substituted/unsubstituted aryl groups. Preferably, R is selected from methyl, ethyl, propyl, isopropyl, tertbutyl; and substituted/unsubstituted anthracenyl, fluorenyl, indanyl, indenyl, naphthyl, and phenyl groups. Some examples of formula VII are listed as following (L1-L10):

##STR00009## ##STR00010##

[0021] The compound of formula (II) can be prepared by the reaction of an aldehyde, oxalohydrazide and ammonia acetate as showed in following scheme:

##STR00011##

EXAMPLE

[0022] Detailed experimental parameters suitable for the preparation of Vortioxetine according to the present invention are provided by the following examples, which are intended to be illustrative and not limiting.

[0023] Unless otherwise noted, all materials, solvents and reagents, including anhydrous solvents such as DMF and DCM, were obtained from commercial suppliers, of the best grade, and used without further purification. All reactions involving air- or moisture-sensitive compounds were performed under nitrogen or argon atmosphere, unless otherwise noted.

[0024] The .sup.1H (400 MHz) and .sup.13C NMR (100 MHz) data were recorded on Bruker AVANCE II 400 MHz spectrometer using CDCl.sub.3 or DMSO-D.sub.6 as solvent. The chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz. .sup.1H NMR spectra was recorded with tetramethylsilane (δ=0.00 ppm) as internal reference; .sup.13C NMR spectra was recorded with CDCl.sub.3 (δ=77.00 ppm) or DMSO-D.sub.6 (δ=39.5 ppm) as internal reference.

[0025] The synthesis of L1:

##STR00012##

To a solution of cyclohexanecarbaldehyde (11.2 g, 100 mmol), oxalohydrazide (6.5 g, 55 mmol), and ammonia acetate (8.5 g, 110 mmol) in methanol (200 mL), was added iodine (2.5 g, 10 mmol). The reaction mixture was refluxed for 20 h before being filtered. The resulted solid was washed with methanol (50 mL) three times and ether (50 mL), then dried under vacuum to afford desired L1 as yellow solid. Yield: 12 g, 80%. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.12 (brs, 2H), 2.69-2.75 (m, 2H), 1.61-1.86 (m, 8H), 1.33-1.63 (m, 12H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 163.5, 159.3, 39.5, 33.0, 26.1, 26.4. ESI-TOF-HRMS calculated for C.sub.16H.sub.24N.sub.6Na (M+Na) 323.1960, found 323.1924.

[0026] The synthesis of L5:

##STR00013##

To a solution of 2-phenylacetaldehyde (12 g, 100 mmol), oxalohydrazide (6.5 g, 55 mmol), and ammonia acetate (8.5 g, 110 mmol) in methanol (200 mL), was added iodine (2.5 g, 10 mmol). The reaction mixture was refluxed for 17 h before being filtered. The resulted solid was washed with methanol (50 mL) three times and ether (50 mL), then dried under vacuum to afford desired L5 as yellow solid. Yield: 12 g, 76%. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.12 (brs, 2H), 7.26-7.30 (m, 4H), 7.18-7.25 (m, 6H), 4.02 (s, 4H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 163.5, 159.6, 136.5, 129.1, 128.6, 125.5, 34.2. ESI-TOF-HRMS calculated for C.sub.18H.sub.16N.sub.6Na (M+Na) 339.1329, found 339.1313.

[0027] The synthesis of L6:

##STR00014##

[0028] To a solution of benzaldehyde (10.6 g, 100 mmol), oxalohydrazide (6.5 g, 55 mmol), and ammonia acetate (8.5 g, 110 mmol) in methanol (200 mL), was added iodine (2.5 g, 10 mmol). The reaction mixture was refluxed for 18 h before being filtered. The resulted solid was washed with methanol (50 mL) three times and ether (50 mL), then dried under vacuum to afford desired L6 as yellow solid. Yield: 11 g, 77%. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.12 (brs, 2H), 8.05-8.09 (m, 4H), 7.43-7.51 (m, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 163.5, 157.6, 132.5, 131.1, 129.2, 127.5. ESI-TOF-HRMS calculated for C.sub.16H.sub.12N.sub.6Na (M+Na) 311.1021, found 311.1003.

[0029] The synthesis of L7:

##STR00015##

To a solution of benzaldehyde (14.8 g, 100 mmol), oxalohydrazide (6.5 g, 55 mmol), and ammonia acetate (8.5 g, 110 mmol) in methanol (200 mL), was added iodine (2.5 g, 10 mmol). The reaction mixture was refluxed for 24 h before being filtered. The resulted solid was washed with methanol (50 mL) three times and ether (50 mL), then dried under vacuum to afford desired L7 as yellow solid. Yield: 12 g, 65%. .sup.1H NMR (400 MHz, CDCl.sub.3) δ 11.12 (brs, 2H), 7.01 (s, 4H), 2.57 (s, 12H), 2.48 (s, 6H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 163.5, 157.6, 138.2, 136.1, 128.2, 122.5, 21.9, 19.3. ESI-TOF-HRMS calculated for C.sub.22H.sub.24N.sub.6Na (M+Na) 395.1960, found 395.1932.

[0030] The synthesis of Vortioxetine and its salt with 1,2-diiodobenzene and L1:

##STR00016##

To a solution of 1,2-diiodobenzene (33.0 g, 100 mmol), 2,4-dimethylbenzenethiol (15.2 g, 110 mmol), piperazine (9.5 g, 110 mmol) and K.sub.3PO.sub.4 (23.3 g, 110 mmol) in DMF (100 mL), was added CuI (1.9 g, 10 mmol) and L1 (3 g, 10 mmol). The reaction mixture was stirred at 100° C. for 10 h before being partitioned between ethyl acetate (300 mL) and water (100 mL). The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuum to give a crude product of Vortioxetine, which was purified by being converted to Vortioxetine hydrobromide (Vortioxetine•HBr). The crude product of Vortioxetine was dissolved in acetone (150 mL), then aqueous hydrobromic acid was added at room temperature, the pH of the solution was adjusted to 1-3, leading to the precipitation of white solid which was filtered and washed with acetone (30 mL), dried under vacuum to afford Vortioxetine•HBr as white solid. Yield: 28 g, 74%.

[0031] The synthesis of Vortioxetine and its salt with 1,2-dibromobenzene and L5:

##STR00017##

To a solution of 1,2-dibromobenzene (23.3 g, 100 mmol), 2,4-dimethylbenzenethiol (15.2 g, 110 mmol), piperazine (9.5 g, 110 mmol) and K.sub.3PO.sub.4 (23.3 g, 110 mmol) in DMF (100 mL), was added CuI (1.9 g, 10 mmol) and L5 (3.1 g, 10 mmol). The reaction mixture was stirred at 110° C. for 11 h before being partitioned between ethyl acetate (300 mL) and water (100 mL). The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuum to give a crude product of Vortioxetine, which was purified by being converted to Vortioxetine hydrobromide (Vortioxetine•HBr). The crude product of Vortioxetine was dissolved in acetone (150 mL), then aqueous hydrobromic acid was added at room temperature, the pH of the solution was adjusted to 1-3, leading to the precipitation of white solid which was filtered and washed with acetone (30 mL), dried under vacuum to afford Vortioxetine•HBr as white solid. Yield: 27 g, 71%.

[0032] The synthesis of Vortioxetine and its salt with 1,2-dichlorobenzene and L6:

##STR00018##

To a solution of 1,2-dichlorobenzene (14.6 g, 100 mmol), 2,4-dimethylbenzenethiol (15.2 g, 110 mmol), piperazine (9.5 g, 110 mmol) and K.sub.2CO.sub.3 (15.2 g, 110 mmol) in DMSO (100 mL), was added Cu(OTf).sub.2 (3.6 g, 10 mmol) and L6 (2.9 g, 10 mmol). The reaction mixture was stirred at 120° C. for 12 h before being partitioned between ethyl acetate (300 mL) and water (100 mL). The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuum to give a crude product of Vortioxetine, which was purified by being converted to Vortioxetine hydrobromide (Vortioxetine•HBr). The crude product of Vortioxetine was dissolved in acetone (150 mL), then aqueous hydrobromic acid was added at room temperature, the pH of the solution was adjusted to 1-3, leading to the precipitation of white solid which was filtered and washed with acetone (30 mL), dried under vacuum to afford Vortioxetine•HBr as white solid. Yield: 29 g, 77%.

[0033] The synthesis of Vortioxetine and its salt with 1-bromo-2-chlorobenzene and L6:

##STR00019##

To a solution of 1-bromo-2-chlorobenzene (19.0 g, 100 mmol), 2,4-dimethylbenzenethiol (15.2 g, 110 mmol), piperazine (9.5 g, 110 mmol) and Cs.sub.2CO.sub.3 (35.8 g, 110 mmol) in DMSO (100 mL), was added Cu(acac).sub.2 (2.6 g, 10 mmol) and L6 (2.9 g, 10 mmol). The reaction mixture was stirred at 110° C. for 10 h before being partitioned between ethyl acetate (300 mL) and water (100 mL). The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuum to give a crude product of Vortioxetine, which was purified by being converted to Vortioxetine hydrobromide (Vortioxetine•HBr). The crude product of Vortioxetine was dissolved in acetone (150 mL), then aqueous hydrobromic acid was added at room temperature, the pH of the solution was adjusted to 1-3, leading to the precipitation of white solid which was filtered and washed with acetone (30 mL), dried under vacuum to afford Vortioxetine•HBr as white solid. Yield: 28 g, 74%.

[0034] The synthesis of Vortioxetine and its salt with 1-chloro-2-iodobenzene and L7:

##STR00020##

To a solution of 1-chloro-2-iodobenzene (23.8 g, 100 mmol), 2,4-dimethylbenzenethiol (15.2 g, 110 mmol), piperazine (9.5 g, 110 mmol) and K.sub.2CO.sub.3 (15.2 g, 110 mmol) in CH.sub.3CN (100 mL), was added CuCl (1.0 g, 10 mmol) and L7 (3.7 g, 10 mmol). The reaction mixture was stirred at 110° C. for 10 h before being partitioned between ethyl acetate (300 mL) and water (100 mL). The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuum to give a crude product of Vortioxetine, which was purified by being converted to Vortioxetine hydrobromide (Vortioxetine•HBr). The crude product of Vortioxetine was dissolved in acetone (150 mL), then aqueous hydrobromic acid was added at room temperature, the pH of the solution was adjusted to 1-3, leading to the precipitation of white solid which was filtered and washed with acetone (30 mL), dried under vacuum to afford Vortioxetine•HBr as white solid. Yield: 26.5 g, 70%.

[0035] The synthesis of Vortioxetine and its salt with 1-bromo-2-iodobenzene and L5:

##STR00021##

To a solution of 1-bromo-2-iodobenzene (28.2 g, 100 mmol), 2,4-dimethylbenzenethiol (15.2 g, 110 mmol), piperazine (9.5 g, 110 mmol) and K.sub.2CO.sub.3 (15.2 g, 110 mmol) in DMF (100 mL), was added CuCl (1.0 g, 10 mmol) and L5 (3.1 g, 10 mmol). The reaction mixture was stirred at 100° C. for 9 h before being partitioned between ethyl acetate (300 mL) and water (100 mL). The combined organics were dried over MgSO.sub.4, filtered and concentrated in vacuum to give a crude product of Vortioxetine, which was purified by being converted to Vortioxetine hydrobromide (Vortioxetine•HBr). The crude product of Vortioxetine was dissolved in acetone (150 mL), then aqueous hydrobromic acid was added at room temperature, the pH of the solution was adjusted to 1-3, leading to the precipitation of white solid which was filtered and washed with acetone (30 mL), dried under vacuum to afford Vortioxetine•HBr as white solid. Yield: 29 g, 77%.
Vortioxetine•HBr obtained from above examples has the following characteristics:
.sup.1H NMR (d.sub.6-DMSO, 400 MHz): 7.40 (m, 1H), 7.14 (m, 3H), 7.06 (m, 1H), 6.87(m, 2H), 3.13(br, 8H), 2.41 (s, 3H), 2.38(s, 3H). ESI-TOF-HRMS calculated for C.sub.18H.sub.23N.sub.2S.sup.+(Vortioxetine+H.sup.+) 299.1576, found 299.1543.