Method for producing vortioxetine

Abstract

To provide a method for efficiently producing high-quality vortioxetine, specifically a method for producing vortioxetine with reduced formation of impurity VOR-PP and a fast reaction process.SOLUTION: A method for producing vortioxetine comprises a step of reacting 1-bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine in a solvent in the presence of a base, a palladium reagent, and tol-BINAP or xyl-BINAP, at a reaction temperature of 60°C to 120°C.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to an industrial production method of vortioxetine useful for the treatment of depressive symptoms.

Background Art

[0002] The following formula (1)

Chemical formula

[0003] For example, in Patent Document 1, a method for producing vortioxetine is reported in which 1-bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine are reacted in a solvent in the presence of a base and a palladium catalyst (a palladium reagent and a phosphine ligand (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthylene (hereinafter referred to as "rac-BINAP")). This method consists of a first reaction in which 1-bromo-2-iodobenzene and 2,4-dimethylbenzenethiol are condensed to convert to 1-(2-bromophenylsulfanyl)-2,4-dimethylbenzene (hereinafter referred to as "bromo intermediate") (7), and a second reaction in which the bromo intermediate and piperazine are condensed to convert to vortioxetine.

Chemical formula

[0004] When using rac-BINAP, it has a promoting effect on both the first reaction and the second reaction. Therefore, after the first reaction is completed, without isolating the bromo intermediate, it is possible to continuously add piperazine, which is the raw material for the second reaction, and react it, that is, a so-called one-pot reaction. Furthermore, interestingly, since the reaction rate of the first reaction is faster than that of the second reaction, even if piperazine, which is the raw material for the second reaction, is added and reacted in advance, voltioxetine is given as the main product. Therefore, this method can be expected to be used as an industrial production method for voltioxetine.

[0005] On the other hand, reducing the impurities contained in pharmaceuticals is very important in patient protection. The method using rac-BINAP described in Patent Document 1 by-produces many impurities, especially the following formula (8)

Chemical formula

[0006] Regarding VOR-PP, for example, Example 7 of Patent Document 2 has the following description. That is, when 1-bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine are reacted in a toluene solvent in the presence of sodium tert-butoxide, 0.4 mol% of bis(dibenzylideneacetone)palladium, and 0.8 mol% of rac-BINAP, the reaction is completed in 5 hours, but the product obtained by performing general post-treatment is described as containing 0.64% of VOR-PP. Also, in Example 4 of Patent Document 3, when 1-bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine are reacted in a toluene solvent in the presence of sodium tert-butoxide, 0.4 mol% of bis(dibenzylideneacetone)palladium, and 0.8 mol% of rac-BINAP, the reaction is completed in 6 hours, but the product obtained by performing general post-treatment is described as containing 1.1% of VOR-PP. In the method of reacting in the presence of a palladium catalyst using rac-BINAP as a ligand, it is comprehensively evaluated in Patent Document 3 (paragraph number 0008) that 0.5 to 4.8% of VOR-PP is produced.

[0007] A method for producing voltioxetine that avoids the formation of VOR-PP is described in Patent Document 3. This is a method of reacting 2-bromobenzenethiol, 2,4-dimethyl iodobenzene, and piperazine in one pot in a solvent in the presence of a base, a palladium reagent, and rac-BINAP. Compared with the method described in Patent Document 1, it produces fewer by-products of impurities, and in particular, it does not produce VOR-PP as a by-product. Therefore, it is described that the troublesome purification operation of converting the voltioxetine described in Patent Document 2 into an isopropanol solvate is unnecessary.

Chemical formula

[0008] In order to confirm the usefulness of the method reported in Patent Document 3, the present inventors conducted a reproduction experiment of Example 1 of the same document. Certainly, in the reaction, VOR-PP was not by-produced, and voltioxetine could be obtained in high yield. However, the product obtained by performing general post-treatment contained 0.6% of 1-(2,4-dimethylphenyl)piperazine represented by the following formula (9). [Chemical formula] In the reaction, 0.7% of 1-(2,4-dimethylphenyl)piperazine was by-produced, and it was difficult to remove by general post-treatment. Therefore, in order to use the product obtained by the method reported in Patent Document 3 as a pharmaceutical, a further purification step is required.

[0009] Against such a background, further improvement of the method for producing voltioxetine is desired. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] Japanese Patent No. 5763609 [Patent Document 2] Japanese Patent No. 5738774 [Patent Document 3] Japanese Patent No. 6018644 [Non-patent documents]

[0011] [Non-patent Document 1] Journal of Medicinal Chemistry, 2011, 54(9), 3206-3221 [Summary of the invention] [Problems to be solved by the invention]

[0012] The object of the present invention is to provide a method for efficiently producing high-quality volitinib. Specifically, it is an object of the present invention to provide a method for producing volitinib with a small amount of impurity VOR-PP generated and a fast reaction.

Means for Solving the Problems

[0013] The present inventors considered the production route of VOR-PP. When the reaction rate difference between the first reaction of condensing 1-bromo-2-iodobenzene and 2,4-dimethylbenzenethiol to give a bromo intermediate and the unwanted side reaction of 1-bromo-2-iodobenzene reacting with piperazine is insufficient, a large amount of 1-(2-bromophenyl)piperazine (hereinafter referred to as "BPP") (10) and 1,2-bis(piperazin-1-yl)benzene (hereinafter referred to as "DPB") (11) are by-produced. VOR-PP is converted by the condensation of BPP and volitinib or the condensation of DPB and the bromo intermediate. That is, when rac-BINAP is used as a ligand, although the first reaction is indeed prioritized, since the reaction rate difference with the unwanted side reaction is insufficient, it was considered that a large amount of VOR-PP is generated. Therefore, the present inventors found a ligand having a superior promoting effect on the first reaction than rac-BINAP and conducted intensive studies to reduce the generation of impurity VOR-PP.

Chemical formula

[0014] A ligand having an excellent promoting effect in the first reaction needs to effectively promote the second reaction of condensing piperazine to the bromo intermediate. In the second reaction, the palladium catalyst undergoes oxidative addition to the bromo intermediate, piperazine coordinates to the palladium catalyst in the presence of a base, and finally the palladium catalyst undergoes reductive elimination to give volitinib. On the other hand, when β-hydrogen elimination is prioritized, volitinib is not given, and 2,4-dimethyldiphenyl sulfide (hereinafter referred to as "reduced product") (12) is given. Therefore, first, a phosphine ligand (also referred to as a "ligand") that effectively promotes the target reaction was searched for in the condensation reaction of the bromo intermediate and piperazine. [Chem.]

[0015] The reaction was carried out using a bromo intermediate and piperazine in a toluene solvent with sodium tert-butoxide, 1 mol% of bis(dibenzylideneacetone)palladium, and 4 mol% of a phosphine ligand. In addition to rac-BINAP as the phosphine ligand, 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthalene (hereinafter referred to as "tol-BINAP"), 2,2'-bis(di-3,5-xylylphosphino)-1,1'-binaphthalene (hereinafter referred to as "xyl-BINAP"), (R)-(+)-SEGPHOS (trademark, Takasago Perfumery Co., Ltd.), SPhos, RuPhos, DavePhos, MePhos, tert-Bu-MePhos, dppf, Cy-vBRIDP (trademark, Takasago Perfumery Co., Ltd.), APhos, BrettPhos, XPhos, tert-Bu-XPhos, and Xantphos were used.

[0016]

Table 1

[0017] As shown in Table 1, the reactions using rac-BINAP, tol-BINAP, and xyl-BINAP as the phosphine ligand gave boltioxetine with high selectivity. The reaction using (R)-(+)-SEGPHOS (trademark) also gave boltioxetine preferentially, but the progress of the reaction was slow. Xantphos is described in Patent Document 1 as a ligand useful for the first reaction to synthesize the bromo intermediate, but its promoting effect on the second reaction of condensing with piperazine was slight. The other ligands gave many reduced products and were not useful for this reaction.

[0018] Next, the inventors examined a one-pot reaction using tol-BINAP and xyl-BINAP as phosphine ligands and adding piperazine, the raw material for the second reaction, in advance. 1-Bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine were reacted in a toluene solvent using sodium tert-butoxide, 0.2 mol% of bis(dibenzylideneacetone)palladium, and 0.4 mol% of a phosphine ligand. For comparison, the reaction was carried out under the same conditions using rac-BINAP.

[0019]

Table 2

[0020] As shown in Table 2, when tol-BINAP was used in the reaction, the reaction was completed within 5 hours even when the palladium reagent was reduced to 0.2 mol%, and voltioxetine was obtained with high selectivity. The reaction was also completed within 5 hours using xyl-BINAP, and voltioxetine was obtained with high selectivity. On the other hand, when rac-BINAP was used, the reaction was not completed within 5 hours, and it took approximately 20 hours for the bromo intermediate to disappear.

[0021] Furthermore, the inventors investigated the production amount of VOR-PP. It is reported in the prior literature that when rac-BINAP is used, the product contains 0.5 - 4.8% of VOR-PP. On the other hand, in the reactions using tol-BINAP and xyl-BINAP, surprisingly, despite the fast reaction rate, the production amount of VOR-PP was extremely small, and the product obtained by performing general post-treatment did not contain VOR-PP.

[0022] As a further surprising effect, after the reaction using tol-BINAP and xyl-BINAP, through general post-treatment, that is, adding water to the reaction solution to stop the reaction, separating the layers, washing the organic layer with brine, adding hydrobromic acid to the organic layer, filtering the precipitate, washing with toluene and water, and drying, high-quality voltioxetine with a total impurity content of 1.0% or less and individual impurities of 0.15% or less was obtained.

[0023] These effects indicate that since tol-BINAP and xyl-BINAP have a superior effect in promoting the first reaction of condensing 1-bromo-2-iodobenzene with 2,4-dimethylbenzenethiol compared to rac-BINAP, the generation of an undesirable group of impurities resulting from the reaction of 1-bromo-2-iodobenzene with piperazine could be effectively suppressed.

[0024] That is, the present invention is a method for producing voltioxetine represented by the following formula (1)

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0025] Also, the present invention is a method for producing voltioxetine, which comprises reacting 1-bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine in a solvent in the presence of a base, a palladium reagent, and the following formula (6)

Chemical formula

Advantages of the Invention

[0026] According to the present invention, it becomes possible to easily produce voltixetine suitable for use as a pharmaceutical raw material, in which the total amount of impurities is 1.0% or less and each individual impurity is 0.15% or less. Further, according to the present invention, in the production of voltioxetine, it becomes possible to further reduce the amount of rare palladium reagent used. Furthermore, according to the present invention, it becomes possible to provide a simple method for producing voltioxetine even when the amount of palladium reagent used is suppressed. Due to such effects of the present invention, it is possible to significantly reduce the reagents, solvents, and energy used in the production of pharmaceutical raw materials, and achieve environmental protection and energy conservation.

Brief Description of the Drawings

[0027]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Embodiments for Carrying Out the Invention

[0028] Hereinafter, the method of the present invention will be described in detail.

[0029] The present invention is a method including a step of reacting 1-bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine as raw materials in a solvent in the presence of a base and a palladium catalyst at a reaction temperature of 60°C to 120°C. In the present specification, the palladium catalyst refers to a ligand formed by using a palladium reagent and a phosphine ligand together, or a ligand composed of a palladium reagent and a phosphine ligand.

[0030] As the raw material 1-bromo-2-iodobenzene, the target product can be obtained by changing it to 1,2-dibromobenzene, but 1-bromo-2-iodobenzene is more preferable.

[0031] The raw material 2,4-dimethylbenzenethiol reacts after being converted to a thiolate in the presence of a base such as sodium tert-butoxide. Alternatively, 2,4-dimethylbenzenethiol can be used after being made into a salt with an alkali metal and an alkaline earth metal in advance.

[0032] The raw material 1-bromo-2-iodobenzene is preferably reacted in an equimolar amount with respect to 2,4-dimethylbenzenethiol. Specifically, it is preferably 0.9 equivalent or more, or 0.95 equivalent or more, and 1.1 equivalent or less, or 1.05 equivalent or less.

[0033] In the present invention, as the raw material piperazine, unprotected piperazine or a piperazine derivative in which one amino group is protected by a protecting group such as a Boc group, a Bz group, or a Cbz group can be used, but unprotected piperazine is more preferable.

[0034] The raw material piperazine can be used in an excess amount with respect to 2,4-dimethylbenzenethiol. Specifically, for example, it can be 3 equivalents or more, 4 equivalents or more, or 5 equivalents or more, and 10 equivalents or less, 9 equivalents or less, or 8 equivalents or less. When the equivalent amount of piperazine is small, the bromo intermediate condenses with borthioxetine, and the following formula (13)

Chemical formula

[0035] The solvent should be inert to the raw materials, reagents, and products, and a solvent capable of reaching the desired reaction temperature can be used. Specifically, for example, one or more selected from toluene, xylene, tetrahydrofuran, and dioxane can be used. Among them, toluene can be preferably used. The amount of the solvent is not particularly limited, but for example, it can be 5 times or more, 6 times or more, 7 times or more, 8 times or more, 9 times or more, or 10 times or more, and 20 times or less, 18 times or less, 17 times or less, or 15 times or less with respect to 2,4-dimethylbenzenethiol.

[0036] As the base, an organic base such as sodium tert-butoxide or potassium tert-butoxide, or an inorganic base such as sodium carbonate, potassium carbonate, or cesium carbonate can be used. These can be used alone or in combination. Among them, sodium tert-butoxide can be preferably used. The equivalent amount of the base is not particularly limited, but for example, it can be 2 equivalents or more, or 3 equivalents or more, and 10 equivalents or less, 9 equivalents or less, 8 equivalents or less, 7 equivalents or less, or 6 equivalents or less.

[0037] As the palladium reagent used as a reagent, bis(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)palladium, or palladium acetate can be used. These can be used alone or in combination. Among them, bis(dibenzylideneacetone)palladium or tris(dibenzylideneacetone)palladium can be preferably used. The equivalent amount of the palladium reagent is not particularly limited. For example, it can be about 1 mol% or less, or 1 mol% or less of the equivalent amount relative to the starting material 2,4-dimethylbenzenethiol. More specifically, the palladium reagent can be 1 mol% or less, 0.8 mol% or less, 0.5 mol% or less, 0.2 mol% or less, or 0.1 mol% or less relative to the starting material 2,4-dimethylbenzenethiol. Since the palladium reagent is rare and expensive, it is preferable to reduce the usage equivalent as much as possible. However, when the equivalent amount is reduced, there is a problem that the reaction rate decreases. However, in the method of the present invention, by using a specific phosphine ligand, even if the usage equivalent of the palladium reagent is reduced, it has no effect on industrial production.

[0038] As the phosphine ligand, tol-BINAP or xyl-BINAP is used. Since these ligands have atropisomerism based on rotation inhibition, there are racemates and optically active forms. In the present invention, either the racemate or the optically active form of the phosphine ligand can be used. The equivalent amount of the phosphine ligand can be about 4 mol% or less, or 4 mol% or less of the equivalent amount relative to the starting material 2,4-dimethylbenzenethiol. More specifically, in accordance with the reduction of the usage equivalent of the palladium reagent, it can be 3.2 mol% or less, 2.0 mol% or less, 0.8 mol% or less, or 0.4 mol% or less relative to 2,4-dimethylbenzenethiol.

[0039] The reaction temperature can be in the range of about 60°C to about 120°C. Or, the reaction temperature can be 60°C or higher, 65°C or higher, 70°C or higher, 75°C or higher, 80°C or higher, or 85°C or higher, and 120°C or lower, 115°C or lower, 110°C or lower, 105°C or lower, 100°C or lower, or 95°C or lower. When the reaction temperature is high, the time until the reaction is completed can be shortened, but the reaction selectivity decreases and impurities increase. Also, when using unprotected piperazine as a raw material, since unprotected piperazine has sublimability, it is preferable to avoid a long reaction time at a high temperature.

[0040] The reaction can be terminated at an optimal time by observing the residues of 2,4-dimethylbenzenethiol and the bromo intermediate using analytical methods such as thin-layer chromatography or high-performance liquid chromatography. The reaction termination time depends on the type of phosphine ligand of the palladium catalyst used, the usage equivalents of the palladium reagent and the phosphine ligand, and the reaction temperature. For example, when using 0.2 mol% of bis(dibenzylideneacetone)palladium as the palladium reagent and 0.4 mol% of tol-BINAP as the phosphine ligand and reacting at 88°C, the raw materials and intermediates are consumed to 1% or less within 5 hours.

[0041] As the reaction proceeds, salts that are presumably sodium iodide and sodium bromide are by-produced. Since these salts do not dissolve in the reaction solvent, the amount of the by-product precipitate increases as the reaction progresses. When tol-BINAP or xyl-BINAP is used as the phosphine ligand in the reaction, the reaction is fast, so the precipitation of these salts also becomes fast, and the reaction solution can maintain a good slurry state. On the other hand, when rac-BINAP is used as the phosphine ligand in the reaction, since the reaction is slow, the catalyst equivalent needs to be reduced to 0.2 mol% or the reaction temperature needs to be set low, for example, about 88 °C, for impurity suppression, and it takes a long time (for example, about 20 hours) to complete the reaction. At this time, the salts precipitated at the initial stage of the reaction adhere to the wall of the reaction vessel, the shaft of the stirring device, the thermometer, etc., and as the reaction progresses, the precipitate grows locally and greatly starting from these deposits. For this reason, unreacted raw materials and catalysts are incorporated into large lumps of the precipitate, and there may be places where the reaction does not proceed as intended, resulting in an increase in impurities. Also, when large lumps of the precipitate break off during stirring, there is a risk of damaging the reaction vessel, the stirring device, the instruments, etc. From such a perspective, it is preferable to complete the reaction in a short time of about 5 hours.

[0042] Generally, a palladium catalyst loses its function of promoting the reaction in the presence of oxygen. As a countermeasure, it is effective to remove oxygen in advance from the raw materials, reagents, and solvents used in the reaction. Also, when charging the raw materials into the reaction vessel, air may flow into the reaction vessel. Therefore, an operation of depressurizing the reaction vessel after charging the raw materials and then repressurizing with an inert gas such as nitrogen or argon is effective. Also, there is a possibility that air may flow in from the sliding part of the stirring device or the opening of the reflux device during the reaction. As a countermeasure, it is also effective to continuously supply an inert gas such as nitrogen or argon to the reaction vessel and make the reaction vessel slightly positively pressurized.

[0043] After the reaction is completed, a post-treatment step for isolating voltiopexetine may further be included. In the post-treatment step, the reaction solution is cooled, water is added to stop the reaction, and excess reagents and by-produced salts are dissolved. Subsequently, the aqueous layer is separated, and the organic layer is washed several times with brine. An acid that forms a salt with the free base of voltiopexetine is added to this organic layer to precipitate voltiopexetine in the salt form. As the acid, for example, hydrochloric acid, hydrobromic acid, maleic acid, etc. can be used. Further, the precipitate and the mother liquor are separated, the precipitate is washed with an organic solvent or water to wash away the mother liquor, and then dried to obtain voltiopexetine.

[0044] When using a metal catalyst such as palladium, the catalyst metal may be mixed into the target product. In such a case, a treatment of contacting with a resin or silica gel modified with a functional group that captures the metal may further be performed. For capturing palladium, silica gel modified with a thiol group, for example, mercaptopropyl silica gel, is effective. Also in the present invention, in the solution stage before adding the acid, mercaptopropyl silica gel is added and stirred for a short time, and then the silica gel is filtered off, whereby palladium can be effectively removed from the solution containing voltiopexetine. When the used equivalent amount of the palladium reagent is large, a large amount of such special silica gel is required. However, in the present invention, by using tol-BINAP or xyl-BINAP as the phosphine ligand, the used equivalent amount of the palladium reagent can be reduced. Therefore, even when palladium capture is required, the amount of silica gel modified with a thiol group, for example, mercaptopropyl silica gel, used can be reduced compared to the conventional method.

Examples

[0045] The present invention will be described below with specific embodiments, but the present invention is not limited to those embodiments, and various changes and modifications therein can be implemented by those skilled in the art without departing from the scope or spirit of the present invention defined in the appended claims.

[0046] The HPLC method was used to observe the progress of the reaction and evaluate the quality of the product. For the structural confirmation of the product, the NMR method, powder X-ray diffraction method, and thermal analysis method were used. The measurement conditions are shown below.

[0047] HPLC test conditions Apparatus: High Performance Liquid Chromatography LC-20A manufactured by Shimadzu Corporation Detector: Ultraviolet Absorbance Photometer (measurement wavelength: 254 nm) Column: SunShell C18, φ4.6 mm × 100 mm, 2.6 μm (ChromaNik Technologies Inc.) Column temperature: Constant temperature around 40 °C Mobile phase A: 0.05 wt% trifluoroacetic acid aqueous solution Mobile phase B: Acetonitrile Liquid delivery of the mobile phase: The concentration gradient control is performed by changing the mixing ratio of mobile phase A and mobile phase B as follows

Table 3

[0048]

Table 4

[0049] “PP” represents 1-phenylpiperazine (14) shown by the following formula (14)

Chemical formula

[0050] NMR test conditions Apparatus: JNM-ECS400 manufactured by JEOL RESONANCE, Ltd. Method: 4 mg of the product was dissolved in approximately 1 mL of deuterated dimethyl sulfoxide, and the 1H NMR spectrum was measured using tetramethylsilane as an internal standard. 1 Data description: The following abbreviations were used. That is, singlet was abbreviated as s, doublet as d, triplet as t, multiplet as m, and broad as b.

[0051] Powder X-ray diffraction test conditions Apparatus: MiniFlex manufactured by Rigaku Corporation Method: Wavelength CuKα characteristic X-ray, detector D / teX Ultra, scan speed 10 deg / min, step width 0.02 deg, scan axis 2θ / θ, scan range 2 - 45 deg

[0052] Thermal analysis test conditions Apparatus: Thermo plus EVO2 DSC manufactured by Rigaku Corporation Method: Approximately 5 mg of the sample, reference Al 2 O 3 , container aluminum pan, nitrogen atmosphere, heating rate 20 °C / min

[0053] (Example 1) Synthesis of voltioxetine hydrobromide: 0.2 mol% of palladium reagent, 0.8 mol% of tol-BINAP ​151.5 g (1.58 mol) of sodium tert-butoxide, 186.5 g (2.17 mol) of piperazine, and 450 mL of toluene were placed in a dried reaction vessel and stirred at room temperature for 1 hour. Subsequently, 0.42 g (0.73 mmol) of bis(dibenzylideneacetone)palladium, 1.96 g (2.89 mmol) of (R)-(+)-tol-BINAP, and 10 mL of toluene were added and stirred at room temperature for 30 minutes. Further, 50.0 g (0.36 mol) of 2,4-dimethylbenzenethiol, 102.3 g (0.36 mol) of 1-bromo-2-iodobenzene, and 250 mL of toluene were added, and the mixture was heated in an oil bath set at 102 °C. After the internal temperature reached 88 °C, it was stirred in the range of 88 °C to 102 °C for 5 hours. The reaction solution was sampled, and it was confirmed by HPLC that the bromo intermediate was 0.3 HPLC area%. Heating was stopped, 500 mL of water was added, and the mixture was stirred overnight and then separated. The aqueous layer was extracted twice with 50 mL of toluene. The organic layers were combined and washed three times with 100 mL of water and three times with 100 mL of 15% brine. 42 mL (0.37 mol) of 48% hydrobromic acid was added to the obtained organic layer, and the mixture was heated to 75 °C, then allowed to cool and stirred overnight at room temperature. The precipitated solid was filtered, washed with 300 mL of toluene and 200 mL of water, and dried under reduced pressure at 50 °C to obtain 124.8 g of voltioxetine hydrobromide (yield 91%, HPLC purity 99.6%, VOR-PP not detected, β-form crystal (see Figure 1 - PXRD chart, Figure 2 - DSC chart)). 1 H NMR (DMSO-d6) δ = 2.25 (s, 3H), 2.33 (s, 3H), 3.20 - 3.26 (m, 8H), 6.42 (dd, 1H), 6.97 (dt, 1H), 7.10 - 7.19 (m, 3H), 7.26 (s, 1H), 7.34 (d, 1H), 8.82 (b, 2H)

[0054] (Example 2) Synthesis of voltioxetine maleate: 0.2 mol% of palladium reagent, 0.8 mol% of tol-BINAP 136.1 g (1.42 mol) of sodium tert-butoxide, 181.0 g (2.10 mol) of piperazine, and 300 mL of toluene were placed in a dried reaction vessel and stirred at room temperature for 20 minutes. Subsequently, 0.42 g (0.73 mmol) of bis(dibenzylideneacetone)palladium, 1.96 g (2.89 mmol) of (R)-(+)-tol-BINAP, and 50 mL of toluene were added, and the mixture was stirred at room temperature for 40 minutes. Further, 102.3 g (0.36 mol) of 1-bromo-2-iodobenzene was added and washed in with 1000 mL of toluene, and a solution of 50.0 g (0.36 mol) of 2,4-dimethylbenzenethiol diluted with 70 mL of toluene was added dropwise over 1 hour and washed in with 100 mL of toluene. Subsequently, the mixture was heated in an oil bath set at 95°C, and after the internal temperature reached 88°C, it was stirred in the range of 88°C to 92°C for 5 hours. The reaction solution was sampled, and it was confirmed by HPLC that the bromo intermediate was 0.2 HPLC area%. Heating was stopped, 800 mL of water was added, and after stirring for 1 hour, the layers were separated, and the aqueous layer was extracted twice with 50 mL of toluene. The organic layers were combined and washed three times with 150 mL of 15% brine. 0.1 g of mercaptopropylsilica gel and 0.1 g of activated carbon were added to the obtained organic layer, and after stirring at room temperature for 1 hour, they were filtered off. To this filtrate, 43.3 g (0.37 mol) of maleic acid dissolved in 60 mL of water was added, heated to 65°C, then allowed to cool, and stirred overnight at room temperature. The precipitated solid was filtered, washed with 500 mL of toluene and 200 mL of water, and dried under reduced pressure at 50°C to obtain 138.5 g of voltioxetine maleate (yield 92%, HPLC purity 99.9%, VOR-PP not detected, hydrate crystals (see Figure 3 - PXRD chart, Figure 4 - DSC chart)). 1 H NMR (DMSO-d6) δ = 2.20 (s, 3H), 2.29 (s, 3H), 3.13 - 3.22 (m, 8H), 5.98 - 5.99 (m, 2H), 6.36 (dd, 1H), 6.93 (dt, 1H), 7.06 - 7.14 (m, 3H), 7.21 (s, 1H), 7.30 (d, 1H), 8.64 (b, 2H)

[0055] (Example 3) Synthesis of voltioxetine hydrochloride: 0.2 mol% of palladium reagent, 0.4 mol% of tol-BINAP Into a dried reaction vessel, 135.8 g (1.41 mol) of sodium tert-butoxide, 180.8 g (2.10 mol) of piperazine, 0.42 g (0.73 mmol) of bis(dibenzylideneacetone)palladium, 0.98 g (1.44 mmol) of (R)-(+)-tol-BINAP, and 300 mL of toluene were added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 102.3 g (0.36 mol) of 1-bromo-2-iodobenzene was added and washed in with 200 mL of toluene, and further diluted with 70 mL of toluene. A solution of 50.0 g (0.36 mol) of 2,4-dimethylbenzenethiol was added dropwise over 1 hour and washed in with 80 mL of toluene. The mixture was heated in an oil bath set at 95 °C, and after the internal temperature reached 88 °C, it was stirred in the range of 85 °C to 88 °C for 5 hours. The reaction solution was sampled, and it was confirmed by HPLC that the bromo intermediate was 0.1 HPLC area%. Heating was stopped, 300 mL of water was added, and the mixture was stirred for 1 hour and then separated. The organic layer was washed 3 times with 150 mL of 15% brine. 1.0 g of mercaptopropyl silica gel and 1.0 g of activated carbon were added to the obtained organic layer, and the mixture was stirred at room temperature for 1 hour and then filtered off. The filtrate was heated to 70 °C, 31 mL (0.35 mol) of concentrated hydrochloric acid was added, and the mixture was allowed to cool and stirred overnight at room temperature. The precipitated solid was filtered, washed with 500 mL of toluene and 200 mL of water, and dried under reduced pressure at 50 °C to obtain 104.1 g of voltioxetine hydrochloride (yield 81%, HPLC purity 99.9%, VOR-PP not detected). 1 H NMR (DMSO-d6) δ = 2.25 (s, 3H), 2.33 (s, 3H), 3.21 - 3.22 (m, 8H), 6.41 (dd, 1H), 6.98 (dt, 1H), 7.10 - 7.17 (m, 3H), 7.25 (s, 1H), 7.34 (d, 1H), 9.17 (b, 2H)

[0056] (Example 4) Synthesis of voltioxetine hydrochloride: 0.2 mol% of palladium reagent, 0.4 mol% of tol-BINAP 677.8 g (7.05 mol) of sodium tert-butoxide and 903.6 g (10.49 mol) of piperazine were placed in a dried reaction vessel and purged with nitrogen. Subsequently, 1000 mL of toluene was added and the mixture was purged with nitrogen while stirring. Subsequently, 2.08 g (3.62 mmol) of bis(dibenzylideneacetone)palladium, 4.91 g (7.23 mmol) of (R)-(+)-tol-BINAP, and 500 mL of toluene were added and the mixture was stirred at room temperature for 0.5 hour. Further, 511.7 g (1.81 mol) of 1-bromo-2-iodobenzene was added and washed in with 1000 mL of toluene, and a solution of 250.0 g (1.81 mol) of 2,4-dimethylbenzenethiol diluted with 500 mL of toluene was added dropwise over 0.5 hour and washed in with 250 mL of toluene. The mixture was heated in an oil bath set at 100 °C, and after the internal temperature reached 88 °C, it was stirred in the range of 88 °C to 94 °C for 5 hours. The reaction solution was sampled, and it was confirmed by HPLC that the bromo intermediate was 0.1 HPLC area%, and heating was stopped. 2500 mL of water was added and the mixture was stirred, then separated, and the organic layer was washed three times with 370 mL of 15% brine. 5.0 g of mercaptopropyl silica gel and 5.0 g of activated carbon were added to the obtained organic layer, and the mixture was stirred at room temperature for 1.5 hours, then filtered off and washed in with 250 mL of toluene. The filtrate was heated to 60 °C, 196.3 g (1.84 mol) of concentrated hydrochloric acid was added, and the mixture was allowed to cool and stirred overnight at room temperature. The precipitated solid was filtered, washed with 2300 mL of toluene and 1000 mL of water, and dried under reduced pressure at 50 °C to obtain 509.0 g of the hydrochloride salt of voltioxetine (yield 80%, HPLC purity 99.9%, not detected by VOR-PP, hydrate crystals (see Figure 5 - PXRD chart, Figure 6 - DSC chart)).

[0057] (Example 5) Synthesis of voltioxetine hydrochloride: 0.2 mol% of palladium reagent, 0.4 mol% of xyl-BINAP To a dried reaction vessel were added 136.3 g (1.42 mol) of sodium tert-butoxide, 180.8 g (2.10 mol) of piperazine, 0.42 g (0.73 mmol) of bis(dibenzylideneacetone)palladium, 1.07 g (1.46 mmol) of (R)-(+)-xyl-BINAP, and 300 mL of toluene, and the mixture was stirred at room temperature for 0.5 hour. Subsequently, 102.3 g (0.36 mol) of 1-bromo-2-iodobenzene was added, rinsed with 200 mL of toluene, and further diluted with 70 mL of toluene. A solution of 50.0 g (0.36 mol) of 2,4-dimethylbenzenethiol was added dropwise over 0.5 hour, and rinsed with 80 mL of toluene. After heating in an oil bath set at 94 °C and reaching an internal temperature of 88 °C, the mixture was stirred for 5 hours in the range of 85 °C to 92 °C of the internal temperature. The reaction solution was sampled, and it was confirmed by HPLC that the bromo intermediate was 0.0 HPLC area%. Heating was stopped, 400 mL of water was added, and the mixture was stirred for 0.5 hour and then separated. The organic layer was washed three times with 150 mL of 15% brine. To the obtained organic layer were added 1.0 g of mercaptopropyl silica gel and 1.0 g of activated carbon, and the mixture was stirred at room temperature for 2.5 hours and then filtered. The filtrate was heated to 60 °C, 34.5 mL (0.39 mol) of concentrated hydrochloric acid was added, and the mixture was allowed to cool and stirred overnight at room temperature. The precipitated solid was filtered, washed with 500 mL of toluene and 200 mL of water, and dried under reduced pressure at 50 °C to obtain 96.5 g of voltioxetine hydrochloride (yield 76%, HPLC purity 99.9%, VOR-PP not detected).

[0058] Regarding the above examples, the HPLC test results of the reaction solution and the product, etc. are summarized in Table 5. Comparative Example 1 is Example 4 of Patent Document 3 (Patent No. 6018644), and Comparative Example 2 is Example 1 of the same document.

[0059]

Table 5

[0060] When the production method of the present invention is used, the amount of VOR-PP produced is less compared with the prior art, and a product (voltioxetine) with good quality can be obtained.

Industrial Applicability

[0061] According to the present invention, it is possible to provide a simple method for producing voltixetine that greatly suppresses the generation of impurities compared to conventional methods and shortens or omits the purification process. Further, according to the present invention, it is possible to provide a method for producing voltixetine that is industrially advantageous in terms of simplicity even when the amount of rare palladium reagent used is suppressed. Furthermore, according to the present invention, it is possible to provide a method for producing a pharmaceutical raw material that is environmentally friendly and contributes to the realization of a sustainable society by suppressing reagents, solvents, and energy.

Claims

1. A method for producing voltioxetine represented by the following formula (1), comprising reacting 1-bromo-2-iodobenzene represented by the following formula (2), 2,4-dimethylbenzenethiol represented by the following formula (3), and piperazine represented by the following formula (4) in a solvent in the presence of a base, a palladium reagent, and 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthalene (tol-BINAP) represented by the following formula (5) at a reaction temperature of 60°C to 120°C. 【Chemical 1】 A method for producing voltioxetine represented by the following formula (1), comprising reacting 1-bromo-2-iodobenzene represented by the following formula (2), 2,4-dimethylbenzenethiol represented by the following formula (3), and piperazine represented by the following formula (4) in a solvent in the presence of a base, a palladium reagent, and 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthalene (tol-BINAP) represented by the following formula (5) at a reaction temperature of 60°C to 120°C. [Chemical 2] 1-bromo-2-iodobenzene represented by the following formula (2) [Chemical Formula 3] 2,4-dimethylbenzenethiol represented by the following formula (3) 【Chemical Formula 4】 and piperazine represented by the following formula (4) in a solvent in the presence of a base, a palladium reagent, and 2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthalene (tol-BINAP) represented by the following formula (5) 【Chemical Formula 5】 at a reaction temperature of 60°C to 120°C.

2. The method according to claim 1, wherein the solvent is toluene.

3. The method according to claim 1, wherein the base is sodium tert-butoxide.

4. The method according to claim 1, wherein the palladium reagent is bis(dibenzylideneacetone)palladium or tris(dibenzylideneacetone)palladium.

5. The method according to claim 1, wherein the solvent is toluene, the base is sodium tert-butoxide, and the palladium reagent is bis(dibenzylideneacetone)palladium or tris(dibenzylideneacetone)palladium.

6. The method according to claim 1, wherein 0.9 to 1.1 equivalents of 1-bromo-2-iodobenzene and 5 to 8 equivalents of piperazine are reacted with 2,4-dimethylbenzenethiol in toluene in the presence of 3 to 6 equivalents of sodium tert-butoxide, 0.05 to 0.2 mol% of bis(dibenzylideneacetone)palladium or tris(dibenzylideneacetone)palladium, and 0.1 to 0.8 mol% of tol-BINAP at a reaction temperature of 85°C to 105°C.

7. A method for producing voltioxetine, comprising reacting 1-bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine in a solvent in the presence of a base, a palladium reagent, and 2,2'-bis(di-3,5-xylylphosphino)-1,1'-binaphthalene (xy l-BINAP) represented by the following formula (6) at a reaction temperature of 60°C to 120°C. 1-bromo-2-iodobenzene, 2,4-dimethylbenzenethiol, and piperazine in a solvent in the presence of a base, a palladium reagent, and 2,2'-bis(di-3,5-xylylphosphino)-1,1'-binaphthalene (xy l-BINAP) represented by the following formula (6) 【Chemical Formula 6】 at a reaction temperature of 60°C to 120°C.

8. The method according to claim 7, wherein the solvent is toluene.

9. The method according to claim 7, wherein the base is sodium tert-butoxide.

10. The method according to claim 7, wherein the palladium reagent is bis(dibenzylideneacetone)palladium or tris(dibenzylideneacetone)palladium.

11. The method according to claim 7, wherein the solvent is toluene, the base is sodium tert-butoxide, and the palladium reagent is bis(dibenzylideneacetone)palladium or tris(dibenzylideneacetone)palladium.

12. The method according to claim 7, wherein 0.9 to 1.1 equivalents of 1-bromo-2-iodobenzene and 5 to 8 equivalents of piperazine are reacted with 2,4-dimethylbenzenethiol in toluene in the presence of 3 to 6 equivalents of sodium tert-butoxide, 0.05 to 0.2 mol% of bis(dibenzylideneacetone)palladium or tris(dibenzylideneacetone)palladium, and 0.1 to 0.8 mol% of xyI-BINAP at a reaction temperature of 85°C to 105°C.

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