Synthesis method of 1-(2-bromophenyl)-4-(2-((2, 4-dimethylphenyl) sulfenyl) phenyl) piperazine

Abstract

The invention belongs to the technical field of compound synthesis, and particularly discloses a synthesis method of 1-(2-bromophenyl)-4-(2-((2, 4-dimethylphenyl) sulfenyl) phenyl) piperazine. The synthesis method comprises the following steps: in an inert atmosphere, performing a coupling reaction on votioxetine and o-bromo iodobenzene in a system containing a cuprous catalyst, ethylene glycol, inorganic alkali and an alcohol solvent to obtain 1-(2-bromophenyl)-4-(2-((2, 4-dimethylphenyl) sulfenyl) phenyl) piperazine. According to the synthesis method provided by the invention, a cuprous substance is taken as a catalyst, ethylene glycol is taken as a specific ligand, inorganic base is taken as an acid-binding agent, and an alcohol solvent is taken as an organic solvent, so that the coupling reaction can be fully carried out on the vothioxetine and the o-bromoiodobenzene in a reaction system, and the yield of the 1-(2-bromophenyl)-4-(2-((2, 2-dibromophenyl)-4-(2-((2, 2-dibromophenyl)-2-bromophenyl)-2-(2, 2-dibromophenyl)-2 the purity and the yield of the (2, 4-dimethylphenyl) sulfenyl) phenyl) piperazine are improved.

Description

Technical Field

[0001] The invention belongs to the field of compound synthesis, and particularly relates to a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine. Background Art

[0002] Vortioxetine hydrobromide was jointly developed by Takeda Pharmaceutical Company Limited of Japan and Lundbeck Pharmaceuticals Ltd. of Denmark. It was approved for marketing in the United States and the European Union in 2013, and was approved by NMPA in 2017. So far, it has been approved by regulatory agencies in more than 70 countries and regions around the world for the treatment of major depressive disorder in adults. Its chemical structure is as follows:

[0003]

[0004] Vortioxetine hydrobromide is considered to be a new multi-model antidepressant drug. In vitro studies have shown that it can antagonize 5-HT3, 5-HT7 and 5-HT1D receptors, activate 5-HT1A receptors, partially activate 5-HT1B receptors and inhibit the transport of 5-HT. It is the first antidepressant drug with multiple pharmacodynamic activities.

[0005] The key to the synthesis of vortioxetine hydrobromide lies in the control of its impurities, so the study of the impurity synthesis of vortioxetine hydrobromide is of great significance. 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine is an impurity produced by the condensation of piperazine and 1-[(2-bromophenyl)thio]-2,4-dimethylbenzene in the production of vortioxetine hydrobromide and the residual o-bromoiodobenzene and vortioxetine. Its structural formula is as follows:

[0006]

[0007] There is no report on the structure of the impurity, which is not conducive to the qualitative and quantitative analysis and quality control of impurities in the production of vortioxetine hydrobromide. Therefore, it is of great significance to provide a simple and efficient synthesis method of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, which can be used for the qualitative and quantitative analysis of impurities in the production of vortioxetine hydrobromide, thereby improving the quality standard of vortioxetine hydrobromide and providing important guidance for safe drug use. Summary of the invention

[0008] In view of this, the present invention provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, which uses cuprous substances as catalysts, ethylene glycol as a specific ligand, an inorganic base as an acid-binding agent, and an alcohol solvent as an organic solvent, so that vortioxetine and o-bromoiodobenzene can fully undergo coupling reaction in a reaction system, thereby further improving the purity and yield of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine.

[0009] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0010] The first aspect of the present invention provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, comprising the following steps:

[0011] Under an inert atmosphere, vortioxetine and o-bromoiodobenzene are subjected to a coupling reaction in a system containing a cuprous catalyst, ethylene glycol, an inorganic base and an alcohol solvent to obtain 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine as shown in formula I;

[0012]

[0013] Compared with the prior art, the method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine provided by the present invention selects a cuprous substance as a catalyst for a coupling reaction. The cuprous catalyst can accurately control the reaction activity and can selectively promote the target coupling reaction, reduce the occurrence of side reactions, and thus improve the purity and yield of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine; ethylene glycol is used as a ligand containing the cuprous catalyst, which can promote the dissolution of cuprous ions in an alcohol solvent, and can also better regulate the activity and selectivity of the cuprous catalyst, so that the coupling reaction proceeds according to the expected coupling path, reduces the occurrence of side reactions, and thus improves the purity and yield of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine. The invention also selects an inorganic base as an acid-binding agent and maintains appropriate reaction conditions to ensure that the coupling reaction proceeds in the forward direction, thereby improving the purity and yield of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine. Vortioxetine and o-bromoiodobenzene have excellent solubility and dispersibility in an alcohol solvent. The alcohol solvent makes the reactants evenly dispersed in the reaction system, thereby making the coupling reaction more evenly and fully proceed in the reaction system, avoiding the defect of side reactions caused by excessively high local concentrations of reactants in the reaction system. The specific alcohol solvent greatly improves the purity and yield of the reaction product 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine.

[0014] The invention provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine. The method uses cuprous substances as catalysts, ethylene glycol as a specific ligand, an inorganic base as an acid-binding agent, and an alcohol solvent as an organic solvent, so that vortioxetine and o-bromoiodobenzene can fully undergo coupling reaction in a reaction system, thereby further improving the purity and yield of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine.

[0015] The synthetic route of the 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine is as follows:

[0016]

[0017] Preferably, the cuprous catalyst is at least one of cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide.

[0018] More preferably, the cuprous catalyst is cuprous iodide.

[0019] The preferred cuprous catalyst can precisely control the reaction activity, and can also selectively promote the target coupling reaction, reduce the occurrence of side reactions, and thus improve the yield and purity of the reaction product.

[0020] Preferably, the inorganic base is at least one of potassium carbonate, tripotassium phosphate or cesium carbonate.

[0021] More preferably, the inorganic base is tripotassium phosphate.

[0022] The present invention further limits the specific composition of the inorganic base, which can better maintain appropriate reaction conditions and thus improve the purity and yield of the reaction product.

[0023] Preferably, the alcohol solvent is at least one of methanol, anhydrous ethanol, n-propanol, isopropanol or isobutanol.

[0024] More preferably, the alcohol solvent is isopropanol.

[0025] By further limiting the specific composition of the alcohol solvent, it is beneficial to evenly disperse the reactants in the reaction system, thereby allowing the coupling reaction to proceed more evenly and fully in the reaction system, thereby improving the yield and purity of the reaction product.

[0026] Preferably, the molar ratio of o-bromoiodobenzene to vortioxetine is 1:(0.8-1).

[0027] Preferably, the molar ratio of o-bromoiodobenzene to the cuprous catalyst is 1:(0.03-0.1).

[0028] Further preferably, the molar ratio of o-bromoiodobenzene to the cuprous catalyst is 1:0.05.

[0029] Preferably, the molar ratio of o-bromoiodobenzene to ethylene glycol is 1:(1.5-2.5).

[0030] Further preferably, the molar ratio of o-bromoiodobenzene to ethylene glycol is 1:2.

[0031] Preferably, the molar ratio of o-bromoiodobenzene to the inorganic base is 1:(1.5-2.5).

[0032] Further preferably, the molar ratio of o-bromoiodobenzene to the inorganic base is 1:2.

[0033] Preferably, the mass volume ratio of the o-bromoiodobenzene to the alcohol solvent is 1 g:(5-15) mL.

[0034] Further preferably, the mass volume ratio of the o-bromoiodobenzene and the alcohol solvent is 1 g:(7-10) mL.

[0035] The present invention further limits the dosage of the cuprous catalyst, ethylene glycol, inorganic base and alcohol solvent, which is beneficial for the reactants to fully carry out a forward coupling reaction in the reaction system, avoid the occurrence of side reactions, and thus improve the purity and yield of the reaction product.

[0036] Preferably, the coupling reaction temperature is 60°C-80°C.

[0037] Further preferably, the coupling reaction temperature is 70°C-80°C.

[0038] The preferred reaction temperature is conducive to making the coupling reaction more complete, thereby improving the purity and yield of the reaction product.

[0039] Preferably, the coupling reaction time is 5h-10h.

[0040] Further preferably, the coupling reaction time is 7h-8h.

[0041] Preferably, after the coupling reaction is completed, the process further comprises: rotary evaporating the reactants, extracting, solid-liquid separation, standing for liquid separation, washing the organic phase with water, drying, and rotary evaporating to obtain the 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine.

[0042] Preferably, the temperature of the rotary evaporation is 40°C-50°C.

[0043] Preferably, the specific conditions for extraction are: adding dichloromethane and water to the oil obtained by rotary evaporation, and stirring at a rate of 60 rpm-120 rpm for 10 min-20 min.

[0044] Preferably, the specific condition for the solid-liquid separation is: filtration using diatomaceous earth.

[0045] Preferably, the specific conditions for washing the organic phase are: washing twice with a 15% by mass sodium chloride aqueous solution and once with deionized water.

[0046] Preferably, the drying is drying with anhydrous magnesium sulfate. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on the drawings without creative work.

[0048] Figure 1 The hydrogen spectrum of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine provided in Example 1 of the present invention;

[0049] Figure 2 This is the carbon spectrum of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0050] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0051] Example 1

[0052] This embodiment provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, comprising the following steps:

[0053] Add o-bromoiodobenzene 282.91 g (1 mol), vortioxetine 238.76 g (0.8 mol), cuprous iodide 9.52 g (0.05 mol), ethylene glycol 124.14 g (2 mol), isopropanol 1980.37 mL, and tripotassium phosphate 424.53 g (2 mol) into the bottle in sequence, introduce nitrogen gas under normal pressure and room temperature stirring, evacuate and replace three times, react at 80 ° C for 8 h, stop heating, and wait for the reaction solution to cool to room temperature and then heat at 45 ° C The reaction solution was rotary evaporated, dichloromethane and water were added to the concentrated residue, and the mixture was stirred at 60 rpm for 20 min at room temperature. The mother liquor was filtered through diatomaceous earth, and the mother liquor was separated and washed twice with a 15% sodium chloride aqueous solution and once with deionized water. The mixture was dried over anhydrous magnesium sulfate for more than 4 h and rotary evaporated to obtain 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine as a light yellow oil with a yield of 90.7% and a purity of 93.6%.

[0054] Example 2

[0055] This embodiment provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, comprising the following steps:

[0056] Add o-bromoiodobenzene 282.91 g (1 mol), vortioxetine 298.45 g (1 mol), cuprous oxide 4.29 g (0.03 mol), ethylene glycol 155.17 g (2.5 mol), methanol 2829.1 mL, potassium carbonate 207.31 g (1.5 mol) into the bottle in sequence, introduce nitrogen under normal pressure and room temperature stirring, evacuate and replace three times, react at 70 ° C for 7 h, stop heating, wait for the reaction solution to cool to room temperature and then cool to 45 ° C The reaction solution was rotary evaporated, and dichloromethane and water were added to the concentrated residue. The mixture was stirred at 120 rpm for 10 min at room temperature, filtered through diatomaceous earth, and the mother liquor was separated. The mixture was washed twice with a 15% sodium chloride aqueous solution and once with deionized water. The mixture was dried over anhydrous magnesium sulfate for more than 4 h, and rotary evaporated to obtain 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine as a light yellow oil with a yield of 85.2% and a purity of 88.8%.

[0057] Example 3

[0058] This embodiment provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, comprising the following steps:

[0059] Add o-bromoiodobenzene 282.91 g (1 mol), vortioxetine 268.61 g (0.9 mol), cuprous chloride 9.9 g (0.1 mol), ethylene glycol 93.1 g (1.5 mol), anhydrous ethanol 1414.55 mL, cesium carbonate 814.55 g (2.5 mol) into the bottle in sequence, introduce nitrogen under normal pressure and room temperature stirring, evacuate and replace three times, react at 60 ° C for 5 h, stop heating, wait for the reaction solution to cool to room temperature and then cool at 40 ° C The reaction solution was rotary evaporated, and dichloromethane and water were added to the concentrated residue. The mixture was stirred at 100 rpm for 15 min at room temperature, filtered through diatomaceous earth, and the mother liquor was separated. The mixture was washed twice with a 15% sodium chloride aqueous solution and once with deionized water. The mixture was dried over anhydrous magnesium sulfate for more than 4 h, and rotary evaporated to obtain 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine as a light yellow oil with a yield of 85.4% and a purity of 85.9%.

[0060] Example 4

[0061] This embodiment provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, comprising the following steps:

[0062] To the bottle, 282.91 g (1 mol) of o-bromoiodobenzene, 238.76 g (0.8 mol) of vortioxetine, 9.52 g (0.05 mol) of cuprous iodide, 124.14 g (2 mol) of ethylene glycol, 4243.65 mL of isopropanol, and 424.53 g (2 mol) of tripotassium phosphate were added in sequence, and nitrogen was introduced under stirring at room temperature and pressure, and the mixture was replaced by vacuum three times. The reaction was carried out at 75 ° C for 10 h, and the heating was stopped. After the reaction solution was cooled to room temperature for 50 min, the mixture was stirred for 2 hours. The reaction solution was rotary evaporated at 370 °C, dichloromethane and water were added to the concentrated residue, stirred at 80 rpm for 18 min at room temperature, filtered through diatomaceous earth, the mother liquor was separated, washed twice with a 15% sodium chloride aqueous solution, washed once with deionized water, dried over anhydrous magnesium sulfate for more than 4 h, and rotary evaporated to obtain 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine as a light yellow oil with a yield of 87.4% and a purity of 92.3%.

[0063] Comparative Example 1

[0064] This comparative example provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, which is different from Example 1 in that:

[0065] Replace ethylene glycol with an equal amount of ethylenediamine;

[0066] The other components and preparation steps are the same as those in Example 1.

[0067] Result: No reaction occurred.

[0068] Comparative Example 2

[0069] This comparative example provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, which is different from Example 1 in that:

[0070] Replace cuprous iodide with an equal amount of tris(dibenzylideneacetone)dipalladium;

[0071] The other components and preparation steps are the same as those in Example 1.

[0072] Result: No reaction occurred.

[0073] Comparative Example 3

[0074] This comparative example provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, which is different from Example 1 in that:

[0075] Replace isopropanol with an equal amount of acetonitrile;

[0076] The other components and preparation steps are the same as those in Example 1.

[0077] Results: The yield of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine was 37.2%, and the purity was 72.3%.

[0078] Comparative Example 4

[0079] This comparative example provides a method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, which is different from Example 1 in that:

[0080] Replace tripotassium phosphate with an equal amount of triethylamine;

[0081] The other components and preparation steps are the same as those in Example 1.

[0082] Results: The yield of 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine was 42.3%, and the purity was 70.9%.

[0083] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine, characterized in that: The steps include: Under an inert atmosphere, vortioxetine and o-bromoiodobenzene are subjected to a coupling reaction in a system containing a cuprous catalyst, ethylene glycol, an inorganic base and an alcohol solvent to obtain 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine as shown in formula I; 2. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: The cuprous catalyst is at least one of cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide; and / or The inorganic base is at least one of potassium carbonate, tripotassium phosphate or cesium carbonate.

3. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: The alcohol solvent is at least one of methanol, anhydrous ethanol, n-propanol, isopropanol or isobutanol.

4. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: The molar ratio of o-bromoiodobenzene to vortioxetine is 1:(0.8-1).

5. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: The molar ratio of the o-bromoiodobenzene to the cuprous catalyst is 1:(0.03-0.1).

6. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: The molar ratio of o-bromoiodobenzene to ethylene glycol is 1:(1.5-2.5).

7. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: The molar ratio of o-bromoiodobenzene to the inorganic base is 1:(1.5-2.5).

8. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: The mass volume ratio of the o-bromoiodobenzene and the alcohol solvent is 1g:(5-15)mL.

9. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: The temperature of the coupling reaction is 60° C.-80° C., and the time of the coupling reaction is 5 h-10 h.

10. The method for synthesizing 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine according to claim 1, characterized in that: After the coupling reaction is completed, the following steps are further performed: rotary evaporation of the reactants, extraction, solid-liquid separation, standing for liquid separation, washing the organic phase with water, drying, and rotary evaporation to obtain the 1-(2-bromophenyl)-4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine.

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