CN108191792B - Preparation method of vortioxetine hydrobromide and intermediate thereof - Google Patents

Preparation method of vortioxetine hydrobromide and intermediate thereof Download PDF

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CN108191792B
CN108191792B CN201711457801.0A CN201711457801A CN108191792B CN 108191792 B CN108191792 B CN 108191792B CN 201711457801 A CN201711457801 A CN 201711457801A CN 108191792 B CN108191792 B CN 108191792B
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vortioxetine
vortioxetine intermediate
bromobenzenesulfinic
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CN108191792A (en
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陈健
乔岩河
王婷婷
应述欢
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Shanghai Yunshengyan Neoplasm Technology Co ltd
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Shanghai Bocimed Pharmaceutical Co Ltd
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Abstract

The invention discloses vortioxetine hydrobromide and a preparation method of an intermediate thereof. The invention providesA preparation method of vortioxetine intermediate IV is provided, which comprises the following steps: and carrying out Grignard reaction on the vortioxetine intermediate V, 2, 4-dimethyl iodobenzene and isopropyl magnesium chloride in an organic solvent to obtain the vortioxetine intermediate IV. The preparation method does not use volatile thiophenol derivatives with foul smell, is environment-friendly, simple and safe to operate, has high yield, ensures that the prepared vortioxetine hydrobromide has high purity, can meet the requirements of raw material medicaments, and is suitable for industrial production.

Description

Preparation method of vortioxetine hydrobromide and intermediate thereof
Technical Field
The invention relates to vortioxetine hydrobromide and a preparation method of an intermediate thereof.
Background
Vortioxetine hydrobromide (I) is a new drug for the treatment of depression, developed by the united states pharmaceutical research and development of danish north and japan wutian pharmaceuticals, approved by the U.S. Food and Drug Administration (FDA) for marketing at 30 days 9/2013 under the trade name brinellix, and used for the treatment of major depression. Formally releasing the European market in 1 month in 2014.
Figure BDA0001529563890000011
Major depression causes troubles to the working ability, sleep, learning and diet of patients. Vortioxetine hydrobromide exerts an antidepressant effect mainly by increasing the serotonin concentration in the central nervous system, and has little effect on norepinephrine and dopaminergic neurons compared to other selective 5-HT reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors. A plurality of clinical trials show that the vortioxetine hydrobromide has better effectiveness, safety and tolerance for treating major depression.
The published synthetic methods of vortioxetine hydrobromide under the prior art conditions are reported in patent documents such as WO2013102573, CN101472906, CN103788020 and CN 105339361.
The method reported in patent document WO2013102573 and the like is: two-step sequential metal palladium catalyzed coupling of bromothiophenols.
Figure BDA0001529563890000021
The method reported in patent document CN101472906 and the like is: two-step sequential metal palladium catalyzed coupling of dimethylthiophenol.
Figure BDA0001529563890000022
The method reported in patent document CN103788020 and the like is: the metal palladium of the dimethyl thiophenol is used for catalyzing coupling, reduction and cyclization.
Figure BDA0001529563890000023
The patent document CN105339361 and the like report the following methods: the metal palladium of the dimethyl thiophenol is used for catalyzing, coupling, oxidizing, coupling and reducing.
Figure BDA0001529563890000024
The common points of the above methods are that the starting material must be 2, 4-dimethyl thiophenol or 2-halogenated thiophenol, and these thiophenol derivatives are volatile liquids with foul smell, such as large amount of liquid production which has great harm to operators, serious pollution to environment, difficult later purification, and the purity of the prepared product is poor, can not reach the standard of raw material medicine, and is not suitable for industrial production. Therefore, the prior art conditions are urgently needed to be changed, a preparation method of vortioxetine hydrobromide, which does not use volatile thiophenol derivatives with foul odor, is safe to operate, environment-friendly and easy to purify, and the prepared vortioxetine hydrobromide meets the requirements of raw material medicines and is suitable for industrial production.
Disclosure of Invention
The invention aims to overcome the defects that in the preparation method of vortioxetine hydrobromide in the prior art, volatile thiophenol derivatives with foul smell are required to be used as starting materials, the environmental pollution is serious, the purification is difficult, the purity of the prepared product is poor and cannot reach the standard of raw material medicines, and the like, and provides the preparation method of vortioxetine hydrobromide and the intermediate thereof. The preparation method does not use volatile thiophenol derivatives with foul smell, is environment-friendly, is simple and safe to operate, has high yield, and is suitable for industrial production, and the prepared vortioxetine hydrobromide has high purity and can meet the requirements of raw material medicaments.
The invention provides a preparation method of a vortioxetine intermediate IV, which comprises the following steps: performing Grignard reaction on the vortioxetine intermediate V, 2, 4-dimethyl iodobenzene and isopropyl magnesium chloride in an organic solvent to obtain a vortioxetine intermediate IV;
Figure BDA0001529563890000031
the preparation method of vortioxetine intermediate IV can adopt the conventional method of the grignard reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
the preparation method of the vortioxetine intermediate IV is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
In the preparation method of vortioxetine intermediate IV, the organic solvent is preferably an ether solvent; the ether solvent is preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran and 1, 4-dioxane.
In the preparation method of vortioxetine intermediate IV, the volume-to-mass ratio of the organic solvent to the sitagliptin intermediate V is preferably 1mL/g to 30mL/g, more preferably 2mL/g to 16mL/g, such as 2mL/g, 4mL/g, 6mL/g, 8mL/g or 16 mL/g.
In the preparation method of vortioxetine intermediate IV, the molar ratio of the 2, 4-dimethyl iodobenzene to the vortioxetine intermediate V is preferably 1.0 to 5.0, more preferably 1.1 to 2.0, such as 1.2, 1.3, or 2.0.
In the preparation method of vortioxetine intermediate IV, the molar ratio of the isopropyl magnesium chloride to the vortioxetine intermediate V is preferably 1.0 to 5.0, more preferably 1.1 to 2.0, for example 1.1, 1.2 or 2.0.
In the preparation method of vortioxetine intermediate IV, the temperature of the grignard reaction is preferably-5 ℃ to 35 ℃, more preferably 10 ℃ to 30 ℃, for example 10 ℃ to 20 ℃, 15 ℃ to 25 ℃, or 20 ℃ to 30 ℃.
In the preparation method of vortioxetine intermediate IV, the progress of the grignard reaction can be monitored by a detection method (e.g. TLC, HPLC or NMR) which is conventional in the art, and is generally regarded as the end point of the reaction when vortioxetine intermediate V disappears, and the time of the grignard reaction is preferably 1 hour to 10 hours, and more preferably 2 hours to 5 hours, such as 2 hours, 3 hours or 5 hours.
The preparation method of the vortioxetine intermediate IV preferably adopts the following steps: adding a solution formed by isopropyl magnesium chloride and an organic solvent into a mixture formed by 2, 4-dimethyl iodobenzene and the organic solvent, and stirring; and then adding a solution formed by the vortioxetine intermediate V and an organic solvent, and carrying out a Grignard reaction to obtain the vortioxetine intermediate IV. The adding mode is preferably dropwise adding; the dropping speed is based on the condition that the temperature of the reaction system is not more than 35 ℃. The stirring time is preferably 1 hour to 5 hours, for example 1 hour, 1.5 hours or 3 hours.
The preparation method of the vortioxetine intermediate IV preferably adopts the following post-treatment steps: and after the reaction is finished, quenching the reaction, extracting, washing, drying and removing the solvent to obtain the vortioxetine intermediate IV. The quenching reaction preferably adopts ammonium chloride aqueous solution; the mass concentration of the ammonium chloride aqueous solution is preferably 1% to 50%, more preferably 5% to 25%, for example, 5%, 10% or 20%. The extraction, washing, drying and removal of the solvent can be carried out by methods conventional in the art. The solvent adopted for extraction is preferably an ether solvent; the ether solvent is preferably methyl tert-butyl ether. The number of extractions is preferably 1 to 3, for example 1, 2 or 3. The washing is preferably performed by using saline solution, and the mass concentration of the saline solution is preferably 10-25%, such as 10%, 15% or 25%; the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution. The number of washing is preferably 1 to 3, for example 2. The drying is preferably carried out by adopting a drying agent; the drying agent is preferably anhydrous sodium sulfate. The solvent is preferably removed and concentrated in vacuum, the pressure of the vacuum concentration is preferably-0.085 MPa to-0.1 MPa, and the temperature of the vacuum concentration is preferably 45 ℃ to 55 ℃.
The vortioxetine intermediate IV prepared by the preparation method of vortioxetine intermediate IV can be directly used for preparing the vortioxetine intermediate III without further purification.
The preparation method of vortioxetine intermediate IV preferably further comprises a preparation method of vortioxetine intermediate V, which comprises the following steps: in an organic solvent, under the catalysis of tris (dibenzylideneacetone) dipalladium and 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine and in the presence of alkali, carrying out nucleophilic substitution reaction on 2-bromobenzenesulfinic acid methyl ester and 1-tert-butoxycarbonylpiperazine to obtain the vortioxetine intermediate V;
Figure BDA0001529563890000051
the preparation method of vortioxetine intermediate V can adopt a conventional method of such nucleophilic substitution reaction in the field, and the following reaction method and conditions are particularly preferred in the present invention:
the preparation method of the vortioxetine intermediate V is preferably performed under the protection of a protective gas, and the protective gas is preferably nitrogen and/or argon.
In the preparation method of vortioxetine intermediate V, the organic solvent is preferably an aromatic solvent, and the aromatic solvent is preferably one or more of toluene, benzene, xylene, and ethylbenzene.
In the preparation method of vortioxetine intermediate V, the volume-to-mass ratio of the organic solvent to the methyl 2-bromobenzenesulfinate VI is preferably 1mL/g to 50mL/g, more preferably 10mL/g to 20mL/g, such as 10mL/g, 12mL/g or 20 mL/g.
In the preparation method of vortioxetine intermediate V, the base is preferably an inorganic base; the inorganic base is preferably sodium tert-butoxide.
In the preparation method of vortioxetine intermediate V, the molar ratio of the base to the methyl 2-bromobenzenesulfinate VI is preferably 1 to 5, more preferably 1 to 3, such as 1.3, 2 or 3.
In the preparation method of vortioxetine intermediate V, the molar ratio of the 1-tert-butyloxycarbonyl piperazine (Boc piperazine) to the methyl 2-bromobenzenesulfinate VI is preferably 1 to 5, more preferably 1 to 2, for example 1.2, 1.5 or 2.0.
In the preparation method of vortioxetine intermediate V, the molar ratio of the tris (dibenzylideneacetone) dipalladium to the methyl 2-bromobenzenesulfinate VI is preferably 0.001 to 0.1, and more preferably 0.002 to 0.01, such as 0.002, 0.005 or 0.01.
In the preparation method of vortioxetine intermediate V, the molar ratio of 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine to 2-bromobenzenesulfinic acid methyl ester VI is preferably 0.002-0.2, and more preferably 0.004-0.02, such as 0.005, 0.01 or 0.02.
In the preparation method of vortioxetine intermediate V, the temperature of the nucleophilic substitution reaction is preferably 40 ℃ to 100 ℃, more preferably 70 ℃ to 90 ℃, for example 70 ℃, 80 ℃ or 90 ℃.
In the preparation method of vortioxetine intermediate V, the progress of the nucleophilic substitution reaction can be detected by a monitoring method (e.g. TLC, HPLC or NMR) conventional in the art, and is generally regarded as the end point of the reaction when methyl 2-bromobenzenesulfonate VI disappears, and the time of the nucleophilic substitution reaction is preferably 10 hours to 30 hours, and more preferably 15 hours to 20 hours, such as 15 hours, 18 hours or 20 hours.
The preparation method of the vortioxetine intermediate V preferably adopts the following post-treatment steps: and after the reaction is finished, cooling, filtering, washing, drying, decoloring and removing the solvent to obtain the vortioxetine intermediate V. The filtration, washing, drying, decolorization and solvent removal can be carried out by methods conventional in the art. The washing is preferably performed with an aqueous inorganic alkali solution and brine. The inorganic base is preferably sodium bicarbonate and/or potassium bicarbonate. The mass concentration of the inorganic base is preferably 1% to 30%, for example 5%, 10% or 15%; the mass concentration refers to the mass percentage of the inorganic alkali in the total mass of the inorganic alkali water solution. The mass concentration of the salt solution is preferably 10-25%, such as 10%, 15% or 25%; the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution. The number of washing is preferably 1 to 3, for example 1, 2 or 3. The drying is preferably carried out by adopting a drying agent; the drying agent is preferably anhydrous sodium sulfate. The solvent is preferably removed and concentrated in vacuum, the pressure of the vacuum concentration is preferably-0.085 MPa to-0.1 MPa, and the temperature of the vacuum concentration is preferably 45 ℃ to 55 ℃.
The preparation method of the vortioxetine intermediate IV preferably further comprises a preparation method of 2-bromobenzenesulfinic acid methyl ester VI, and the preparation method comprises the following steps: under the condition of the existence of a condensing agent and a catalyst, 2-bromobenzenesulfinic acid VII and methanol are subjected to condensation reaction to obtain 2-bromobenzenesulfinic acid methyl ester VI;
Figure BDA0001529563890000071
the preparation method of the 2-bromobenzenesulfinic acid methyl ester VI can adopt the conventional method operated in the field, and the following reaction method and conditions are particularly preferred in the invention:
the preparation method of the 2-bromobenzenesulfinic acid methyl ester VI is preferably carried out under the protection of protective gas; the protective gas is preferably nitrogen and/or argon.
In the preparation method of the methyl 2-bromobenzenesulfinate VI, the methanol can be used as a reaction solvent or a reaction reagent. The volume-to-mass ratio of the methanol to the 2-bromobenzsulfinic acid VII is preferably 1mL/g to 30mL/g, more preferably 5mL/g to 15mL/g, such as 5.0mL/g, 9.8mL/g or 14.8 mL/g.
In the preparation method of the methyl 2-bromobenzenesulfinate VI, the catalyst is preferably 4-dimethylaminopyridine.
In the preparation method of the 2-bromobenzene sulfinic acid methyl ester VI, the molar ratio of the catalyst to the 2-bromobenzene sulfinic acid VII is preferably 0.001-0.1; further preferably 0.005 to 0.05; for example 0.005, 0.01 or 0.05.
In the preparation method of the methyl 2-bromobenzenesulfinate VI, the condensing agent is preferably dicyclohexylcarbodiimide.
In the preparation method of methyl 2-bromobenzenesulfinate VI, the molar ratio of the condensing agent to the 2-bromobenzenesulfinate VII is preferably 1.0-3.0, more preferably 1.1-2.0, such as 1.1, 1.4 or 1.9.
In the method for preparing methyl 2-bromobenzenesulfinate VI, the condensation reaction temperature is preferably 0 to 35 ℃, more preferably 10 to 30 ℃, for example 10 to 15 ℃, 15 to 20 ℃ or 25 to 30 ℃.
In the preparation method of methyl 2-bromobenzenesulfinate VI, the progress of the condensation reaction can be detected by a monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and generally the end point of the reaction is the disappearance of 2-bromobenzenesulfinate VII, and the time of the condensation reaction is preferably 10 minutes to 5 hours; further preferably 0.5 to 2 hours; for example 0.5 hours, 1 hour or 2 hours.
The preparation method of the 2-bromobenzenesulfinic acid methyl ester VI preferably adopts the following reaction steps: adding dicyclohexylcarbodiimide and 4-dimethylaminopyridine into a mixture formed by 2-bromobenzenesulfinic acid VII and methanol, and carrying out condensation reaction to obtain the 2-bromobenzenesulfinic acid methyl ester VI.
The preparation method of the 2-bromobenzenesulfinic acid methyl ester VI preferably adopts the following post-treatment steps: and after the reaction is finished, extracting, washing, drying, filtering and removing the solvent to obtain the 2-bromobenzenesulfinic acid methyl ester VI.
The extraction, washing, drying, filtration and solvent removal can be carried out by methods conventional in the art. The solvent used for extraction is preferably an ester solvent; the ester solvent is preferably ethyl acetate. The number of extractions is preferably 1 to 3, for example 1, 2 or 3. The washing is preferably carried out by washing with an aqueous inorganic acid solution, an aqueous inorganic base solution and brine in this order. The inorganic acid is preferably hydrochloric acid. The hydrochloric acid may be a conventional commercially available hydrochloric acid reagent. The mass concentration of the inorganic acid is preferably 1% to 37%, more preferably 1% to 10%, for example, 3%, 5% or 10%; the mass concentration refers to the mass percentage of the inorganic acid in the total mass of the inorganic acid aqueous solution. The inorganic base is preferably sodium bicarbonate and/or potassium bicarbonate. The mass concentration of the inorganic base is preferably 10-30%, such as 10%, 15% or 20%; the mass concentration refers to the mass percentage of the inorganic alkali in the total mass of the inorganic alkali water solution. The mass concentration of the salt solution is preferably 10-30%, such as 10%, 15% or 25%; the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution. The number of washing is preferably 1 to 3, for example 1 or 2. The drying is preferably carried out by adopting a drying agent; the drying agent is preferably anhydrous sodium sulfate. The solvent is preferably removed and concentrated in vacuum, the pressure of the vacuum concentration is preferably-0.085 MPa to-0.1 MPa, and the temperature of the vacuum concentration is preferably 45 ℃ to 55 ℃.
The preparation method of the vortioxetine intermediate V preferably further comprises a preparation method of 2-bromobenzenesulfinic acid VII, which comprises the following steps: carrying out condensation reaction on 2-bromobenzene sulfonyl chloride VIII and sodium sulfite in the presence of alkali to obtain 2-bromobenzene sodium sulfinate; then the 2-bromobenzenesulfonic acid sodium salt and acid are subjected to neutralization reaction to obtain the 2-bromobenzenesulfinic acid VII;
Figure BDA0001529563890000091
the preparation method of the 2-bromobenzenesulfinic acid VII can adopt the conventional method of the reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
in the preparation method of the 2-bromobenzenesulfinic acid VII, the base is preferably an inorganic base; the inorganic base is preferably sodium carbonate. The base may be used in the form of an aqueous solution thereof.
In the preparation method of the 2-bromobenzenesulfinic acid VII, the molar ratio of the base to the 2-bromobenzenesulfonyl chloride VIII is preferably 1-5, more preferably 2-4, such as 2.0, 2.9 or 4.0.
In the preparation method of the 2-bromobenzenesulfinic acid VII, the molar ratio of the sodium sulfite to the 2-bromobenzenesulfonyl chloride VIII is preferably 1-5, more preferably 1.5-2.5, such as 1.5, 1.8 or 2.5.
In the preparation method of the 2-bromobenzenesulfinic acid VII, the acid is preferably an inorganic acid; the inorganic acid is preferably hydrochloric acid. The hydrochloric acid may be a conventional commercially available hydrochloric acid reagent, and the mass concentration of the hydrochloric acid is preferably 0.5mol/L to 3mol/L, more preferably 0.5mol/L to 2mol/L, for example 0.5mol/L, 1mol/L or 2 mol/L.
In the preparation method of the 2-bromobenzenesulfinic acid VII, the molar ratio of the acid to the 2-bromobenzenesulfonyl chloride VIII is preferably 1-5, and more preferably 1.5-2.5.
In the method for producing 2-bromobenzenesulfinic acid VII, the temperature of the condensation reaction is preferably 20 to 80 ℃, more preferably 30 to 60 ℃, for example 30 ℃, 50 ℃ or 60 ℃.
In the preparation method of the 2-bromobenzenesulfinic acid VII, the progress of the condensation reaction can be detected by a monitoring method (such as TLC) which is conventional in the field, and the progress of the condensation reaction is generally regarded as the end point of the reaction when the 2-bromobenzenesulfonyl chloride VIII disappears, and the time of the condensation reaction is preferably 10 minutes to 5 hours; further preferably 10 minutes to 3 hours; for example 10 minutes, 1 hour or 3 hours.
In the method for preparing 2-bromobenzenesulfinic acid VII, the temperature of the neutralization reaction is preferably 0 ℃ to 40 ℃, more preferably 5 ℃ to 25 ℃, for example 10 ℃ to 20 ℃, 15 ℃ to 25 ℃ or 5 ℃ to 15 ℃.
In the process for the preparation of 2-bromobenzenesulfinic acid VII, the time of the neutralization reaction is preferably 10 minutes to 2 hours, for example 0.5 hour, 1 hour or 2 hours.
The preparation method of the 2-bromobenzenesulfinic acid VII preferably adopts the following reaction steps: dripping 2-bromobenzene sulfinyl chloride VIII into a solution formed by sodium sulfite and inorganic base for condensation reaction to obtain 2-bromobenzene sulfinic acid sodium sulfonate; then neutralizing with acid in solvent to obtain the 2-bromobenzenesulfinic acid VII. The dropping speed is based on the maintenance of the temperature of the system not to exceed 60 ℃. The temperature of the solution of sodium sulfite with inorganic base is preferably 30 to 60 c, for example 30 c, 50 c or 60 c.
In the invention, the preparation method of the vortioxetine intermediate IV preferably adopts the following route:
Figure BDA0001529563890000111
the invention also provides a preparation method of the vortioxetine intermediate III, which comprises the following steps: after the vortioxetine intermediate IV is prepared according to the method, performing a reaction of removing an amino protecting group on the vortioxetine intermediate IV and an acid in an organic solvent to obtain a vortioxetine intermediate III;
Figure BDA0001529563890000112
the preparation method of the vortioxetine intermediate III can adopt the conventional method for removing the amino protecting group in the field, and the following reaction methods and conditions are particularly preferred in the invention:
the preparation method of the vortioxetine intermediate III is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
In the preparation method of vortioxetine intermediate III, the organic solvent is preferably an alcohol solvent, and the alcohol solvent is preferably one or more of methanol, ethanol, isopropanol and n-propanol, and is further preferably methanol.
In the preparation method of vortioxetine intermediate III, the volume-to-mass ratio of the organic solvent to vortioxetine intermediate IV is preferably 1mL/g to 20mL/g, more preferably 4mL/g to 12mL/g, for example 8 mL/g.
In the preparation method of the vortioxetine intermediate III, the acid is preferably an inorganic acid; the inorganic acid is preferably hydrochloric acid; the hydrochloric acid may be used in the form of a solution thereof; the hydrochloric acid solution is preferably a hydrogen chloride methanol solution and/or a hydrogen chloride ethanol solution. The molar concentration of the hydrochloric acid solution is preferably 1 to 6mol/L, more preferably 2 to 3mol/L, for example 2 mol/L.
In the preparation method of vortioxetine intermediate III, the molar ratio of the acid to vortioxetine intermediate IV is preferably 1 to 10, more preferably 4 to 8, for example 6.7.
In the preparation method of vortioxetine intermediate III, the reaction temperature for removing the amino protecting group is preferably 0 to 40 ℃, more preferably 5 to 35 ℃, for example 15 to 25 ℃.
In the preparation method of vortioxetine intermediate III, the progress of the reaction for removing the amino protecting group can be detected by a conventional monitoring method in the art (e.g. TLC, HPLC or NMR), and is generally regarded as the end point of the reaction when vortioxetine intermediate IV disappears, and the reaction time for removing the amino protecting group is preferably 1 hour to 5 hours, more preferably 2 hours to 3 hours, for example 2 hours.
In the invention, the vortioxetine intermediate III is preferably prepared by the following preparation route:
Figure BDA0001529563890000121
the invention also provides a preparation method of the vortioxetine intermediate II, which comprises the following steps: after the vortioxetine intermediate III is prepared according to the method, carrying out reduction reaction on the vortioxetine intermediate III and a reducing agent in an organic solvent in the presence of a catalyst to obtain the vortioxetine intermediate II;
Figure BDA0001529563890000122
the preparation method of the vortioxetine intermediate III can adopt a conventional method in the field for such reduction reaction, and the following reaction methods and conditions are particularly preferred in the invention:
the preparation method of the vortioxetine intermediate II is preferably carried out under the protection of protective gas, and the protective gas is preferably nitrogen and/or argon.
In the preparation method of vortioxetine intermediate II, the organic solvent is preferably an alcohol solvent; the alcohol solvent is preferably one or more of methanol, ethanol, isopropanol and n-propanol, and is further preferably methanol.
In the preparation method of vortioxetine intermediate II, the volume-to-mass ratio of the organic solvent to vortioxetine intermediate III is preferably 1mL/g to 50mL/g, more preferably 5mL/g to 15mL/g, for example 10 mL/g.
In the preparation method of the vortioxetine intermediate II, the catalyst is preferably iodine.
In the preparation method of vortioxetine intermediate II, the molar ratio of the catalyst to vortioxetine intermediate III is preferably 0.001 to 0.1, and more preferably 0.005 to 0.05; such as 0.01.
In the preparation method of vortioxetine intermediate II, the reducing agent is preferably magnesium.
In the preparation method of the vortioxetine intermediate II, the molar ratio of the reducing agent to the vortioxetine intermediate III is preferably 1-50, and more preferably 10-20; such as 15.
In the preparation method of vortioxetine intermediate II, the temperature of the reduction reaction is preferably 0 to 40 ℃, more preferably 5 to 35 ℃, for example 15 to 25 ℃.
In the preparation method of vortioxetine intermediate II, the progress of the reduction reaction can be detected by a monitoring method (e.g. TLC, HPLC or NMR) which is conventional in the art, and generally takes the time when vortioxetine intermediate III disappears as the end point of the reaction, and the time of the reduction reaction is preferably 1 hour to 30 hours, more preferably 5 hours to 25 hours, for example 18 hours.
In the invention, the vortioxetine intermediate II preferably adopts the following preparation route:
Figure BDA0001529563890000131
Figure BDA0001529563890000141
the invention also provides a preparation method of vortioxetine I, which comprises the following steps: after the vortioxetine intermediate II is prepared according to the method, carrying out a salt forming reaction on the vortioxetine intermediate II and hydrobromic acid in an organic solvent to obtain vortioxetine I;
Figure BDA0001529563890000142
the preparation method of vortioxetine II can adopt the conventional method of such salt forming reaction in the field, and the following reaction method and conditions are particularly preferred in the invention:
the preparation method of vortioxetine I is preferably performed under the protection of a protective gas, and the protective gas is preferably nitrogen and/or argon.
In the preparation method of vortioxetine I, the organic solvent is preferably an aromatic hydrocarbon solvent; the aromatic hydrocarbon solvent is preferably one or more of toluene, benzene, xylene and ethylbenzene, and is further preferably toluene.
In the preparation method of vortioxetine I, the volume-to-mass ratio of the organic solvent to vortioxetine intermediate II is preferably 1mL/g to 50mL/g, more preferably 5mL/g to 20mL/g, for example 10 mL/g.
In the preparation method of vortioxetine I, the hydrobromic acid can be a conventional commercially available hydrobromic acid reagent, and the mass concentration of the hydrobromic acid is preferably 10% to 48%, for example, 40%, and the mass concentration refers to the percentage of the mass of the hydrogen bromide to the total mass of the aqueous hydrobromic acid solution.
In the preparation method of vortioxetine I, the temperature of the salt forming reaction is preferably 40 ℃ to 80 ℃, more preferably 50 ℃ to 70 ℃, for example 60 ℃.
In the preparation method of vortioxetine I, the progress of the salt-forming reaction can be detected by a monitoring method (e.g. TLC, HPLC, or NMR) which is conventional in the art, and generally takes the time when vortioxetine intermediate II disappears as the end point of the reaction, and the time of the salt-forming reaction is preferably 1 hour to 10 hours, more preferably 1 hour to 5 hours, such as 1 hour, 2 hours, or 3 hours.
In the invention, the preparation method of vortioxetine I preferably adopts the following reaction route:
Figure BDA0001529563890000151
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.
The positive progress effects of the invention are as follows: the preparation method does not use volatile thiophenol derivatives with foul smell, is environment-friendly, simple and safe to operate, ensures that the vortioxetine hydrobromide product prepared from the intermediate has high purity (> 99.5%, less than 0.1% of single impurity and less than 10ppm of metal palladium residue, meets the raw material drug standard), has high total yield (reaching 42-44%), and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1: preparation of 2-bromobenzenesulfinic acid VII
Figure BDA0001529563890000161
17.93g of sodium sulfite was dissolved in water at 30 ℃ to prepare a 100mL solution, 23.90g of sodium carbonate was dissolved in water at 30 ℃ to prepare a 100mL solution, and the two solutions were mixed and heated to 50 ℃ and stirred for 10 minutes. Under the protection of nitrogen, 20g of 2-bromobenzenesulfonyl chloride VIII are slowly added dropwise at 50 ℃ and stirred for 2 hours at 50 ℃. Vacuum concentrating (temperature 55-75 ℃, pressure-0.085 MPa-0.1 MPa) to remove most of the solvent, adding 160mL of ethanol, stirring at 75 ℃ for 0.5 hour, then cooling to 10-20 ℃ and stirring for 0.5 hour. Filtration afforded an off-white solid. Adding 80mL of acetonitrile, and stirring at 10-20 ℃ for 1 hour. Filtration afforded an off-white solid. Adding 80mL of water and 80mL of toluene, dropwise adding 1mol/L hydrochloric acid at 10-20 ℃ to adjust the pH value to 3-4, and stirring for 1 hour. Standing for layering, extracting the aqueous phase twice with 40mL of toluene, combining the organic phases, washing twice with a saline solution with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution), and drying with anhydrous sodium sulfate. Filtering, and vacuum concentrating (temperature 45-55 deg.C, pressure-0.085 MPa-0.1 MPa) to obtain light yellow oily substance 15.1g of 2-bromobenzenesulfinic acid VII with yield 87.2% and HPLC purity 98.52%;1H-NMR(d6-DMSO,400MHz)：7.78(m,1H)，7.50(m,2H)，7.32(m,1H)。
example 2: preparation of 2-bromobenzenesulfinic acid VII
Figure BDA0001529563890000162
15.00g of sodium sulfite was dissolved in water at 30 ℃ to prepare a 100mL solution, 16.50g of sodium carbonate was dissolved in water at 30 ℃ to prepare a 100mL solution, and the two solutions were mixed and heated to 60 ℃ and stirred for 10 minutes. Under the protection of nitrogen, 20g of 2-bromobenzenesulfonyl chloride VIII are slowly added dropwise at 60 ℃ and stirred for 1 hour at 60 ℃. Vacuum concentrating (temperature 55-75 ℃, pressure-0.085 MPa-0.1 MPa) to remove most of the solvent, adding 160mL of ethanol, stirring at 75 ℃ for 0.5 hour, then cooling to 10-20 ℃ and stirring for 0.5 hour. Filtration afforded an off-white solid. Adding 80mL of acetonitrile, and stirring at 10-20 ℃ for 1 hour. Filtration afforded an off-white solid. Adding 80mL of water and 80mL of toluene, dropwise adding 0.5mol/L hydrochloric acid at 15-25 ℃ to adjust the pH value to 3-4, and stirring for 2 hours. Standing for layering, extracting the aqueous phase twice with 40mL of toluene, combining the organic phases, washing twice with a saline solution with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution), and drying with anhydrous sodium sulfate. Filtering, and vacuum concentrating (temperature 45-55 deg.C, pressure-0.085 MPa-0.1 MPa) to obtain light yellow oily substance 15.0g of 2-bromobenzenesulfinic acid VII with yield 86.6% and HPLC purity 98.47%.
Example 3: preparation of 2-bromobenzenesulfinic acid VII
Figure BDA0001529563890000171
24.90g of sodium sulfite was dissolved in water at 30 ℃ to prepare a 150mL solution, 33.00g of sodium carbonate was dissolved in water at 30 ℃ to prepare a 150mL solution, and the two solutions were mixed and stirred at 30 ℃ for 10 minutes. Under the protection of nitrogen, 20g of 2-bromobenzenesulfonyl chloride VIII are slowly added dropwise at 30 ℃ and stirred for 3 hours at 30 ℃. Vacuum concentrating (temperature 55-75 ℃, pressure-0.085 MPa-0.1 MPa) to remove most of the solvent, adding 160mL of ethanol, stirring at 75 ℃ for 0.5 hour, then cooling to 10-20 ℃ and stirring for 0.5 hour. Filtration afforded an off-white solid. Adding 80mL of acetonitrile, and stirring at 10-20 ℃ for 1 hour. Filtration afforded an off-white solid. Adding 80mL of water and 80mL of toluene, dropwise adding 2mol/L hydrochloric acid at 5-15 ℃ to adjust the pH value to 3-4, and stirring for 0.5 hour. Standing for layering, extracting the aqueous phase twice with 40mL of toluene, combining the organic phases, washing twice with a saline solution with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution), and drying with anhydrous sodium sulfate. Filtering, and vacuum concentrating (temperature 45-55 deg.C, pressure-0.085 MPa-0.1 MPa) to obtain light yellow oily substance 15.3g of 2-bromobenzenesulfinic acid VII with yield of 88.4% and HPLC purity of 98.49%.
Example 4: preparation of methyl 2-bromobenzenesulfinate VI
Figure BDA0001529563890000181
Under the protection of nitrogen, 12.2g of 2-bromobenzenesulfinic acid VII is added into 120mL of methanol, stirring at 15-20 ℃, adding 14.8g of dicyclohexylcarbodiimide and 68mg of 4-dimethylaminopyridine, stirring for 1 hour at 15-20 ℃, adding 200mL of water and 100mL of ethyl acetate, stirring, standing for layering, extracting the aqueous phase twice with 50mL of ethyl acetate, combining the organic phase with 100mL of hydrochloric acid with the mass concentration of 5% (the mass concentration refers to the mass percentage of hydrogen chloride to the total mass of the aqueous solution of hydrochloric acid), 100mL of sodium bicarbonate aqueous solution with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium bicarbonate to the total mass of the aqueous solution of sodium bicarbonate), and 100mL of saline solution with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride to the total mass of the saline solution), washing twice, and drying with anhydrous sodium sulfate. Filtering, and vacuum concentrating (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 13.0g of light yellow oily matter which is 2-bromobenzenesulfinic acid methyl ester VI, the yield is 100%, and the HPLC purity is 95.81%.
Example 5: preparation of methyl 2-bromobenzenesulfinate VI
Figure BDA0001529563890000182
Under the protection of nitrogen, adding 12.2g of 2-bromobenzenesulfinic acid VII into 180mL of methanol, stirring at 10-15 ℃, adding 20.1g of dicyclohexylcarbodiimide and 340mg of 4-dimethylaminopyridine, stirring for 0.5 hour at 10-15 ℃, adding 200mL of water and 100mL of ethyl acetate, stirring, standing for layering, extracting the aqueous phase with 50mL of ethyl acetate for three times, combining the organic phase with 100mL of hydrochloric acid with the mass concentration of 3% (the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution), 100mL of sodium bicarbonate aqueous solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of sodium bicarbonate in the total mass of the sodium bicarbonate aqueous solution), and 100mL of saline solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the sodium bicarbonate aqueous solution), washing for three times, and drying with anhydrous sodium sulfate. Filtering, and vacuum concentrating (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 13.0g of light yellow oily matter which is 2-bromobenzenesulfinic acid methyl ester VI, the yield is 100%, and the HPLC purity is 94.76%.
Example 6: preparation of methyl 2-bromobenzenesulfinate VI
Figure BDA0001529563890000191
12.2g 2-bromobenzenesulfinic acid VII was added to 61mL of methanol under nitrogen, stirring at 25-30 ℃, adding 12.1g of dicyclohexylcarbodiimide and 34mg of 4-dimethylaminopyridine, stirring for 2 hours at 25-30 ℃, adding 200mL of water and 100mL of ethyl acetate, stirring, standing for layering, extracting the aqueous phase once with 50mL of ethyl acetate, combining the organic phase with 100mL of hydrochloric acid with the mass concentration of 10% (the mass concentration refers to the mass percentage of hydrogen chloride to the total mass of the hydrochloric acid aqueous solution), 100mL of potassium bicarbonate aqueous solution with the mass concentration of 20% (the mass concentration refers to the mass percentage of potassium bicarbonate to the total mass of the potassium bicarbonate aqueous solution), and 100mL of saline solution with the mass concentration of 25% (the mass concentration refers to the mass percentage of sodium chloride to the total mass of the saline solution), washing once, and drying with anhydrous sodium sulfate. Filtering, and vacuum concentrating (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 13.0g of light yellow oily matter which is 2-bromobenzenesulfinic acid methyl ester VI, the yield is 100%, and the HPLC purity is 95.75%.
Example 7: preparation of vortioxetine intermediate V
Figure BDA0001529563890000192
Under nitrogen protection, 120mL of toluene was charged with 10.0g of methyl 2-bromobenzenesulfinate VI and 11.9g of Boc piperazine, and after vacuum degassing and nitrogen substitution, 0.122g of tris (dibenzylideneacetone) dipalladium and 0.265g of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine and 8.2g of sodium tert-butoxide were added, and after further vacuum degassing and nitrogen substitution, the mixture was heated to 80 ℃ and stirred for 18 hours. After cooling, the mixture was filtered, and the filtrate was washed twice with 100mL of a 10% by mass aqueous sodium bicarbonate solution (the mass concentration is the mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 100mL of a 15% by mass saline solution (the mass concentration is the mass percentage of sodium chloride to the total mass of the saline solution), and dried over anhydrous sodium sulfate. Adding 0.5g of activated carbon, heating to 95 ℃, stirring for 2 hours, cooling, filtering, and concentrating under vacuum (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 13.8g of light yellow oily matter which is the vortioxetine intermediate V, wherein the yield is 95.3%, and the HPLC purity is 91.76%.
Example 8: preparation of vortioxetine intermediate V
Figure BDA0001529563890000201
Under nitrogen protection, 10.0g of methyl 2-bromobenzenesulfinate VI and 15.9g of Boc piperazine were added to 200mL of xylene, and after vacuum degassing and nitrogen substitution, 0.244g of tris (dibenzylideneacetone) dipalladium and 0.530g of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine and 12.3g of sodium tert-butoxide were added, and after further vacuum degassing and nitrogen substitution, the mixture was heated to 70 ℃ and stirred for 15 hours. After cooling, the mixture was filtered, and the filtrate was washed once with 100mL of a 5% by mass aqueous sodium bicarbonate solution (the mass concentration is a mass percentage of sodium bicarbonate to the total mass of the aqueous sodium bicarbonate solution) and 100mL of a 25% by mass saline solution (the mass concentration is a mass percentage of sodium chloride to the total mass of the saline solution), and dried over anhydrous sodium sulfate. Adding 0.5g of activated carbon, heating to 95 ℃, stirring for 2 hours, cooling, filtering, and concentrating under vacuum (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 13.9g of light yellow oily matter which is the vortioxetine intermediate V, wherein the yield is 96.0%, and the HPLC purity is 91.96%.
Example 9: preparation of vortioxetine intermediate V
Figure BDA0001529563890000202
Under nitrogen protection, 10.0g of methyl 2-bromobenzenesulfinate VI and 9.12g of Boc piperazine were added to 100mL of benzene, and after vacuum degassing and nitrogen substitution, 0.061g of tris (dibenzylideneacetone) dipalladium and 0.133g of 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine and 5.2g of sodium tert-butoxide were added, and after further vacuum degassing and nitrogen substitution, the mixture was heated to 90 ℃ and stirred for 20 hours. After cooling, filtering, washing the filtrate for three times by 100mL of potassium bicarbonate aqueous solution with the mass concentration of 15% (the mass concentration refers to the mass percentage of the potassium bicarbonate to the total mass of the potassium bicarbonate aqueous solution) and 100mL of saline solution with the mass concentration of 10% (the mass concentration refers to the mass percentage of the sodium chloride to the total mass of the saline solution), and drying by using anhydrous sodium sulfate. Adding 0.5g of activated carbon, heating to 95 ℃, stirring for 2 hours, cooling, filtering, and concentrating under vacuum (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 13.5g of light yellow oily matter which is the vortioxetine intermediate V, wherein the yield is 93.2%, and the HPLC purity is 92.07%.
Example 10: preparation of vortioxetine intermediate IV
Figure BDA0001529563890000211
Under the protection of nitrogen, 9.8g of 2, 4-dimethyl iodobenzene is added into 46mL of tetrahydrofuran, 21mL of isopropyl magnesium chloride tetrahydrofuran solution (2mol/L) is added dropwise at 15-25 ℃, and the mixture is stirred for 1.5 hours at 15-25 ℃ to obtain a mixed solution. Dissolving 11.5g of vortioxetine intermediate V in 46mL of tetrahydrofuran, dropwise adding the mixed solution into the tetrahydrofuran solution of the vortioxetine intermediate V at 15-25 ℃, and stirring for 3 hours at 15-25 ℃. Then, 20mL of aqueous solution of ammonium chloride with the mass concentration of 10% (the mass concentration refers to the mass percentage of the ammonium chloride in the total mass of the aqueous solution of the ammonium chloride) is dripped to carry out quenching reaction, 80mL of water is added, and the mixture is stirred, kept stand and layered; after the water layer is separated out, extracting twice by using 50mL of methyl tert-butyl ether, combining organic phases, washing twice by using 50mL of saline solution with the mass concentration of 15% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution), drying by using anhydrous sodium sulfate, filtering, and concentrating under vacuum (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 14.7g of yellow oily matter which is the vortioxetine intermediate IV, wherein the yield is 100%, and the yellow oily matter is directly put into the next step.
Example 11: preparation of vortioxetine intermediate III
Figure BDA0001529563890000221
Under the protection of nitrogen, 118mL of methanolic hydrogen chloride solution (2mol/L) was added with IV14.7g of the vortioxetine intermediate obtained in example 10, and stirred at 15-25 ℃ for 2 hours. Vacuum concentration (-0.085MPa to-0.1 MPa, 45-55 ℃) to remove the organic solvent. Adding 88mL of isopropanol and 44mL of isopropyl acetate, heating to 70-75 ℃, stirring for 1 hour, cooling to 5-10 ℃, stirring for 1 hour, filtering, washing with 22mL of isopropyl acetate, and drying in vacuum (the temperature is 45-55 ℃, the vacuum degree is-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 8.57g of a white-like solid which is the vortioxetine intermediate III, wherein the yield is 72.3%, and the HPLC purity is 99.42%.
Example 12: preparation of vortioxetine intermediate IV
Figure BDA0001529563890000222
Under the protection of nitrogen, 15.7g of 2, 4-dimethyl iodobenzene is added into 92mL of 2-methyl tetrahydrofuran, 34mL of isopropyl magnesium chloride tetrahydrofuran solution (2mol/L) is added dropwise at 10-20 ℃, and the mixture is stirred for 1 hour at 10-20 ℃ to obtain a mixed solution. Dissolving 11.5g of vortioxetine intermediate V in 92mL of 2-methyltetrahydrofuran, dropwise adding the mixed solution into a 2-methyltetrahydrofuran solution of the vortioxetine intermediate V at the temperature of 10-20 ℃, and stirring for 5 hours at the temperature of 10-20 ℃. Then, 20mL of aqueous solution of ammonium chloride with the mass concentration of 20% (the mass concentration refers to the mass percentage of the ammonium chloride in the total mass of the aqueous solution of the ammonium chloride) is added dropwise for quenching reaction, 80mL of water is added, and the mixture is stirred, kept stand and layered; after the water layer is separated out, extracting with 50mL of methyl tert-butyl ether for three times, combining the organic phases, washing with 50mL of 10% saline solution (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution) for three times, drying with anhydrous sodium sulfate, filtering, and concentrating under vacuum (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 15.2g of yellow oily matter which is the vortioxetine intermediate IV, wherein the yield is 100%, and the yellow oily matter is directly put into the next step.
Example 13: preparation of vortioxetine intermediate III
Figure BDA0001529563890000231
To 122mL of a methanolic hydrogen chloride solution (2mol/L) was added IV15.2g of the vortioxetine intermediate obtained in example 12 under a nitrogen atmosphere, and the mixture was stirred at 15 to 25 ℃ for 2 hours. Vacuum concentration (-0.085MPa to-0.1 MPa, 45-55 ℃) to remove the organic solvent. Adding 88mL of isopropanol and 44mL of isopropyl acetate, heating to 70-75 ℃, stirring for 1 hour, cooling to 5-10 ℃, stirring for 1 hour, filtering, washing with 22mL of isopropyl acetate, and drying in vacuum (the temperature is 45-55 ℃, the vacuum degree is-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 8.49g of a white-like solid which is the vortioxetine intermediate III, wherein the yield is 71.6%, and the HPLC purity is 99.49%.
Example 14: preparation of vortioxetine intermediate IV
Figure BDA0001529563890000232
Under the protection of nitrogen, 9.02g of 2, 4-dimethyl iodobenzene is added into 23mL of 1, 4-dioxane, 19.3mL of isopropyl magnesium chloride tetrahydrofuran solution (2mol/L) is added dropwise at 10-20 ℃, and the mixture is stirred for 3 hours at 10-20 ℃ to obtain a mixed solution. Dissolving 11.5g of vortioxetine intermediate V in 23mL of 1, 4-dioxane, dropwise adding the mixed solution into the 1, 4-dioxane solution of vortioxetine intermediate V at the temperature of 20-30 ℃, and stirring for 2 hours at the temperature of 20-30 ℃. Then, 30mL of aqueous solution of ammonium chloride with the mass concentration of 5% (the mass concentration refers to the mass percentage of the ammonium chloride in the total mass of the aqueous solution of the ammonium chloride) is dripped for quenching reaction, 80mL of water is added, and the mixture is stirred, kept stand and layered; extracting the separated water layer once by using 70mL of methyl tert-butyl ether, combining the organic phases, washing the combined organic phases once by using 70mL of saline solution with the mass concentration of 25% (the mass concentration refers to the mass percentage of sodium chloride in the total mass of the saline solution), drying the organic phases by using anhydrous sodium sulfate, filtering and concentrating the organic phases in vacuum (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 14.6g of yellow oily matter which is the vortioxetine intermediate IV, wherein the yield is 100%, and directly putting the yellow oily matter into the next step.
Example 15: preparation of vortioxetine intermediate III
Figure BDA0001529563890000241
Under the protection of nitrogen, 117mL of methanolic hydrogen chloride solution (2mol/L) was added with 14.6g of vortioxetine intermediate IV14 obtained in example 14, and stirred at 15-25 ℃ for 2 hours. Vacuum concentration (-0.085MPa to-0.1 MPa, 45-55 ℃) to remove the organic solvent. Adding 88mL of isopropanol and 44mL of isopropyl acetate, heating to 70-75 ℃, stirring for 1 hour, cooling to 5-10 ℃, stirring for 1 hour, filtering, washing with 22mL of isopropyl acetate, and drying in vacuum (the temperature is 45-55 ℃, the vacuum degree is-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 8.51g of a white-like solid which is the vortioxetine intermediate III, wherein the yield is 71.8%, and the HPLC purity is 99.26%.
Example 16: preparation of vortioxetine intermediate II
Figure BDA0001529563890000242
Under the protection of nitrogen, adding 8.0g of vortioxetine intermediate III, 58mg of iodine and 8.2g of magnesium chips into 80mL of methanol, and stirring at 15-25 ℃ for 18 hours. Filtering, adding 100mL of sodium thiosulfate aqueous solution with the mass concentration of 5% (the mass concentration refers to the mass percentage of the sodium thiosulfate in the total mass of the sodium thiosulfate aqueous solution), and carrying out vacuum concentration (-0.085MPa to-0.1 MPa, 45-55 ℃) to remove most of methanol. 100mL of a 10% sodium bicarbonate aqueous solution (the mass concentration refers to the mass percentage of the sodium bicarbonate to the total mass of the sodium bicarbonate aqueous solution) was added, and the mixture was extracted twice with 50mL of ethyl acetate. And the organic phase is combined, washed twice by 50mL of saturated saline solution, dried by anhydrous sodium sulfate, filtered and concentrated in vacuum (-0.085MPa to-0.1 MPa, 45-55 ℃) to obtain 6.55g of light yellow oily matter which is the vortioxetine intermediate II, the yield is 96.3%, and the HPLC purity is 98.41%.
Example 17: preparation of vortioxetine hydrobromide I
Figure BDA0001529563890000251
Under the protection of nitrogen, 6.5g of vortioxetine intermediate II is added into 65mL of toluene, 26mL of hydrobromic acid aqueous solution with the mass concentration of 40% (the mass concentration refers to the mass percentage of hydrogen bromide in the total mass of the hydrobromic acid aqueous solution) is added under stirring at 15-25 ℃, the mixture is heated to 60 ℃, stirred for 1 hour, and then cooled to 0-5 ℃ and stirred for 2 hours. Filtering, and vacuum drying (the temperature is 45-55 ℃, the vacuum degree is-0.01 MPa to-0.1 MPa) for 12-16 hours to obtain a white-like solid 7.74g which is a crude vortioxetine hydrobromide I product. Adding 15.5mL of anhydrous methanol and 46.5mL of ethyl acetate into the vortioxetine hydrobromide I crude product, heating to 60 ℃, stirring for 1 hour, cooling to 0-5 ℃, and stirring for 2 hours. Filtering, washing with 20mL of ethyl acetate, and vacuum drying (the temperature is 45-55 ℃, the vacuum degree is-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 6.23g of an off-white solid which is vortioxetine hydrobromide I. The yield was 75.4%, the HPLC purity was 99.76%, the maximum single impurity was 0.068%, and the palladium content remained at 6 ppm. LC-MS: 299.2(M + H)+)，1H-NMR(d6-DMSO,400MHz)：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)。
Comparative examples
Figure BDA0001529563890000261
Under nitrogen protection, 8.15g of sodium tert-butoxide, 8.44g of piperazine, 0.066g of tris (dibenzylideneacetone) dipalladium, and 0.136g of 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine were added to 80mL of toluene, and after stirring for 50 minutes, 8.40g of 2-bromoiodobenzene and 30mL of toluene were added, and further stirring was carried out for 30 minutes. 3.91g of 2, 4-dimethylthiophenol and 30mL of toluene were added, and the mixture was heated to 110 ℃ and refluxed for 5 hours. After cooling, 80mL of water was added and the mixture was stirred for 1 hour. Filtering, washing and vacuum drying (the temperature is 45-55 ℃, the vacuum degree is-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 7.61g of yellow solid which is the crude product of the vortioxetine hydrobromide I. Adding 15.5mL of anhydrous methanol and 46.5mL of ethyl acetate into the vortioxetine hydrobromide I crude product, heating to 60 ℃, stirring for 1 hour, cooling to 0-5 ℃, and stirring for 2 hours. Filtering, washing with 20mL of ethyl acetate, and vacuum drying (the temperature is 45-55 ℃, the vacuum degree is-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 4.97g of a white-like solid which is a one-time refined product of vortioxetine hydrobromide, the yield is 46.3%, the HPLC purity is 98.79%, and the maximum single impurity is 0.56%. 25ppm of palladium remained.
Adding 28mL of anhydrous methanol into the primary refined vortioxetine hydrobromide product, and adsorbing and removing palladium by using N-acetyl-L-cysteine to obtain 4.49g of the refined vortioxetine hydrobromide product after palladium removal, wherein the yield is 90.3%. 7ppm of palladium remained.
Adding 8.5mL of anhydrous methanol and 25.2mL of ethyl acetate into the refined product of vortioxetine hydrobromide after palladium removal, heating to 60 ℃, stirring for 1 hour, cooling to 0-5 ℃, and stirring for 2 hours. Filtering, washing with 11mL of ethyl acetate, and vacuum drying (the temperature is 45-55 ℃, the vacuum degree is-0.01 MPa-0.1 MPa) for 12-16 hours to obtain 3.37g of an off-white solid which is vortioxetine hydrobromide I. Yield 75.1% (total yield of the whole route 31.4%), HPLC purity 99.75%, maximum single impurity 0.079%.

Claims (10)

1. A preparation method of vortioxetine intermediate IV is characterized by comprising the following steps: performing Grignard reaction on the vortioxetine intermediate V, 2, 4-dimethyl iodobenzene and isopropyl magnesium chloride in an organic solvent to obtain a vortioxetine intermediate IV; the molar ratio of the 2, 4-dimethyl iodobenzene to the vortioxetine intermediate V is 1.0-5.0; the molar ratio of the isopropyl magnesium chloride to the vortioxetine intermediate V is 1.0-5.0; the temperature of the Grignard reaction is-5 ℃ to 35 ℃; the time of the Grignard reaction is 1 to 10 hours;
Figure FDA0002250927370000011
the preparation method of vortioxetine intermediate IV further comprises a preparation method of vortioxetine intermediate V, and comprises the following steps: in an organic solvent, under the catalysis of tris (dibenzylideneacetone) dipalladium and 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine and in the presence of alkali, carrying out nucleophilic substitution reaction on 2-bromobenzenesulfinic acid methyl ester and 1-tert-butoxycarbonylpiperazine to obtain the vortioxetine intermediate V;
Figure FDA0002250927370000012
2. the process for preparing vortioxetine intermediate IV according to claim 1, wherein:
the preparation method of the vortioxetine intermediate IV is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate IV, the organic solvent is an ether solvent;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate IV, the volume-to-mass ratio of the organic solvent to the sitagliptin intermediate V is 1 mL/g-30 mL/g;
and/or the presence of a gas in the gas,
the preparation method of the vortioxetine intermediate IV comprises the following steps: adding a solution formed by isopropyl magnesium chloride and an organic solvent into a mixture formed by 2, 4-dimethyl iodobenzene and the organic solvent, and stirring; and then adding a solution formed by the vortioxetine intermediate V and an organic solvent, and carrying out a Grignard reaction to obtain the vortioxetine intermediate IV.
3. The process for preparing vortioxetine intermediate IV according to claim 1, wherein:
the preparation method of the vortioxetine intermediate V is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate V, the organic solvent is an aromatic solvent;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate V, the volume-mass ratio of the organic solvent to the methyl 2-bromobenzenesulfinate VI is 1 mL/g-50 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of vortioxetine intermediate V, the base is an inorganic base;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate V, the molar ratio of the alkali to the 2-bromobenzenesulfinic acid methyl ester VI is 1-5;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate V, the molar ratio of the 1-tert-butyloxycarbonyl piperazine to the 2-bromobenzenesulfinic acid methyl ester VI is 1-5;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate V, the molar ratio of the tris (dibenzylideneacetone) dipalladium to the 2-bromobenzenesulfinic acid methyl ester VI is 0.001-0.1;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate V, the molar ratio of the 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine to the 2-bromobenzenesulfinic acid methyl ester VI is 0.002-0.2;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate V, the temperature of the nucleophilic substitution reaction is 40-100 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the vortioxetine intermediate V, the time of the nucleophilic substitution reaction is 10 hours to 30 hours.
4. The process for preparing vortioxetine intermediate IV according to claim 1, wherein:
the preparation method of the vortioxetine intermediate IV further comprises a preparation method of 2-bromobenzenesulfinic acid methyl ester VI, and comprises the following steps: under the condition of the existence of a condensing agent and a catalyst, 2-bromobenzenesulfinic acid VII and methanol are subjected to condensation reaction to obtain 2-bromobenzenesulfinic acid methyl ester VI;
Figure FDA0002250927370000031
5. the process for preparing vortioxetine intermediate IV according to claim 4, wherein:
the preparation method of the 2-bromobenzenesulfinic acid methyl ester VI is carried out under the protection of protective gas;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid methyl ester VI, the methanol is used as a reaction solvent and a reaction reagent; the volume-mass ratio of the methanol to the 2-bromobenzenesulfinic acid VII is 1 mL/g-30 mL/g;
and/or the presence of a gas in the gas,
in the preparation method of the methyl 2-bromobenzenesulfinate VI, the catalyst is 4-dimethylaminopyridine;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid methyl ester VI, the molar ratio of the catalyst to the 2-bromobenzenesulfinic acid VII is 0.001-0.1;
and/or the presence of a gas in the gas,
in the preparation method of the methyl 2-bromobenzenesulfinate VI, the condensing agent is dicyclohexylcarbodiimide;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzene sulfinic acid methyl ester VI, the molar ratio of the condensing agent to the 2-bromobenzene sulfinic acid VII is 1.0-3.0;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid methyl ester VI, the temperature of the condensation reaction is 0-35 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid methyl ester VI, the condensation reaction time is 10 minutes to 5 hours;
and/or the presence of a gas in the gas,
the preparation method of the 2-bromobenzenesulfinic acid methyl ester VI adopts the following reaction steps: adding dicyclohexylcarbodiimide and 4-dimethylaminopyridine into a mixture formed by 2-bromobenzenesulfinic acid VII and methanol, and carrying out condensation reaction to obtain the 2-bromobenzenesulfinic acid methyl ester VI.
6. The process for preparing vortioxetine intermediate IV according to claim 4, wherein:
the preparation method of the vortioxetine intermediate V further comprises a preparation method of 2-bromobenzenesulfinic acid VII, and comprises the following steps: carrying out condensation reaction on 2-bromobenzene sulfonyl chloride VIII and sodium sulfite in the presence of alkali to obtain 2-bromobenzene sodium sulfinate; then the 2-bromobenzenesulfonic acid sodium salt and acid are subjected to neutralization reaction to obtain the 2-bromobenzenesulfinic acid VII;
Figure FDA0002250927370000051
7. the process for preparing vortioxetine intermediate IV according to claim 6, wherein:
in the preparation method of the 2-bromobenzenesulfinic acid VII, the base is an inorganic base;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid VII, the molar ratio of the alkali to the 2-bromobenzenesulfonyl chloride VIII is 1-5;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid VII, the molar ratio of the sodium sulfite to the 2-bromobenzenesulfonyl chloride VIII is 1-5;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid VII, the acid is an inorganic acid;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid VII, the molar ratio of the acid to the 2-bromobenzenesulfonyl chloride VIII is 1-5;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid VII, the temperature of the condensation reaction is preferably 20-80 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid VII, the time of the condensation reaction is 10 minutes to 5 hours;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid VII, the temperature of the neutralization reaction is 0-40 ℃;
and/or the presence of a gas in the gas,
in the preparation method of the 2-bromobenzenesulfinic acid VII, the time of the neutralization reaction is 10 minutes to 2 hours;
and/or the presence of a gas in the gas,
the preparation method of the 2-bromobenzenesulfinic acid VII adopts the following reaction steps: dripping 2-bromobenzene sulfinyl chloride VIII into a solution formed by sodium sulfite and inorganic base for condensation reaction to obtain 2-bromobenzene sulfinic acid sodium sulfonate; then neutralizing with acid in solvent to obtain the 2-bromobenzenesulfinic acid VII.
8. A preparation method of vortioxetine intermediate III is characterized by comprising the following steps: after the vortioxetine intermediate IV is prepared according to the preparation method of any one of claims 1 to 7, performing an amino protecting group removing reaction on the vortioxetine intermediate IV and an acid in an organic solvent to obtain the vortioxetine intermediate III;
Figure FDA0002250927370000061
9. a preparation method of vortioxetine intermediate II is characterized by comprising the following steps: after the vortioxetine intermediate III is prepared by the preparation method according to claim 8, performing a reduction reaction on the vortioxetine intermediate III and a reducing agent in an organic solvent in the presence of a catalyst to obtain the vortioxetine intermediate II;
Figure FDA0002250927370000071
10. a preparation method of vortioxetine I is characterized by comprising the following steps: preparing vortioxetine intermediate II according to the preparation method of claim 9, and then subjecting said vortioxetine intermediate II to a salt forming reaction with hydrobromic acid in an organic solvent to obtain vortioxetine I;
Figure FDA0002250927370000072
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