CN113501795A

CN113501795A - Preparation method of novel medicine Vothiocetin for treating major depressive disorder

Info

Publication number: CN113501795A
Application number: CN202110763581.4A
Authority: CN
Inventors: 张轶
Original assignee: Beijing Zhenlv Tianyuan Technology Co ltd
Current assignee: Beijing Zhenlv Tianyuan Technology Co ltd
Priority date: 2021-07-06
Filing date: 2021-07-06
Publication date: 2021-10-15

Abstract

The invention provides a preparation method of a novel medicine vortioxetine for treating major depressive disorder, belonging to the field of medicine synthesis. The specific scheme of the invention is as follows: the thiocetin is prepared by a one-pot method by using 2, 4-dimethylthiophenol, 2-bromoiodobenzene and piperazine as starting materials and cuprous iodide as a catalyst, and organic alkali is added into a reaction system. The preparation process can effectively enable the reaction to be carried out in a homogeneous phase, so that the reaction speed is obviously increased, and the product yield is greatly improved. Solves the problems that the prior art can not form a homogeneous phase in a reaction system, has the reaction time of more than 40 hours and is not beneficial to greatly reducing the cost in the industrial production. As organic amines such as triethylamine, N-diisopropylethylamine and the like are adopted, the reaction can be carried out in a homogeneous phase, side reactions are reduced, and the yield and the purity are greatly improved. Piperazine and the initial material are not added simultaneously, the feeding step is optimized, the generation of side reactions is reduced, the processes such as filtration and the like are not added, and the processes and the equipment are not added in the industrialization.

Description

Preparation method of novel medicine Vothiocetin for treating major depressive disorder

Technical Field

The invention belongs to the field of drug development, and particularly relates to a preparation method of a drug vortioxetine.

Background

Depression is classified as one of the major non-fatal health-related disorders worldwide, with over 5400 million Chinese patients accounting for 4.2% of the population and having a prevalence of about 4.4%. Causing a serious social and economic burden. The overall diagnostic and cure rates for depression are still at a lower level compared to other diseases. Depression is a multi-dimensional disorder involving emotional, somatic, and cognitive symptoms, with the goal of treatment being a recovery of symptoms and function, and a return to normal quality of life. Drug therapy is the most common and preferred effective treatment for depression.

Vortioxetine (Vortioxetine) is a new drug for major adult depressionCompared with other depression drugs, the mean elimination half-life of the vortioxetine is as long as 66 hours, and the vortioxetine can be taken once a day; its absorption is not affected by food. The medicine has relatively mild adverse reaction. The dosage of the medicine is not required to be adjusted by a person with renal function impairment, and the dosage of the medicine is not required to be adjusted by a person with mild and moderate hepatic function impairment. The oral administration bioavailability of the product is high, reaches about 75%, the plasma binding rate is about 98%, the curative effect is obvious, and the product can be used for treating major depressive disorder. Vortioxetine is a novel antidepressant drug developed by North Pharmaceutical Danmate (Lundbeck) and Wutan drug company, Japan (Takeda Pharmaceutical). The drug was approved by the U.S. Food and Drug Administration (FDA) on the market in 2013, under the trade name brinellix. The medicine is 5-HT3, 5-HT7, 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter inhibitor, has antidepressant effect by regulating 5-HT, and mainly acts on various serotonin (5-HT) receptors. Has high affinity with 5-HT transporter and lower affinity with noradrenaline transporter and dopamine transporter. Increasing the level of norepinephrine and acetylcholine, improving mood and cognition, enhancing SSRIs and SNRIs effects, and exerting resistance for treating adult major depressive disorder. A plurality of clinical researches show that the vortioxetine has better curative effect on treating adult major depression (MDD), is superior to medicaments such as doloxetine, citalopram and the like, and has good safety and tolerance. The chemical name of vortioxetine is: 1- [2- (2, 4-Dimethylphenylsulfanyl) -phenyl]Piperazine of formula C₁₈H₂₃BrN₂S, molecular weight of 378.08, structure as follows:

at present, the synthetic methods reported by Vortioxetine are more, and the methods related to the invention are listed as follows:

(1) reacting 2, 4-dimethylthiophenol serving as a raw material with o-chloroiodobenzene to generate 2- (2, 4-dimethylthiophenyl) iodobenzene, reacting with piperazine to generate vortioxetine, and salifying to obtain the target compound. The reaction route has low yield, needs expensive palladium and phosphine ligand for catalysis, has high cost and is not suitable for industrial production.

(2)2, 4-dimethyl iodobenzene, 2-bromobenzothiophenol and piperazine are catalyzed by bis (dibenzylideneacetone) palladium and sodium tert-butoxide to prepare vortioxetine by one-pot boiling; the reaction route has competing side reactions of double halogens, more byproducts, low product purity, low yield, complex subsequent purification problems and difficulty in industrial production.

(3)2, 4-dimethylthiophenol, 2-bromoiodobenzene and piperazine (or 1-BOC-piperazine) are catalyzed by bis (dibenzylideneacetone) palladium, 1 '-binaphthyl-2, 2' -bis-diphenylphosphine and sodium tert-butoxide to prepare vortioxetine or vortioxetine protected by Boc, and the process method also has the problem of low product purity;

(4) preparing (2-bromophenyl) (2, 4-dimethylphenyl) sulfide from 2, 4-dimethylthiophenol and 2-bromoiodobenzene under the catalysis of bis (dibenzylideneacetone) palladium, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine and sodium tert-butoxide, and preparing vortioxetine or BOC-protected vortioxetine from piperazine (or 1-BOC-piperazine) under the catalysis of bis (dibenzylideneacetone) palladium, 1 '-binaphthyl-2, 2' -bisdiphenylphosphine and sodium tert-butoxide. Compared with a one-pot method, the preparation method has the advantages that the steps are complicated, the reaction time can be shortened only by adding a filtering step in the middle of the process, and the conversion rate is improved.

The methods (1) to (4) all adopt a palladium complex catalyst and ligand phosphine, are expensive and difficult to purchase, have high toxicity of the ligand phosphine, are limited in application and are not beneficial to industrial production. In addition, in order to meet the medicinal requirements of vortioxetine hydrobromide, the content of metal palladium in the final product needs to be strictly controlled, and a medicine purification step and monitoring indexes need to be added.

(5) The synthesis method reported in pharmaceutical research 2014,33(4): 241-one 243 adopts 2, 4-dimethylthiophenol, 2-bromoiodobenzene and piperazine as raw materials, and cuprous iodide, ethylene glycol and potassium phosphate are adopted for catalysis to prepare the vortioxetine by adopting a one-pot method. However, the reaction rate is too slow to improve the industrial efficiency.

The existing synthesis method has the problems of expensive catalyst, high cost, slow reaction rate and the like.

Disclosure of Invention

Aiming at the defects, the invention provides the preparation method of the Vortictin with the advantages of easily obtained raw materials, simple process, low cost, high purity and suitability for industrial production.

The purpose of the invention is realized by the following technical scheme.

The invention provides a preparation method of vortioxetine, which comprises the following synthetic steps:

the thiocetin is prepared by using 2, 4-dimethylthiophenol, 2-bromoiodobenzene and piperazine as starting materials and cuprous iodide as a catalyst through a one-pot method, and is characterized in that the alkali is organic alkali.

Preferably, the organic base is triethylamine or N, N-diisopropylethylamine.

Further preferably, the organic base is 1.5 to 3.0 times the mole number of the starting material, 2, 4-dimethylthiophenol.

Preferably, the cuprous iodide is 3-10% of the mole number of the starting material, 2, 4-dimethylthiophenol.

Preferably, the solvent in the reaction system is isopropanol.

The invention also aims to provide a preparation method of vortioxetine hydrobromide, which comprises the following synthetic steps:

the preparation method is characterized in that the thiocetin is prepared by a one-pot method by using 2, 4-dimethylthiophenol, 2-bromoiodobenzene and piperazine as starting materials and cuprous iodide as a catalyst, and then salified with hydrobromic acid, and the method is characterized in that the alkali is organic alkali.

Preferably, the organic base is triethylamine or N, N-diisopropylethylamine.

Preferably, the organic base is 1.5 to 3.0 times the mole number of the 2, 4-dimethylthiophenol as the starting material.

Preferably, the solvent in the reaction system is isopropanol; the concentration of the hydrobromic acid is 1.0-2.0 mol/L.

Compared with the prior art, the invention has the advantages that:

the invention adopts a one-pot method to prepare the target product and has simple operation. Meanwhile, cheap cuprous iodide catalyst is used, and the reaction cost is reduced. In addition, organic amines such as triethylamine, N-diisopropylethylamine and the like are adopted, so that the reaction can be carried out in a homogeneous phase, and the reaction speed is increased. The alkali disclosed by the prior art is potassium phosphate, is organic weak alkali, cannot form a homogeneous phase in a reaction system, so that the reaction time is as long as more than 40 hours, and the industrial production is not facilitated. The technical scheme provided by the invention effectively solves the problems, and the reaction raw materials with the same mole number can be completely reacted only in 4-5 h.

Although the compounds prepared by the one-pot method are mostly prepared by the one-pot method, the reaction can be carried out in a homogeneous phase due to the adoption of organic amines such as triethylamine, N-diisopropylethylamine and the like, so that the side reaction is reduced, and the yield is greatly improved. And the purity of the vortioxetine compound and the hydrobromic acid is greatly improved. In addition, piperazine and the starting materials are not added at the same time, the feeding step is optimized, the generation of side reactions is reduced, the processes such as filtration and the like are not added, and the processes, the equipment and the like are not added in the industrialization. The detection of metal palladium is not needed, and the toxicity of ligand phosphine is not limited.

Detailed Description

The invention is described in detail below with reference to the description and the specific examples.

Example 1

The reaction route is as follows:

under the protection of nitrogen, 2, 4-dimethylthiophenol (13.8g, 0.1mol), 2-bromoiodobenzene (28.3g, 0.1mol), piperazine (8.6g, 0.1mol), triethylamine (27.7mL, 0.2mol) and cuprous iodide (1g, 0.005mol) are sequentially put into a 500mL reaction bottle, isopropanol (300mL) is added, the temperature is raised to reflux under stirring, the reaction is carried out for 5 hours, the temperature is reduced to room temperature, the filtration is carried out, the filtrate is decompressed and evaporated to dryness, and the residue is added with 300mL acetonitrile for recrystallization to obtain a white solid.

This solid was dissolved in 100mL of isopropanol, 67mL (30mmol) of 1.5mol/L hydrobromic acid was added dropwise at room temperature, stirred for 1h, then cooled in ice water and stirred for 1h, filtered, the filter cake was washed with isopropanol (10mL × 2), dried under vacuum at 50 ℃ to give 33.8g of white solid with a yield of 89%. Purity 99.7%, maximum single hetero 1%.¹H-NMR(DMSO－d6)δ:8.83(bs，2H)，7.34(d，1H)，7.26(s，1H)，7.14(m，3H)，6.97(dd，1H)，6.42(d，1H)，3.26(bm，4H)，3.21(bm，4H)，2.33(s，3H)，2.25(s，3H)。

The purity determination method comprises the following steps: column chromatography was used for X-Eridge (50 × 4.6mm, 2.5 μm), with ph4.5 ammonium acetate buffer, buffer: water: methanol 10:55:35 as mobile phase a, ammonium acetate buffer: methanol 10:90 as mobile phase B, gradient elution according to the following table, flow rate of 1.8mL per minute, detection wavelength of 226nm, column temperature of 40 ℃. (the following examples also test according to this method)

Example 2

The reaction route is as follows:

under the protection of nitrogen, 2, 4-dimethylthiophenol (13.8g, 0.1mol), 2-bromoiodobenzene (28.3g, 0.1mol), piperazine (8.6g, 0.1mol), DIPEA (34.8mL, 0.2mol) and cuprous iodide (1g, 0.005mol) are sequentially put into a 500mL reaction bottle, isopropanol (300mL) is added, the temperature is raised to reflux under stirring, the reaction is carried out for 4h, the temperature is reduced to room temperature, the filtration is carried out, the filtrate is decompressed and evaporated to dryness, and the residue is added with 300mL acetonitrile for recrystallization to obtain a white solid.

The solid was dissolved in 100mL of isopropanol, 67mL (30mmol) of 1.5mol/L hydrobromic acid was added dropwise at room temperature, stirred for 1h, then cooled in ice water and stirred for 1h, filtered, the filter cake was washed with isopropanol (10mL × 2), dried under vacuum at 50 ℃ to give 34.1g of white solid, yield 90%, purity: 99.5 percent and maximum single impurity of 0.10 percent.

Example 3

The reaction route is as follows:

under the protection of nitrogen, 2, 4-dimethylthiophenol (13.8g, 0.1mol), 2-bromoiodobenzene (28.3g, 0.1mol), pyridine (24.1mL, 0.3mol), piperazine (8.6g, 0.1mol) and cuprous iodide (1g, 0.005mol) are sequentially put into a 500mL reaction bottle, isopropanol (300mL) is added, the temperature is raised to reflux under stirring, the reaction is carried out for 25h, the temperature is reduced to room temperature, suction filtration is carried out, filtrate is decompressed and evaporated to dryness, 300mL acetonitrile is added into residues for recrystallization, 16.68g of solid is obtained, the yield is 56.0%, and the purity is 85%.

Through parallel experiments of examples 1-3, triethylamine, DIPEA and pyridine can react, but the triethylamine and DIPEA are used as bases, and the preferable scheme is that the yield and the purity are better.

Example 4

The reaction route is as follows:

under the protection of nitrogen, 2, 4-dimethylthiophenol (13.8g, 0.1mol), 2-bromoiodobenzene (28.3g, 0.1mol), DIPEA (34.8mL, 0.2mol) and cuprous iodide (1g, 0.005mol) are sequentially put into a 500mL reaction bottle, isopropanol (300mL) is added, the temperature is raised to reflux under stirring, the reaction is carried out for 2h, piperazine (8.6g, 0.1mol) is added, the reaction is carried out for 2h, the temperature is reduced to room temperature, the filtration is carried out, the filtrate is decompressed and evaporated to dryness, and the residue is added with 300mL acetonitrile for recrystallization to obtain a white solid.

The solid was dissolved in 100mL of isopropanol, 67mL (30mmol) of 1.5mol/L hydrobromic acid was added dropwise at room temperature, stirred for 1h, then cooled in ice water and stirred for 1h, filtered, the filter cake was washed with isopropanol (10mL × 2), dried under vacuum at 50 ℃ to give 36.3g of white solid, yield 96%, purity 99.1%, max mono 0.09.

Example 5

The reaction route is as follows:

under the protection of nitrogen, 2, 4-dimethylthiophenol (13.8g, 0.1mol), 2-bromoiodobenzene (28.3g, 0.1mol), triethylamine (27.7mL, 0.2mol) and cuprous iodide (1g, 0.005mol) are sequentially put into a 500mL reaction bottle, isopropanol (300mL) is added, the temperature is raised to reflux under stirring, the reaction is carried out for 3h, piperazine (8.6g, 0.1mol) is added for reaction for 2h, the reaction is carried out at room temperature, the filtration is carried out, the filtrate is decompressed and evaporated to dryness, and the residue is added with 300mL acetonitrile for recrystallization to obtain a white solid.

This solid was dissolved in 100mL of isopropanol, 67mL (30mmol) of 1.5mol/L hydrobromic acid was added dropwise at room temperature, stirred for 1h, then cooled in ice water and stirred for 1h, filtered, the filter cake was washed with isopropanol (10mL × 2), dried under vacuum at 50 ℃ to give 35.6g of a white solid with a yield of 94%. Purity 99.7%, maximum single impurity 0.05%.

Example 6

The preparation method of vortioxetine disclosed by zhangchunhua et al (pharmaceutical research, 2014,33 (1), 241-.

Under the protection of nitrogen, 2, 4-dimethylthiophenol (13.8g, 0.1mo1), 2-bromoiodobenzene (28.3g, 0.1mo1), piperazine (8.6g, 0.1mo1), potassium phosphate (42.4g, 0.2mo1) and cuprous iodide (1g, 0.005mol), ethylene glycol (12.4g, 0.005mo1) are sequentially put into a 500mL four-port bottle, isopropanol (300mL) is added, the temperature is raised to reflux under stirring, the reaction is carried out for 40h, the reaction is cooled to room temperature, the filtration is carried out, the filtrate is decompressed and evaporated to dryness, and the residue is recrystallized by adding 300mL of acetonitrile to obtain a white solid. The solid was dissolved in 200mL of isopropanol, 67mL (30mmol) of 1.5mol/L hydrobromic acid was added dropwise at room temperature, the mixture was stirred for 1 hour, and the mixture was filtered under suction to obtain 27.2g of a white solid, yield 71.7%, purity 86.0%, maximum single impurity 2.70%.

Example 7

Bis (dibenzylideneacetone) palladium (0) (0.610g, 1.06mmol), racemic 2,2 '-bis (diphenylphosphino) -1, 1' -binaphthyl (1.34g, 2.15mmol), sodium tert-butoxide (31.0g, 323mmol) and toluene (150mL) were combined. The reaction mixture was stirred at room temperature (23 ℃) under nitrogen atmosphere for 2 hours.

To the above mixture was added piperazine (23.0g, 267mmol), 1-iodo-2, 4-dimethylbenzene (25.0g, 108mmol), and 2-bromothiophenol (20.5g, 108 mmol). The reaction mixture was then heated at 100 ℃ for 5 hours and then cooled to room temperature. To the reaction mixture was added water (80mL), filtered through celite, and the toluene phase was washed with water.

The solid was dissolved in 100mL of isopropanol, 67mL (30mmol) of 1.5mol/L hydrobromic acid was added dropwise at room temperature, stirred for 1h, then cooled in ice water and stirred for 1h, filtered, the filter cake was washed with isopropanol (10mL × 2), dried under vacuum at 50 ℃ to give 28.8g of white solid in 76% yield. Purity 88.5%, maximum single impurity 2.30%.

The invention adopts the process to prepare the vortioxetine hydrobromide, and the yield or purity of the vortioxetine hydrobromide has certain advantages compared with the process reported in the literature, and the comparison table is as follows:

by the comparison, the yield and purity can be improved by adopting the piperazine post-addition process. Compared with the prior published literature methods, the methods of the embodiments 4 and 5 of the invention have the advantages of higher product and high purity.

The above embodiments are merely illustrative of the technical concepts and features of the present invention, and the purpose of the embodiments is to enable those skilled in the art to understand the contents of the present invention and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes and modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.

Claims

1. A preparation method of vortioxetine comprises the following synthesis steps:

2. The method of claim 1, wherein the organic base is triethylamine or N, N-diisopropylethylamine.

3. The method of claim 1, wherein the organic base is 1.5 to 3.0 times the mole of the starting material 2, 4-dimethylthiophenol.

4. The process for the preparation of vortioxetine according to claim 1, wherein the cuprous iodide is 3-10% mole of the starting material 2, 4-dimethylthiophenol.

5. The method for preparing vortioxetine according to claim 1, wherein the solvent in the reaction system is isopropanol.

6. A preparation method of vortioxetine hydrobromide comprises the following synthesis steps:

7. The method of claim 6, wherein the organic base is triethylamine or N, N-diisopropylethylamine.

8. The method of claim 6, wherein the organic base is 1.5 to 3.0 times the molar amount of the starting material, 2, 4-dimethylthiophenol.

9. The method of claim 6, wherein the cuprous iodide is 3-10% mole of 2, 4-dimethylthiophenol as starting material.

10. The method for preparing vortioxetine hydrobromide according to claim 6, wherein the solvent in the reaction system is isopropanol; the concentration of the hydrobromic acid is 1.0-2.0 mol/L.