Method for preparing vortioxetine prodrug precursor by catalytic c-s coupling reaction with mechanical grinding

Abstract

The application discloses a method for preparing a vortioxetine drug precursor by a mechanical grinding method catalyzed C-S coupling reaction. The technical scheme is as follows: 2,2'-diamino diphenyl disulfide and 2,4-dimethyl bromobenzene are used as raw materials, a C-S coupling reaction is carried out by using a Ni catalysis and a trace liquid assisted mechanical grinding method under a normal temperature and a solvent-free condition to prepare 2,4-dimethyl phenyl-2-piperazine phenyl sulfide, and the coupling product is obtained in a green and safe manner. The C-S coupling reaction is carried out by using the mechanical force method to prepare the vortioxetine drug precursor, the operation and treatment are simple, the raw materials are green and safe, the method is environment-friendly, a metal Ni is used for catalysis, the reaction condition is mild, and the reaction can be completed in 99 minutes.

Description

Technical Field

[0001] This invention relates to a novel method for preparing vortioxetine drug precursors through mechanical grinding and CS coupling reaction with the assistance of a trace amount of liquid, without inert gas protection or prolonged high-temperature reflux, and belongs to the field of catalysis in the synthesis of drug intermediates. Background Technology

[0002] Organosulfur compounds are an important class of organic compounds, widely found in natural products, agrochemicals, and pharmaceuticals. Sulfur atoms possess large atomic radii, strong nucleophilicity, and the ability to poison metals, making them commonly used to regulate the heterocyclic chemical arrangement in molecules, such as in penicillin, sulfonated diketopiperazine, bleomycin, and thiazolyl peptide antibiotics. Currently, there are limited methods for synthesizing sulfides, and substrate limitations are significant. Developing new synthetic methods for sulfur-containing compounds remains a hot topic and a challenging problem in synthetic and medicinal chemistry.

[0003] Vortioxetine hydrobromide is an organosulfur compound commonly used to treat depression and anxiety. It is a multi-acting antidepressant that works by inhibiting the reuptake of serotonin by neurons, thereby increasing serotonin levels and improving symptoms of depression and anxiety. It exerts its effects by altering signaling pathways of multiple neurotransmitters. It is primarily used to treat depression in adults and adolescents (13-17 years old) and can improve mood, sleep, appetite, and cognitive function. Clinical studies have shown that vortioxetine hydrobromide significantly reduces depressive symptoms and provides better tolerability compared to placebo. As an antidepressant with multiple pharmacodynamic activities, it was approved by the FDA in September 2013 under the brand name Brintellix and by the China National Medical Products Administration on November 21, 2017.

[0004] The synthesis of vortioxetine hydrobromide is relatively complex and is typically prepared through chemical synthesis. To ensure the safety and purity of the synthesis process, pharmaceutical companies usually employ more complex and efficient synthetic methods. These methods aim to improve yield, reduce the generation of byproducts and chemical waste, and ensure the purity of the final product. Some publicly disclosed synthetic routes are as follows:

[0005] Route 1:

[0006]

[0007] Route 2:

[0008]

[0009] The publicly available routes can be broadly categorized into two types: Route 1 and Route 2. Route 1 is cumbersome and lengthy, and reduces overall atom economy. Route 2 involves the use of palladium catalysts and ligands such as BINAP, the high price of which increases manufacturing costs and extends to the high price of the drug after commercialization. Summary of the Invention

[0010] To address the aforementioned technical problems, this invention provides a method for preparing vortioxetine prodrugs via a CS-catalyzed reaction under mechanical force. This invention employs mechanical grinding and a nickel-catalyzed CS-catalyzed CS-catalyzed reaction to obtain the vortioxetine prodrug. The overall route is shorter, the catalyst is reasonably priced, and production costs are effectively reduced.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is: a method for preparing vortioxetine drug precursor by mechanical grinding catalyzing CS coupling reaction, wherein the vortioxetine drug precursor is 2,4-dimethylphenyl-2-piperazine phenyl sulfide, and the preparation method includes the following steps: using 2,2'-diaminodiphenyl disulfide and 2,4-dimethylbromobenzene as raw materials, 2,4-dimethylphenyl-2-piperazine phenyl sulfide is prepared by CS coupling reaction under solvent-free conditions at room temperature using Ni catalysis and micro-liquid-assisted mechanical grinding.

[0012] Preferably, the method includes the following steps: under normal temperature conditions, 2,2'-diaminodiphenyl disulfide, 2,4-dimethylbromobenzene, zinc powder, sodium iodide, nickel iodide hydrate, 2,2'-bipyridine and trace amounts of N,N-dimethylformamide are placed in a grinding steel jar, steel balls are added, the jar is sealed, and then placed in a Retsch mixing ball mill and ground at 30 Hz for 95-100 min. The crude product obtained is then separated and purified to obtain 2,4-dimethylphenyl-2-piperazine phenyl sulfide.

[0013] Preferably, the molar ratio of 2,2'-diaminodiphenyl disulfide:2,4-dimethylbromobenzene:zinc powder:sodium iodide:nickel iodide hydrate:2,2'-bipyridine is 1:3-4.5:8:5:0.2:0.3.

[0014] More preferably, in a molar ratio of 2,2'-diaminodiphenyl disulfide:2,4-dimethylbromobenzene:zinc powder:sodium iodide:nickel iodide hydrate:2,2'-bipyridine = 1:4.2:8:5:0.2:0.3.

[0015] Preferably, the amount of trace N,N-dimethylformamide used is: 200 μL of N,N-dimethylformamide added for every 0.5 mmol of 2,2'-diaminodiphenyl disulfide.

[0016] Preferably, the steel ball has a diameter of 14 mm and a weight of 11 g.

[0017] Preferably, grinding is performed at 30 Hz for 99 minutes.

[0018] Preferably, the separation and purification are as follows: the crude product is dissolved in ethyl acetate, filtered, the resulting filtrate is washed with water, the organic phase is collected, dried with anhydrous magnesium sulfate and concentrated by vacuum distillation, and silica gel column chromatography is performed using a mixed solution of petroleum ether and ethyl acetate as eluent to obtain 2,4-dimethylphenyl-2-piperazine phenyl thioether.

[0019] Preferably, the volume ratio of petroleum ether to ethyl acetate is 65–40:1.

[0020] The beneficial effects of this invention are:

[0021] 1. The method provided by this invention employs mechanical grinding to carry out a catalytic reaction under mechanical force. The energy for the reaction comes from the mechanical energy generated by ball milling, rather than traditional thermal energy. This method not only improves the reaction yield but also increases the reaction rate and significantly shortens the reaction time. The experimental process is simplified, and the excessive use of toxic and harmful solvents is avoided, thus protecting the environment and conforming to the principles of green chemistry.

[0022] 2. The method provided by this invention uses inexpensive Ni compounds instead of Pd metal catalysts, which greatly reduces costs while achieving a reaction yield of 20%.

[0023] 3. The method provided by this invention uses mechanical catalysis to prepare CS coupling products, and only uses trace amounts of liquid to assist grinding, eliminating the use of large amounts of organic solvents, reducing reaction costs, and minimizing environmental harm. It is a green, mild, and environmentally friendly organic synthesis method.

[0024] 4. The method provided by this invention allows all reactions to be carried out under conventional conditions, without the need for high temperature, high pressure or inert gas protection, thus simplifying the experimental steps. Attached Figure Description

[0025] Figure 1 It is the 2,4-dimethylphenyl-2-piperazine phenyl sulfide prepared in Example 1. 1 H NMR spectrum.

[0026] Figure 2 It is the 2,4-dimethylphenyl-2-piperazine phenyl sulfide prepared in Example 1. 13 C NMR spectrum.

[0027] Figure 3a This is a gas chromatogram of 2,4-dimethylphenyl-2-piperazine phenyl sulfide prepared in Example 1.

[0028] Figure 3bThis is an MS chromatogram of 2,4-dimethylphenyl-2-piperazine phenyl sulfide prepared in Example 1. Detailed Implementation

[0029] To better understand the present invention, the following description, in conjunction with the embodiments, will further illustrate the present invention.

[0030] Example 1: Preparation of 2,4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding-catalyzed CS coupling reaction

[0031] The reaction formula is as follows:

[0032]

[0033] The method is as follows:

[0034] Under normal temperature conditions, 2,2'-diaminodiphenyl disulfide (0.124 g, 0.5 mmol), 2,4-dimethylbromobenzene (0.386 g, 2.1 mmol), zinc powder (0.261 g, 4 mmol), sodium iodide (0.374 g, 2.5 mmol), nickel iodide hydrate (0.042 g, 0.1 mmol), 2,2'-bipyridine (0.024 g, 0.15 mmol), and N,N-dimethylformamide (200 μL) were placed in a 25 mL grinding steel jar, and a steel ball with a diameter of 14 mm and a weight of 11 g was added. After sealing the steel container, the mixture was placed in a Retsch mixed ball mill (MM400) and ground at 30 Hz for 99 min. The resulting black solid was then dissolved in 3 × 10 mL of ethyl acetate and filtered. The filtrate was collected, washed three times with water, and the organic phases were combined. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent. The eluent was eluted sequentially at volume ratios of 65:1 → 55:1 → 45:1 → 40:1 to obtain 45.5 mg of a yellow-green oily substance, namely 2,4-dimethylphenyl-2-piperazine phenyl sulfide, with a yield of 20%.

[0035] The preparation of 2,4-dimethylphenyl-2-piperazine phenyl sulfide 1 H NMR image as follows Figure 1 , 13 C NMR spectrum as shown Figure 2 Gas chromatogram as follows Figure 3a MS diagram Figure 3b The structure is characterized as follows:

[0036] 1H NMR (300MHz, CDCl3) δ = 7.37-7.34 (d, J1 = 1.2, 10.5Hz, 1H), 7.24-7.19 (m, 1H), 7.00 (s, 1H) ,6.87-6.76(m,3H),6.74-6.69(t,J=14.58Hz,1H),4.25(s,2H),2.39(s,3H),2.26(s,3H).

[0037] 13 C NMR (75MHz, CDCl3) δ = 148.06 (s), 136.52 (s), 135.78 (s), 135.36 (s), 131.63 (s), 131.16 (s), 130.41(s),128.81(s),127.28(s),126.56(s),118.99(s),115.41(s),20.76(s),18.85(s).

[0038] Example 2: Preparation of 2,4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding-catalyzed CS coupling reaction

[0039] Under normal temperature conditions, 2,2'-diaminodiphenyl disulfide (0.124 g, 0.5 mmol), 2,4-dimethylbromobenzene (0.275 g, 1.5 mmol), zinc powder (0.261 g, 4 mmol), sodium iodide (0.374 g, 2.5 mmol), nickel iodide hydrate (0.042 g, 0.1 mmol), 2,2'-bipyridine (0.024 g, 0.15 mmol), and N,N-dimethylformamide (200 μL) were placed in a 25 mL grinding steel jar, and a steel ball with a diameter of 14 mm and a weight of 11 g was added. After sealing the steel container, it was placed in a Retsch mixed ball mill (MM400) and ground at 30 Hz for 99 min. The resulting black solid was then dissolved in 3 × 10 mL of ethyl acetate and filtered. The filtrate was collected, washed three times with water, and the organic phases were combined. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent. The eluent was eluted sequentially at volume ratios of petroleum ether:ethyl acetate = 65:1 → 55:1 → 45:1 → 40:1 to obtain 23 mg of a yellow-green oily substance, namely 2,4-dimethylphenyl-2-piperazine phenyl sulfide, with a yield of 10%.

[0040] Example 3: Preparation of 2,4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding-catalyzed CS coupling reaction

[0041] Under normal temperature conditions, 2,2'-diaminodiphenyl disulfide (0.124 g, 0.5 mmol), 2,4-dimethylbromobenzene (0.367 g, 2.0 mmol), zinc powder (0.261 g, 4 mmol), sodium iodide (0.374 g, 2.5 mmol), nickel iodide hydrate (0.042 g, 0.1 mmol), 2,2'-bipyridine (0.024 g, 0.15 mmol), and N,N-dimethylformamide (200 μL) were placed in a 25 mL grinding steel jar, and a steel ball with a diameter of 14 mm and a weight of 11 g was added. After sealing the steel container, the mixture was placed in a Retsch mixed ball mill (MM400) and ground at 30 Hz for 99 min. The resulting black solid was then dissolved in 3 × 10 mL of ethyl acetate and filtered. The filtrate was collected, washed three times with water, and the organic phases were combined. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as the eluent. The eluent was eluted sequentially at volume ratios of petroleum ether:ethyl acetate = 65:1 → 55:1 → 45:1 → 40:1 to obtain 38.8 mg of a yellow-green oily substance, namely 2,4-dimethylphenyl-2-piperazine phenyl sulfide, with a yield of 17%.

[0042] Example 4: Preparation of 2,4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding-catalyzed CS coupling reaction

[0043] Under normal temperature conditions, 2,2'-diaminodiphenyl disulfide (0.124 g, 0.5 mmol), 2,4-dimethylbromobenzene (0.413 g, 2.25 mmol), zinc powder (0.261 g, 4 mmol), sodium iodide (0.374 g, 2.5 mmol), nickel iodide hydrate (0.042 g, 0.1 mmol), 2,2'-bipyridine (0.024 g, 0.15 mmol), and N,N-dimethylformamide (200 μL) were placed in a 25 mL grinding steel jar, and a steel ball with a diameter of 14 mm and a weight of 11 g was added. After sealing the steel container, the mixture was placed in a Retsch mixed ball mill (MM400) and ground at 30 Hz for 99 min. The resulting black solid was then dissolved in 3 × 10 mL of ethyl acetate and filtered. The filtrate was collected, washed three times with water, and the organic phases were combined. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as eluent. The eluent was eluted sequentially at volume ratios of petroleum ether:ethyl acetate = 65:1 → 55:1 → 45:1 → 40:1 to obtain 40.8 mg of a yellow-green oily substance, namely 2,4-dimethylphenyl-2-piperazine phenyl sulfide, with a yield of 18%.

[0044] Example 5: Preparation of 2,4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding-catalyzed CS coupling reaction

[0045] Under normal temperature conditions, 2,2'-diaminodiphenyl disulfide (0.124 g, 0.5 mmol), 2,4-dimethylbromobenzene (0.367 g, 2.0 mmol), zinc powder (0.261 g, 4 mmol), sodium iodide (0.374 g, 2.5 mmol), nickel iodide hydrate (0.042 g, 0.1 mmol), 2,2'-bipyridine (0.024 g, 0.15 mmol), and N,N-dimethylformamide (200 μL) were placed in a 25 mL grinding steel jar, and a steel ball with a diameter of 14 mm and a weight of 11 g was added. After sealing the steel container, it was placed in a Retsch mixed ball mill (MM400) and ground at 30 Hz for 119 min. The resulting black solid was then dissolved in 3 × 10 mL of ethyl acetate and filtered. The filtrate was collected, washed three times with water, and the organic phases were combined. The mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography using a mixture of petroleum ether and ethyl acetate as eluent. The eluent was eluted sequentially at volume ratios of petroleum ether:ethyl acetate = 65:1 → 55:1 → 45:1 → 40:1 to obtain 20.5 mg of a yellow-green oily substance, namely 2,4-dimethylphenyl-2-piperazine phenyl sulfide, with a yield of 9%.

Claims

1. A method for preparing vortioxetine prodrugs via a mechanical grinding-catalyzed CS-coupled reaction, characterized in that, The vortioxetine prodrug is 2,4-dimethylphenyl-2-piperazine phenyl sulfide, and its preparation method includes the following steps: using 2,2'-diaminodiphenyl disulfide and 2,4-dimethylbromobenzene as raw materials, 2,4-dimethylphenyl disulfide is prepared by CS coupling reaction under room temperature conditions using zinc powder, sodium iodide, nickel iodide hydrate, 2,2'-bipyridine and trace amounts of N,N-dimethylformamide to assist mechanical grinding; 200 μL of N,N-dimethylformamide is added to every 0.5 mmol of 2,2'-diaminodiphenyl disulfide.

2. The method according to claim 1, characterized in that, The method includes the following steps: Under normal temperature conditions, 2,2'-diaminodiphenyl disulfide, 2,4-dimethylbromobenzene, zinc powder, sodium iodide, nickel iodide hydrate, 2,2'-bipyridine, and trace amounts of N,N-dimethylformamide are placed in a grinding steel jar, steel balls are added, the jar is sealed, and then placed in a Retsch mixing ball mill and ground at 30 Hz for 95–100 min. The crude product obtained is separated and purified to obtain 2,4-dimethylphenyl-2-piperazine phenyl sulfide.

3. The method according to claim 2, characterized in that, The molar ratio of 2,2'-diaminodiphenyl disulfide:2,4-dimethylbromobenzene:zinc powder:sodium iodide:nickel iodide hydrate:2,2'-bipyridine is 1:3-4.5:8:5:0.2:0.

3.

4. The method according to claim 3, characterized in that, The molar ratio of 2,2'-diaminodiphenyl disulfide:2,4-dimethylbromobenzene:zinc powder:sodium iodide:nickel iodide hydrate:2,2'-bipyridine is 1:4.2:8:5:0.2:0.

3.

5. The method according to claim 2, characterized in that, The steel ball has a diameter of 14 mm and a weight of 11 g.

6. The method according to claim 2, characterized in that, Grind at 30Hz for 99 minutes.

7. The method according to claim 2, characterized in that, The separation and purification process is as follows: the crude product is dissolved in ethyl acetate, filtered, the filtrate is washed with water, the organic phase is collected, dried with anhydrous magnesium sulfate, and the crude product is concentrated by vacuum distillation. A mixed solution of petroleum ether and ethyl acetate is used as the eluent for silica gel column chromatography to obtain 2,4-dimethylphenyl-2-piperazine phenyl thioether.

8. The method according to claim 7, characterized in that, The volume ratio of petroleum ether to ethyl acetate is 65–40:1.

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