CN117756749A - Method for preparing vortioxetine prodrug by catalyzing C-S coupling reaction through mechanical grinding method - Google Patents
Method for preparing vortioxetine prodrug by catalyzing C-S coupling reaction through mechanical grinding method Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 39
- 238000000227 grinding Methods 0.000 title claims abstract description 27
- 238000005859 coupling reaction Methods 0.000 title claims abstract description 19
- YQNWZWMKLDQSAC-UHFFFAOYSA-N vortioxetine Chemical compound CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 YQNWZWMKLDQSAC-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 229940002612 prodrug Drugs 0.000 title claims abstract description 10
- 239000000651 prodrug Substances 0.000 title claims abstract description 10
- 229960002263 vortioxetine Drugs 0.000 title claims abstract description 10
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 claims abstract description 18
- YSFLQVNTBBUKEA-UHFFFAOYSA-N 1-bromo-2,4-dimethylbenzene Chemical compound CC1=CC=C(Br)C(C)=C1 YSFLQVNTBBUKEA-UHFFFAOYSA-N 0.000 claims abstract description 14
- YYYOQURZQWIILK-UHFFFAOYSA-N 2-[(2-aminophenyl)disulfanyl]aniline Chemical compound NC1=CC=CC=C1SSC1=CC=CC=C1N YYYOQURZQWIILK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 7
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- 239000002994 raw material Substances 0.000 claims abstract description 4
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 33
- 229910000831 Steel Inorganic materials 0.000 claims description 31
- 239000010959 steel Substances 0.000 claims description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 239000012043 crude product Substances 0.000 claims description 16
- 239000003208 petroleum Substances 0.000 claims description 14
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 11
- IBSOYFJDSVROOT-UHFFFAOYSA-L diiodonickel;hexahydrate Chemical compound O.O.O.O.O.O.I[Ni]I IBSOYFJDSVROOT-UHFFFAOYSA-L 0.000 claims description 11
- 235000009518 sodium iodide Nutrition 0.000 claims description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 7
- 238000004821 distillation Methods 0.000 claims description 7
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- 238000002360 preparation method Methods 0.000 claims description 6
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims description 2
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- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 5
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- 229960004030 vortioxetine hydrobromide Drugs 0.000 description 4
- VNGRUFUIHGGOOM-UHFFFAOYSA-N vortioxetine hydrobromide Chemical compound Br.CC1=CC(C)=CC=C1SC1=CC=CC=C1N1CCNCC1 VNGRUFUIHGGOOM-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
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- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a method for preparing vortioxetine prodrug by catalyzing C-S coupling reaction through a mechanical grinding method. The technical scheme adopted is as follows: 2,2' -diaminodiphenyl disulfide and 2, 4-dimethyl bromobenzene are used as raw materials, and under the condition of no solvent at normal temperature, a Ni catalysis and micro liquid auxiliary mechanical grinding mode is adopted to carry out C-S coupling reaction to prepare 2, 4-dimethylphenyl-2-piperazine phenyl sulfide, so that a coupling product is obtained safely and environmentally. The invention adopts a mechanical force method to quickly and simply carry out C-S coupling reaction to prepare the vortioxetine prodrug, has simple operation and treatment, green and safe raw materials, is environment-friendly, adopts metal Ni for catalysis, has mild reaction conditions and can finish the reaction within 99 minutes.
Description
Technical Field
The invention relates to a novel method for preparing vortioxetine prodrug by mechanical grinding and catalyzing C-S coupling reaction under the assistance of trace liquid without inert gas protection and long-time high-temperature reflux, belonging to the catalysis field of drug intermediate synthesis.
Background
Organosulfides are an important class of organic compounds that are widely found in natural products, agrochemicals and pharmaceutical compounds. The sulfur atom has the physical and chemical properties of large atomic radius, strong nucleophilicity and easy poisoning metal, and is commonly used for regulating chemical arrangement of heterocycle in molecules, such as penicillin, sulfonyldiketopiperazine, bleomycin, thiazole peptide antibiotics and the like. The methods for synthesizing sulfide are few, the limitation of the substrate is large, and the novel synthesis method of the sulfur-containing compound is always a hot spot and a serious problem in the fields of synthesis and pharmaceutical chemistry.
Vortioxetine hydrobromide is an organosulfur compound commonly used to treat depression and anxiety. Vortioxetine hydrobromide, an antidepressant of a multi-acting drug, improves the concentration of 5-hydroxytryptamine by inhibiting the reuptake of neurons on 5-hydroxytryptamine, and improves symptoms of depression and anxiety. Functions by altering the signaling pathways of multiple neurotransmitters. It is mainly used for treating depression of adults and teenagers (13-17 years old) and can improve problems in mood, sleep, appetite, cognitive functions and the like. Clinical studies have shown that vortioxetine hydrobromide significantly reduces depression symptoms and provides better tolerability than placebo. As antidepressant drugs having various pharmacodynamic activities, FDA approval was obtained in 9 of 2013, the trade name was Brintellix, and approval was obtained by the national drug administration in 21 of 11 of 2017.
The synthesis of vortioxetine hydrobromide is relatively complex and is typically prepared by chemical synthesis. To ensure the safety and purity of the synthesis process, pharmaceutical companies often employ more complex, more efficient synthetic methods. These methods aim at improving the yield, reducing the formation of by-products and chemical waste, and ensuring the purity of the final product. The partial synthetic route disclosed is as follows:
route one:
route two:
routes have been disclosed that fall largely into two types, route one and route two, route one being cumbersome, tedious, and reducing overall atomic economy. Route two involves the use of palladium catalysts and ligands such as BINAP, the expensive price of which increases the manufacturing costs, also from the front end, i.e. the radiation, to the expensive price after commercialization of the drug.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for preparing vortioxetine prodrug by catalyzing C-S coupling reaction under mechanical force. According to the invention, mechanical grinding is adopted, C-S coupling reaction is carried out under the catalysis of metallic nickel to prepare the vortioxetine prodrug, the steps of the whole route are shorter, the price of the catalyst is proper, and the production cost is effectively reduced.
In order to achieve the above purpose, the invention adopts the following technical scheme: the method for preparing vortioxetine prodrug by catalyzing C-S coupling reaction through a mechanical grinding method comprises the following steps of: 2,2' -diaminodiphenyl disulfide and 2, 4-dimethyl bromobenzene are used as raw materials, and under the condition of no solvent at normal temperature, a Ni catalysis and micro liquid auxiliary mechanical grinding mode is adopted to carry out C-S coupling reaction to prepare the 2, 4-dimethylphenyl-2-piperazine phenyl sulfide.
Preferably, the method comprises the steps of: under normal temperature, 2 '-diaminodiphenyl disulfide, 2, 4-dimethylbromobenzene, zinc powder, sodium iodide, nickel iodide hydrate, 2' -bipyridine and trace N, N-dimethylformamide are placed in a grinding steel tank, a steel ball is added, the steel tank is closed, the steel tank is placed in a Retsch mixed ball mill, the crude product obtained by grinding for 95-100 min at 30Hz is separated and purified, and the 2, 4-dimethylphenyl-2-piperazine phenyl sulfide is obtained.
Preferably, the molar ratio of 2,2 '-diaminodiphenyl disulfide to 2, 4-dimethylbromobenzene to zinc powder to sodium iodide to nickel iodide hydrate to 2,2' -bipyridine=1:3-4.5:8:5:0.2:0.3.
More preferably, the molar ratio of 2,2 '-diaminodiphenyl disulfide to 2, 4-dimethylbromobenzene to zinc powder to sodium iodide to nickel iodide hydrate to 2,2' bipyridine=1:4.2:8:5:0.2:0.3.
Preferably, the trace amount of N, N-dimethylformamide is used in an amount of; 200 mu L N, N-dimethylformamide was added per 0.5mmol of 2,2' -diaminodiphenyl disulfide.
Preferably, the diameter of the steel ball is 14mm, and the weight of the steel ball is 11g.
Preferably, grinding is carried out at 30Hz for 99min.
Preferably, the separation and purification are: dissolving the crude product in ethyl acetate, filtering, washing the obtained filtrate with water, collecting an organic phase, drying by anhydrous magnesium sulfate, concentrating the crude product by reduced pressure distillation, and performing silica gel column chromatography by using petroleum ether and ethyl acetate mixed solution as an eluent to obtain the 2, 4-dimethylphenyl-2-piperazine phenyl sulfide.
Preferably, the petroleum ether and the ethyl acetate are in a volume ratio of 65-40:1.
The beneficial effects of the invention are as follows:
1. the method provided by the invention adopts mechanical grinding to carry out catalytic reaction under the condition of mechanical force, and the energy of the reaction is from mechanical energy generated by ball milling rather than traditional heat energy. The method can improve the reaction yield, simultaneously can improve the reaction rate, greatly shorten the reaction time, simplify the experimental process, simultaneously avoid the excessive use of toxic and harmful solvents, protect the environment and meet the green chemical concept.
2. The method provided by the invention uses cheap Ni compounds to replace Pd metal catalysts, and the reaction yield reaches 20% while greatly reducing the cost.
3. The method provided by the invention uses mechanocatalysis to prepare the C-S coupling product, only uses a trace amount of liquid to assist in grinding, avoids the use of a large amount of organic solvents, reduces the reaction cost, simultaneously reduces the harm to the environment as much as possible, and is a green and mild organic synthesis method which is friendly to the environment.
4. According to the method provided by the invention, all reactions are carried out under the conventional conditions, high-temperature and high-pressure or inert gas protection is not needed, and the experimental steps are simplified.
Drawings
FIG. 1 is a schematic illustration of 2, 4-dimethylphenyl-2-piperazinophenyl sulfide prepared in example 1 1 H NMR chart.
FIG. 2 is a schematic diagram of 2, 4-dimethylphenyl prepared in example 1-2-piperazinophenyl sulfide 13 C NMR chart.
FIG. 3a is a gas chromatogram of 2, 4-dimethylphenyl-2-piperazinephenyl sulfide prepared in example 1.
FIG. 3b is an MS plot of 2, 4-dimethylphenyl-2-piperazinephenyl sulfide prepared in example 1.
Detailed Description
For a better understanding of the present invention, the present invention is further described below with reference to the following examples.
EXAMPLE 1 preparation of 2, 4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding method catalyzing C-S coupling reaction
The reaction formula is as follows:
the method comprises the following steps:
2,2 '-diaminodiphenyl disulfide (0124. G,0.5 mmol), 2, 4-dimethylbromobenzene (0.3836 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' -bipyridine (0.024 g,0.15 mmol), N, N-dimethylformamide (200. Mu.L) were placed in a 25mL grinding steel pot at room temperature, and a steel ball having a diameter of 14mm and a weight of 11g was added. After the steel tank is closed, the steel tank is put into a Retsch mixed ball mill (MM 400) and ground for 99min at 30Hz, then the obtained black solid substance is dissolved in 3X 10mL of ethyl acetate for filtration, the obtained filtrate is collected, the organic phases are combined after washing 3 times with water, anhydrous magnesium sulfate is dried and concentrated by reduced pressure distillation to obtain a crude product, the crude product is subjected to silica gel column chromatography separation and purification, petroleum ether and ethyl acetate mixed solution are adopted as eluent, and gradient elution is sequentially carried out according to the volume ratio of petroleum ether to ethyl acetate=65:1 to 55:1 to 45:1 to 40:1, thus obtaining 45.5mg of yellow-green oily substance, namely, 2, 4-dimethylphenyl-2-piperazine phenyl sulfide, and the yield is 20 percent.
2, 4-dimethylphenyl-2-piperazinephenyl sulfide prepared 1 The H NMR chart is shown in figure 1, 13 c NMR chart as shown in FIG. 2, gas chromatogram as shown in FIG. 3a, MS chart as shown in FIG. 3b, structureThe characterization is as follows:
1 H NMR(300MHz,CDCl 3 )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).
13 C NMR(75MHz,CDCl 3 )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).
EXAMPLE 2 preparation of 2, 4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding method catalyzing C-S coupling reaction
2,2 '-diaminodiphenyl disulfide (0124. 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' -bipyridine (0.024 g,0.15 mmol), N, N-dimethylformamide (200. Mu.L) were placed in a 25mL grinding steel pot at room temperature, and a steel ball having a diameter of 14mm and a weight of 11g was added. After the steel tank is closed, the steel tank is put into a Retsch mixed ball mill (MM 400) and ground for 99min at 30Hz, then the obtained black solid substance is dissolved in 3X 10mL of ethyl acetate for filtration, the obtained filtrate is collected, the organic phases are combined after washing 3 times with water, anhydrous magnesium sulfate is dried and concentrated by reduced pressure distillation to obtain a crude product, the crude product is subjected to silica gel column chromatography separation and purification, and petroleum ether and ethyl acetate mixed solution are adopted as eluent, and gradient elution is sequentially carried out according to the volume ratio of petroleum ether to ethyl acetate=65:1- & gt 55:1- & gt45:1- & gt40:1, thus obtaining 23mg of yellow-green oily substance, namely 2, 4-dimethylphenyl-2-piperazine phenyl sulfide, and the yield is 10%.
EXAMPLE 3 preparation of 2, 4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding method catalyzing C-S coupling reaction
2,2 '-diaminodiphenyl disulfide (0124. 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' -bipyridine (0.024 g,0.15 mmol), N, N-dimethylformamide (200. Mu.L) were placed in a 25mL mill steel pot at room temperature, and a steel ball having a diameter of 14mm and a weight of 11g was added. After a steel tank is closed, the steel tank is placed into a Retsch mixed ball mill (MM 400) and ground for 99min at 30Hz, then the obtained black solid matter is dissolved in 3X 10mL of ethyl acetate for filtration, the obtained filtrate is collected, the organic phases are combined after washing 3 times with water, anhydrous magnesium sulfate is dried and concentrated by reduced pressure distillation to obtain a crude product, the crude product is subjected to silica gel column chromatography separation and purification, petroleum ether and ethyl acetate mixed solution are adopted as eluent, and petroleum ether and ethyl acetate=65:1- & gt 55:1- & gt 45:1- & gt 40:1 are sequentially subjected to gradient elution according to the volume ratio, so that the yellow-green oily matter 38.8mg, namely the 2, 4-dimethylphenyl-2-piperazine phenyl sulfide is obtained, and the yield is 17%.
EXAMPLE 4 preparation of 2, 4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding method catalyzing C-S coupling reaction
2,2 '-diaminodiphenyl disulfide (0124. 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' -bipyridine (0.024 g,0.15 mmol), N, N-dimethylformamide (200. Mu.L) were placed in a 25mL grinding steel pot at room temperature, and a steel ball having a diameter of 14mm and a weight of 11g was added. After a steel tank is closed, the steel tank is placed into a Retsch mixed ball mill (MM 400) and ground for 99min at 30Hz, then the obtained black solid matter is dissolved in 3X 10mL of ethyl acetate for filtration, the obtained filtrate is collected, the organic phases are combined after washing 3 times with water, anhydrous magnesium sulfate is dried and concentrated by reduced pressure distillation to obtain a crude product, the crude product is subjected to silica gel column chromatography separation and purification, petroleum ether and ethyl acetate mixed solution are adopted as eluent, and petroleum ether and ethyl acetate=65:1- & gt 55:1- & gt 45:1- & gt 40:1 are sequentially subjected to gradient elution according to the volume ratio, thus obtaining yellow-green oily matter 40.8mg, namely 2, 4-dimethylphenyl-2-piperazine phenyl sulfide, and the yield is 18%.
EXAMPLE 5 preparation of 2, 4-dimethylphenyl-2-piperazine phenyl sulfide by mechanical grinding method catalyzing C-S coupling reaction
2,2 '-diaminodiphenyl disulfide (0124. 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' -bipyridine (0.024 g,0.15 mmol), N, N-dimethylformamide (200. Mu.L) were placed in a 25mL mill steel pot at room temperature, and a steel ball having a diameter of 14mm and a weight of 11g was added. After a steel tank is closed, the steel tank is placed into a Retsch mixed ball mill (MM 400), grinding is carried out for 119min at 30Hz, then the obtained black solid substance is dissolved in 3X 10mL of ethyl acetate for filtration, the obtained filtrate is collected, the organic phases are combined after washing for 3 times by water, anhydrous magnesium sulfate is used for drying, reduced pressure distillation and concentration are carried out to obtain a crude product, silica gel column chromatography separation and purification are carried out on the crude product, petroleum ether and ethyl acetate mixed solution are adopted as eluent, petroleum ether and ethyl acetate=65:1- & gt 55:1- & gt 45:1- & gt 40:1 are sequentially carried out gradient elution according to the volume ratio, and thus, 20.5mg of yellow-green oily substance, namely 2, 4-dimethylphenyl-2-piperazine phenyl sulfide is obtained, and the yield is 9%.
Claims (9)
1. The method for preparing vortioxetine prodrug by catalyzing C-S coupling reaction through a mechanical grinding method is characterized in that the vortioxetine prodrug is 2, 4-dimethylphenyl-2-piperazine phenyl sulfide, and the preparation method comprises the following steps: 2,2' -diaminodiphenyl disulfide and 2, 4-dimethyl bromobenzene are used as raw materials, and under the condition of no solvent at normal temperature, a Ni catalysis and micro liquid auxiliary mechanical grinding mode is adopted to carry out C-S coupling reaction to prepare the 2, 4-dimethylphenyl-2-piperazine phenyl sulfide.
2. The method according to claim 1, characterized in that the method comprises the steps of: under normal temperature, 2 '-diaminodiphenyl disulfide, 2, 4-dimethylbromobenzene, zinc powder, sodium iodide, nickel iodide hydrate, 2' -bipyridine and trace N, N-dimethylformamide are placed in a grinding steel tank, a steel ball is added, the steel tank is closed, the steel tank is placed in a Retsch mixed ball mill, grinding is carried out for 95-100 min at 30Hz, and the obtained crude product is separated and purified to obtain the 2, 4-dimethylphenyl-2-piperazine phenyl sulfide.
3. The process according to claim 2, wherein the molar ratio of 2,2 '-diaminodiphenyl disulfide to 2, 4-dimethylbromobenzene to zinc powder to sodium iodide to nickel iodide hydrate to 2,2' bipyridine = 1:3-4.5:8:5:0.2:0.3.
4. A process according to claim 3, characterized in that the molar ratio of 2,2 '-diaminodiphenyl disulfide to 2, 4-dimethylbromobenzene to zinc powder to sodium iodide to nickel iodide hydrate to 2,2' bipyridine = 1:4.2:8:5:0.2:0.3.
5. The method of claim 2, wherein the trace amount of N, N-dimethylformamide is used in an amount of; 200 mu L N, N-dimethylformamide was added per 0.5mmol of 2,2' -diaminodiphenyl disulfide.
6. The method of claim 2, wherein the steel ball has a diameter of 14mm and a weight of 11g.
7. The method of claim 2, wherein grinding is performed at 30Hz for 99min.
8. The method according to claim 2, wherein the separation and purification is: dissolving the crude product in ethyl acetate, filtering, washing the obtained filtrate with water, collecting an organic phase, drying by anhydrous magnesium sulfate, concentrating the crude product by reduced pressure distillation, and performing silica gel column chromatography by using petroleum ether and ethyl acetate mixed solution as an eluent to obtain the 2, 4-dimethylphenyl-2-piperazine phenyl sulfide.
9. The method according to claim 8, wherein the petroleum ether/ethyl acetate=65-40:1 by volume ratio.
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