Method for preparing tetraethylthiuram disulfide through combined catalysis of metal catalyst and solid alkali

Abstract

The invention discloses a method for preparing tetraethylthiuram disulfide through combined catalysis of a metal catalyst and solid alkali, and belongs to the technical field of organic synthesis. The method comprises the following steps: filling a continuous flow fixed bed with molybdenum disulfide and calcium hydroxide to form a composite multi-catalyst, preparing a reaction raw material solution from carbon disulfide and diethylamine as raw materials, controlling the flow of the reaction raw material solution and the flow of gas entering a reactor, and carrying out a temperature-controlled and pressure-controlled reaction to obtain a reaction solution; and carrying out post-treatment on the reaction liquid to obtain tetraethylthiuram disulfide. Molybdenum disulfide and calcium hydroxide are adopted to form a composite multi-term catalyst, a heterogeneous catalysis reaction is accurately controlled, the tetraethylthiuram disulfide crystal is obtained only through crystallization, filtration and drying of a prepared crude product, the purity and yield of the obtained tetraethylthiuram disulfide are high, and the method is environmentally friendly, high in atom economy and suitable for industrial production. Conditions are mild, the catalyst can be recycled, and products are easy to separate.

Description

Technical Field

[0001] This invention belongs to the field of rubber accelerator and pharmaceutical production technology, and relates to the synthesis method of tetraethylthiuram disulfide (disulfiram) compounds, especially the green synthesis method thereof. Background Technology

[0002] Tetraethylthiuram disulfide, also known as disulfide, or TETD for short, has the following structural formula:

[0003]

[0004] Rubber vulcanization accelerators are essential materials in the modern rubber industry. They effectively accelerate the vulcanization process, lower the required vulcanization temperature, reduce the amount of vulcanizing agent used, and improve the mechanical properties of rubber products. Commonly used tetraalkyl thiurams include tetramethyl thiuram disulfide (TMTD), tetraethyl thiuram disulfide (TETD), and tetrabenzyl thiuram disulfide (TBzTD). Among them, tetraethyl thiuram disulfide has attracted widespread attention due to its ability to form non-carcinogenic nitrosamines during vulcanization. It can vulcanize rubber without sulfur in the rubber compound, significantly improving vulcanization efficiency and degree. Notably, tetraethyl thiuram disulfide (known as "disulfiram" in medicinal chemistry) was approved by the U.S. Food and Drug Administration in 1948 for the treatment of chronic alcoholism. Furthermore, tetraethyl thiuram disulfide has shown potential value in the treatment of various other diseases, including cancer, SARS-CoV-2, acute leukemia, and Lyme disease.

[0005] Traditionally, the industrial production of TETD mainly employs a two-step synthesis method. Carbon disulfide and diethylamine are added dropwise to a sodium hydroxide solution to first generate sodium diethyldithiocarbamate, then hydrogen peroxide is used to oxidize the intermediate to produce the target product, and the reaction solution is neutralized with sulfuric acid. While this technology offers fast reaction speeds, the excessive amounts of hydrogen peroxide used in the reaction can easily over-oxidize the reactants, increasing the cost of treating saline wastewater. Secondly, the addition of strong acids and bases during the reaction can corrode the reaction equipment to some extent. Furthermore, all three steps of the reaction (addition, oxidation, and neutralization) are exothermic, especially the oxidation step, which releases a tremendous amount of heat, making precise temperature control difficult and potentially leading to safety issues. CN110526845 discloses a method for constructing a reaction system in n-butanol solution, using diethylamine and carbon disulfide as reactants to prepare tetraethylthiuram disulfide via a condensation oxidation reaction, and finally recovering and recycling the n-butanol using a one-step liquid-liquid separation method. Although this method is environmentally friendly and pollution-free, and can separate tert-butanol and water without evaporation, it generates a large amount of heat during the reaction, is complex to operate, consumes a lot of energy, is difficult to control the temperature precisely, and is prone to the generation of by-products. Therefore, this method still has great limitations in industrial applications.

[0006] CN112358428A discloses a method for the photocatalytic oxidation of tetraethylthiuram disulfide, which involves reacting a secondary amine, carbon disulfide, and a catalyst under light irradiation, using the inexpensive and non-toxic dye eosin Y as the photocatalyst. CN115819304A discloses a preliminary route for the preparation of TETD from transition metal sulfides, which involves reacting a secondary amine, carbon disulfide, and molybdenum disulfide under alkaline conditions, with triethylamine acting as the alkaline reagent. Both of these methods achieve green and efficient synthesis of thiuram under mild conditions. However, both require additional steps to remove the catalyst or excess reagent (such as alkali) during the purification of the target product, increasing the difficulty of product purification. Specifically, the use of eosin Y leads to product staining; and in the metal-catalyzed method, the overstoichiometric amount of triethylamine not only increases the complexity of purification but also increases costs. Summary of the Invention

[0007] To address the technical limitations of traditional methods for producing tetraethylthiuram disulfide, particularly the use of corrosive raw materials such as strong acids, strong alkalis, and strong oxidants, which can easily lead to equipment corrosion, product over-oxidation, and the generation of inorganic salt byproducts, this invention provides a method for the co-catalytic preparation of tetraethylthiuram disulfide using a metal catalyst and a solid alkali. This method offers advantages such as rapid conversion, no byproduct generation, simple post-processing, and high product purity.

[0008] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0009] A method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base is disclosed. The method uses a continuous flow fixed bed reactor. First, a composite multi-element catalyst composed of molybdenum disulfide and calcium hydroxide is loaded into the continuous flow fixed bed. Then, a reaction feed liquid is prepared using carbon disulfide and diethylamine as raw materials. The flow rates of the reaction feed liquid and gas entering the reactor are controlled, and the reaction is carried out under controlled temperature and pressure to obtain a reaction solution. The reaction solution is then post-treated to obtain tetraethylthiuram disulfide.

[0010] The method for preparing tetraethylthiuram disulfide by co-catalysis of metal catalyst and solid base has a molar ratio of molybdenum disulfide to calcium hydroxide of 25:(1-4).

[0011] In the method for preparing tetraethylthiuram disulfide by co-catalysis of metal catalyst and solid base, the molar ratio of diethylamine to carbon disulfide is 1:(1.0-1.5).

[0012] In the method for preparing tetraethylthiuram disulfide by co-catalysis of metal catalyst and solid base, anhydrous ethanol is used as the solvent for preparing the reaction stock solution.

[0013] The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base uses oxygen or compressed air as the reaction gas.

[0014] In the method for preparing tetraethylthiuram disulfide by co-catalysis of metal catalyst and solid base, the residence time of the reaction solution in the fixed bed in the continuous flow fixed bed method is 10-30 min.

[0015] The method for preparing tetraethylthiuram disulfide by co-catalysis of metal catalyst and solid base has a reaction temperature of 25-65℃.

[0016] The method for preparing tetraethylthiuram disulfide by co-catalysis of metal catalyst and solid base, wherein the pressure of the entire continuous flow system of continuous flow fixed bed is 0.8-1.0 MPa.

[0017] The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base, wherein the gas-liquid intermittent flow ratio is gas:liquid = (1-3):1

[0018] The method for preparing tetraethylthiuram disulfide by co-catalysis of metal catalyst and solid base, wherein the post-treatment is only: cooling the reaction solution to crystallize into needle-like crystals, followed by filtration and drying.

[0019] Beneficial effects: Compared with the prior art, this application has the following technical advantages:

[0020] 1) This application uses calcium hydroxide as a solid base, which, together with molybdenum disulfide, forms a composite catalyst. Compared with traditional synthesis methods, this reaction process has 100% atom utilization, produces no byproducts, and the product can be separated simply by crystallization and filtration, simplifying the product purification steps. Compared with traditional metal salt catalysts such as copper acetate and manganese acetate, it does not produce byproducts formed by sulfides and metal salts.

[0021] 2) This application employs a continuous flow fixed-bed reactor, which significantly shortens the reaction time and minimizes scale-up effects compared to traditional reactors, thereby greatly increasing production capacity. The plant's footprint can also be significantly reduced, saving land resources. Furthermore, compared to traditional batch production in intermittent reactors, continuous flow technology offers more stable and superior product quality, resulting in stronger market competitiveness. The gas-liquid-solid three-phase mixing technology in this reactor provides a fast reaction rate, mild conditions, reduces the risk of over-oxidation, and eliminates the production of inorganic salt byproducts. The product yield is high, and the purity is high. Examples confirm that the obtained tetraethylthiuram disulfide product is needle-like crystal with a purity of over 99%. Attached Figure Description

[0022] Figure 1 This is a schematic diagram of the continuous flow fixed bed reaction process used in this application. Detailed Implementation

[0023] To better understand the purpose, features, and significance of this invention, the invention will be further described below in conjunction with specific embodiments.

[0024] Example 1

[0025] The one-pot method for preparing tetraethylthiuram disulfide in ethanol solution comprises the following steps:

[0026] Add 8 mL of anhydrous ethanol to a flask, then add 4.8 mmol of carbon disulfide and 4.0 mmol of diethylamine sequentially while stirring. After the additions are complete, add 0.5 mmol of molybdenum disulfide and 0.04 mmol of calcium hydroxide to the reaction system. Finally, attach an oxygen balloon to the top of the flask and stir the mixture continuously on a magnetic stirrer at room temperature for 14 h. After the reaction, add styrene (internal standard, 2.0 mmol) to the resulting mixture, centrifuge at 10,000 rpm, and take the supernatant (100 μL) and dilute it with ethanol (1.50 mL).

[0027] The product was analyzed by high performance liquid chromatography (HPLC). Styrene was used as an internal standard. Water (pH=3, adjusted with formic acid, as phase A) and acetonitrile (as phase B) were used as eluents. The isocratic elution conditions were A:B=1:9. The detection wavelength was 254 nm and the flow rate was 1 mL / min. The chromatographic yield of TETD was 84%.

[0028] Example 2

[0029] The one-pot method for preparing tetraethylthiuram disulfide in ethanol solution is the same as in Example 1, except that the type of solid base added to the reaction system is different: ① sodium tungstate, ② disodium hydrogen phosphate, ③ hydroxyapatite. High-performance liquid chromatography (HPLC) analysis of the products, using styrene as an internal standard, yielded the following chromatographic yields for TETD: ① 50.6%; ② 68.7%; ③ 63.5%.

[0030] Example 3

[0031] The one-pot method for preparing tetraethylthiuram disulfide in ethanol solution is the same as in Example 1, except that the molar amount of calcium hydroxide added to the reaction system is different: ① 0.02 mmol, ② 0.08 mmol, ③ 0.2 mmol. High-performance liquid chromatography (HPLC) analysis of the products, using styrene as an internal standard, yielded the following chromatographic yields for TETD: ① 72.3%; ② 69.4%; ③ 54.9%.

[0032] Example 4

[0033] In continuous flow fixed bed ( Figure 1 The method for preparing tetraethylthiuram disulfide in [the following text is missing from the original] is as follows:

[0034] 1) Preparation of a fixed bed filled with molybdenum disulfide: 2.0 g of molybdenum disulfide and 74 mg of calcium hydroxide were filled into a fixed bed with an inner diameter of 4.6 mm and a length of 150 mm, and both ends were sealed with degreased cotton for filtration.

[0035] 2) Take 50 mL of ethanol and, under stirring, add 30 mmol of carbon disulfide and 25 mmol of diethylamine dropwise to prepare a reaction solution. Use a syringe pump to draw the reaction solution, and a mass flow controller to precisely control the gas flow rate. The reactor liquid and gas are mixed at the mixer, forming an intermittent flow with a gas-liquid volume ratio of 2:1, which enters the pre-filled fixed bed. The liquid remains in the fixed bed for 20 minutes, and intermittent local heating is used to ensure the reaction proceeds smoothly without clogging. After exiting the fixed bed, the liquid flows through a 45 psi back pressure valve, bringing the system pressure to 0.8 MPa, and finally flows into a collection tank.

[0036] 3) After the reaction reached steady state, the reaction mixture solution (1.0 mL) was collected at equal time intervals, and a portion (200 μL) was extracted from each sample and diluted to 4 mL with anhydrous ethanol. The product was analyzed by high performance liquid chromatography using the external standard method, and the chromatographic yield of TETD was 69.9%.

[0037] Example 5

[0038] The method for preparing tetraethylthiuram disulfide in a continuous flow fixed bed is the same as in Example 3, except that the fixed bed, back pressure valve, and outlet coil are placed in water baths at different temperatures: ① 35°C; ② 45°C; ③ 65°C. The product was analyzed by high-performance liquid chromatography using the external standard method. The chromatographic yields of TETD were: ① reaction pipeline blockage; ② 92.1%; ③ 85.7%.

[0039] Example 6

[0040] The method for preparing tetraethylthiuram disulfide in a continuous flow fixed bed is the same as in Example 3, except that the reaction residence time was adjusted to ① 15 min and ② 10 min under the condition of controlling the water bath temperature at 45°C. The products were analyzed by high-performance liquid chromatography using the external standard method, and the chromatographic yields of TETD were ① 78.7% and ② 76.6%.

[0041] Example 7

[0042] The method for preparing tetraethylthiuram disulfide in a continuous flow fixed bed comprises the following steps:

[0043] 1) Preparation of a fixed bed filled with molybdenum disulfide: 2.0 g of molybdenum disulfide and 74 mg of calcium hydroxide were filled into a fixed bed with an inner diameter of 4.6 mm and a length of 150 mm, and both ends were sealed with degreased cotton for filtration.

[0044] 2) Take 50 mL of ethanol and add 30 mmol of carbon disulfide and 25 mmol of diethylamine dropwise under stirring to prepare a reaction solution. Use a syringe pump to draw the reaction solution, and use a mass flow controller to precisely control the molar flow rate of the gas. The reactor liquid and gas are mixed at the mixer and enter the pre-filled fixed bed. The fixed bed, back pressure valve, and outlet coil are placed in a 45°C water bath. After staying in the fixed bed for 20 minutes, the liquid flows out of the fixed bed and through the 45 psi back pressure valve. The system pressure is 0.8 MPa, and the liquid finally flows into the collection tank.

[0045] 3) The reaction liquid in the collection tank is cooled and crystallized to form needle-like crystals. After filtration and drying (at 50°C for 0.5 h), tetraethylthiuram disulfide solid is obtained, which appears as pale yellow crystals.

[0046] The resulting product was tested, and the main results were: purity 99% (calculated based on NMR results) and separation yield 86.4% (the ratio of the product quality after drying to the theoretical quality).

[0047] Nuclear magnetic resonance spectroscopy (NMR): 1 H NMR (400MHz, CDCl3) δ (ppm): δ4.03 (s, 8H), 1.48 (m, 6H), 1.38–1.19 (m, 6H). 13 C NMR (110MHz, CDCl3) δ (ppm): δ192.71, 52.04, 47.62, 13.50, 11.47.

[0048] High-resolution mass spectrometry (HRMS): Theoretical calculations yield C 10 H 21 N2S4 + ([M+H)) + =297.0583, but the actual value in the graph is 297.0573.

[0049] Inductively coupled plasma optical emission spectroscopy (ICP-OES): Molybdenum content was 68.2 mg / kg, and calcium was not detected.

[0050] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for the co-catalytic preparation of tetraethylthiuram disulfide using a metal catalyst and a solid base, comprising a continuous flow fixed bed reactor, characterized in that, First, a composite multi-element catalyst consisting of molybdenum disulfide and calcium hydroxide is loaded into a continuous flow fixed bed. Then, a reaction feed liquid is prepared using carbon disulfide and diethylamine as raw materials. The flow rates of the reaction feed liquid and gas entering the reactor are controlled, and the reaction is carried out under controlled temperature and pressure to obtain a reaction liquid. The reaction liquid is then post-treated to obtain tetraethylthiuram disulfide.

2. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The molar ratio of molybdenum disulfide to calcium hydroxide is 25:(1-4).

3. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The molar ratio of diethylamine to carbon disulfide is 1:(1.0 to 1.5).

4. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The solvent used to prepare the reaction stock solution is anhydrous ethanol.

5. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The reacting gas is oxygen or compressed air.

6. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The residence time of the reaction liquid in the fixed bed in the continuous flow fixed bed method is 10 to 30 minutes.

7. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The reaction temperature is 25–65℃.

8. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The pressure of the entire continuous flow system of the continuous flow fixed bed is 0.8 to 1.0 MPa.

9. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The volume ratio of intermittent gas-liquid flow is gas:liquid = (1~3):

1.

10. The method for preparing tetraethylthiuram disulfide by co-catalysis of a metal catalyst and a solid base according to claim 1, characterized in that: The post-processing is simply: the reaction solution is cooled and crystallized to form needle-shaped crystals, which are then filtered and dried.

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