A high-efficiency catalytic synthesis process of thiabendazole

Abstract

The application discloses a kind of synthesis process of high-efficiency catalytic thiophalimethyl, it is related to thiophalimethyl technical field, including by 1,4-diazabicyclo [2.2.2] octane and zinc triflate consisting of hindered Lewis acid base pair catalyst, by reverse titration method methyl isothiocyanate formate is dropped into the organic solution of o-phenylenediamine and is condensed to prepare thiophalimethyl.The application uses 1,4-diazabicyclo [2.2.2] octane and zinc triflate to form hindered Lewis acid base pair catalyst, the main reaction rate is significantly improved, so that methyl isothiocyanate formate is rapidly consumed as soon as it is dropped, to inhibit the generation of triazine thione and other by-products from the source, while accelerating the consumption of free o-phenylenediamine, combined with weak reducing property and inert gas protection, effectively prevent oxidation discoloration, realize the synergistic catalytic effect far beyond linear superposition.

Description

Technical Field

[0001] This invention relates to the field of thiophanate-methyl technology, and particularly to a highly efficient catalytic synthesis process for thiophanate-methyl. Background Technology

[0002] Thiophanate-methyl is a benzimidazole broad-spectrum systemic fungicide. Within plants, it is converted to carbendazim, which exerts its fungicidal effect by interfering with the formation of the spindle apparatus during mitosis in pathogens, thus preventing normal bacterial division. Thiophanate-methyl not only possesses multiple effects including systemic, preventative, and curative action, but also, due to its low toxicity to higher animals and fish, is widely used to control over 180 diseases in more than 80 crops, including wheat, rice, vegetables, fruit trees, and flowers. Currently, the mainstream industrial method for preparing thiophanate-methyl involves a condensation reaction of o-phenylenediamine and methyl isothiocyanate in the presence of a catalyst. N,N-dimethylaniline is the most widely used conventional catalyst in this process. Traditionally, o-phenylenediamine is added intermittently in multiple batches to an excess of methyl isothiocyanate solution, and condensation occurs under the catalysis of N,N-dimethylaniline. However, the addition reaction of o-phenylenediamine with methyl isothiocyanate is highly exothermic, and the batch feeding method makes it difficult to accurately control the feeding rate, which can easily lead to local overheating and temperature runaway in the reactor, or even material overflow accidents, threatening production safety and the health of operators.

[0003] To overcome the problems of violent reactions and high risk of material spillage caused by improper feeding sequence in traditional processes, improved processes for synthesizing methyl thiophanate using a reverse-dropping method have emerged in recent years. This process involves uniformly adding methyl isothiocyanate dropwise into a mixed solution of o-phenylenediamine, solvent, and catalyst, thus avoiding localized overheating of o-phenylenediamine in an environment of excess isothiocyanate.

[0004] However, the core raw material used in the reverse-dropping method, methyl isothiocyanate, has poor thermal stability and is prone to dimerization and other side reactions at high temperatures, generating stable triazine thionyl derivatives that lose their reactivity with o-phenylenediamine, directly leading to a decrease in product yield. Although the reverse-dropping method avoids direct exposure of solid o-phenylenediamine at high temperatures, there is still a risk of o-phenylenediamine being oxidized by contact with air during the feeding, dissolving, and heating stages. The colored impurities generated by the oxidation of o-phenylenediamine are mixed into the product, causing the product to turn yellow and affecting the product's whiteness and the stability of its main content. Summary of the Invention

[0005] The purpose of this invention is to provide a highly efficient catalytic synthesis process for methyl thiophanate, in order to solve the technical problems in the prior art where methyl isothiocyanate is prone to dimerization and deactivation at high temperatures, resulting in a decrease in yield, and o-phenylenediamine is still prone to oxidation and discoloration during the feeding and dissolution processes.

[0006] The technical problem to be solved by this invention can be achieved through the following technical solution: A highly efficient catalytic synthesis process for methyl thiophanate includes a hindered Lewis acid-base pair catalyst composed of 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate. Methyl isothiocyanate is added dropwise to a solution of o-phenylenediamine via a back-dropping method to carry out a condensation reaction, thereby obtaining methyl thiophanate.

[0007] Preferably, the preparation of the hindered Lewis acid-base pair catalyst includes the following steps: under a nitrogen atmosphere, 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate in a molar ratio of (1-1.2):1 are added to anhydrous toluene and stirred at room temperature for 1-2 hours to obtain the hindered Lewis acid-base pair catalyst.

[0008] Through the above technical solution, the preparation of the hindered Lewis acid-base pair catalyst of the present invention needs to be controlled under anhydrous conditions and a nitrogen atmosphere to avoid the reaction of moisture in the air with zinc trifluoromethanesulfonate. 2+ Coordination forms hydrated ions, while preventing side reactions between oxygen and 1,4-diazabicyclo[2.2.2]octane. Only in an anhydrous and oxygen-free environment can the steric hindrance of the rigid bicyclic framework effectively prevent direct coordination addition between acid and base centers, thereby obtaining a hindered Lewis acid-base pair catalyst with non-addition independent active sites.

[0009] Preferably, the concentration of the hindered Lewis acid-base pair catalyst in anhydrous toluene is 0.4–0.6 mol / L.

[0010] Preferably, the total amount of hindered Lewis acid-base pair catalyst is 5-10 mol relative to o-phenylenediamine.

[0011] Through the above technical solution, the hindered Lewis acid-base pair catalyst of the present invention is formed by mixing 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate in anhydrous toluene. 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate form a hindered Lewis acid-base pair. Due to steric hindrance and coordination equilibrium, they form a non-adduct, each retaining its active site, while simultaneously activating both nucleophiles and electrophiles, thus significantly increasing the main reaction rate. This catalyst solves the problems of low main reaction rates in single-component or simple mixtures leading to numerous byproducts and easy oxidation and discoloration of o-phenylenediamine.

[0012] In contrast, N,N-dimethylaniline is only a Lewis base and cannot provide a Lewis acid center that can coordinate with the sulfur atom in methyl isothiocyanate. Therefore, it cannot activate electrophilic substrates and can only act on nucleophilic substrates unilaterally, failing to achieve simultaneous activation of both substrates. N,N-dimethylaniline is a flexible molecule without a rigid bicyclic skeleton, and cannot generate sufficient steric hindrance to prevent it from forming tight adducts with other components. Due to the lack of independent acid-base dual active sites, N,N-dimethylaniline cannot simultaneously and independently activate two different substrates in the same catalytic microenvironment, making it difficult to significantly increase the main reaction rate and shorten the residence time of methyl isothiocyanate to below its dimerization induction period. Therefore, it cannot inhibit the formation of byproducts such as triazine thione at the source. N,N-dimethylaniline lacks the weak reducing properties similar to 1,4-diazabicyclo[2.2.2]octane, and cannot synergistically inhibit the oxidative discoloration of o-phenylenediamine during the reaction. In addition, the low main reaction rate leads to a long residence time of free o-phenylenediamine, making the oxidation problem more serious.

[0013] Preferably, a highly efficient catalytic synthesis process for thiophanate-methyl includes the following steps: S1. o-Dichlorobenzene is subjected to ammonolysis with liquid ammonia in the presence of a copper catalyst to prepare o-phenylenediamine; S2. Thiourea reacts with methyl chloroformate in the presence of liquid alkali to produce methyl isothiocyanate; S3. Under inert gas protection, o-phenylenediamine obtained in step S1 is mixed with toluene and hindered Lewis acid-base pair catalyst, and the temperature is raised to 55-60°C. Then, methyl isothiocyanate obtained in step S2 is added dropwise to the above mixed solution at a uniform rate. After the addition is complete, the reaction is kept at the temperature, cooled, filtered, washed, and dried to obtain methylthiophanate.

[0014] More preferably, the copper catalyst in step S1 includes at least one of cuprous chloride, cuprous bromide and cuprous iodide.

[0015] Through the above technical solution, the present invention prepares o-phenylenediamine by ammonolysis of o-dichlorobenzene. In the presence of a copper catalyst, liquid ammonia undergoes a nucleophilic substitution reaction on the aromatic ring of o-dichlorobenzene, and the two chlorine atoms are successively replaced by amino groups to generate o-phenylenediamine.

[0016] Preferably, in step S1, the molar ratio of o-dichlorobenzene to liquid ammonia is 1:(3-8), the reaction temperature is 150-220℃, the pressure is 4-8MPa, and the reaction time is 8-16 hours.

[0017] Through the above technical solution, this invention uses liquid ammonia as both a reactant and a solvent. Excess ammonia is beneficial for shifting the equilibrium towards the product direction, thereby increasing the conversion rate of o-dichlorobenzene; however, excessive ammonia will increase the recovery load.

[0018] More preferably, in step S1, the copper catalyst is used in conjunction with a nitrogen-containing ligand, which includes at least one of pyridine, 2,2'-bipyridine, and 1,10-o-phenanthroline.

[0019] Through the above technical solution, the present invention reduces the activation energy of the reaction by forming a complex between a copper catalyst and a nitrogen-containing ligand.

[0020] Preferably, in step S2, the molar ratio of thiourea to methyl chloroformate is (0.9–1.2):1, the liquid alkali is a 30–40% sodium hydroxide solution, and the reaction temperature is 45–55°C.

[0021] Preferably, in step S3, the molar ratio of methyl isothiocyanate to o-phenylenediamine is (2.1-2.3):1, the dropping time is 1.5-2.5 hours, and the reaction time is 1-2 hours.

[0022] More preferably, the molar ratio of methyl isothiocyanate to o-phenylenediamine is 2:1.

[0023] Using a slight excess of isothiocyanate can ensure complete conversion of o-phenylenediamine, but too much excess will exacerbate side reactions.

[0024] Preferably, the inert gas in step S3 is selected from nitrogen or argon; the amount of toluene used is 18 to 37 times the mass of o-phenylenediamine; and the toluene is recovered and recycled after the reaction is completed.

[0025] Through the above technical solution, this invention generates methyl isothiocyanate by reacting thiourea with methyl chloroformate. Thiourea and methyl chloroformate undergo condensation under alkaline conditions to generate methyl isothiocyanate. A hindered Lewis acid-base pair catalyzes a back-drop condensation reaction, in which 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate form a hindered Lewis acid-base pair, Zn... 2+ The 1,4-diazabicyclo[2.2.2]octane coordinates with the sulfur atom of isothiocyanate, and the amino group of o-phenylenediamine undergoes hydrogen bonding. This dual activation significantly lowers the activation energy of the addition reaction, resulting in a substantial increase in the reaction rate. The reverse-dropping method ensures that o-phenylenediamine is always in a relatively excess state, avoiding overheating and side reactions caused by local accumulation of isothiocyanate.

[0026] The beneficial effects of this invention are: 1. The hindered Lewis acid-base pair catalyst of this invention is formed by mixing 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate in anhydrous toluene. The steric hindrance of the bicyclic rigid framework prevents direct coordination and addition between the two substrates, solving problems such as the inability of a single component or simple mixture to simultaneously activate two substrates, low main reaction rate leading to numerous byproducts, easy oxidation of o-phenylenediamine, and the water sensitivity of Lewis acids. Through simultaneous dual activation, the main reaction rate is significantly improved, allowing methyl isothiocyanate to be rapidly consumed upon addition, inhibiting the formation of byproducts such as triazine thione at the source, while simultaneously accelerating the consumption of free o-phenylenediamine. Combined with weak reducing properties and inert gas protection, it effectively prevents oxidation and discoloration, achieving a synergistic catalytic effect far exceeding linear superposition.

[0027] 2. This invention effectively disperses the heat of reaction by combining reverse dropping with dual activation catalysis, making the process more stable and controllable. At the same time, neither 1,4-diazabicyclo[2.2.2]octane nor zinc trifluoromethanesulfonate are highly toxic or precursor chemicals, thus improving the safety of the process.

[0028] 3. This invention utilizes a hindered Lewis acid-base pair catalyst composed of 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate. This catalyst requires a small amount and does not contain aniline structures, significantly reducing wastewater toxicity and allowing it to be directly treated in conventional biochemical systems. Furthermore, toluene can be recovered and reused through simple distillation, reducing the total discharge of organic solvents, lowering the environmental impact, and reducing post-treatment processes and energy consumption. Detailed Implementation

[0029] Preparation Example Preparation Example 1: A method for preparing a hindered Lewis acid-base pair catalyst, comprising the following steps: Under a nitrogen atmosphere, 200 mL of anhydrous toluene, 11.2 g (0.10 mol) of 1,4-diazabicyclo[2.2.2]octane, and 36.4 g (0.10 mol) of zinc trifluoromethanesulfonate were added to a dry 500 mL volumetric flask. The mixture was stirred at room temperature for 1 hour to obtain a homogeneous, colorless, and transparent solution, which is the hindered Lewis acid-base pair catalyst with a concentration of 0.5 mol / L.

[0030] Preparation Example 2: A method for preparing a 1,4-diazabicyclo[2.2.2]octane catalyst, comprising the following steps: dissolving 11.2 g (0.10 mol) of 1,4-diazabicyclo[2.2.2]octane in 200 mL of anhydrous toluene, stirring until homogeneous, to obtain a toluene solution of 1,4-diazabicyclo[2.2.2]octane, which is the 1,4-diazabicyclo[2.2.2]octane catalyst with a concentration of 0.5 mol / L.

[0031] Preparation Example 3: A method for preparing a zinc trifluoromethanesulfonate catalyst, comprising the following steps: adding 36.4 g (0.10 mol) of zinc trifluoromethanesulfonate to 200 mL of anhydrous toluene and stirring until homogeneous to obtain a zinc trifluoromethanesulfonate catalyst with a concentration of 0.5 mol / L.

[0032] Preparation Example 4: A method for preparing an N,N-dimethylaniline catalyst, comprising the following steps: 12.1 g (0.10 mol) of N,N-dimethylaniline was dissolved in 200 mL of anhydrous toluene and stirred until homogeneous to obtain an N,N-dimethylaniline catalyst with a concentration of 0.5 mol / L.

[0033] Preparation Example 5: A method for preparing a Lewis acid-base adduct, comprising the following steps: 11.2 g (0.10 mol) of 1,4-diazabicyclo[2.2.2]octane, 36.4 g (0.10 mol) of zinc trifluoromethanesulfonate, and 200 mL of toluene (undried, water content >500 ppm) were added to the toluene simultaneously, and the mixture was stirred at room temperature for 10 minutes until the solids were completely dissolved, yielding a homogeneous solution. Due to the presence of water and the lack of inert gas protection, 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate rapidly formed a stable Lewis acid-base adduct with a concentration of 0.5 mol / L.

[0034] Example Example 1: A highly efficient catalytic synthesis process for thiophanate-methyl includes the following steps: S1. Preparation of o-phenylenediamine: In a high-pressure reactor, 1470 g (10.0 mol) of o-dichlorobenzene, 9.9 g of cuprous chloride, and 7.9 g of pyridine were added and the reactor was sealed. The air inside the reactor was purged with nitrogen three times, and then 850 g (50 mol) of liquid ammonia was introduced. Stirring was started, the temperature was raised to 180 °C, the pressure was about 5.0 MPa, and the reaction was maintained at this temperature for 12 hours. After cooling, the residual ammonia was released, and the material was transferred to a distillation apparatus for vacuum distillation at 95 °C / 10 mmHg. The distillate was collected to obtain white, flaky crystalline o-phenylenediamine.

[0035] S2. Preparation of methyl isothiocyanate: In a four-necked flask, 600 mL of toluene and 760 g (10.0 mol) of thiourea were added, and the mixture was heated to 45 °C with stirring. 945 g (10.0 mol) of methyl chloroformate and 1333 g of 30% sodium hydroxide solution (containing 10.0 mol NaOH) were placed in two separate dropping funnels and slowly added dropwise to the flask simultaneously, maintaining the reaction temperature at 55 °C for 1.5 hours. After the addition was complete, the mixture was kept at 50 °C with stirring for 30 minutes. The mixture was allowed to stand and separate into layers; the lower layer was an aqueous phase, and the upper organic phase was a toluene solution containing methyl isothiocyanate.

[0036] S3. Hindered Lewis acid-base pair catalytic back-dropping condensation: Under nitrogen protection, 800 mL of anhydrous toluene, 108.1 g (1.0 mol) of o-phenylenediamine, and 20 mL of the hindered Lewis acid-base pair catalyst from Preparation Example 1 were added to a 2 L four-necked flask. The mixture was stirred to dissolve and heated to 55 °C. The toluene solution containing methyl isothiocyanate obtained in step S2 was transferred to a constant-pressure dropping funnel and added dropwise to the flask at a uniform rate over 2.0 hours, maintaining the reaction temperature at 55 °C. After the addition was complete, the mixture was stirred at this temperature for 1.5 hours. After natural cooling to room temperature, the mixture was filtered, and the filter cake was washed twice with cold toluene (100 mL each time). The cake was then dried under vacuum at 50 °C to obtain a white crystalline powder of methyl thiophanate.

[0037] Example 2 The only difference between this embodiment and Example 1 is that in step S3, 10 mL of the hindered Lewis acid-base pair catalyst of Example 1 is taken.

[0038] Example 3 The only difference between this embodiment and Example 1 is that in step S3, 24 mL of the hindered Lewis acid-base pair catalyst of Example 1 is taken.

[0039] Example 4 The only difference between this embodiment and Embodiment 1 is that 7.9g of pyridine is not added in step S1.

[0040] Comparative Example Comparative Example 1: A highly efficient catalytic synthesis process for methyl thiophanate includes the following steps: S1. Preparation of o-phenylenediamine: In a high-pressure reactor, 1470 g (10.0 mol) of o-dichlorobenzene, 9.9 g of cuprous chloride, and 7.9 g of pyridine were added and the reactor was sealed. The air inside the reactor was purged with nitrogen three times, and then 850 g (50 mol) of liquid ammonia was introduced. Stirring was started, the temperature was raised to 180 °C, the pressure was about 5.0 MPa, and the reaction was maintained at this temperature for 12 hours. After cooling, the residual ammonia was released, and the material was transferred to a distillation apparatus for vacuum distillation at 95 °C / 10 mmHg. The distillate was collected to obtain white, flaky crystalline o-phenylenediamine.

[0041] S2. Preparation of methyl isothiocyanate: In a four-necked flask, 600 mL of toluene and 760 g (10.0 mol) of thiourea were added, and the mixture was heated to 45 °C with stirring. 945 g (10.0 mol) of methyl chloroformate and 1333 g of 30% sodium hydroxide solution (containing 10.0 mol NaOH) were placed in two separate dropping funnels and slowly added dropwise to the flask simultaneously, controlling the reaction temperature to not exceed 55 °C, over a period of 1.5 hours. After the addition was complete, the mixture was kept at 50 °C with stirring for 30 minutes. The mixture was allowed to stand and separate into layers; the lower layer was an aqueous phase, and the upper organic phase was a toluene solution containing methyl isothiocyanate.

[0042] S3. Under nitrogen protection, add 800 mL of anhydrous toluene, 108.1 g (1.0 mol) of o-phenylenediamine, and 20 mL of the 1,4-diazabicyclo[2.2.2]octane catalyst from Preparation Example 2 to a 2 L four-necked flask. Stir to dissolve and heat to 55 °C. Transfer the toluene solution containing methyl isothiocyanate obtained in step S2 to a constant pressure dropping funnel and add it dropwise to the flask at a uniform rate, controlling the dropping time to 2.0 hours and maintaining the reaction temperature at 55 °C. After the addition is complete, keep warm and stir for 1.5 hours. Cool naturally to room temperature, filter, wash the filter cake twice with cold toluene (100 mL each time), and dry under vacuum at 50 °C to obtain a white crystalline powder of methyl thiophanate.

[0043] Comparative Example 2: A highly efficient catalytic synthesis process for methyl thiophanate, comprising the following steps: S1. Preparation of o-phenylenediamine: In a high-pressure reactor, 1470 g (10.0 mol) of o-dichlorobenzene, 9.9 g of cuprous chloride, and 7.9 g of pyridine were added and the reactor was sealed. The air inside the reactor was purged with nitrogen three times, and then 850 g (50 mol) of liquid ammonia was introduced. Stirring was started, the temperature was raised to 180 °C, the pressure was about 5.0 MPa, and the reaction was maintained at this temperature for 12 hours. After cooling, the residual ammonia was released, and the material was transferred to a distillation apparatus for vacuum distillation at 95 °C / 10 mmHg. The distillate was collected to obtain white, flaky crystalline o-phenylenediamine.

[0044] S2. Preparation of methyl isothiocyanate: In a four-necked flask, 600 mL of toluene and 760 g (10.0 mol) of thiourea were added, and the mixture was heated to 45 °C with stirring. 945 g (10.0 mol) of methyl chloroformate and 1333 g of 30% sodium hydroxide solution (containing 10.0 mol NaOH) were placed in two separate dropping funnels and slowly added dropwise to the flask simultaneously, controlling the reaction temperature to not exceed 55 °C, over a period of 1.5 hours. After the addition was complete, the mixture was kept at 50 °C with stirring for 30 minutes. The mixture was allowed to stand and separate into layers; the lower layer was an aqueous phase, and the upper organic phase was a toluene solution containing methyl isothiocyanate.

[0045] S3. Under nitrogen protection, add 800 mL of anhydrous toluene, 108.1 g (1.0 mol) of o-phenylenediamine, and 20 mL of the zinc trifluoromethanesulfonate catalyst from Preparation Example 3 to a 2 L four-necked flask. Stir to dissolve and heat to 55 °C. Transfer the toluene solution containing methyl isothiocyanate obtained in step S2 to a constant pressure dropping funnel and add it dropwise to the flask at a uniform rate, controlling the dropping time to 2.0 hours and maintaining the reaction temperature at 55 °C. After the addition is complete, keep warm and stir for 1.5 hours. Cool naturally to room temperature, filter, wash the filter cake twice with cold toluene (100 mL each time), and dry under vacuum at 50 °C to obtain a white crystalline powder of methyl thiophanate.

[0046] Comparative Example 3: A highly efficient catalytic synthesis process for methyl thiophanate, comprising the following steps: S1. Preparation of o-phenylenediamine: In a high-pressure reactor, 1470 g (10.0 mol) of o-dichlorobenzene, 9.9 g of cuprous chloride, and 7.9 g of pyridine were added and the reactor was sealed. The air inside the reactor was purged with nitrogen three times, and then 850 g (50 mol) of liquid ammonia was introduced. Stirring was started, the temperature was raised to 180 °C, the pressure was about 5.0 MPa, and the reaction was maintained at this temperature for 12 hours. After cooling, the residual ammonia was released, and the material was transferred to a distillation apparatus for vacuum distillation at 95 °C / 10 mmHg. The distillate was collected to obtain white, flaky crystalline o-phenylenediamine.

[0047] S2. Preparation of methyl isothiocyanate: In a four-necked flask, 600 mL of toluene and 760 g (10.0 mol) of thiourea were added, and the mixture was heated to 45 °C with stirring. 945 g (10.0 mol) of methyl chloroformate and 1333 g of 30% sodium hydroxide solution (containing 10.0 mol NaOH) were placed in two separate dropping funnels and slowly added dropwise to the flask simultaneously, controlling the reaction temperature to not exceed 55 °C, over a period of 1.5 hours. After the addition was complete, the mixture was kept at 50 °C with stirring for 30 minutes. The mixture was allowed to stand and separate into layers; the lower layer was an aqueous phase, and the upper organic phase was a toluene solution containing methyl isothiocyanate.

[0048] S3. Under nitrogen protection, add 800 mL of anhydrous toluene, 108.1 g (1.0 mol) of o-phenylenediamine, and 20 mL of the N,N-dimethylaniline catalyst from Preparation Example 4 to a 2 L four-necked flask. Stir to dissolve and heat to 55 °C. Transfer the toluene solution containing methyl isothiocyanate obtained in step S2 to a constant pressure dropping funnel and add it dropwise to the flask at a uniform rate, controlling the dropping time to 2.0 hours and maintaining the reaction temperature at 55 °C. After the addition is complete, keep warm and stir for 1.5 hours. Cool naturally to room temperature, filter, wash the filter cake twice with cold toluene (100 mL each time), and dry under vacuum at 50 °C to obtain a white crystalline powder of methyl thiophanate.

[0049] Comparative Example 4: A highly efficient catalytic synthesis process for thiophanate-methyl, comprising the following steps: S1. Preparation of o-phenylenediamine: In a high-pressure reactor, 1470 g (10.0 mol) of o-dichlorobenzene, 9.9 g of cuprous chloride, and 7.9 g of pyridine were added and the reactor was sealed. The air inside the reactor was purged with nitrogen three times, and then 850 g (50 mol) of liquid ammonia was introduced. Stirring was started, the temperature was raised to 180 °C, the pressure was about 5.0 MPa, and the reaction was maintained at this temperature for 12 hours. After cooling, the residual ammonia was released, and the material was transferred to a distillation apparatus for vacuum distillation at 95 °C / 10 mmHg. The distillate was collected to obtain white, flaky crystalline o-phenylenediamine.

[0050] S2. Preparation of methyl isothiocyanate: In a four-necked flask, 600 mL of toluene and 760 g (10.0 mol) of thiourea were added, and the mixture was heated to 45 °C with stirring. 945 g (10.0 mol) of methyl chloroformate and 1333 g of 30% sodium hydroxide solution (containing 10.0 mol NaOH) were placed in two separate dropping funnels and slowly added dropwise to the flask simultaneously, controlling the reaction temperature to not exceed 55 °C, over a period of 1.5 hours. After the addition was complete, the mixture was kept at 50 °C with stirring for 30 minutes. The mixture was allowed to stand and separate into layers; the lower layer was an aqueous phase, and the upper organic phase was a toluene solution containing methyl isothiocyanate.

[0051] S3. Methyl isothiocyanate (2.2 mol) and the catalyst from Preparation Example 1 were added to a reaction flask, along with 800 mL of toluene. The mixture was heated to 55 °C. o-Phenylenediamine (108.1 g, 1.0 mol) was dissolved in 200 mL of toluene and added dropwise over a constant-pressure dropping funnel to the reaction flask at a uniform rate over 2 hours. After the reaction was complete, a pale yellow powder of methyl thiophanate was obtained.

[0052] Comparative Example 5 The only difference between this preparation example and Example 1 is that in step S3, the hindered Lewis acid-base pair catalyst of Preparation Example 1 is replaced with the Lewis acid-base adduct of Preparation Example 5.

[0053] Performance testing.

[0054] 1. Purity determination: Instrument: Agilent 1260 high-performance liquid chromatograph; Chromatographic conditions: Column: C18 reversed-phase column; Mobile phase: methanol to water (v / v) 65:3; Flow rate: 1.0 mL / min; Detection wavelength: 254 nm; Column temperature: 30℃; Injection volume: 20 μL. Inject the sample solution into the high-performance liquid chromatograph, record the chromatogram, and calculate the purity of methyl thiophanate using the area normalization method. The calculation formula is as follows:

[0055] 2. Yield determination: The yield was calculated based on o-phenylenediamine, using the following formula:

[0056] The theoretical yield (g) = o-phenylenediamine feed amount (mol) × thiophanate-methyl molecular weight (342.4 g / mol).

[0057] 3. Color evaluation: Take 5g of dried thiophanate-methyl sample, place it on white filter paper or a petri dish, observe the color visually under natural light, and record the results.

[0058] 4. Whiteness Measurement: The blue light whiteness (R457) of thiophanate-methyl technical powder was measured using a whiteness meter. This is the percentage of the sample's light reflectance in the 457nm wavelength band relative to the reflectance of a standard white plate. Each sample was measured three times, and the sample was reloaded after each measurement. The arithmetic mean was taken as the final whiteness value.

[0059] The results of the above experiments are shown in Table 1: Table 2. Performance test results of the examples and comparative examples.

[0060] Combining Example 1 and Comparative Example 1, it can be seen that Comparative Example 1 uses only 1,4-diazabicyclo[2.2.2]octane as a catalyst, which forms hydrogen bonds or partially deprotonates the amino group of o-phenylenediamine, thus improving the nucleophilicity of the nitrogen atom. However, the isothiocyanate group of methyl isothiocyanate is not activated, and its carbon atom has limited electrophilicity. Under this single-base catalytic condition, although the main reaction rate is improved compared to no catalyst, it does not reach the level of instantaneous capture. After being added, methyl isothiocyanate needs to remain in the reaction system for a certain period of time before it can collide and react with the activated o-phenylenediamine. During this residence time, isothiocyanate is prone to dimerization at high temperatures of 55-60°C, generating inert triazine thiones as byproducts, losing its reactivity with o-phenylenediamine. These byproducts cannot be converted into methyl thiophanate, resulting in a decrease in yield to only 90.1%. Due to the insufficient main reaction rate, a certain concentration of free o-phenylenediamine always exists in the system. These free amines, upon contact with trace amounts of oxygen during dissolution, heating, and reaction, are oxidized to form colored impurities such as 2,3-diaminophenazine. These colored impurities mix into the product crystals, causing the product to appear yellowish, its whiteness to decrease to only 86.5%, and its purity to only 94.8%. In Example 1, the addition of zinc trifluoromethanesulfonate compensated for the deficiencies of Comparative Example 1. Zn 2+Preferential coordination with the sulfur atom of isothiocyanate enhances the electrophilicity of the carbon atom in isothiocyanate. 1,4-Diazabicyclo[2.2.2]octane forms a hindered Lewis acid-base pair with zinc trifluoromethanesulfonate. Due to steric hindrance and coordination equilibrium, they cannot form a stable adduct, each retaining its active site, while simultaneously activating both the nucleophile and electrophile. The main reaction rate is thus significantly increased; the isothiocyanate is rapidly captured and consumed upon addition, before dimerization side reactions can occur. Simultaneously, the accelerated main reaction causes a rapid decrease in the concentration of free o-phenylenediamine. Combined with the weak reducing properties of 1,4-diazabicyclo[2.2.2]octane and the protection of an inert gas, oxidation and discoloration are effectively prevented, resulting in a product whiteness of up to 93.2% and a purity of 98.6%.

[0061] As can be seen from Example 1 and Comparative Example 2, Comparative Example 2 only used zinc trifluoromethanesulfonate as a catalyst, Zn 2+ As a soft Lewis acid, it coordinates with the sulfur atom of methyl isothiocyanate, enhancing the electrophilicity of the carbon atom in the isothiocyanate and making it more susceptible to nucleophilic attack. However, the amino group of o-phenylenediamine is not activated, resulting in limited nucleophilicity. Under monoacid catalysis, although the isothiocyanate is activated, the reactivity of the nucleophile is insufficient, and the main reaction rate remains limited. The isothiocyanate has a longer residence time in the system, leading to a higher proportion of dimerization side reactions and a lower yield than in Comparative Example 1. Because o-phenylenediamine is not activated, its reaction consumption rate is slower, and free o-phenylenediamine exists in the system for a longer time, increasing the chance of oxidation. At the same time, zinc trifluoromethanesulfonate lacks reducing properties and cannot consume dissolved oxygen in the system, resulting in a more severe oxidation and discoloration problem than in Comparative Example 1, with the product whiteness dropping to 85.9%. The addition of 1,4-diazabicyclo[2.2.2]octane resolved the defects of Comparative Example 2. 1,4-Diazabicyclo[2.2.2]octane activates the amino group of o-phenylenediamine, significantly enhancing its nucleophilicity. This, combined with the zinc trifluoromethanesulfonate-activated isothiocyanate, results in an exponential increase in the main reaction rate. Simultaneously, the weak reducing properties of 1,4-diazabicyclo[2.2.2]octane consume trace amounts of dissolved oxygen, which, in conjunction with the inert gas protection, effectively prevents oxidation. The product's whiteness is restored to 93.2%.

[0062] Based on Examples 1 and 3, N,N-dimethylaniline belongs to the tertiary amine class of nucleophilic catalysts. Its mechanism of action is similar to that of 1,4-diazabicyclo[2.2.2]octane, enhancing its nucleophilicity through the interaction of the nitrogen atom with the amino group of o-phenylenediamine. Similar to Comparative Example 1, the single-base catalyst can only activate nucleophiles, not electrophiles, resulting in a limited main reaction rate. The isothiocyanate dimerization problem persists, with a yield of only 89.0%. N,N-dimethylaniline lacks the weak reducing properties of 1,4-diazabicyclo[2.2.2]octane, failing to consume trace amounts of dissolved oxygen in the system. This exacerbates the o-phenylenediamine oxidation problem, reducing the product whiteness to 83.2%. In Example 1, 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate were used to replace N,N-dimethylaniline. This not only accelerated the main reaction and suppressed the side reaction through dual activation, but also prevented oxidation through the weak reducing properties of 1,4-diazabicyclo[2.2.2]octane. The yield was increased by 5.2% and the whiteness was increased by 10.0%.

[0063] Combining Example 1 and Comparative Example 4, it can be seen that although Comparative Example 4 used the same hindered Lewis acid-base pair catalyst composed of 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate as Example 1, the order of addition was reversed, resulting in a significant decrease in yield, purity, and whiteness. During the positive dropping process, methyl isothiocyanate and the catalyst were pre-added to the reaction flask. o-Phenylenediamine was slowly added dropwise from the dropping funnel. At the dropping point, the concentration of o-Phenylenediamine was instantaneously high, while the surrounding area contained a large amount of excess isothiocyanate. The addition reaction of o-Phenylenediamine and isothiocyanate is a strongly exothermic reaction. The heat of reaction was released instantaneously in a localized area, forming a hot spot. The high temperature accelerated the dimerization and decomposition of isothiocyanate, generating inert byproducts such as triazine thione, and the localized high temperature intensified the oxidation of o-Phenylenediamine. In the reverse addition process, o-phenylenediamine and a catalyst are pre-added to the reaction flask. Methyl isothiocyanate is slowly added dropwise from the dropping funnel. Each isothiocyanate molecule is surrounded by a large amount of excess o-phenylenediamine at the moment of addition. The heat of reaction is absorbed by the large amount of solvent and excess o-phenylenediamine. The temperature is stable and controllable, with no hot spots forming. Isothiocyanate has no opportunity to accumulate; it is consumed dropwise, and the dimerization side reaction is suppressed. Free o-phenylenediamine is rapidly consumed, and oxidation is inhibited. Therefore, the forward addition leads to localized overheating, causing a significant increase in the isothiocyanate dimerization ratio and a 7.7% decrease in yield; o-phenylenediamine oxidation is intensified, resulting in an 11.7% decrease in whiteness.

[0064] Based on Examples 1 and 5, compared to Example 1, Comparative Example 5 showed a 7.2% decrease in yield, a 6.6% decrease in purity, and a 10.2% decrease in whiteness, with the appearance changing from white to slightly yellow. Furthermore, its catalytic effect was essentially the same as that of a single component, exhibiting no synergistic catalysis. This may be because Comparative Example 5 contained trace amounts of water during its preparation process, and water preferentially reacts with Zn. 2+Coordination generates hydrated zinc ions, occupying coordination vacancies and weakening acidity. Simultaneously, water molecule bridging induces the formation of tight adducts, causing mutual closure of the acid and base active sites, resulting in the loss of synergistic dual activation. The polarity of water also alters the dielectric constant of toluene, accelerating adduct formation. In common adducts, the nitrogen atom of diazabicyclo[2.2.2]octane interacts with Zn... 2+ Stable coordination bonds are formed, and the active centers are mutually closed, relying only on a very small amount of free species to provide a weak single catalytic effect, resulting in serious side reactions. In contrast, the hindered Lewis acid-base pair in Example 1 utilizes the steric hindrance of the rigid framework of the diazabicyclo[2.2.2]octane bicyclic ring to prevent strong coordination in an anhydrous nonpolar medium. The two only maintain a weak reversible electrostatic interaction, each independently retaining its acid and base active sites, achieving simultaneous dual activation, rapidly consuming the substrate, inhibiting dimerization, and preventing oxidation. Therefore, it is superior to Comparative Example 5 in terms of yield, purity, and whiteness.

[0065] The above-disclosed embodiments are merely a few specific examples of the present invention. However, the embodiments of the present invention are not limited thereto, and any variations that can be conceived by those skilled in the art should fall within the protection scope of the present invention.

Claims

1. A highly efficient catalytic synthesis process for methyl thiophanate, characterized in that, Methylthiocarbamate was prepared by a hindered Lewis acid-base pair catalyst consisting of 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate, through a reverse-dropping method to add methyl isothiocyanate to a solution of o-phenylenediamine to carry out a condensation reaction.

2. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 1, characterized in that, The preparation of the hindered Lewis acid-base pair catalyst includes the following steps: under a nitrogen atmosphere, 1,4-diazabicyclo[2.2.2]octane and zinc trifluoromethanesulfonate in a molar ratio of (1-1.2):1 are added to anhydrous toluene and stirred at room temperature for 1-2 hours to obtain the hindered Lewis acid-base pair catalyst.

3. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 1, characterized in that, The concentration of the hindered Lewis acid-base pair catalyst in anhydrous toluene is 0.4–0.6 mol / L.

4. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 1, characterized in that, The total amount of the hindered Lewis acid-base pair catalyst is 5-10 mol relative to o-phenylenediamine.

5. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 1, characterized in that, Includes the following steps: S1. o-Dichlorobenzene is subjected to ammonolysis with liquid ammonia in the presence of a copper catalyst to prepare o-phenylenediamine; S2. Thiourea reacts with methyl chloroformate in the presence of liquid alkali to produce methyl isothiocyanate; S3. Under inert gas protection, the o-phenylenediamine obtained in step S1 is mixed with toluene and a hindered Lewis acid-base pair catalyst to obtain a mixed solution. The temperature is raised to 55-60°C, and then methyl isothiocyanate is added dropwise to the mixed solution at a uniform rate. After the addition is complete, the reaction is maintained at the temperature. Finally, after cooling, filtration, washing, and drying, methyl thiophanate is obtained.

6. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 5, characterized in that, In step S1, the molar ratio of o-dichlorobenzene to liquid ammonia is 1:(3-8), the reaction temperature is 150-220℃, the pressure is 4-8MPa, and the reaction time is 8-16 hours.

7. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 5, characterized in that, In step S2, the molar ratio of thiourea to methyl chloroformate is (0.9–1.2):1, the alkali solution is a 30–40% sodium hydroxide solution, the reaction temperature is 45–55°C, and the reaction time is 1–2 hours.

8. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 5, characterized in that, In step S3, the molar ratio of methyl isothiocyanate to o-phenylenediamine is (2.1-2.3):1, the dropping time is 1.5-2.5 hours, and the reaction time is 1-2 hours.

9. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 5, characterized in that, The copper catalyst in step S1 includes at least one of cuprous chloride, cuprous bromide, and cuprous iodide.

10. The highly efficient catalytic synthesis process for methyl thiophanate according to claim 5, characterized in that, In step S3, the inert gas is selected from nitrogen or argon; the amount of toluene used is 18 to 37 times the mass of o-phenylenediamine; after the reaction is completed, the toluene is recovered and recycled.

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