A process for the production of cycloxaprid
By optimizing the production process of cycloazinone, and adopting addition reaction, phase transfer catalytic reaction and one-pot design, the problems of high ammonia nitrogen wastewater and high solvent consumption in traditional processes have been solved, realizing efficient and environmentally friendly synthesis of cycloazinone, improving product yield and purity, and reducing production costs.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- ANHUI GUANGXIN CHENGCHEN TECHNOLOGY CO LTD
- Filing Date
- 2026-03-12
- Publication Date
- 2026-06-19
AI Technical Summary
Traditional cycloazinone synthesis processes generate high ammonia nitrogen and high COD wastewater, posing safety risks and incurring high costs. Furthermore, they consume a large amount of solvent, making it difficult to achieve efficient and environmentally friendly synthesis.
By employing addition reactions, phase transfer catalysis, thiourea reactions, and cyclization-amine hydrolysis one-pot reactions, and utilizing the miscibility of anhydrous toluene and methanol, the intermediate products can be reacted directly and continuously without separation. Through the design of the "cyclization-amine hydrolysis one-pot method", the catalyst and raw materials are optimized, and safety risks and solvent consumption are reduced.
It significantly reduces wastewater COD, increases product yield and purity, lowers the cost of treating waste gas, wastewater, and solid waste, and enhances the economic efficiency and environmental friendliness of industrial production. It is suitable for large-scale preparation of pesticide-grade cycloazinone.
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Abstract
Description
Technical Field
[0001] This invention belongs to the technical field of organic synthesis, and more specifically, relates to a process for producing cycloazinone. Background Technology
[0002] Hexazinone, chemically known as 3-cyclohexyl-6-dimethylamino-1-methyl-1,3,5-triazine-2,4(1H,3H)-dione, is a selective systemic triazine herbicide. It is commonly traded under names such as Lincaojing or Wilbur. Since its commercialization by DuPont in the 1970s, it has been widely used in forestry tending, sugarcane fields, tea gardens, coffee plantations, and non-cultivated land weed control due to its broad-spectrum efficacy, moderate soil residual time, and high safety for trees such as pine and eucalyptus. Bamboo, large trees, and many shrubs, with their extensive root systems, are difficult to kill with ordinary herbicides. Therefore, hexazinone, with its unique mechanism of action and outstanding control effect, has become the preferred agent for killing bamboo, shrubs, and trees, and is widely used for controlling weeds, shrubs, and bamboo, pre-afforestation land preparation, tending of young and middle-aged forests, establishing and maintaining tourist attractions, and forest firebreaks. However, the environmental problems associated with its traditional synthesis process have become a prominent bottleneck restricting the green upgrading of the industry.
[0003] Traditional synthesis processes focus on two main pathways: (1) Cyanoguanidine-cyclohexylamine method: Cyanoguanidine is condensed with cyclohexylamine to generate amidourea, which is then cyclized with ethyl chloroformate and methylated with dimethylamine to obtain cycloazinone. The cyclization step in this route requires reaction at 120°C for 6-8 hours in an excess ammonia (or liquid ammonia) medium, resulting in a large amount of unreacted ammonia and organic amine hydrolysis products remaining. This type of wastewater has poor biodegradability, high treatment costs, and poses a risk of excessive ammonia nitrogen emissions.
[0004] (2) Guanidinium salt-cyclohexylformyl chloride process: Although it avoids some ammonia sources, the cyclization process uses strong bases such as sodium methoxide, and produces a mixture of methanol and organic amines as byproducts, resulting in relatively high ammonia nitrogen levels in the wastewater. Furthermore, chloroformate reagents release phosgene precursors upon contact with water, posing significant safety risks. The equipment requires Hastelloy corrosion protection, leading to high investment costs. In addition, the multi-step reaction relies on highly toxic solvents such as DMF and toluene, which may pose health hazards.
[0005] To address the aforementioned pain points, the industry has attempted various optimization approaches, but these approaches have limitations such as focusing on repairing a single link (e.g., catalyst replacement, solvent adjustment) or introducing new risks (highly toxic reagents, complex waste), and no greener, more environmentally friendly, and effective solutions have yet emerged. Summary of the Invention
[0006] The purpose of this invention is to provide a cycloazinone production process that simplifies the process, effectively avoids the source of high ammonia nitrogen / high COD wastewater, and achieves efficient synthesis.
[0007] The objective of this invention can be achieved through the following technical solutions: A process for producing cycloazinone includes the following steps: S1. Addition reaction: Cyclohexyl isocyanate is added dropwise to a 30-50% aqueous solution of methylamine in anhydrous toluene at 20-25°C with stirring. After the addition is complete, the temperature is raised to 25-30°C and the reaction is maintained for 1-1.5 hours. Then, the mixture is allowed to stand and separate into layers to obtain an organic phase. After drying, intermediate product A is obtained. Intermediate product A is N-cyclohexyl-N'-methylurea. S2. Phase transfer catalytic reaction: Sodium thiocyanate and deionized water are mixed to obtain an aqueous solution of sodium thiocyanate; a quaternary ammonium salt catalyst is added, and methyl chloroformate is added dropwise to the aqueous solution of sodium thiocyanate at 30~35℃. After the addition is complete, the reaction is kept at the temperature for 3~5h, and the mixture is allowed to stand and separated. The organic phase is taken to obtain intermediate product B, which is methoxycarbonyl isothiocyanate. S3. Thiourea reaction: In anhydrous toluene at 20-25°C, add intermediate product A obtained in step S1, then add an organic tertiary amine catalyst to obtain a mixed system. Add intermediate product B obtained in step S2 dropwise to the mixed system. After the addition is complete, heat to 35-40°C and keep reacting for 3-4 hours. Wash with water and separate the liquids. Take the organic phase to obtain intermediate product C; the intermediate product C is a thiourea derivative. S4. Cycloning-amine hydrolysis one-pot reaction: Add a 20-40% sodium methoxide-methanol solution to the intermediate product C obtained in step S3, and cyclize at 35-40℃ for 3-5 hours. Then add a 30-50% dimethylamine aqueous solution and amine hydrolyze at 40-50℃ for 4-6 hours to obtain a reaction solution containing the final product. S5. Post-processing purification: The reaction solution obtained in step S4 is separated into layers to obtain an organic phase. The organic phase is then acid-washed, salt-washed, dried, and concentrated to obtain a concentrated solution. The concentrated solution is crystallized with an ethanol-water mixed solvent and dried to obtain the cycloazinone product.
[0008] Further, in step S1, the molar ratio of the cyclohexyl isocyanate to the aqueous methylamine solution is 1:(1~1.1); the amount of anhydrous toluene used is 4~6 times the mass of the cyclohexyl isocyanate.
[0009] In this reaction, anhydrous toluene is used as the reaction solvent. First, anhydrous toluene is added to the reaction vessel, then an aqueous methylamine solution is dispersed in it, and finally, cyclohexyl isocyanate is added dropwise to the anhydrous toluene system containing the aqueous methylamine solution.
[0010] More preferably, the molar ratio of cyclohexyl isocyanate to methylamine is 1:(1.02~1.08).
[0011] Preferably, in step S1, the stirring speed is 200~250 rpm, the dripping time is controlled at 1-1.5 hours, and the dripping temperature is controlled at ≤30℃.
[0012] Further, in step S2, the molar ratio of methyl chloroformate, sodium thiocyanate and deionized water is 1:(1.05~1.15):(3~5).
[0013] Further, in step S2, the quaternary ammonium salt catalyst is selected from at least one of tetrabutylammonium bromide, tetrabutylammonium chloride, trioctylmethylammonium chloride, and benzyltriethylammonium chloride, and the amount of the quaternary ammonium salt catalyst is 5 to 8% of the molar amount of methyl chloroformate.
[0014] Further, in step S3, the amount of anhydrous toluene used is 3 to 5 times the total mass of N-cyclohexyl-N'-methylurea and methoxycarbonyl isothiocyanate; the molar ratio of intermediate product A to intermediate product B is (1.02 to 1.08):1.
[0015] Further, in step S3, the organic tertiary amine catalyst is selected from at least one of triethylamine, tripropylamine, tributylamine or pyridine, and the amount of the organic tertiary amine catalyst is 2 to 4% of the molar amount of methoxycarbonyl isothiocyanate.
[0016] Further, in step S4, the molar ratio of sodium methoxide to thiourea derivative in the sodium methoxide-methanol solution is (1.3~1.7):1; the molar ratio of dimethylamine to thiourea derivative is (2.8~3.2):1.
[0017] Step S4 involves the following two reactions: the first step is a cyclization reaction between the thiourea derivative and sodium methoxide-methanol solution to generate a triazinone precursor, and the triazinone precursor and dimethylamine undergo an aminolysis reaction to generate cycloazinone (3-cyclohexyl-6-dimethylamino-1-methyl-1,3,5-triazin-2,4-dione).
[0018] Sodium methoxide exists stably in anhydrous methanol, providing a high concentration of CH3O. - The acid generated in the neutralization reaction drives the equilibrium toward the cyclization product and activates nucleophilic sites (carbonyl or isothiocyanate groups), promoting intramolecular cyclization. Methanol, as a solvent, ensures the reaction proceeds in a homogeneous system, increasing the reaction rate; it also reduces the surface tension of sodium methoxide, improving its contact efficiency with the reactants.
[0019] The thiourea derivative is 1-(cyclohexylcarbamoyl)-1-methyl-3-(methoxycarbonyl)thiourea or its tautomer. The triazinone precursor is 3-cyclohexyl-6-methylthio-1-methyl-1,3,5-triazin-2,4-dione.
[0020] Furthermore, in step S5, the volume ratio of the ethanol-water mixed solvent is 2~4:1, and the amount used is 2~4 times the mass of the concentrated solution.
[0021] Further, in step S5, the acid washing refers to using 5-8% dilute hydrochloric acid to adjust the pH to 6-7; the salt washing refers to washing with saturated brine.
[0022] Further, in step S5, the drying in the drying and concentration process refers to drying with at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, or molecular sieve for 1-2 hours; the concentration process refers to concentrating the mixture to 1 / 3 to 1 / 5 of its original volume under a vacuum of 0.08-0.095 MPa and a temperature of 40-50°C.
[0023] Further, in step S5, the crystallization refers to dissolving the concentrated solution in an ethanol-water mixed solvent at 70-75°C, then cooling it to 0-5°C and maintaining the temperature for crystallization for 2-4 hours.
[0024] Furthermore, the cooling process employs a gradual, gradient cooling method to avoid rapid cooling that could result in small crystals or inclusions of impurities. The preferred cooling rate is 5-10°C / h.
[0025] The reaction order of steps S1 and S2 is not important.
[0026] Furthermore, the reactions in steps S1 and S3 are both carried out under a slight positive pressure of nitrogen, with a nitrogen pressure of 0.01~0.03 MPa.
[0027] In this technical solution, the first step involves the synthesis of N-cyclohexyl-N'-methylurea via an addition reaction, with the reaction formula being: C6H 11 NCO + CH3NH2 → C6H 11 -NH-CO-NH-CH3; The second step involves the preparation of methoxycarbonyl isothiocyanate via phase transfer catalysis, with the following reaction formula: NaSCN+ClCOOCH3→CH3OCO-NCS+NaCl; The third step involves a thiourea reaction to generate a thiourea derivative, with the reaction formula: C6H 11 -NH-CO-NH-CH3+CH3OCO-NCS→C6H 11 NHCON(CH3)C(SH)=N-COOCH3; Steps four and five employ a one-pot cyclization-amine hydrolysis method to directly convert the compound into cycloazinone. The reaction equation is: C6H 11 NHCON(CH3)C(SH)=N-COOCH3 +H2O; +(CH3)2NH→ +CH3SH; Finally, the product is obtained through acid washing, salt washing, concentration, crystallization, and purification. The solvents used in each step are compatible, eliminating the need for multiple distillations and significantly improving production efficiency.
[0028] A cycloazinone is prepared using the above-described cycloazinone production process.
[0029] The beneficial effects of this invention are: (1) This invention uses cyclohexyl isocyanate, methylamine, methyl chloroformate, sodium thiocyanate, and dimethylamine as main raw materials. Through addition reaction, phase transfer catalysis, thiourea reaction, cyclization-amine hydrolysis one-pot reaction, and post-treatment purification, cycloazinone is finally obtained. This invention, through the core design of "cyclization-amine hydrolysis one-pot method", achieves direct and continuous reaction of intermediate products without separation by solvent compatibility (toluene and methanol are miscible), which solves the technical bottleneck of "distillation to recover solvent after cyclization before aminolysis" in traditional processes. The recovery rate of toluene and methanol solvent is high; the by-product methanethiol is recovered as sodium methanethiol by alkaline absorption, and the COD of wastewater is reduced; the final product yield is high and the product purity is high. The yield is greatly improved compared with traditional processes, the cost of waste treatment is reduced, the solvent consumption is reduced, and the economic and environmental benefits of industrial production are significantly improved. It is suitable for the large-scale preparation of pesticide-grade cycloazinone.
[0030] (2) The present invention uses cyclohexyl isocyanate and methylamine aqueous solution to replace the highly toxic raw material methyl isocyanate in the traditional process, while optimizing the type and amount of catalyst, thereby improving the selectivity of the reaction and reducing the safety risk.
[0031] (3) The present invention achieves reduced solvent consumption costs and efficient solvent recovery, and solves the problems of difficult recovery and large consumption caused by the incompatibility of multiple solvents in traditional processes. Detailed Implementation
[0032] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described below with reference to specific embodiments, but the scope of protection of this invention is not limited thereto. Experimental methods not specifically described in the embodiments are generally performed under conventional conditions or according to the manufacturer's recommendations. Unless otherwise specified, all reagents and materials used are commercially available.
[0033] Example 1
[0034] A process for producing cycloazinone includes the following steps: S1. Preparation of N-cyclohexyl-N'-methylurea by addition reaction: Raw material dosage: 1.0 mol cyclohexyl isocyanate, 1.05 mol 40% methylamine aqueous solution (methylamine 1.05 mol), anhydrous toluene (5 times the mass of cyclohexyl isocyanate); Procedure: Cyclohexyl isocyanate was added to anhydrous toluene, stirred and dissolved, and then purged with nitrogen three times (pressure 0.02 MPa); 40% methylamine aqueous solution was slowly added dropwise at 20-22℃, with the temperature controlled ≤30℃; after the addition was complete, the reaction was maintained at 28℃ for 1.2 h, and HPLC analysis showed that the residual cyclohexyl isocyanate was <0.2%; the mixture was filtered, washed with 30 g of cold toluene at 0-5℃, and dried under vacuum at 45℃ for 3 h to obtain N-cyclohexyl-N'-methylurea, with a yield of 97.2% and a purity of 98.3%.
[0035] S2, Phase transfer catalytic reaction to prepare methoxycarbonyl isothiocyanate: Raw material usage: methyl chloroformate 1.0 mol), sodium thiocyanate 1.1 mol, deionized water (3 times the mass of sodium thiocyanate), tetrabutylammonium bromide (5% of the molar mass of methyl chloroformate); Procedure: Prepare a sodium thiocyanate solution by mixing deionized water with sodium thiocyanate; add tetrabutylammonium bromide, stir to dissolve, and then slowly add methyl chloroformate dropwise while controlling the temperature to ≤35℃; after the addition is complete, keep the reaction at 32℃ for 4 hours, let stand for 30 minutes, separate the liquid and discard the aqueous phase to obtain methoxycarbonyl isothiocyanate with a yield of 93.5% and a purity of 95.2%.
[0036] S3. Thiourea reaction to prepare thiourea derivatives: Raw material usage: N-cyclohexyl-N'-methylurea obtained in step S1, methoxycarbonyl isothiocyanate obtained in step S2, anhydrous toluene (4 times the total mass), triethylamine (3% of the molar amount of methoxycarbonyl isothiocyanate); Procedure: N-cyclohexyl-N'-methylurea, anhydrous toluene, and triethylamine were mixed and stirred until dissolved, then protected with nitrogen (0.02 MPa). Methoxycarbonyl isothiocyanate was added dropwise at 20-23℃, with the temperature controlled at ≤28℃. After the addition was complete, the reaction was maintained at 38℃ for 3.5 h. The isothiocyanate residue was detected by HPLC as <0.3%. The mixture was washed with deionized water, and the aqueous phase was separated to obtain the organic phase containing the thiourea derivative.
[0037] S4, Cyclolysis-Aminolysis one-pot reaction: Raw material usage: 30% sodium methoxide-methanol solution (sodium methoxide 1.5 mol), 40% dimethylamine aqueous solution (dimethylamine 3.0 mol); Procedure: Add 30% sodium methoxide-methanol solution to the organic phase in step S3, heat to 38℃, and maintain the cyclization reaction for 4 hours. HPLC detection shows that the thiourea derivative residue is <0.6%. Slowly add 40% dimethylamine aqueous solution at 40~45℃, controlling the temperature to ≤50℃. After the addition is complete, maintain the aminolysis reaction at 50℃ for 5 hours. HPLC detection shows that the triazine ketone precursor residue is <0.3%.
[0038] S5. Post-processing purification: The reaction solution obtained in step S4 was cooled to 25°C and allowed to stand for 30 min to separate into layers. The aqueous phase was discarded. The organic phase was washed with 5% dilute hydrochloric acid until pH=6~7, and then washed once with saturated brine. Anhydrous magnesium sulfate was added and dried for 1.5 h, and then filtered. The solution was concentrated under vacuum (0.085 MPa, 45°C) to 1 / 4 of its original volume, and toluene and methanol were recovered. The recovery rate was measured to be 90%. An ethanol-water mixed solvent (volume ratio 3:1, the amount used is 3 times that of the concentrated solution) was added and dissolved at 70°C. The solution was then cooled to 0~5°C and kept at this temperature for 3 h to allow crystallization. The solution was filtered and washed twice with a cold mixed solvent. The solution was dried under vacuum at 50°C for 5 h to obtain the cycloazinone product. The final product yield was 80.5%, and the HPLC purity was 98.8%.
[0039] Example 2
[0040] The main difference between this embodiment and Example 1 is that: In step S1 of this embodiment, the raw material amounts are: 2.0 mol of cyclohexyl isocyanate, 2.08 mol of 40% methylamine aqueous solution, and anhydrous toluene (4 times the mass of cyclohexyl isocyanate). During the operation, the methylamine aqueous solution is added dropwise at 22-25°C, and after the addition is complete, the reaction is maintained at 30°C for 1 hour. The resulting N-cyclohexyl-N'-methylurea has a yield of 97.8% and a purity of 98.5%. In step S2 of this embodiment, the raw materials used are: 2.0 mol methyl chloroformate, 2.1 mol sodium thiocyanate, deionized water (3 times the mass of sodium thiocyanate), and tetrabutylammonium bromide (8% of the molar mass of methyl chloroformate). The reaction is carried out at 34°C for 3.5 h, and the product is separated to obtain methoxycarbonyl isothiocyanate with a yield of 94.2% and a purity of 95.5%. In step S4 of this embodiment, the raw material amounts are: 30% sodium methoxide-methanol solution (sodium methoxide 3.0 mol) and 40% dimethylamine aqueous solution (dimethylamine 6.0 mol); in the operation, the cyclization reaction is maintained at 35°C for 5 hours and the aminolysis reaction is maintained at 45°C for 4 hours. The remaining components and preparation steps are the same. In step S5, the final product yield was 81.2%, and the HPLC purity was 98.9%.
[0041] Example 3
[0042] The main difference between this embodiment and Example 1 is that: In step S3 of this embodiment, methoxycarbonyl isothiocyanate is added dropwise at 23~25℃, and the temperature is controlled at ≤28℃; after the addition is complete, the reaction is kept at 40℃ for 4 hours. In step S4 of this embodiment, the cyclization reaction is carried out at 40°C for 3 hours and the aminolysis reaction is carried out at 40°C for 6 hours. The remaining components and preparation steps are the same. In step S5, the final product yield was 79.8%, and the HPLC purity was 98.6%.
[0043] Comparative Example 1
[0044] The main difference between this comparative example and Example 1 is that: In step S1 of this comparative example, 1.0 mol of cyclohexylamine and 1.05 mol of gaseous methyl isocyanate were mixed and reacted in anhydrous diethyl ether (5 times the mass of cyclohexylamine) at 0~5℃. After filtration and drying, N-cyclohexyl-N'-methylurea was obtained with a yield of 95.0% and a purity of 97.2%.
[0045] The remaining components and preparation steps are the same.
[0046] Comparative Example 2
[0047] The main difference between this comparative example and Example 1 is that: In step S3 of this comparative example, the N-cyclohexyl-N'-methylurea obtained in step S1 and the methoxycarbonyl isothiocyanate obtained in step S2 were reacted in acetone at 25-30°C. After distilling to recover the acetone, a solid thiourea derivative intermediate was obtained, which was then redissolved in toluene for step S4. The loss rate of the thiourea intermediate was 4.2%.
[0048] The remaining components and preparation steps are the same.
[0049] Comparative Example 3
[0050] The main difference between this comparative example and Example 1 is that: In step S4 of this comparative example, a 30% sodium methoxide-methanol solution was added to carry out the cyclization reaction. The cyclization reaction was carried out at a low temperature of 20°C, and the reaction time was extended to 8 hours.
[0051] The remaining components and preparation steps are the same.
[0052] Comparative Example 4
[0053] The main difference between this comparative example and Example 1 is that: In step S4 of this comparative example, a cyclization reaction is carried out first, i.e., 30% sodium methoxide-methanol solution is added to the organic phase of step S3, the temperature is raised to 38°C, and the cyclization reaction is maintained at this temperature for 4 hours. Then, the mixture is vacuum distilled at 50°C and 0.09 MPa for 2 hours to recover methanol. The mixture is then filtered and dried to obtain a solid triazine ketone precursor. Next, new toluene is added to dissolve the solid triazine ketone precursor, and finally, 40% dimethylamine aqueous solution is added to carry out an aminolysis reaction.
[0054] The remaining components and preparation steps are the same.
[0055] Comparative Example 5
[0056] The main difference between this comparative example and Example 1 is that: In step S1 of this comparative example, 1.0 mol of cyclohexylamine and 1.05 mol of gaseous methyl isocyanate were mixed and reacted in anhydrous diethyl ether (5 times the mass of cyclohexylamine) at 0~5℃. After filtration and drying, N-cyclohexyl-N'-methylurea was obtained.
[0057] In step S3 of this comparative example, the N-cyclohexyl-N'-methylurea obtained in step S1 and the methoxycarbonyl isothiocyanate obtained in step S2 are reacted in acetone at 25-30°C. After distilling to recover the acetone, a solid thiourea derivative intermediate is obtained, which is then redissolved in toluene for step S4.
[0058] In step S4 of this comparative example, a cyclization reaction is carried out first, i.e., 30% sodium methoxide-methanol solution is added to the organic phase of step S3, the temperature is raised to 38°C, and the cyclization reaction is maintained at this temperature for 4 hours. Then, the mixture is vacuum distilled at 50°C and 0.09 MPa for 2 hours to recover methanol. The mixture is then filtered and dried to obtain a solid triazine ketone precursor. Next, new toluene is added to dissolve the solid triazine ketone precursor, and finally, 40% dimethylamine aqueous solution is added to carry out an aminolysis reaction.
[0059] The remaining components and preparation steps are the same.
[0060] The test results of the samples prepared in Examples 1-3 and Comparative Examples 1-5 are shown in Table 1.
[0061] Table 1
[0062] As shown in Table 1, the overall performance of Examples 1-3 is superior to that of Comparative Examples 1-5. Specifically, Comparative Examples 1 and 5 used gaseous methyl isocyanate, which is highly toxic. To ensure safety during operation, more cautious and slow feeding and ensuring the sealing of the reaction apparatus were necessary, extending the operation time. The reaction time also varied due to the different raw materials, leading to a longer overall production cycle. In Comparative Example 2, after changing the solvent to acetone, the incompatibility of different solvents necessitated acetone recovery, which not only extended the production cycle but also reduced the yield and purity of the final product. Furthermore, it increased solvent consumption. In Comparative Example 3, due to the lower cyclization reaction temperature, even with an extended reaction time, the reaction degree did not reach the optimal level, and the lower temperature reduced the mass transfer efficiency, increasing the difficulty of impurity separation during post-processing. Therefore, the overall production cycle was extended, and the yield and purity of the final product were also reduced. In Comparative Example 4, the "cyclization-amine hydrolysis one-pot method" was eliminated, resulting in increased product separation losses, increased solvent consumption, and a lower final product yield.
[0063] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.
Claims
1. A process for producing cycloazinone, characterized in that, Includes the following steps: S1. Addition reaction: Cyclohexyl isocyanate is added dropwise to a 30-50% aqueous solution of methylamine in anhydrous toluene at 20-25°C with stirring. After the addition is complete, the temperature is raised to 25-30°C and the reaction is maintained for 1-1.5 hours. Then, the mixture is allowed to stand and separate into layers to obtain an organic phase. After drying, intermediate product A is obtained. Intermediate product A is N-cyclohexyl-N'-methylurea. S2. Phase transfer catalytic reaction: Sodium thiocyanate and deionized water are mixed to obtain an aqueous solution of sodium thiocyanate; a quaternary ammonium salt catalyst is added, and methyl chloroformate is added dropwise to the aqueous solution of sodium thiocyanate at 30~35℃. After the addition is complete, the reaction is kept at the temperature for 3~5h, and the mixture is allowed to stand and separated. The organic phase is taken to obtain intermediate product B, which is methoxycarbonyl isothiocyanate. S3. Thiourea reaction: In anhydrous toluene at 20-25°C, add intermediate product A obtained in step S1, then add an organic tertiary amine catalyst to obtain a mixed system. Add intermediate product B obtained in step S2 dropwise to the mixed system. After the addition is complete, heat to 35-40°C and keep reacting for 3-4 hours. Wash with water and separate the liquids. Take the organic phase to obtain intermediate product C; the intermediate product C is a thiourea derivative. S4. Cycloning-amine hydrolysis one-pot reaction: Add a 20-40% sodium methoxide-methanol solution to the intermediate product C obtained in step S3, and cyclize at 35-40℃ for 3-5 hours. Then add a 30-50% dimethylamine aqueous solution and amine hydrolyze at 40-50℃ for 4-6 hours to obtain a reaction solution containing the final product. S5. Post-processing purification: The reaction solution obtained in step S4 is separated into layers to obtain an organic phase. The organic phase is then acid-washed, salt-washed, dried, and concentrated to obtain a concentrated solution. The concentrated solution is crystallized with an ethanol-water mixed solvent and dried to obtain the cycloazinone product.
2. The process for producing cycloazinone according to claim 1, characterized in that, In step S1, the molar ratio of cyclohexyl isocyanate to aqueous methylamine is 1:(1~1.1); the amount of anhydrous toluene used is 4~6 times the mass of cyclohexyl isocyanate.
3. The process for producing cycloazinone according to claim 1, characterized in that, In step S2, the molar ratio of methyl chloroformate, sodium thiocyanate and deionized water is 1:(1.05~1.15):(3~5).
4. The process for producing cycloazinone according to claim 1, characterized in that, In step S3, the amount of anhydrous toluene used is 3 to 5 times the total mass of N-cyclohexyl-N'-methylurea and methoxycarbonyl isothiocyanate; the molar ratio of intermediate product A to intermediate product B is (1.02 to 1.08):
1.
5. The process for producing cycloazinone according to claim 1, characterized in that, In step S3, the organic tertiary amine catalyst is selected from at least one of triethylamine, tripropylamine, tributylamine or pyridine, and the amount of the organic tertiary amine catalyst is 2 to 4% of the molar amount of methoxycarbonyl isothiocyanate.
6. The process for producing cycloazinone according to claim 1, characterized in that, In step S4, the molar ratio of sodium methoxide to thiourea derivative in the sodium methoxide-methanol solution is (1.3~1.7):1; the molar ratio of dimethylamine to thiourea derivative is (2.8~3.2):
1.
7. The process for producing cycloazinone according to claim 1, characterized in that, In step S5, the volume ratio of the ethanol-water mixed solvent is 2~4:1, and the amount used is 2~4 times the mass of the concentrate. The acid washing refers to using 5-8% dilute hydrochloric acid to adjust the pH to 6-7; the salt washing refers to washing with saturated brine.
8. The process for producing cycloazinone according to claim 1, characterized in that, In step S5, the drying in the drying and concentration process refers to drying with at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, or molecular sieve for 1-2 hours; the concentration process refers to concentrating the mixture to 1 / 3 to 1 / 5 of its original volume under a vacuum of 0.08-0.095 MPa and a temperature of 40-50°C.
9. The process for producing cycloazinone according to claim 1, characterized in that, In step S5, crystallization refers to dissolving the concentrated solution in an ethanol-water mixed solvent at 70-75°C, then cooling it to 0-5°C and maintaining the temperature for crystallization for 2-4 hours.
10. A cycloazinone, characterized in that, It is prepared using the production process of cycloazinone according to any one of claims 1-9.