A method for efficiently preparing methyl cyanoformate

Abstract

This invention relates to a method for the efficient preparation of methyl cyanurate, belonging to the technical field of pharmaceutical intermediate synthesis. The method includes the following steps: mixing 1-hydroxyethyl-3-methylimidazolium acetate with a 28-32% potassium phosphate aqueous solution at a mass ratio of (2.8-3.2):1, followed by allowing the mixture to stand and separate into upper and lower phases; adding a cyanamide aqueous solution to the lower phase; and continuously adding methyl cyanurate to the upper phase; stirring the reaction at 40-50°C for 1.5-2.5 hours; allowing the mixture to stand and separate into upper organic and lower brine phases; diluting the upper organic phase with 1.8-2.2 times its volume of deionized water, precipitating a solid, followed by filtration; collecting the filter cake and filtrate; washing and drying the filter cake to obtain methyl cyanurate. This invention achieves directional distribution of reactants, precise suppression of side reactions, and efficient separation of products by constructing a two-phase aqueous system.

Description

Technical Field

[0001] This invention belongs to the technical field of pharmaceutical intermediate synthesis, and more specifically, relates to a method for the efficient preparation of methyl cyanocarbamate. Background Technology

[0002] Methyl cyanurate is a key precursor in the synthesis of bactericides (such as carbendazim), pharmaceutical intermediates, and polymer materials. However, the existing preparation processes for methyl cyanurate have significant drawbacks: 1) Severe side reactions: cyanamide readily dimerizes in the aqueous phase to form melamine, and even at low temperatures, the cyanamide residue rate remains below 70% within 6 hours; methyl chloroformate hydrolyzes rapidly in water, leading to a decrease in yield and purity.

[0003] 2) High environmental impact: It uses a large amount of volatile organic solvents (VOCs), has a high E-factor (waste generation coefficient), and consumes a lot of energy when operating at low temperatures.

[0004] 3) High safety risks: Organic solvents are flammable and explosive, and cryogenic equipment requires high investment.

[0005] 4) Complex post-processing: The product needs to be washed with water and purified by distillation multiple times. Solvent recovery is costly and difficult, and the on-site working environment is poor.

[0006] 5) It causes severe corrosion to the equipment.

[0007] Although studies have attempted aqueous synthesis or homogeneous ionic liquid systems, the former exacerbates cyanamide dimerization, while the latter, due to the miscibility of hydrophilic ionic liquids with water, makes efficient separation of the product from the catalyst impossible, and ionic liquid recovery is difficult. Therefore, developing an efficient method for preparing methyl cyanurate has significant industrial value. Summary of the Invention

[0008] The purpose of this invention is to provide a method for the efficient preparation of methyl cyanurate, which is environmentally friendly and highly selective.

[0009] The objective of this invention can be achieved through the following technical solutions: A method for efficiently preparing methyl cyanurate includes the following steps: S1. Preparation of a two-phase aqueous system: Mix 1-hydroxyethyl-3-methylimidazolium acetate with a potassium phosphate aqueous solution of 28-32% by mass at a mass ratio of (2.8-3.2):1, and then allow it to stand to separate phases, forming an upper phase and a lower phase, wherein the upper phase is an ionic liquid phase and the lower phase is a potassium phosphate salt phase; S2. Add an aqueous solution of cyanamide with a molar concentration of 1-1.5 mol / L to the lower phase, and continuously add methyl chloroformate to the upper phase; S3. Stir the mixture from step S2 at 40-50℃ for 1.5-2.5 hours. S4. After the reaction is complete, allow the mixture to stand and separate into layers to obtain an upper organic phase and a lower brine phase. S5. Add 1.8-2.2 times the volume of deionized water to the upper organic phase to dilute it, precipitate the solid, then filter it, collect the filter cake and filtrate, wash and dry the filter cake to obtain methyl cyanocarbamate.

[0010] In the preparation of methyl cyanurate, monocyanamide (H2N-CN) readily undergoes spontaneous dimerization under aqueous / thermal conditions, generating dicyandiamide as a byproduct, ultimately affecting the yield of methyl cyanurate. In this technical solution, K3PO4 provides high ionic strength to induce phase separation, constructing a physically isolated reaction microenvironment. In 1-hydroxyethyl-3-methylimidazolium acetate, the acetate ion and hydroxyethyl group form a dynamic hydrogen bond network, selectively encapsulating the -NH2 and -C≡N groups of monocyanamide. The high-salt environment enhances the stability of monocyanamide, significantly reducing its molecular collision probability and reactivity, thereby reducing dimerization byproducts (such as dicyandiamide) at the source.

[0011] Further, in step S1, the mixing refers to stirring at 20-30℃ and 100-300rpm for 5-15 minutes; the settling and phase separation time is 3-15 minutes.

[0012] The upper phase accounts for 70-80% of the total volume, and the interface width between the upper and lower phases is ≤0.3mm.

[0013] Further, in step S2, the molar ratio of methyl chloroformate to cyanamide is (1.02-1.1):1, and the continuous addition refers to adding methyl chloroformate to the upper phase at a rate of 0.5-1.5 mL / min, and controlling the dropping temperature to be 20-30℃.

[0014] In step S2, methyl chloroformate is confined to the upper phase and encapsulated by a high-viscosity medium, significantly reducing its contact with water and suppressing hydrolysis side reactions. Cyanamine directly enters the lower phase; the salting-out effect and the synergistic effect of the ionic liquid hydrogen bonding network inhibit cyanamine dimerization.

[0015] In step S1, the density of the upper phase is approximately 1.21 ± 0.02 g / mL, and the density of the lower phase is approximately 1.28 ± 0.02 g / mL. Methyl chloroformate has a density of approximately 1.25 ± 0.02 g / mL, slightly lower than the upper phase density, and can naturally suspend within the upper phase after addition without settling across the interface. The density of the cyanamide aqueous solution is approximately 1.06 ± 0.02 g / mL, lower than the lower phase density, and rapidly integrates into the lower phase after injection without settling across the interface, thus inhibiting molecular cross-phase diffusion. Furthermore, controlling the droplet acceleration rate avoids excessively high local concentrations that could lead to side reactions.

[0016] Specifically, the cyanamide aqueous solution can be slowly injected into the lower phase through a PTFE conduit at a flow rate controlled at 1.5–2.0 mL / min. Methyl chloroformate can be added dropwise at a rate of 0.8–1.2 mL / min using a constant-pressure dropping funnel with the funnel tip positioned on the upper phase.

[0017] Furthermore, in step S3, the stirring speed is 250-350 rpm, and the stirring operation is performed after the material is added and the mixture is allowed to stand for 0.5-2 minutes.

[0018] Stirring increases the interfacial area, which facilitates the formation of methyl cyanurate at the interface between cyanamide and methyl chloroformate. Simultaneously, the interface provides a "micro-reaction zone," where heat is buffered by the high heat capacity of the ionic liquid, resulting in gentle exothermic reaction. The HCl produced in the reaction is neutralized by the potassium phosphate aqueous solution. Intermediates (such as ROOC-NH-CN)... - It is stabilized by solvation with ionic liquids, which shifts the equilibrium to the right and allows the interfacial reaction to proceed smoothly, thus facilitating the efficient preparation of methyl cyanocarbamate.

[0019] Furthermore, in step S4, the settling time is 5-15 minutes.

[0020] In step S4, the lower brine phase is mainly a potassium phosphate aqueous solution, and may also contain a small amount of residual monohydrogen amine. By detecting the mass fraction of potassium phosphate and residual monohydrogen amine in the lower brine phase, and based on the required concentrations of potassium phosphate aqueous solution and monohydrogen amine aqueous solution in steps S1 and S2, the amount of response to be added can be used as a regenerated phase for the next batch of reaction.

[0021] Further, in step S5, the dilution is carried out at 0-15°C; the specific operation of the precipitated solid is as follows: while maintaining the dilution temperature, continue stirring for 10-60 minutes, and then let it stand to crystallize for 30-120 minutes to obtain crystalline solid; the filtration refers to performing vacuum filtration while maintaining the dilution temperature.

[0022] The main function of dilution is to reduce the polarity of the ionic liquid, causing the product solubility to drop sharply and precipitate. Methyl cyanurate is highly heat-sensitive, and low temperature helps to avoid local overheating that could lead to product decomposition or oil precipitation, thus ensuring crystal purity and yield.

[0023] Further, in step S5, the washing operation is as follows: the filter cake is washed 1-3 times with deionized water at 0-10℃, and the volume of water used for each washing is 0.1-0.4 times the volume of the upper organic phase; the drying operation is as follows: the filter cake is dried at 40-60℃ under vacuum for 1-3 hours.

[0024] In step S5, the water washing is mainly to remove trace amounts of ionic liquid residue.

[0025] Further, in step S5, the filtrate is dehydrated by vacuum distillation to obtain regenerated 1-hydroxyethyl-3-methylimidazolium acetate, which is recycled in step S1.

[0026] Furthermore, the specific steps of the vacuum distillation for dehydration are as follows: the filtrate is distilled under vacuum at 50-65℃ and 5-15mbar until constant weight is achieved; then the distillation product is cooled to room temperature under nitrogen protection at 20-30℃.

[0027] Furthermore, when the regenerated 1-hydroxyethyl-3-methylimidazolium acetate is recycled for ≤20 batches, the methyl cyanocarbamate yield is ≥96%.

[0028] Among them, the residual rate of monohydroamine in the aqueous two-phase system of step S1 is ≥95.5% after 6 hours.

[0029] An efficient method for preparing methyl cyanocarbamate is provided, which is prepared by the method described above.

[0030] The beneficial effects of this invention are: (1) This invention uses 1-hydroxyethyl-3-methylimidazolium acetate [HOEMIM][OAc] and 30% potassium phosphate aqueous solution to construct an aqueous two-phase system (ATPS) to achieve directional distribution of reactants, precise inhibition of side reactions and efficient separation of products. The entire process is carried out under mild conditions of 45℃, without the need for organic solvents or deep temperature control, achieving precise isolation of reactants, stable intermediates, highly selective synthesis and green separation.

[0031] (2) This invention uses 1-hydroxyethyl-3-methylimidazolium acetate and 28-32% potassium phosphate aqueous solution to construct a two-phase aqueous system. Cyanamine is directionally partitioned into the lower brine phase, while methyl chloroformate is confined to the upper ionic liquid phase. The reaction occurs at the interface at 40-50℃. After the reaction, the product is enriched in the upper organic phase. Water is added to precipitate a high-purity product, and the ionic liquid is recovered by vacuum distillation for recycling. This invention significantly suppresses side reactions through a triple mechanism of high salt concentration inhibiting dimerization, hydrolysis of the ionic liquid, and slow-release heat at the interface. The entire process is solvent-free, requires no deep temperature control, and the ionic liquid exhibits excellent biodegradability. It is simple to operate, environmentally friendly, and suitable for industrial production. 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 method for efficiently preparing methyl cyanurate, the specific preparation steps are as follows: S1. Weigh 300g of 1-hydroxyethyl-3-methylimidazolium acetate (purity ≥99%) and add 100g of 30wt% K3PO4 aqueous solution. Stir at 25±2℃ and 200rpm for 10min, then let stand for 5min. The system clearly separates into upper and lower phases: the upper phase is an ionic liquid-enriched phase, and the lower phase is a potassium phosphate salt phase. Density measurements at 25±1℃ show that the upper phase density is approximately 1.22±0.01g / mL, and the lower phase density is approximately 1.29±0.01g / mL. The phase interface is clear and emulsified. Mark the upper / lower phase boundary on the outer wall. S2. A 1.2 mol / L aqueous solution of cyanamide (containing 5.04 g cyanamide and 35 g water) was slowly injected into the lower phase through a PTFE conduit and stirred for 5 min to mix thoroughly. 13.86 g methyl chloroformate (1.05 eq) was added dropwise to the upper phase at a rate of 1 mL / min through a constant-pressure dropping funnel, with the temperature controlled at ≤30℃ during the addition process. Cyanamide is enriched in the high-salt lower phase, and the salting-out effect and the hydrogen bonding network of the ionic liquid synergistically inhibit dimerization. Methyl chloroformate is confined to the upper phase to maximize the isolation of water molecules and inhibit hydrolysis (ClCOOCH3 + H2O → CH3OH + CO2 + HCl).

[0035] S3. After the addition is complete, let it stand for 1 ± 0.5 minutes, then heat to 45 ± 1℃, adjust the stirring speed to 300 rpm, and maintain the temperature for 2 hours, monitoring the system temperature in real time. The measured system temperature change was ≤ 3℃, therefore no external cooling is required.

[0036] S4. After the reaction is complete, stop stirring and let stand for 10 minutes to allow the mixture to separate into two layers: an upper organic phase and a lower brine phase. The upper organic phase mainly contains the product and ionic liquid, while the lower brine phase mainly contains K3PO4 aqueous solution. Separate the upper organic phase using a separatory funnel. The collected lower brine phase can be used to replenish cyanamide for recycling after analysis.

[0037] S5. Under water bath conditions of 10±1℃, add cold water of 2 times the volume of the upper organic phase to dilute it, and continue stirring for 10 min. After standing for 1 hour, solid precipitates out. Filter under reduced pressure, collect the filter cake and filtrate. Wash the filter cake twice with cold water of 0.2 times the volume of the upper organic phase at a temperature of 5±1℃. Then, vacuum dry at 50℃ and -0.095MPa for 2 h to obtain methyl cyanurate.

[0038] The filtrate was distilled under reduced pressure at 60°C and 10 mbar to constant weight. The distillate was then cooled to room temperature under nitrogen protection at 25°C and stored in a brown glass bottle to obtain a regenerated ionic liquid with a recovery rate of 98.5%.

[0039] Example 2

[0040] Compared with Example 1, the difference in this example is that in step S1 of this example, the mass ratio of 1-hydroxyethyl-3-methylimidazolium acetate to 32wt% K3PO4 aqueous solution is 280:100. The remaining components, preparation steps and parameters are the same.

[0041] Example 3

[0042] Compared to Example 1, the difference in this example is that in step S1, the mass ratio of 1-hydroxyethyl-3-methylimidazolium acetate to 28wt% K3PO4 aqueous solution is 320:100. All other components, preparation steps, and parameters remain the same.

[0043] Comparative Example 1

[0044] Compared with Example 1, this comparative example differs in that it omits step S1. Instead, a 1.2 mol / L cyanamide aqueous solution (containing 5.04 g cyanamide and 35 g water) is directly added to the reaction vessel, and 13.86 g methyl chloroformate (1.05 eq) is added dropwise to the reaction vessel at a rate of 1 mL / min through a constant pressure dropping funnel. Then, step S3 is performed. After the reaction is completed, the product is extracted with ethyl acetate and purified by distillation to obtain methyl cyanocarbamate.

[0045] Comparative Example 2

[0046] Compared to Example 1, this comparative example differs in that the 1-hydroxyethyl-3-methylimidazolium acetate in step S1 is replaced with an equal amount of 1-butyl-3-methylimidazolium acetate [BMIM][OAc], while the remaining components, preparation steps, and parameters are identical. Notably, due to the absence of hydroxyethyl, slight emulsification occurred in the system, resulting in a phase separation time >30 minutes.

[0047] Comparative Example 3

[0048] Compared to Example 1, this comparative example differs in that the 30wt% K3PO4 aqueous solution in step S1 is replaced with an equal amount of pure water, resulting in a homogeneous system. All other components, preparation steps, and parameters remain the same. However, due to the similar densities, the system cannot separate into phases after the reaction with the cyanamide aqueous solution and methyl chloroformate, and continuous bubbles are visible. Ethyl acetate is required for extraction and separation after the reaction.

[0049] Comparative Example 4

[0050] Compared to Example 1, this comparative example differs in that the 30wt% K3PO4 aqueous solution in step S1 is replaced with a 35wt% NaCl solution. Hydrometer measurements at 25±1℃ showed that the density of the upper phase was approximately 1.17±0.01 g / mL, and the density of the lower phase was approximately 1.22±0.01 g / mL. The phase interface was blurred. Upon addition of methyl chloroformate, droplets visibly sank into the lower phase, which then foamed. The entire reaction system was turbid with no clear interface.

[0051] Comparative Example 5

[0052] Compared to Example 1, this comparative example differs in that, in step S2, the two reactants, cyanamide aqueous solution and methyl chloroformate, are simultaneously poured from the top of the container into the pre-separated system, and then stirring is started. All other components, preparation steps, and parameters remain the same. Fine bubbles are generated instantaneously upon addition, and methanol, a hydrolysis byproduct, is detected by HPLC.

[0053] The test results of the samples prepared in Examples 1-3 and Comparative Examples 1-5 are shown in Table 1.

[0054] The product yield and purity were determined in accordance with GB / T601 standard and HPLC quantitative specifications. The mobile phase was acetonitrile:0.1% phosphoric acid aqueous solution = 80:20 (v / v), pH 3.0, flow rate 1.0 mL / min, column temperature 30℃, detection wavelength 254 nm, and injection volume 20 μL.

[0055] The 6-hour residual rate of cyanamide was determined by HPLC analysis after placing an aqueous solution of cyanamide in a two-phase system (step S1) without the addition of methyl chloroformate. Comparative Example 1 used a pure water system, free of ionic liquids and salts, and allowed the mixture to stand at 45°C for 6 hours. The residual rate (%) was calculated as (mass of cyanamide after 6 hours / initial mass of cyanamide) × 100%. A higher value indicates a stronger ability to inhibit dimerization, thus demonstrating better stability. This also indirectly indicates that the effective concentration of cyanamide is high when methyl chloroformate is added to initiate the reaction.

[0056] Table 1

[0057] As shown in Table 1, compared with Comparative Examples 1-5, Examples 1-3 exhibited superior product yield and purity, and a high cyanamide residue rate after 6 hours, indicating excellent stability. Comparative Example 1, lacking the aqueous two-phase system of 1-hydroxyethyl-3-methylimidazolium acetate and potassium phosphate aqueous solution, showed significantly lower residue and yield, indicating the lack of a protective aqueous two-phase system and uncontrollable reaction. Comparative Examples 2 and 3 further confirmed the irreplaceable role of both 1-hydroxyethyl-3-methylimidazolium acetate and potassium phosphate aqueous solution in inhibiting dimerization. Comparative Example 4, using NaCl instead of potassium phosphate aqueous solution, showed a significantly reduced yield and phenomena such as methyl chloroformate precipitation and emulsification, demonstrating the density regulation and pH buffering function of potassium phosphate solution within the system. Although Comparative Example 5 had the same system composition as Example 1, its yield was significantly lower, indicating that adding cyanamide aqueous solution to the lower phase and methyl chloroformate to the upper phase is essential to avoid interfacial disturbance and ensure the stability of raw materials and the circulation of the medium.

[0058] 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 method for efficiently preparing methyl cyanurate, characterized in that, Includes the following steps: S1. Preparation of a two-phase aqueous system: Mix 1-hydroxyethyl-3-methylimidazolium acetate with a potassium phosphate aqueous solution of 28-32% by mass at a mass ratio of (2.8-3.2):1, and then allow it to stand to separate phases, forming an upper phase and a lower phase, wherein the upper phase is an ionic liquid phase and the lower phase is a potassium phosphate salt phase; S2. Add an aqueous solution of cyanamide with a molar concentration of 1-1.5 mol / L to the lower phase, and continuously add methyl chloroformate to the upper phase; S3. Stir the mixture from step S2 at 40-50℃ for 1.5-2.5 hours. S4. After the reaction is complete, allow the mixture to stand and separate into layers to obtain an upper organic phase and a lower brine phase. S5. Add 1.8-2.2 times the volume of deionized water to the upper organic phase to dilute it, precipitate the solid, then filter it, collect the filter cake and filtrate, wash and dry the filter cake to obtain methyl cyanocarbamate.

2. The method for efficiently preparing methyl cyanurate according to claim 1, characterized in that, In step S1, the mixing refers to stirring at 20-30℃ and 100-300rpm for 5-15 minutes; the settling and phase separation time is 3-15 minutes.

3. The method for efficiently preparing methyl cyanurate according to claim 1, characterized in that, In step S2, the molar ratio of methyl chloroformate to cyanamide is (1.02-1.1):1, and the continuous addition means adding methyl chloroformate to the upper phase at a rate of 0.5-1.5 mL / min, and controlling the dropping temperature to be 20-30℃.

4. The method for efficiently preparing methyl cyanurate according to claim 1, characterized in that, In step S3, the stirring speed is 250-350 rpm, and the stirring operation is performed after the material is added and the mixture is allowed to stand for 0.5-2 minutes.

5. The method for efficiently preparing methyl cyanurate according to claim 1, characterized in that, In step S4, the settling time is 5-15 minutes.

6. The method for efficiently preparing methyl cyanurate according to claim 1, characterized in that, In step S4, the lower brine phase contains an aqueous solution of potassium phosphate, which was recycled in step S1.

7. The method for efficiently preparing methyl cyanurate according to claim 1, characterized in that, In step S5, the dilution is carried out at 0-15°C; The specific operation for precipitating the solid is as follows: while maintaining the dilution temperature, continue stirring for 10-60 minutes, then allow it to stand for crystallization for 30-120 minutes to obtain the precipitated solid; The filtration refers to vacuum filtration while maintaining the dilution temperature; The specific washing operation is as follows: wash the filter cake 1-3 times with deionized water at 0-10℃, and the volume of water used for each wash is 0.1-0.4 times the volume of the upper organic phase; The specific drying operation is as follows: dry at 40-60℃ under vacuum for 1-3 hours.

8. The method for efficiently preparing methyl cyanurate according to claim 1, characterized in that, In step S5, the filtrate is dehydrated by vacuum distillation to obtain regenerated 1-hydroxyethyl-3-methylimidazolium acetate, which is recycled in step S1.

9. The method for efficiently preparing methyl cyanurate according to claim 8, characterized in that, The specific steps of the vacuum distillation dehydration are as follows: the filtrate is distilled under vacuum at 50-65℃ and 5-15mbar until constant weight is achieved; then the distillation product is cooled to room temperature under nitrogen protection at 20-30℃.

10. A highly efficient method for preparing methyl cyanurate, characterized in that, It is prepared by the preparation method according to any one of claims 1-9.

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