Preparation method of high-yield oxadiazine

Abstract

The invention relates to a preparation method of high-yield oxadiazine. Efficient synthesis is realized through cyclic utilization of concentrated mother liquor and collaborative optimization of key reaction parameters. Specifically, methyl nitroguanidine and paraformaldehyde serve as raw materials and react at the temperature of 70-95 DEG C under the catalysis of sulfuric acid, reaction filtrate is collected to serve as mother liquor to be treated into clear liquid water and concentrated mother liquor, the concentrated mother liquor and the clear liquid water in a certain proportion are mechanically applied to replace a pure water solvent, filtrate generated through mechanical application is collected to be continuously treated and mechanically applied, and mother liquor recycling is achieved. According to the method, the product yield is up to 93%, the purity is greater than or equal to 99%, the reaction time can be greatly shortened, the mother liquor is recycled to reduce the generation of waste liquid by 60% or above, and the use of high-risk reagents such as dimethyl sulfate is avoided. The method is suitable for large-scale production of thiamethoxam insecticide intermediates, has significant cost-reducing and synergistic potential, and provides a high-benefit solution for the green pesticide industry.

Description

Technical Field

[0001] The present invention relates to the field of synthesis technology of important pesticide intermediates, and in particular to a high-yield preparation method of 3-methyl-4-nitroiminetetrahydro-1,3,5-oxadiazine, an important intermediate required for synthesizing thiamethoxam. Background Art

[0002] Thiamethoxam is a second-generation nicotine-based insecticide with high efficiency and low toxicity, and its chemical formula is C8H 10 C l N₅O₃S has stomach, contact, and systemic activity against insect pests and is suitable for foliar spraying and root irrigation. After application, it is rapidly absorbed systemically and distributed throughout the plant, providing effective control against piercing-sucking pests such as aphids, planthoppers, leafhoppers, and whiteflies. Thiamethoxam also offers several other advantages. First, research has shown that thiamethoxam is highly effective and safe in killing insects, and its effectiveness in reducing insect populations in wheat is comparable to other currently registered grain protectants. Second, thiamethoxam promotes plant growth. Furthermore, thiamethoxam exhibits low toxicity accumulation and is readily degradable. Finally, thiamethoxam has a wide range of applications and meets modern agricultural requirements for green pesticides. Therefore, thiamethoxam can serve as a promising alternative to highly toxic and residual insecticides such as organophosphates, carbamates, and organochlorines. Currently, there are numerous synthetic routes for thiamethoxam, but the industrialized route primarily uses oxadiazine as an intermediate. Due to production process limitations, the market price of this product remains high.

[0003] Current research indicates that the mechanism for the synthesis of oxadiazines involves acid-catalyzed protonation of the formaldehyde carbonyl group to form a carbocation, which then reacts with the lone pair of electrons on the nitrogen atom of methylnitroguanidine to form a transition state containing two hydroxyl groups. The two hydroxyl groups in the transition state then undergo acid-catalyzed dehydration to form a cyclic ether, yielding the product oxadiazines. Patent CN115872944A uses urea as the starting material. Under alkaline conditions, it reacts with paraformaldehyde solution to produce 1,3,5-oxadiazin-4-one. This reacts with dimethyl sulfate (a dangerous chemical) to produce 3-methyl-1,3,5-oxadiazin-4-one through nucleophilic substitution. This reacts with hydroxylamine hydrochloride to produce 3-methyl-1,3,5-oxadiazin-4-one oxime, which then undergoes nitration with sodium nitrate to yield the target oxadiazines. This process is complex and involves the use of the hazardous reagent dimethyl sulfate. Patent IN2011CH03857A uses methylnitroguanidine and paraformaldehyde in a hydrochloric acid solution at 80°C for 3 hours to produce oxadiazine with a yield of 63%, a relatively low yield. Patent CN102070607A combines equal volumes of formaldehyde and formic acid with methylnitroguanidine at 80°C for 15 hours. After the reaction, the reaction solution is cooled to 0°C and then sodium hydroxide is added to adjust the pH to 8. The post-treatment yield is 71%. This process takes a long time, and the mother liquor after neutralization cannot be reused, generating a large amount of waste liquid. According to existing reports and actual production practices, the yield of oxadiazine is low, the reaction time is long, and the waste liquid is highly polluting, increasing the production cost of the original drug thiamethoxam.

[0004] The reaction mechanism of oxadiazine synthesis is shown below:

[0005]

[0006] In summary, there are still multiple contradictions in the prior art:

[0007] 1. The contradiction between shortening the reaction time and waste liquid pollution: Patent CN102070607A shortens the reaction time to 15 hours by using formic acid catalysis. However, a large amount of sodium formate is generated after the mother liquor is neutralized, resulting in hundreds of kilograms of high-salt waste liquid per ton of product.

[0008] 2. The contradiction between yield improvement and energy consumption costs: Patent IN2011CH03857A achieves a 63% yield after a 3-hour reaction at 80°C in a hydrochloric acid solution. Further extension of the reaction time may increase the yield, but energy consumption increases significantly.

[0009] 3. Inherent obstacles in mother liquor treatment: The existing process requires neutralization and filtration of the cooled reaction liquid to separate the product, resulting in the loss or conversion of the effective ingredients in the filtrate (i.e., unreacted methylnitroguanidine and hydroxyl intermediates) in the mother liquor from the reaction liquid into solid waste, which cannot be reused by simple concentration.

[0010] Therefore, in the existing technical system, the three goals of "green and environmental protection", "high yield" and "short reaction time" are mutually constrained, which is a technical problem that needs to be urgently solved by technical personnel in this field. Summary of the Invention

[0011] To address the problems of long reaction times, low product yields, high mother liquor production, and significant mother liquor contamination in existing oxadiazine (3-methyl-4-nitroimidatetrahydro-1,3,5-oxadiazine) synthesis processes, the present invention provides a simple, short reaction time, high separation yield and purity, and environmentally friendly process for synthesizing and recycling 3-methyl-4-nitroimidatetrahydro-1,3,5-oxadiazine. The resulting product can meet the needs of practical applications. This process design overturns the traditional "neutralization followed by purification" approach by directly utilizing the active components of the acidic mother liquor, achieving a dual breakthrough in reducing waste liquid and acid catalyst (the amount of sulfuric acid used as the catalyst in the mother liquor recycling process is 1 / 4 of the amount used in aqueous synthesis) while increasing yield.

[0012] The core of the high-yield oxadiazine preparation method of the present invention is to improve the synthesis efficiency by recycling the reaction mother liquor. The specific process is as follows:

[0013] (1) Add methylnitroguanidine, paraformaldehyde, acid catalyst and water to the reaction system, heat to 70-95°C and react for 2-16 hours;

[0014] (2) cooling and crystallizing after the reaction, washing, filtering and drying to obtain an oxadiazine product and a filtrate;

[0015] (3) After the filtrate is evaporated and concentrated, the evaporated clear water and the concentrated mother liquor are recovered; the concentrated mother liquor and the clear water are mixed to prepare a concentrated mother liquor in a mass ratio of 2-10:1; more preferably, the mass ratio is 3-8:1.

[0016] (4) In subsequent cyclic reaction rounds, the concentrated mother liquor or mixed concentrated mother liquor obtained in step (3) is added to the reaction system of step (1) and 70-100 wt% of water is replaced, and steps (1) to (4) are repeated at least 3 times; preferably at least 5 times.

[0017] The key to this process is to achieve the goal of a maximum separation yield of more than 90% and a purity of 99.0% for the product oxadiazine by recycling the residual unreacted raw materials and active ingredients in the mother liquor and quantitative control of the acid catalyst and polyformaldehyde.

[0018] For the technical solution described above, preferably, during the first reaction, the molar ratio of methylnitroguanidine, paraformaldehyde, acid catalyst and water in step (1) is 1:2-4:0.1-0.4:2-7, preferably 1:2.4-3.6:0.18-0.32:2.66-4.65, and more preferably 1:3.4:0.22:3.32.

[0019] For the technical solution described above, preferably, in each cyclic reaction round, the molar ratio of methylnitroguanidine, paraformaldehyde and acid catalyst in step (1) is 1:2-4:0.01-0.08, preferably 1:2.4-3.6:0.036-0.072, and more preferably 1:3.2:0.054; the mass ratio of methylnitroguanidine to concentrated mother liquor or mixed concentrated mother liquor is 1:0.5-1.5, preferably 1:0.81-1.22, and more preferably 1:1.01.

[0020] For the technical solution described above, preferably, the formaldehyde mass fraction of the clear liquid water is 7-15%.

[0021] For the technical solution described above, preferably, the concentration method in step (3) is distillation and reduced pressure distillation.

[0022] For the technical solution described above, preferably, the concentration endpoint of the concentrated mother liquor is calculated as the oxadiazine product, and the oxadiazine concentration in the concentrated mother liquor is 160-220 g / L, more preferably 180-210 g / L, and most preferably 200 g / L.

[0023] For the technical solution described above, preferably, the mass fraction of formaldehyde in the clear water is 7-15%.

[0024] For the technical solution described above, preferably, the acid catalyst is selected from at least one of sulfuric acid, phosphoric acid, hydrochloric acid, and p-toluenesulfonic acid, with sulfuric acid being most preferred.

[0025] For the technical solution described above, preferably, the cooling crystallization temperature is 0 to 10°C.

[0026] Beneficial effects of the present invention:

[0027] (1) The synthesis process of the present invention achieves three breakthroughs: "short reaction time (3 h), high product yield (93%), and environmental protection (waste liquid reduction of 60%+)", while avoiding the use of hazardous reagents, and has a good prospect for industrialization;

[0028] (2) The present invention has developed a mother liquor recycling process for 3-methyl-4-nitroimine tetrahydro-1,3,5-oxadiazine, with the maximum separation yield of oxadiazine being higher than 90% and the purity being 99.0%, which can meet the needs of current practical applications.

[0029] (3) The present invention provides an efficient, economical and environmentally friendly technical solution for the industrial production of oxadiazine by applying the mother liquor and precisely controlling the reaction parameters. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 Apply the process flow for the oxadiazine cycle;

[0031] Figure 2 This is a high performance liquid chromatography (HPLC) detection chart of the oxadiazine product obtained in Example 13; the figure shows the detailed results of peak detection, 1430 DiodeA ray Detector, sample ID: 1UNK001 (Extract, 270 nm), time: 1.

[0032] No. Ingredient name area area% high Peak 1 17694 0.286 3065 Peak 2 8687 0.141 1927 Peak 3 6151926 99.573 753980 6178307 100 758971

[0033] In the process of Example 13, the oxadiazine product has a high purity (product peak area ratio>99.5%), which proves the effectiveness of the concentrated mother liquor in controlling impurities in the product. DETAILED DESCRIPTION

[0034] In order to enable those skilled in the art to better understand the present invention, the present invention is further illustrated by the following examples. However, these examples are not intended to limit the scope of the present invention. The technical means used in the examples are conventional means well known to those skilled in the art.

[0035] In the present invention, unless otherwise specified, the experimental methods used are all conventional methods, and the materials and reagents used can be purchased from commercial channels.

[0036] Example 1 Synthesis of Oxadiazine Mother Solution

[0037] Methyl nitroguanidine (19.76 g, 0.1673 mol) and paraformaldehyde (16.00 g, 0.5333 mol) were mixed in a beaker, and water (10.00, 0.5556 mol) and concentrated sulfuric acid (3.60 g, 0.036 mol) were added to a 100 mL two-necked flask in sequence and mixed. Methyl nitroguanidine and paraformaldehyde were then added to the two-necked flask and reacted at 75 ° C for 16 h. After the reaction, it was completely crystallized at 0-10 ° C. The product was filtered and washed, and dried at 80 ° C to obtain the product oxadiazine (20.64 g, 0.1289 mol) with a yield of 77.1% and a purity of 99.0%. The amount of mother liquor was 24.93 g, and the mother liquor was diluted to 50 mL. The mother liquor contained 3.44 g / L of methyl nitroguanidine and 20.14 g / L of oxadiazine. The filtrate produced by this process was used as the mother liquor and subjected to rotary evaporation at 70°C, 200hPa, and 150rpm for 1 hour. The evaporated clear liquid water and the concentrated liquid were collected separately. The concentrated liquid was used for the oxadiazine mother liquor process and optimization.

[0038] Methyl nitroguanidine (19.76 g, 0.1673 mol) and paraformaldehyde (15.00 g, 0.5 mol) were mixed in a beaker, and concentrated mother liquor (20.00 g) and concentrated sulfuric acid (0.60 g, 0.006 mol) were added to a 100 mL two-necked flask in sequence and mixed. Methyl nitroguanidine and paraformaldehyde were then added to the two-necked flask and reacted at 75 ° C for 16 h. After the reaction, the mixture was cooled at 0-10 ° C for complete crystallization. The product was filtered and washed, and dried at 80 ° C to obtain the product oxadiazine (23.63 g, 0.1476 mol) with a yield of 88.2% and a purity of 99.0%. The amount of mother liquor was 28.06 g, and the mother liquor was diluted to 50 mL. The mother liquor contained 4.14 g / L of methyl nitroguanidine and 44.04 g / L of oxadiazine.

[0039] Example 2-16 Optimization of the process for applying oxadiazine mother liquor

[0040] The optimization of the oxadiazine mother liquor recycling process was investigated. Based on the method steps provided in Example 1, the five parameters of concentrated mother liquor amount, paraformaldehyde amount, concentrated sulfuric acid amount, repeated recycling and time were changed. Under different conditions, the separation yield of the oxadiazine product was tested. The results are shown in Table 1 below:

[0041] Table 1. Isolation yield of oxadiazines under different reaction conditions

[0042]

[0043] In Example 2-16, the mother liquor recycling process with the highest oxadiazine isolation yield was determined to have a mass ratio of methylnitroguanidine to concentrated mother liquor of 1:1.01, and a molar ratio of methylnitroguanidine to paraformaldehyde and concentrated sulfuric acid of 1:3.2:0.05. The reaction temperature was set at 75°C for 16 hours, resulting in an oxadiazine isolation yield exceeding 90% and a purity exceeding 99.0%. In Examples 14, 15, and 16, the reaction efficiency was improved due to the increased reaction temperature. Although the oxadiazine isolation yield decreased, the reaction time was significantly reduced to 3 hours, effectively improving the efficiency of the oxadiazine mother liquor recycling process. The product purities of Examples 2-16 all exceeded 99.0%.

[0044] Example 17: Scale-up experiment of oxadiazine mother liquor application process

[0045] Methylnitroguanidine (98.8 g, 0.8367 mol) and paraformaldehyde (80 g, 2.6667 mol) were mixed in a beaker. The concentrated mother liquor (100 g) and concentrated sulfuric acid (4.5 g, 0.045 mol) were added to a 500 mL two-necked flask in sequence and mixed. Methylnitroguanidine and paraformaldehyde were then added to the two-necked flask and reacted at 90°C for 3 hours. After the reaction, the product completely crystallized at 0-10°C. The product was filtered and washed, and then dried at 80°C to obtain the product oxadiazine (24.14 g, 0.1508 mol) with a yield of 90.1% and a purity of 99.0%. After the oxadiazine mother liquor process was scaled up, the separation yield was improved and the product purity was high.

[0046] Example 18 Mother liquor (80% concentrate + 20% water) once used

[0047] The mother liquor produced in the oxadiazine synthesis process was collected and concentrated by evaporation. 16 g of the concentrated mother liquor was added to a flask, and water (4 g, 0.2222 mol), concentrated sulfuric acid (0.9 g, 0.009 mol), methylnitroguanidine (19.76 g, 0.1673 mol), and paraformaldehyde (16 g, 0.5333 mol) were added. The mixture was reacted at 90°C for 3 h. After the reaction, the product completely crystallized at 0-10°C. The product was filtered and washed, and then dried at 80°C to obtain the product oxadiazine (23.36 g, 0.1459 mol). The yield was 87.2%, the purity was 99.0%, and the impurity content of the filtrate was 13.27%. The reaction filtrate was collected as the mother liquor, and the mother liquor was evaporated and concentrated to 20 g. 16 g of the mother liquor was added to a flask, and water (4 g, 0.2222 mol) was added. The oxadiazine mother liquor was reused for the second to fifth times according to the same process.

[0048] Example 19-24 mother liquor (80% concentrate + 20% water) is applied two to seven times

[0049] Table 2. Separation yield of oxadiazine mother liquor recycled from two to seven times

[0050]

[0051] Table 3. Liquid phase area percentage of components in the filtrate after reusing the oxadiazine mother liquor

[0052] Example Methylnitroguanidine / % Oxadiazine / % Monoaddition intermediate / % Other impurities / % 18 6.41 65.01 15.31 13.27 19 5.38 67.18 15.25 12.19 20 5.41 62.28 20.31 12.00 21 5.98 56.83 25.15 12.04 22 5.06 59.30 23.28 12.36 23 5.61 56.48 24.66 13.25 24 6.08 55.85 20.02 18.05

[0053] Examples 19-24 show that the reaction time is short when the mother liquor (80% concentrate + 20% water) is reused two to seven times, and the oxadiazine isolation yield is close to 80%, with high purity. As shown in Table 3, the impurity content in the filtrate is stable, indicating that a high oxadiazine isolation yield and quality can be guaranteed when a single batch of mother liquor is reused with water.

[0054] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included in the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be based on the scope of protection of the claims.

Claims

1. A method for preparing oxadiazine with high yield, characterized in that: The steps include: (1) Add methylnitroguanidine, paraformaldehyde, acid catalyst and water to the reaction system, heat to 70-95°C and react for 2-16 hours; (2) cooling and crystallizing after the reaction, washing, filtering and drying to obtain an oxadiazine product and a filtrate; (3) After the filtrate is evaporated and concentrated, the evaporated clear water and the concentrated mother liquor are recovered; the concentrated mother liquor and the clear water are prepared in a mass ratio of 2-10:1 to obtain a mixed concentrated mother liquor. (4) In subsequent cyclic reaction rounds, the concentrated mother liquor or mixed concentrated mother liquor obtained in step (3) is added to the reaction system of step (1) and replaces 70-100 wt% of water, and steps (1)-(4) are repeated at least 3 times.

2. The preparation method according to claim 1, characterized in that During the first reaction, the molar ratio of methylnitroguanidine, paraformaldehyde, acid catalyst and water in step (1) is 1:2-4:0.1-0.4:2-7.

3. The preparation method according to claim 1, characterized in that During the first reaction, the molar ratio of methylnitroguanidine, paraformaldehyde, acid catalyst and water in step (1) is 1:2.4-3.6:0.18-0.32:2.66-4.

65.

4. The preparation method according to claim 1, characterized in that In each cyclic reaction round, the molar ratio of methylnitroguanidine, paraformaldehyde and acid catalyst is 1:2-4:0.01-0.08; the mass ratio of methylnitroguanidine to concentrated mother liquor or mixed concentrated mother liquor is 1:0.5-1.

5.

5. The preparation method according to claim 1, characterized in that In each cyclic reaction round, the molar ratio of methylnitroguanidine, paraformaldehyde and acid catalyst is 1:2.4-3.6:0.036-0.072; the mass ratio of methylnitroguanidine to concentrated mother liquor or mixed concentrated mother liquor is 1:0.81-1.

22.

6. The preparation method according to claim 1, characterized in that The concentration method of step (3) is distillation and reduced pressure distillation.

7. The preparation method according to claim 1, characterized in that The concentration end point of the concentrated mother liquor is calculated based on the oxadiazine-containing product, and the oxadiazine concentration in the concentrated mother liquor is 160-220 g / L; the formaldehyde mass fraction of the clear liquid water is 7-15%.

8. The preparation method according to claim 1, characterized in that The concentration endpoint of the concentrated mother liquor is calculated based on the oxadiazine product, and the oxadiazine concentration in the concentrated mother liquor is 180-210 g / L.

9. The preparation method according to claim 1, characterized in that The acid catalyst is selected from at least one of sulfuric acid, phosphoric acid, hydrochloric acid and p-toluenesulfonic acid.

10. The preparation method according to claim 1, characterized in that The cooling crystallization temperature is 0-10°C.

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