A method for synthesizing thiamethoxam

Abstract

The present invention relates to the technical field of drug synthesis, and specifically discloses a method for synthesizing thiamethoxam. The method comprises: a. Reacting 3-methyl-4-nitroimino-1,3,5-oxadiazine with an organic strong base in an organic solvent to form an oxadiazine salt. When the mass content of oxadiazine is lower than 0.5%, an oxadiazine salt reaction solution is obtained; b. Adjusting the pH value of the oxadiazine salt reaction solution to neutral, then adding 2-chloro-5-(chloromethyl)thiazole, and reacting at 50-60°C until the mass content of oxadiazine salt is lower than 0.5% to obtain a thiamethoxam salt reaction solution; c. Adding water to the thiamethoxam salt reaction solution, washing away impurities, cooling, and centrifuging to obtain thiamethoxam. The thiamethoxam synthesis method provided by the present invention no longer uses potassium carbonate, reduces the production cost, reduces the water consumption during product purification, is environmentally friendly, and at the same time avoids the decomposition of 2-chloro-5-(chloromethyl)thiazole under alkaline conditions, improving the reaction yield.

Description

Technical Field

[0001] The present invention relates to the technical field of insecticidal drug synthesis, and particularly relates to a method for synthesizing thiamethoxam. Background Art

[0002] As a second-generation nicotinic insecticide with a brand-new structure, thiamethoxam has stomach toxicity, contact toxicity and systemic activity against pests, and is used for foliar spraying and soil drenching treatment. After application, it is quickly absorbed and conducted to all parts of the plant, and has good control effects on piercing-sucking pests such as aphids, planthoppers, leafhoppers, whiteflies, etc.

[0003] Currently, thiamethoxam is mainly synthesized using DMF (N,N-dimethylformamide) as a solvent and potassium carbonate as an acid-binding agent. Thiamethoxam is obtained by reacting oxadiazine with 2-chloro-5-(chloromethyl)thiazole, as shown in Reaction Formula I.

[0004]

[0005] In the above synthesis method, the amount of potassium carbonate used is large, resulting in high production costs. At the same time, a large amount of potassium bicarbonate and potassium chloride will be produced in the product. To purify the product, a large amount of water needs to be added to dissolve potassium bicarbonate and potassium chloride, generating a large amount of wastewater. Secondly, under alkaline conditions, 2-chloro-5-(chloromethyl)thiazole is prone to decomposition, resulting in a low yield of thiamethoxam. Summary of the Invention

[0006] In view of the above problems, the present invention provides a method for synthesizing thiamethoxam with high yield and high product purity.

[0007] To achieve the above invention objective, the embodiments of the present invention adopt the following technical solutions:

[0008] A method for synthesizing thiamethoxam, comprising the following steps:

[0009] a. Adding 3-methyl-4-nitroimino-1,3,5-oxadiazine (hereinafter referred to as oxadiazine) and an organic strong base to an organic solvent for reaction to form an oxadiazine salt. When the mass content of oxadiazine is lower than 0.5%, an oxadiazine salt reaction solution is obtained;

[0010] b. Adjusting the pH value of the oxadiazine salt reaction solution to neutral, then adding 2-chloro-5-(chloromethyl)thiazole, and reacting at 50-60°C until the mass content of the oxadiazine salt is lower than 0.5% to obtain a thiamethoxam reaction solution;

[0011] c. Adding water to the thiamethoxam reaction solution to wash away impurities, cooling, and centrifuging to obtain thiamethoxam.

[0012] The reaction equations of the embodiments of the present invention are shown in Formulas II and III:

[0013]

[0014]

[0015] Compared with the prior art, the preparation method provided by the present invention has the following advantages: The present invention uses an organic strong base to react with oxadiazine to obtain an oxadiazine salt. After neutralizing the reaction solution, the oxadiazine salt reacts with 2-chloro-5-(chloromethyl)thiazole, and finally thiamethoxam is generated through hydrolysis. On the one hand, potassium carbonate is no longer used in this synthesis method, reducing the production cost, reducing the water consumption during product purification, and being environmentally friendly; on the other hand, in a neutral environment, the decomposition of 2-chloro-5-(chloromethyl)thiazole under alkaline conditions in the prior art is avoided, improving the reaction yield. The product yield of this synthesis method can reach more than 95%, and the purity of thiamethoxam can reach more than 98%.

[0016] Optionally, the organic strong base in step a is sodium methoxide, sodium ethoxide or sodium tert-butoxide.

[0017] Optionally, the reaction temperature of step a is 40 - 60 °C.

[0018] Optionally, the organic solution in step a is DMF, dichloroethane, dichloromethane or dimethyl carbonate.

[0019] Under the above optional experimental conditions, the reaction rate of step a is fast and the product yield is high.

[0020] Optionally, the molar ratio of the oxadiazine to the organic strong base in step a is 1:1 - 1.05.

[0021] Optionally, the acidic solution in step b includes acetic acid, hydrochloric acid, formic acid or dilute sulfuric acid with a mass fraction of 20%.

[0022] Optionally, the reaction temperature of step b is 40 - 60 °C.

[0023] When the temperature is lower than 40 °C, the reaction rate is slower. The reaction time is as long as 12 - 20 hours at 20 - 30 °C, and the reaction cannot proceed when the temperature is lower than 20 °C.

[0024] Optionally, the molar ratio of 2-chloro-5-(chloromethyl)thiazole to oxadiazine in step b is 1 - 1.2:1.

[0025] Preferably, the molar ratio of 2-chloro-5-(chloromethyl)thiazole to oxadiazine in step b is 1.05:1

[0026] Optionally, in step c, after cooling to 1 - 10 °C, centrifugal feeding is carried out. Specific embodiments

[0027] In order to make the objectives, technical solutions and advantages of the present invention more clear and understandable, the present invention will be further described in detail below in conjunction with embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0028] Example 1

[0029] A synthesis method of thiamethoxam, comprising the following steps:

[0030] a. Add 84.8 g of oxadiazine (0.53 mol) and 29.2 g of sodium methoxide (0.54 mol) to a reaction flask, then add 95 ml of DMF, and react at 40°C. React for 4 hours, monitor by HPLC, and obtain the oxadiazine salt reaction solution after the oxadiazine content is less than 0.5%;

[0031] b. Add acetic acid to the oxadiazine salt reaction solution to adjust the pH value to neutral, then add 93.4 g of 2-chloro-5-chloromethylthiazole (0.556 mol), and the reaction temperature is 50°C. React for 4 hours, monitor by HPLC, and obtain the thiamethoxam reaction solution after the sodium oxadiazine content is less than 0.5%;

[0032] c. Add 120 ml of water to the above thiamethoxam reaction solution to wash away impurities, then cool down to 1°C, and centrifuge to obtain 151.0 g of thiamethoxam, with a content of 98.5% and a yield of 97.6%, and 242.0 g of wastewater is generated.

[0033] Example 2

[0034] A synthesis method of thiamethoxam, comprising the following steps:

[0035] a. Add 84.8 g of oxadiazine (0.53 mol) and 36.0 g of sodium ethoxide (0.53 mol) to a reaction flask, then add 95 ml of dichloroethane, and react at 50°C. React for 4 hours, monitor by HPLC, and obtain the oxadiazine salt reaction solution after the oxadiazine content is less than 0.5%;

[0036] b. Add hydrochloric acid to the oxadiazine salt reaction solution to adjust the pH value to neutral, then add 105.8 g of 2-chloro-5-chloromethylthiazole (0.63 mol), and the reaction temperature is 55°C. Monitor by HPLC, and obtain the thiamethoxam reaction solution after the oxadiazine salt content is less than 0.5%;

[0037] c. Add 120 ml of water to the above thiamethoxam reaction solution to wash away impurities, then cool down to 3°C, and centrifuge to obtain 146.0 g of thiamethoxam, with a content of 98.1% and a yield of 94.3%, and 240.0 g of wastewater is generated.

[0038] Example 3

[0039] A synthesis method of thiamethoxam, comprising the following steps:

[0040] a. Add 84.8 g of oxadiazine (0.53 mol) and 51.9 g of sodium tert-butoxide (0.54 mol) into a reaction flask, then add 95 ml of dichloromethane, and react at 40 °C. React for 4 hours, monitor by HPLC, and obtain the oxadiazine salt reaction solution after the content of oxadiazine is lower than 0.5%;

[0041] b. Add formic acid to the oxadiazine salt reaction solution to adjust the pH value to neutral, then add 97.4 g of 2-chloro-5-(chloromethyl)thiazole (0.58 mol), and the reaction temperature is 40 °C. Monitor by HPLC, and obtain the thiamethoxam reaction solution after the content of oxadiazine salt is lower than 0.5%;

[0042] c. Add 120 ml of water to the above thiamethoxam reaction solution to wash away impurities, then cool down to 5 °C, and centrifuge to obtain 150.0 g of thiamethoxam, with a content of 98.3% and a yield of 96.9%, and 243.0 g of waste water is generated.

[0043] Example 4

[0044] A synthesis method of thiamethoxam, comprising the following steps:

[0045] a. Add 84.8 g of oxadiazine (0.53 mol) and 29.2 g of sodium methoxide (0.54 mol) into a reaction flask, then add 95 ml of dimethyl carbonate, and react at 50 °C. React for 4 hours, monitor by HPLC, and obtain the oxadiazine salt reaction solution after the content of oxadiazine is lower than 0.5%;

[0046] b. Add acetic acid to the above oxadiazine salt reaction solution to adjust the pH value to neutral, then add 89 g of 2-chloro-5-(chloromethyl)thiazole (0.53 mol), and the reaction temperature is 60 °C. Monitor by HPLC, and obtain the thiamethoxam reaction solution after the content of oxadiazine salt is lower than 0.5%;

[0047] c. Add 120 ml of water to the thiamethoxam reaction solution to wash away impurities, then cool down to 8 °C, and centrifuge to obtain 148.0 g of thiamethoxam, with a content of 98.2% and a yield of 95.6%, and 243.0 g of waste water is generated.

[0048] Example 5

[0049] A synthesis method of thiamethoxam, comprising the following steps:

[0050] a. Add 84.8 g of oxadiazine (0.53 mol) and 29.2 g of sodium methoxide (0.54 mol) into a reaction flask, then add 95 ml of DMF, and react at 40 °C. React for 4 hours, monitor by HPLC, and obtain the oxadiazine salt reaction solution after the content of oxadiazine is lower than 0.5%;

[0051] b. Add acetic acid to the dioxazine salt reaction solution to adjust the pH value to neutral, then add 93.4 g of 2-chloro-5-(chloromethyl)thiazole (0.556 mol), and the reaction temperature is 50 °C. Monitor by HPLC. After the content of the dioxazine salt is lower than 0.5%, the thiamethoxam reaction solution is obtained;

[0052] c. Add 120 ml of water to the thiamethoxam reaction solution to wash away impurities, then cool down to 1 °C and centrifuge to obtain 151.0 g of thiamethoxam with a content of 98.5% and a yield of 97.6%. 242.0 g of wastewater is generated.

[0053] Comparative Example 1

[0054] Thiamethoxam was prepared using potassium carbonate. The specific preparation steps are as follows:

[0055] a. Add 84.8 g of dioxazine (0.53 mol), 90 g of potassium carbonate (0.65 mol), 93.5 g of 2-chloro-5-(chloromethyl)thiazole (0.556 mol) to the reaction flask, then add 95 ml of DMF, and react at 60 °C. Monitor by HPLC. After the content of dioxazine is lower than 0.5%, the thiamethoxam reaction solution is obtained;

[0056] b. Add 250 ml of water to the thiamethoxam reaction solution to wash away impurities, then cool down to 5 °C and centrifuge to obtain 135.0 g of thiamethoxam with a content of 98.1% and a yield of 87.0%. 400.0 g of wastewater is generated.

[0057] Comparative Example 2

[0058] Thiamethoxam was prepared using potassium carbonate. The specific preparation steps are as follows: a. Add 84.8 g of dioxazine (0.53 mol), 90 g of potassium carbonate (0.65 mol), 93.5 g of 2-chloro-5-(chloromethyl)thiazole (0.556 mol) to the reaction flask, then add 95 ml of DMF, and react at 56 °C. Monitor by HPLC. After the content of dioxazine is lower than 0.5%, the thiamethoxam reaction solution is obtained;

[0059] b. Add 120 ml of water to the thiamethoxam reaction solution to wash away impurities, then cool down to 5 °C and centrifuge to obtain 156.0 g of thiamethoxam with a content of 88.0% and a yield of 89.0%. 270.0 g of wastewater is generated.

[0060] Comparative Example 3

[0061] Replace sodium methoxide with potassium hydroxide to prepare thiamethoxam. The other materials and reaction steps are the same as those in Example 1. The specific steps are as follows:

[0062] 84.8 g of oxadiazine (0.53 mol) and 30.2 g of potassium hydroxide (0.54 mol) were added to a reaction flask, and then 95 ml of DMF was added. The reaction was carried out at 60 °C. Monitored by HPLC, after 10 hours of reaction, the content of oxadiazine was greater than 99%, and the reaction could not proceed.

[0063] Comparative Example 4

[0064] 84.8 g of oxadiazine (0.53 mol) and 29.2 g of sodium methoxide (0.54 mol) were added to a reaction flask, and then 95 ml of DMF was added. The reaction was carried out at 25 °C. The reaction was carried out for 8 hours and monitored by HPLC. The content of oxadiazine was still greater than 10%.

[0065] Table 1 Summary of Experimental Results

[0066] Product quality Content Yield Wastewater quality Example 1 151 98.5 97.6 242 Example 2 146 98.1 94.3 240 Example 3 150 98.3 96.9 243 Example 4 148 98.2 95.6 243 Example 5 149 98.3 96.3 246 Comparative example 1 135 98.1 87.0 400 Comparative example 2 156 88.0 89.0 270 Comparative example 3 / / / /

[0067] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements or improvements made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A synthesis method of thiamethoxam, characterized in that, it comprises the following steps: a. Adding 3-methyl-4-nitroimino-1,3,5-oxadiazine and an organic strong base into an organic solvent for reaction to generate an oxadiazine salt. When the mass content of oxadiazine is lower than 0.5%, an oxadiazine salt reaction solution is obtained; b. Adjusting the pH value of the oxadiazine salt reaction solution to neutral, then adding 2-chloro-5-(chloromethyl)thiazole and reacting at 50-60 °C until the mass content of oxadiazine salt is lower than 0.5% to obtain a thiamethoxam salt reaction solution; c. Adding water to the thiamethoxam salt reaction solution, washing away impurities, cooling, and centrifuging to obtain thiamethoxam; The organic strong base in step a is sodium methoxide, potassium methoxide, sodium ethoxide or sodium tert-butoxide.

2. The synthesis method of thiamethoxam according to claim 1, characterized in that, the organic solvent is DMF, dichloroethane, dichloromethane or dimethyl carbonate.

3. The synthesis method of thiamethoxam according to claim 2, characterized in that, the organic strong base is sodium methoxide and the organic solvent is DMF.

4. The synthesis method of thiamethoxam according to claim 1, characterized in that, the reaction temperature in step a is 40-60 °C and the reaction time is 0.5 h - 1.5 h.

5. The thiamethoxam synthesis method according to claim 1 or 2, characterized in that, the molar ratio of 3-methyl-4-nitroimino-1,3,5-oxadiazine to the organic strong base in step a is 1:1 - 1.

05.

6. The synthesis method of thiamethoxam according to claim 1, characterized in that, the pH value of the oxadiazine salt reaction solution is adjusted with an acidic solution in step b, wherein the acidic solution is acetic acid, hydrochloric acid, formic acid or dilute sulfuric acid with a mass fraction of 20%.

7. The synthesis method of thiamethoxam according to claim 1 or 6, characterized in that, the molar ratio of 2-chloro-5-(chloromethyl)thiazole to oxadiazine salt in step b is 1 - 1.2:1 and the reaction time is 2.5 - 5 h.

8. The synthesis method of thiamethoxam according to claim 1 or 6, characterized in that, the molar ratio of 2-chloro-5-(chloromethyl)thiazole to oxadiazine salt is 1.05:

1.

9. The synthesis method of thiamethoxam according to claim 1, characterized in that, in step a or step b, the content of oxadiazine or sodium oxadiazine is monitored by high performance liquid chromatography.

10. In the synthesis method of thiamethoxam according to claim 1, in step c, after cooling to 1 - 10 °C, centrifugal feeding is carried out.

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