Synthesis method of prothioconazole

Abstract

The invention discloses a method for preparing prothioconazole with high yield, wherein compound 1 is reacted at 0-100° C. in the presence of hydrogen peroxide and a solvent using titanium silicon molecular sieve as a catalyst, and the catalyst is filtered and recovered after the reaction, and then prothioconazole is obtained by post-processing. The method is simple to operate, has a smooth process, mild conditions, is green and environmentally friendly, has good atomic economy, the catalyst can be repeatedly reused, and the raw material conversion rate is high and the product yield is high. It has high industrial production value.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a method for synthesizing prothioconazole with high yield. Background Art

[0002] The chemical name of prothioconazole is 2-[2-(1-chlorocyclopropyl)-3-(2-chlorophenyl)-2-hydroxypropyl]-1,2-dihydro-3H-1,2,4-triazole-3-thione. It is a demethylation inhibitor (DMIs) developed by Bayer. Its mechanism of action is to inhibit the 14-position demethylation of lanosterol, the precursor of true mesosterol. It has the advantages of a wide spectrum of fungicides, good systemic activity, high protection, treatment and eradication activity, and a long effective period. Through a large number of field efficacy tests, the results show that prothioconazole not only has good safety for crops, but also has obvious disease prevention and treatment effects and good yield increase effects. Prothioconazole is mainly used to prevent and control many diseases of cereal crops such as wheat, barley, rapeseed, peanuts, rice and legumes, and has a good control effect on almost all wheat diseases, such as powdery mildew, sheath blight, wilt, leaf spot, rust, sclerotinia, web spot, and moire of wheat and barley.

[0003] Most of the synthetic processes reported so far for high prothioconazole have the problems of large material consumption, large amount of wastewater, large amount of solid waste, low yield, and poor process fluency. For example, in the synthetic route of US6559317, when prothioconazole is prepared from compound 1, an excess of ferric chloride is used as a reaction reagent, resulting in the generation of a large amount of solid waste by the reaction. CN108689952A uses ferric chloride as an oxidizing agent, and the aqueous phase needs to be oxidized with hydrogen peroxide after the reaction is completed before it can be reused, which is cumbersome to operate and has poor process fluency. CN106986838A uses hydrogen peroxide or meta-chloroperbenzoic acid as an oxidant, and this method uses a large amount of oxidant. And after repeated experiments and verification by the inventor, it was found that the final product obtained by the method has more impurities and a very low yield, and the viscosity of the product obtained by the reaction is large, which makes separation and purification very difficult. CN109912522 uses nitric acid as an oxidizing agent, and nitric acid is an easily made explosive product, and there is a great safety risk in participating in chemical reactions.

[0004] Therefore, there is an urgent need in the art for a synthesis process that is simple and smooth, has a high synthesis yield, a high content of prothioconazole, and is suitable for industrial scale-up production. Summary of the invention

[0005] The purpose of the present invention is to provide a new synthesis process of prothioconazole, which should have the advantages of being simple and smooth, having a high synthesis yield, and being suitable for industrialized scale-up production.

[0006] In a first aspect, the present invention provides a method for synthesizing prothioconazole, and the synthesis method is as follows:

[0007]

[0008] The synthesis method comprises the following steps:

[0009] 1) adding compound 1 into a solvent;

[0010] 2) Compound 1 is reacted in the presence of titanium silicalite and an oxidant to obtain prothioconazole.

[0011] In a preferred embodiment, the oxidant is hydrogen peroxide, m-chloroperbenzoic acid, or sodium hypochlorite; preferably hydrogen peroxide.

[0012] In a specific embodiment, the synthesis method further comprises step 3) adding a solvent to the obtained prothioconazole for pulping and refining, thereby obtaining high-purity prothioconazole.

[0013] In a specific embodiment, the synthesis method further includes the step of recovering and reusing the titanium silicalite.

[0014] In a specific embodiment, the weight ratio of titanium silicon molecular sieve to compound 1 is 0.001-1:1, preferably 0.01-0.1:1.

[0015] In a specific embodiment, the oxidant is added at a temperature between 0°C and 100°C, preferably between 20°C and 50°C.

[0016] In a specific embodiment, the molar ratio of the oxidant to compound 1 is 1.0-1.5:1.

[0017] In a specific embodiment, step 2) comprises reacting compound 1 in the presence of titanium silicalite and an oxidant at a temperature of 0°C-100°C, preferably 20°C-50°C, to obtain prothioconazole.

[0018] In a specific embodiment, the solvent in step 1) is one or more of the following solvents: toluene, xylene, benzene, chlorobenzene, petroleum ether, ethyl acetate, dichloromethane, dichloroethane, chloroform, cyclohexane, methylcyclohexane, etc.; preferably dichloroethane and toluene.

[0019] In a specific embodiment, the amount of the solvent used is 1-10 times the mass of compound 1; preferably 3-4 times.

[0020] In a specific embodiment, the refined pulping solvent in step 3) is one or more of the following solvents: toluene, xylene, benzene, chlorobenzene, petroleum ether, ethyl acetate, dichloromethane, dichloroethane, chloroform, cyclohexane, methylcyclohexane, etc.; preferably toluene, ethyl acetate, dichloromethane, and dichloroethane.

[0021] In a specific embodiment, the synthesis method comprises the following steps:

[0022] 1') adding compound 1 to a solvent, adding a certain amount of titanium silicon molecular sieve, adding a certain amount of hydrogen peroxide dropwise at a certain temperature, keeping the temperature for a period of time after the addition is completed, and monitoring the raw material by liquid chromatography within 1%; filtering under a certain temperature condition, recovering the catalyst titanium silicon molecular sieve for application, letting the filtrate stand and separate the aqueous phase, and desolventizing the organic phase to obtain the product prothioconazole;

[0023] 2') Compound 1 is added to a solvent, and a recovered titanium silicon molecular sieve is added. A certain amount of hydrogen peroxide is added dropwise under a certain temperature condition. After the addition is completed, the temperature is kept for a period of time, and the raw material is monitored by liquid chromatography within 1%; filtering is performed under a certain temperature condition, and the catalyst titanium silicon molecular sieve is recovered and applied. The filtrate is allowed to stand for stratification to separate the aqueous phase, and the organic phase is desolventized to obtain a crude product of prothioconazole. The crude product is added with a solvent and pulped to obtain a high-purity product of prothioconazole.

[0024] In a specific embodiment, the amount of solvent used in step 2') is 0.1-3 times the mass of compound 1; preferably 0.5-1 times.

[0025] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 is the HPLC spectrum of the reaction product of Example 1 of the present invention;

[0027] Figure 2 It is the HPLC spectrum of the reaction product of Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0028] After extensive and in-depth research, the inventor unexpectedly found that using titanium silicon molecular sieve as a catalyst and hydrogen peroxide as an oxidizing agent can synthesize prothioconazole with high conversion rate and high yield. The method of the present invention has smooth process, mild conditions, green and environmental protection, simple operation, high industrial production value, and can realize the reuse of the catalyst. On this basis, the present invention was completed.

[0029] Titanium silicate molecular sieve

[0030] Titanium silicate molecular sieve was first reported by Taramasso in 1983. Its regular structure and suitable pore size endow it with a wide range of applications. Titanium silicate molecular sieve is synthesized with tetraethyl orthosilicate, tetraethyl titanate and tetrapropylammonium hydroxide as raw materials. Titanium silicate molecular sieve has a unique ten-membered ring cross-channel system. In its molecular structure, titanium enters the molecular sieve framework structure and is highly evenly dispersed. The active center of titanium silicate molecular sieve is Ti4 + , Ti4 + Lewis acid center. In the reaction system catalyzed by titanium silicalite, the reaction environment of the reactants (uniform Ti4 + The active center) is the same, and the skeleton titanium atoms can activate hydrogen peroxide. Therefore, the catalytic process of the titanium silicon molecular sieve hydrogen peroxide system has excellent reaction selectivity and is not prone to deep processes.

[0031] Prothioconazole synthesis method of the present invention

[0032] The present invention provides a method for synthesizing prothioconazole with high yield, wherein the method uses titanium silicon molecular sieve as a catalyst and uses hydrogen peroxide as an oxidizing agent. The method of the present invention can synthesize prothioconazole with high conversion rate and high yield, and can reuse the titanium silicon molecular sieve. Therefore, the method of the present invention has high industrial production value.

[0033] In a specific embodiment, the synthesis process route of high-yield prothioconazole provided by the present invention is as follows:

[0034]

[0035] The synthesis method of high-yield prothioconazole and post-treatment thereof comprise the following steps:

[0036] 1) Compound 1 is added to a solvent, a certain amount of titanium silicalite is added, a certain amount of hydrogen peroxide is added dropwise under a certain temperature condition, and after the addition is completed, the temperature is kept for a period of time, and the raw material is monitored by liquid chromatography within 1%; filtering is performed under a certain temperature condition, the catalyst titanium silicalite is recovered and applied, the filtrate is allowed to stand for stratification to separate the aqueous phase, and the organic phase is desolvated to obtain the product prothioconazole;

[0037] Steps for applying titanium silicate molecular sieve:

[0038] 2) Compound 1 is added to a solvent, and the recovered titanium silicalite is added. A certain amount of hydrogen peroxide is added dropwise under a certain temperature condition. After the addition is completed, the temperature is kept for a period of time, and the raw material is monitored by liquid chromatography within 1%; filtering is performed under a certain temperature condition, and the catalyst titanium silicalite is recovered and applied. The filtrate is allowed to stand for stratification to separate the aqueous phase, and the organic phase is desolventized to obtain a crude prothioconazole product. The crude product is added with a solvent for pulping and refining to obtain a high-purity product prothioconazole.

[0039] In a preferred embodiment, the weight ratio of titanium silicalite to compound 1 is 0.001-1:1; more preferably 0.01-0.1:1.

[0040] In a preferred embodiment, the temperature for dropping hydrogen peroxide is 0°C-100°C, preferably 20°C-50°C.

[0041] In a preferred embodiment, the molar ratio of hydrogen peroxide to compound 1 is 1.0-1.5:1.

[0042] In a preferred embodiment, the insulation temperature is 0°C-100°C; more preferably 20-50°C.

[0043] In a preferred embodiment, the solvent in step 1) and step 2) is one or more of the following commonly used solvents: toluene, xylene, benzene, chlorobenzene, petroleum ether, ethyl acetate, dichloromethane, dichloroethane, chloroform, cyclohexane, methylcyclohexane, etc., preferably dichloroethane and toluene.

[0044] In a preferred embodiment, the amount of solvent used in step 1) is 1-10 times the mass of compound 1; preferably 3-4 times.

[0045] In a preferred embodiment, the refined pulping solvent in step 2) is one or more of the following commonly used solvents: toluene, xylene, benzene, chlorobenzene, petroleum ether, ethyl acetate, dichloromethane, dichloroethane, chloroform, cyclohexane, methylcyclohexane, etc., preferably toluene, ethyl acetate, dichloromethane, and dichloroethane.

[0046] In a preferred embodiment, the amount of solvent used in step 2) is 0.1-3 times the mass of compound 1, preferably 0.5-1 times;

[0047] Advantages of the present invention:

[0048] Compared with the synthesis process provided in the prior art, the production process of the present invention has the following advantages:

[0049] 1) The process of the present invention is simple and smooth, the reaction conditions are mild, the product yield is high, the content is high, and it is suitable for industrial scale-up production;

[0050] 2) The catalyst of the present invention can be recycled, thereby significantly reducing production costs.

[0051] The technical scheme of the present invention is further described below in conjunction with specific implementation cases, but the following implementation cases do not constitute a limitation of the present invention, and all various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0052] Example 1

[0053] Compound 1,2-(1-chloro-cyclopropyl-1-yl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (69.2g, 0.2mol) was added to 210g toluene, titanium silicalite 2.07g was added, the temperature was raised to 40°C, 10% hydrogen peroxide (68.0g, 0.2mmol) was added dropwise, and the reaction liquid temperature was controlled to 40-45°C. After the addition was completed, the temperature was kept at 40°C for 3 hours. After the reaction was completed, the temperature was lowered to 25°C, the titanium silicalite was filtered and recovered, the filtrate was allowed to stand for stratification, and the organic phase was desolventized to obtain a white solid, i.e., 68.0g of prothioconazole, with a content of 98.4% and a yield of 97.3%.

[0054] The NMR data of the obtained product are: 1 HNMR (600MHz, DMSO-d6) δ (ppm) 13.67 (lH, s), 8.43 (lH, s), 7.53-7.55 (lH, m), 7.37-7.39 (lH, m), 7.21-7.26 (2H, m ), 5.06 (lH, s), 4.48 (2H, s), 3.34 (lH, d, J = 21.0Hz), 3.18 (lH, d, J = 21.0Hz), 0.81-0.91 (2H, m), 0.71-0.75 (2H, m).

[0055] The HPLC spectrum of the obtained product is as follows Figure 1 shown.

[0056] Example 2

[0057] Compound 1,2-(1-chloro-cyclopropyl-1-yl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (69.2g, 0.2mol) was added to 180g of ethylene dichloride, 2.07g of titanium silicalite molecular sieve was added, the temperature was raised to 40°C, 10% hydrogen peroxide (68.0g, 0.2mmol) was added dropwise, and the reaction liquid temperature was controlled to 40-45°C. After the addition was completed, the temperature was kept at 40°C for 3 hours. After the reaction was completed, the temperature was lowered to 25°C, the titanium silicalite molecular sieve was filtered and recovered, the filtrate was allowed to stand for stratification, and the organic phase was desolventized to obtain a white solid, i.e. 67.9g of prothioconazole, with a content of 98.4% and a yield of 97.2%.

[0058] Example 3

[0059] Compound 1,2-(1-chloro-cyclopropyl-1-yl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (69.2g, 0.2mol) was added to 210g toluene, 0.69g titanium silicon molecular sieve was added, the temperature was raised to 40°C, 10% hydrogen peroxide (68.0g, 0.2mmol) was added dropwise, and the reaction liquid temperature was controlled to 40-45°C. After the addition was completed, the temperature was kept at 40°C for 3 hours. After the reaction was completed, the temperature was lowered to 25°C, the titanium silicon molecular sieve was filtered and recovered, the filtrate was allowed to stand for stratification, and the organic phase was desolventized to obtain a white solid, i.e. 67.0g of prothioconazole, with a content of 98.1% and a yield of 95.5%.

[0060] Example 4

[0061] Compound 1,2-(1-chloro-cyclopropyl-1-yl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (69.2g, 0.2mol) was added to 210g toluene, 1.38g titanium silicon molecular sieve was added, the temperature was raised to 30°C, 10% hydrogen peroxide (68.0g, 0.2mmol) was added dropwise, and the reaction liquid temperature was controlled to 30-35°C, and the temperature was kept at 40°C for 4 hours after the addition was completed. After the reaction was completed, the temperature was lowered to 25°C, the titanium silicon molecular sieve was filtered and recovered, the filtrate was allowed to stand for stratification, and the organic phase was desolventized to obtain a white solid, i.e. 67.6g of prothioconazole, with a content of 98.2% and a yield of 96.4%.

[0062] Example 5

[0063] Compound 1,2-(1-chloro-cyclopropyl-1-yl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (69.2g, 0.2mol) was added to 210g toluene, 1.38g titanium silicalite was added, the temperature was raised to 40°C, 10% hydrogen peroxide (68.0g, 0.2mmol) was added dropwise, and the reaction liquid temperature was controlled to 40-45°C. After the addition was completed, the temperature was kept at 40°C for 4 hours. After the reaction was completed, the temperature was lowered to 25°C, the titanium silicalite was filtered and recovered, the filtrate was allowed to stand for stratification, and the organic phase was desolventized to obtain a white solid, i.e. 67.8g of prothioconazole, with a content of 98.1% and a yield of 96.7%.

[0064] Example 6

[0065] Titanium silicate molecular sieve application:

[0066] The molecular sieve obtained by filtration was added to compound 1 (69.2g, 0.2mol) and 210g toluene, the temperature was raised to 40°C, 10% hydrogen peroxide (68.0g, 0.2mmol) was added dropwise, and the reaction liquid temperature was controlled to 40-45°C. After the addition was completed, it was kept warm at 40°C for 4 hours. After the reaction was completed, the temperature was lowered to 25°C, the titanium silicon molecular sieve was filtered and recovered, the filtrate was allowed to stand for stratification, and the organic phase was desolventized to obtain 67.5g of white solid, with a content of 98.0% and a yield of 96.2%. Repeat the above operation. When the product content cannot reach 98% when applied for the second time, the crude prothioconazole obtained at this time is added to 40g ethyl acetate, stirred and beaten at 25°C for 1 hour, and filtered. The content can reach more than 98%. The application situation is as follows:

[0067] catalyst Product quantity content Yield Fresh titanium silicate molecular sieve used 0 times 67.8g 98.1％ 96.7％ Recycling titanium silicon molecular sieve for 1 time 67.5g 98.0％ 96.2％ Recycle titanium silicon molecular sieve and use it twice 67.0g 98.1％ 95.5％ Recycled titanium silicon molecular sieve for 3 times 66.7g 98.1％ 95.1％ Recycled titanium silicon molecular sieve for 4 times 66.4g 98.0％ 94.6％

[0068] Comparative Example 1

[0069] Referring to the method described in CN106986838A, compound 1,2-(1-chloro-cyclopropyl-1-yl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (34.6g, 0.1mol) was dissolved in 50ml acetone, and then hydrogen peroxide (0.15mol) was added dropwise, and the reaction solution was reacted at 25°C for 2 hours. After the reaction was completed, sodium sulfite (6.5g) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and then tested with starch potassium iodide paper. Water (50ml) was added to the reaction system, followed by extraction with ethyl acetate (extraction three times, 50ml each time), and the organic phase was combined and dried over anhydrous sodium sulfate and concentrated. 26.4g of viscous material was obtained, with a content of 61.8%. The crude product yield was 47.4%.

[0070] The HPLC spectrum of the obtained product is as follows Figure 2 shown.

[0071] Comparative Example 2

[0072] Referring to the method described in CN106986838A, compound 1,2-(1-chloro-cyclopropyl-1-yl)-1-(2-chlorophenyl)-2-hydroxy-3-(1,2,4-triazolidine-5-thione-1-yl)-propane (34.6g, 0.1mol) was dissolved in 50ml of dichloromethane, followed by dropwise addition of hydrogen peroxide (0.15mol), and the reaction solution was reacted at 25°C for 2 hours. After the reaction was completed, sodium sulfite (6.5g) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour and then tested with starch potassium iodide paper. Water (50ml) was added to the reaction system for washing, and the organic phase was dried over anhydrous sodium sulfate and concentrated. 30.4g of a viscous substance was obtained, with a content of 51.2%. The crude product yield was 45.2%.

[0073] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for synthesizing prothioconazole, characterized in that: The synthesis method is as follows: The synthesis method comprises the following steps: 1) adding compound 1 into a solvent; 2) reacting compound 1 in the presence of titanium silicon molecular sieve and an oxidant to obtain prothioconazole; The oxidant is hydrogen peroxide; Furthermore, the molar ratio of the oxidant to the compound 1 is 1:

1.

2. The synthesis method according to claim 1, characterized in that The synthesis method further comprises step 3) adding a solvent to the obtained prothioconazole for pulping and refining, thereby obtaining high-purity prothioconazole.

3. The synthesis method according to claim 1 or 2, characterized in that: The synthesis method also includes the steps of recovering and reusing the titanium silicon molecular sieve.

4. The synthesis method according to claim 1 or 2, characterized in that: The weight ratio of titanium silicon molecular sieve to compound 1 is 0.001-1:

1.

5. The synthesis method according to claim 4, characterized in that The weight ratio of titanium silicalite to compound 1 is 0.01-0.1:

1.

6. The synthesis method according to claim 1 or 2, characterized in that: The adding temperature of the oxidant is between 0°C and 100°C.

7. The synthesis method according to claim 6, characterized in that The addition temperature of the oxidant is between 20°C and 50°C.

8. The synthesis method according to claim 1 or 2, characterized in that: Step 2) comprises reacting compound 1 at a temperature of 0° C. to 100° C. in the presence of titanium silicalite and an oxidant to obtain prothioconazole.

9. The synthesis method according to claim 8, characterized in that Step 2) comprises reacting compound 1 at a temperature of 20° C. to 50° C. in the presence of titanium silicalite and an oxidant to obtain prothioconazole.

10. The synthesis method according to claim 1 or 2, characterized in that: The solvent in step 1) is one or more of the following solvents: toluene, xylene, benzene, chlorobenzene, petroleum ether, ethyl acetate, dichloromethane, dichloroethane, chloroform, cyclohexane, and methylcyclohexane.

11. The synthesis method according to claim 10, characterized in that The solvent in step 1) is one or more of the following solvents: ethylene dichloride, toluene.

12. The synthesis method according to claim 10, characterized in that The amount of the solvent used is 1-10 times the mass of compound 1.

13. The synthesis method according to claim 12, characterized in that: The amount of the solvent used is 3-4 times the mass of compound 1.

14. The synthesis method according to claim 2, characterized in that: The refined pulping solvent in step 3) is one or more of the following solvents: toluene, xylene, benzene, chlorobenzene, petroleum ether, ethyl acetate, dichloromethane, dichloroethane, chloroform, cyclohexane, and methylcyclohexane.

15. The synthesis method according to claim 14, characterized in that The refined pulping solvent in step 3) is one or more of the following solvents: toluene, ethyl acetate, dichloromethane, and dichloroethane.

16. The synthesis method according to claim 1 or 2, characterized in that: The synthesis method is as follows: 1') adding compound 1 to a solvent, adding a certain amount of titanium silicalite molecular sieve, adding a certain amount of hydrogen peroxide dropwise at a certain temperature, keeping the temperature for a period of time after the addition is completed, and monitoring the raw material by liquid chromatography within 1%; filtering at a certain temperature, recovering the catalyst titanium silicalite molecular sieve for application, allowing the filtrate to stand for stratification to separate the aqueous phase, and desolventizing the organic phase to obtain the product prothioconazole; or 2') Compound 1 is added to a solvent, and a recovered titanium silicon molecular sieve is added. A certain amount of hydrogen peroxide is added dropwise under a certain temperature condition. After the addition is completed, the temperature is kept for a period of time, and the raw material is monitored by liquid chromatography within 1%; filtering is performed under a certain temperature condition, and the catalyst titanium silicon molecular sieve is recovered and applied. The filtrate is allowed to stand for stratification to separate the aqueous phase, and the organic phase is desolventized to obtain a crude product of prothioconazole. The crude product is added with a solvent and pulped to obtain a high-purity product of prothioconazole.

17. The synthesis method according to claim 16, characterized in that In step 2'), the amount of solvent used is 0.1-3 times the mass of compound 1.

18. The synthesis method according to claim 17, characterized in that In step 2'), the amount of solvent used is 0.5-1 times the mass of compound 1.

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