Synthesis method of tebuconazole

Abstract

The invention relates to a tebuconazole synthesis method, and belongs to the technical field of organic synthesis, the method flow comprises the following steps: Step 1: adding 1, 2, 4-triazole, DMF or NMP as a solvent, sodium hydroxide alkali liquor or potassium hydroxide alkali liquor, sodium iodide or potassium iodide as a catalyst and pentanone into a reaction flask, and heating to 80-90 DEG C; 2, methylation reagents are added in batches, the methylation reagents are preferably dimethyl sulfide sulfuric acid dimethyl ester onium salt, after addition is completed, heat preservation stirring is conducted, and the heat preservation time is 1-2 hours. P-chlorobenzyl cyanide and cyclopropyl methyl ketone are used as main raw materials, p-chlorobenzyl cyanide is subjected to halogenation at a benzyl position and then subjected to a Darzen reaction with cyclopropyl methyl ketone under the alkaline condition of potassium hydroxide to obtain an epoxide, a target product is obtained through one-pot cyano hydrolysis and deacidification under the acidic condition of sulfuric acid, the synthesis route is short, the process is simple, the raw material cost is low, and the method is suitable for industrial production. The process is simple and smooth, green and environment-friendly, and suitable for industrial large-scale production.

Description

Technical Field

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

[0002] Tebuconazole is a highly effective, broad-spectrum and low-toxic triazole fungicide developed by Bayer AG in Germany. It is widely used globally and has functions such as protection, treatment, and eradication. Tebuconazole can effectively control diseases caused by genera such as Blumeria, Puccinia, Pyrenophora, and Septoria, such as powdery mildew, root rot, smut, and various rusts of cereal crops. Tebuconazole has great economic and social benefits, and it is very necessary to develop, produce, and optimize its synthesis process.

[0003] Currently, the reported synthesis methods in the literature all use pentylene oxide and 1,2,4-triazole as raw materials to synthesize tebuconazole. The "Synthesis Process of the New Fungicide Tebuconazole" reported by Huang Xinhui et al. (Journal of Anhui Agricultural Sciences, 2007, 35(1), 144 - 192) discloses a method for synthesizing tebuconazole. It uses cyclohexanol as a solvent, heats to 150 °C and holds for 20 hours, and the yield of tebuconazole is 53.8%; another example is the "Synthesis of Tebuconazole and Its Control Effect on Wheat Sharp Eyespot" reported by Gao Renjun (Master's Thesis of China Agricultural University, 2002). In the research paper, it is reported that n-butanol is used as a solvent, potassium hydroxide is used as a catalyst, and it is held at 133 °C for 4 hours, and the yield of tebuconazole is 79%; another example is the "Synthesis Research of the Fungicide Tebuconazole" reported by Zhang Zhixing et al. (Pesticide Science and Administration, 2004, 25(5), 23 - 25). Under certain conditions of solvent, catalyst, and potassium carbonate, CO2 gas is slowly introduced and refluxed, and the yield of tebuconazole is about 83%; in these synthesis methods, the yield and content of tebuconazole are both relatively low and need to be further optimized and improved; another example is the synthesis method reported in Chinese Patent CN109705048. In the solvent diethylene glycol monomethyl ether, pentylene oxide and 1,2,4-triazole are heated and held for reaction in inorganic base potassium hydroxide, and tebuconazole is obtained after post-treatment. All of them use pentylene oxide as a raw material, and pentanone needs to be prepared and separated to obtain pentylene oxide first, with a long process route and high raw material cost.

[0004] Therefore, seeking a method for synthesizing tebuconazole that is economical, environmentally friendly, and has a green and efficient process is still a research hotspot in this field. Summary of the Invention

[0005] The present invention provides a method for synthesizing tebuconazole, which solves the problems raised in the above background art. The synthesis method is simpler and more efficient and is suitable for industrial production.

[0006] The solution of the present invention to the above technical problems is as follows: A method for synthesizing tebuconazole, the synthesis method includes the following: Step 1: Add 1,2,4-triazole into a reaction flask, add DMF or NMP as a solvent, add sodium hydroxide solution or potassium hydroxide solution, add sodium iodide or potassium iodide as a catalyst, add pentanone, and heat to 80 - 90 °C; Step 2: Add the methylation reagent in batches. The methylation reagent is preferably dimethyl sulfide dimethyl sulfate onium salt. After adding, keep warm and stir for 1 - 2 hours; Step 3: After the reaction is completed, cool down to room temperature, then add water to crystallize and obtain the crude tebuconazole; Step 4: Pulp the crude tebuconazole with 50% methanol aqueous solution, then filter, and finally dry the filter cake to obtain the finished product of tebuconazole. The synthetic process route is as follows 。

[0007] Based on the above technical solutions, the present invention can also be improved as follows.

[0008] Further, the dosage of the catalyst is 1% - 5% of the dosage of pentanone.

[0009] The beneficial effects of the present invention are: The present invention provides a method for synthesizing tebuconazole, which has the following advantages: Compared with the traditional method for synthesizing tebuconazole, the method for synthesizing tebuconazole of the present invention does not need to prepare and separate pentene oxide first, but directly synthesizes tebuconazole by a "one-pot method" with triazole under the conditions of a methylation reagent and a base. Compared with the traditional synthesis method, the process route is simpler, and at the same time, the environmental protection pressure is reduced.

[0010] 2. The synthesis method of the present invention has a simple and smooth process, simple reaction conditions, high yield, green and environmentally friendly process, and is suitable for industrial scale-up production.

[0011] The above description is only an overview of the technical solutions of the present invention. In order to understand the technical means of the present invention more clearly and implement it according to the content of the specification, the following takes the preferred embodiments of the present invention as detailed examples. The specific implementation manners of the present invention are given in detail by the following examples. Specific Embodiments

[0012] The principles and features of the present invention are described below. The examples given are only for explaining the present invention and are not used to limit the scope of the present invention. The present invention is described more specifically by way of example in the following paragraphs. The advantages and features of the present invention will be clearer according to the following description and claims.

[0013] It should be noted that when a component is referred to as "fixed to" another component, it can be directly on the other component or there can also be an intermediate component. When a component is considered to be "connected to" another component, it can be directly connected to the other component or there may be an intermediate component at the same time. When a component is considered to be "disposed on" another component, it can be directly disposed on the other component or there may be an intermediate component at the same time. The terms "vertical", "horizontal", "left", "right" and similar expressions used herein are for illustrative purposes only.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the technical field to which this invention belongs. The terms used herein in the description of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" used herein includes any and all combinations of one or more of the related listed items. Examples

[0015] Step1: Add 7.6 g of 1,2,4-triazole and 45.0 g of the solvent DMF to a three-necked flask, add 4.8 g of sodium hydroxide and 1.1 g of the catalyst sodium iodide, and 22.5 g of pentanone (0.1 mol), heat and control the temperature at 80 - 90 °C; Step2: Add 20.7 g of dimethyl sulfide dimethyl sulfate ammonium salt in batches, and after adding, keep warm and stir for 1 - 2 hours; Step3: After the reaction is completed, cool down to room temperature, then add water, and crystallize to obtain the crude product of tebuconazole; Step4: The crude product of tebuconazole is slurried with 50.0 g of 50% methanol water, filtered, and the filter cake is dried to obtain 29.3 g of the finished product of tebuconazole with a purity of 98.0%. The yield is 93.4%.

[0016] GCMS: 307 (M+); 1H NMR(CDCl3) 8.22(s, 1H), 8.03(s, 1H), 7.21(d, J =8.0Hz, 2H), 6.95(d, J = 8.0Hz, 2H), 4.37(s, 2H), 3.07(s, 1H), 2.42 - 2.48(m,1H), 1.67 - 1.86(m, 3H), 1.03(s, 9H). Examples

[0017] Step1: Add 7.6 g of 1,2,4-triazole and 45.0 g of the solvent NMP to a three-necked flask, add 4.8 g of sodium hydroxide and 1.1 g of the catalyst sodium iodide, and 22.5 g of pentanone (0.1 mol), heat and control the temperature at 80 - 90 °C; Step 2: Add 20.7 g of dimethyl sulfide dimethylsulfate ammonium salt in batches. After addition, keep the temperature and stir for 1 - 2 hours. Step 3: After the reaction is completed, cool down to room temperature, then add water to crystallize and obtain the crude tebuconazole. Step 4: The crude tebuconazole is slurried with 50.0 g of 50% methanol - water, filtered, and the filter cake is dried to obtain 29.6 g of the tebuconazole product with a purity of 98.0% and a yield of 94.3%.

[0018] GCMS: 307 (M+); 1H NMR(CDCl3) 8.22(s, 1H), 8.03(s, 1H), 7.21(d, J =8.0Hz, 2H), 6.95(d, J = 8.0Hz, 2H), 4.37(s, 2H), 3.07(s, 1H), 2.42 - 2.48(m,1H), 1.67 - 1.86(m, 3H), 1.03(s, 9H). Example

[0019] Step 1: Add 7.6 g of 1,2,4 - triazole and 45.0 g of the solvent DMF to a three - necked flask. Add 7.1 g of potassium hydroxide and 1.1 g of the catalyst sodium iodide, and 22.5 g of pentanone (0.1 mol). Heat and control the temperature at 80 - 90 °C. Step 2: Add 20.7 g of dimethyl sulfide dimethylsulfate ammonium salt in batches. After addition, keep the temperature and stir for 1 - 2 hours. Step 3: After the reaction is completed, cool down to room temperature, then add water to crystallize and obtain the crude tebuconazole. Step 4: The crude tebuconazole is slurried with 50.0 g of 50% methanol - water, filtered, and the filter cake is dried to obtain 29.1 g of the tebuconazole product with a purity of 98.0% and a yield of 92.7%.

[0020] GCMS: 307 (M+); 1H NMR(CDCl3) 8.22(s, 1H), 8.03(s, 1H), 7.21(d, J =8.0Hz, 2H), 6.95(d, J = 8.0Hz, 2H), 4.37(s, 2H), 3.07(s, 1H), 2.42 - 2.48(m,1H), 1.67 - 1.86(m, 3H), 1.03(s, 9H). Example

[0021] Step1: Add 7.6 g of 1,2,4-triazole and 45.0 g of the solvent NMP into a three-necked flask. Then add 7.1 g of potassium hydroxide and 1.1 g of the catalyst sodium iodide, and 22.5 g of pentanone (0.1 mol). Heat and control the temperature at 80 - 90 °C; Step2: Add 20.7 g of dimethyl sulfide dimethyl sulfate ammonium salt in batches. After addition, keep stirring at a constant temperature for 1 - 2 hours; Step3: After the reaction is completed, cool down to room temperature, then add water to crystallize and obtain the crude product of tebuconazole; Step4: The crude tebuconazole is slurried with 50.0 g of 50% methanol - water, filtered, and the filter cake is dried to obtain 29.4 g of the tebuconazole finished product with a purity of 98.0%. The yield is 93.7%, GCMS: 307 (M+); 1H NMR(CDCl3) 8.22(s, 1H), 8.03(s, 1H), 7.21(d, J =8.0Hz, 2H), 6.95(d, J = 8.0Hz, 2H), 4.37(s, 2H), 3.07(s, 1H), 2.42 - 2.48(m,1H), 1.67 - 1.86(m, 3H), 1.03(s, 9H). Example

[0022] Step1: Add 7.6 g of 1,2,4-triazole and 45.0 g of the solvent NMP into a three-necked flask. Then add 4.8 g of sodium hydroxide and 1.1 g of the catalyst potassium iodide, and 22.5 g of pentanone (0.1 mol). Heat and control the temperature at 80 - 90 °C; Step2: Add 20.7 g of dimethyl sulfide dimethyl sulfate ammonium salt in batches. After addition, keep stirring at a constant temperature for 1 - 2 hours; Step3: After the reaction is completed, cool down to room temperature, then add water to crystallize and obtain the crude product of tebuconazole; Step4: The crude tebuconazole is slurried with 50.0 g of 50% methanol - water, filtered, and the filter cake is dried to obtain 29.5 g of the tebuconazole finished product with a purity of 98.0%. The yield is 94.0%.

[0023] GCMS: 307 (M+); 1H NMR(CDCl3) 8.22(s, 1H), 8.03(s, 1H), 7.21(d, J =8.0Hz, 2H), 6.95(d, J = 8.0Hz, 2H), 4.37(s, 2H), 3.07(s, 1H), 2.42 - 2.48(m,1H), 1.67 - 1.86(m, 3H), 1.03(s, 9H). The above are only the preferred embodiments of the present invention, and do not impose any form of limitation on the present invention; any ordinary technician in the industry can smoothly implement the present invention according to the above; however, any equivalent changes made by those skilled in the art without departing from the technical solution of the present invention, by making some changes, modifications and evolutions using the technical content disclosed above, are equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A method for synthesizing tebuconazole, comprising the steps of: Step 1: Add 1,2,4-triazole into a reaction bottle, add DMF or NMP as a solvent, add sodium hydroxide lye or potassium hydroxide lye, add sodium iodide or potassium iodide as a catalyst, add pentanone, and heat to 80-90°C; Step 2: Add the methylating agent in batches, preferably dimethyl sulfide dimethyl sulfate onium salt, and after the addition, stir and keep warm for 1-2 hours; Step 3: After the reaction is completed, the temperature is cooled to room temperature, and then water is added to crystallize to obtain a crude product of tebuconazole; Step 4: The crude tebuconazole product is slurried with 50% methanol aqueous solution, and then filtered. Finally, the filter cake is dried to obtain the finished tebuconazole product. The synthetic process route is as follows: 。 2. The method for synthesizing tebuconazole according to claim 1, characterized in that: The amount of the catalyst used is 1%-5% of the amount of pentanone used.

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