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 and dichloromethane into a pressure kettle, adding alkali, heating, and carrying out heat preservation reaction; step 2, after the reaction is finished, cooling to room temperature, filtering, and concentrating filtrate to obtain chloromethyl triazole; step 3, adding a solvent, magnesium chips or zinc powder and a small amount of initiator iodine into the reaction bottle under the protection of nitrogen, dropwise adding a mixed solution of chloromethyl triazole and pentanone, and carrying out heat preservation reaction after dropwise adding; and Step 4, after the reaction is finished, adding dilute acid for neutralization, standing for phase separation, and concentrating an organic phase to obtain tebuconazole. The preparation method comprises the following steps: by taking p-chlorobenzyl cyanide and cyclopropyl methyl ketone as main raw materials, firstly adding halogen on a benzyl position of p-chlorobenzyl cyanide, then carrying out Darzen reaction on p-chlorobenzyl cyanide and cyclopropyl methyl ketone under the alkaline condition of potassium hydroxide to obtain an epoxide, and carrying out'one-pot 'cyano hydrolysis and deacidification under the acidic condition of sulfuric acid to obtain a target product.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly 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 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 it 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 use pentylene oxide as a raw material, and pentanone needs to be first prepared and separated to obtain pentylene oxide, 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 comprising the following steps: Step1, add 1,2,4-triazole and dichloromethane into an autoclave, add an alkali, heat to 70 - 80 °C, and then keep the temperature for reaction for 5 - 6 hours. The alkali is sodium hydroxide or potassium hydroxide; Step2, after the reaction is completed, cool down to room temperature, filter, and concentrate the filtrate to obtain chloromethyltriazole; Step3, in a reaction flask, under nitrogen protection, add a solvent, add magnesium chips or zinc powder, add a small amount of initiator iodine. The solvent is one or a mixture of solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, or toluene. Dropwise add a mixed solution of chloromethyltriazole and pentanone. After the addition is completed, keep the temperature for reaction. The reaction temperature is 20 - 30 °C, and the holding time is 2 - 3 hours; Step4, after the reaction is completed, neutralize with dilute acid, stand for phase separation, and concentrate the organic phase to obtain tebuconazole. The synthetic process route is as follows, 。

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

[0008] Further, the molar ratio of pentanone to chloromethyltriazole is 1.0:1.0 - 1.1.

[0009] The beneficial effects of the present invention are as follows: 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 pentylene oxide first, avoids using methylation reagents such as dimethyl sulfate. First, react 1,2,4-triazole with dichloromethane to obtain chloromethyltriazole, and then use a one-pot method to prepare Grignard reagent and carry out addition reaction with pentanone and chloromethyltriazole to obtain tebuconazole, which can effectively improve the processing efficiency and the safety of the processing process.

[0010] 2. Compared with the traditional synthesis method, the process route is clean and green, reducing the environmental protection pressure. Moreover, the reaction conditions are simple, the yield is high, and it 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 embodiments of the present invention are given in detail by the following examples. Detailed 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 will be described more specifically by way of example in the following paragraphs. According to the following description and claims, the advantages and features of the present invention will be clearer.

[0013] Example 1: Step 1, Add 16.7 g of 1,2,4-triazole and 100.0 g of dichloromethane as the solvent into the autoclave, add 9.7 g of sodium hydroxide, heat up to 70 - 80 °C and keep the reaction for 5 - 6 hours; Step 2, After the reaction is completed, cool down to room temperature, filter, and concentrate the filtrate to obtain chloromethyltriazole, which is directly used for the next step of the reaction; Step 3, Under nitrogen protection, add 50.0 g of tetrahydrofuran and 50.0 g of toluene as the mixed solvent, 6.1 g of magnesium chips into the three-necked flask, and dissolve the above-obtained chloromethyltriazole and 50.0 g (0.22 mol) of pentanone in 50.0 g of tetrahydrofuran, then slowly add it dropwise to the flask, control the temperature at 20 - 30 °C, after addition, keep the temperature for 2 - 3 hours; Step 4, After the reaction is completed, add 5% dilute hydrochloric acid to neutralize, let it stand for phase separation, and concentrate the organic phase to obtain 63.8 g of tebuconazole finished product, with a purity of 98.2% and a yield of 92.6%.

[0014] GC-MS: 307 (M+); 1H NMR(CDCl3) 8.22(s, 1H), 8.OC(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).

[0015] Example 2: Step 1, Add 16.7 g of 1,2,4-triazole and 100.0 g of dichloromethane as the solvent into the autoclave, add 9.7 g of sodium hydroxide, heat up to 70 - 80 °C and keep the reaction for 5 - 6 hours; Step 3, After the reaction is completed, cool down to room temperature, filter, and concentrate the filtrate to obtain chloromethyltriazole, which is directly used for the next step of the reaction; Step 3, Under nitrogen protection, add 50.0 g of tetrahydrofuran and 50.0 g of toluene as the mixed solvent, 16.4 g of zinc powder into the three-necked flask, and dissolve the above-obtained chloromethyltriazole and 50.0 g (0.22 mol) of pentanone in 50.0 g of tetrahydrofuran, then slowly add it dropwise to the flask, control the temperature at 20 - 30 °C, after addition, keep the temperature for 2 - 3 hours; Step 4, After the reaction is completed, add 5% dilute hydrochloric acid to neutralize, let it stand for phase separation, and concentrate the organic phase to obtain 62.6 g of tebuconazole finished product, with a purity of 98.6% and a yield of 91.2%.

[0016] GC-MS: 307 (M+); 1H NMR (CDCl3) δ 8.22 (s, 1H), 8.03 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 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).

[0017] Example 3: Step 1, Add 16.7 g of 1,2,4 - triazole and 100.0 g of dichloromethane as the solvent into the autoclave, add 9.7 g of sodium hydroxide, and heat up to 70 - 80 °C for heat - preservation reaction for 5 - 6 hours; Step 2, After the reaction is completed, cool down to room temperature, filter, and concentrate the filtrate to obtain chloromethyltriazole, which is directly used for the next - step reaction; Step 3, Under nitrogen protection, add 50.0 g of 2 - methyltetrahydrofuran and 50.0 g of toluene as the mixed solvent, 6.1 g of magnesium chips into the three - necked flask, and dissolve the above - obtained chloromethyltriazole and 50.0 g (0.22 mol) of pentanone in 50.0 g of 2 - methyltetrahydrofuran, and slowly drop it into the flask, control the temperature at 20 - 30 °C. After adding, keep the temperature for 2 - 3 hours; Step 4, After the reaction is completed, add 5% dilute hydrochloric acid to neutralize, let it stand for phase separation. After concentrating the organic phase, 63.9 g of tebuconazole finished product is obtained, with a purity of 98.3% and a yield of 92.8%.

[0018] GC - MS: 307 (M+); 1H NMR (CDCl3) δ 8.22 (s, 1H), 8.03 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 6.95 (d, J = 8.0 Hz, 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).

[0019] The above - mentioned 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 this industry can smoothly implement the present invention according to the above - mentioned; however, any minor changes, modifications, and equivalent variations made by those skilled in the art within the scope of the technical solution of the present invention by using the above - disclosed technical content are equivalent embodiments of the present invention; at the same time, any equivalent changes, modifications, and variations made to the above embodiments based on the essence of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A synthesis method of tebuconazole, characterized in that, The synthesis method comprises the following steps: Step1: Add 1,2,4-triazole and dichloromethane into an autoclave, add an alkali, heat to 70 - 80 °C, and then keep the temperature for reaction for 5 - 6 hours. The alkali is sodium hydroxide or potassium hydroxide; Step2: After the reaction is completed, cool to room temperature, filter, and concentrate the filtrate to obtain chloromethyltriazole; Step3: In a reaction flask, under nitrogen protection, add a solvent, add magnesium chips or zinc powder, add a small amount of initiator iodine. The solvent is one or a mixture of tetrahydrofuran, 2-methyltetrahydrofuran, or toluene. Dropwise add a mixed solution of chloromethyltriazole and pentanone. After the addition is completed, keep the temperature for reaction. The reaction temperature is 20 - 30 °C, and the holding time is 2 - 3 hours; Step4: After the reaction is completed, neutralize with dilute acid, stand for phase separation, and concentrate the organic phase to obtain tebuconazole. The synthesis process route is as follows. 。 2. The synthesis method of tebuconazole according to claim 1, characterized in that, The molar ratio of the pentanone to the chloromethyltriazole is 1.0:1.0 - 1.1.

Images