A kind of synthetic method of tebuconazole

Abstract

The present invention relates to a kind of synthetic method of tebuconazole, belong to the technical field of organic synthesis, and its method flow comprises as follows: Step1, adds 1,2,4-triazole and dichloromethane in autoclave, adds alkali, after heating, insulation reaction;Step2, after reaction terminates, cool to room temperature, filter, filtrate is concentrated to obtain chloromethyl triazole;Step3, in reaction flask, under nitrogen protection, add solvent, add magnesium chips or zinc powder, add a small amount of initiator iodine, drip the mixed solution of chloromethyl triazole and pentanone, after completion of dropwise addition, insulation reaction;Step4, reaction terminates, adds dilute acid neutralization, and obtains tebuconazole through standing phase separation and organic phase concentration. The present invention is with p-chlorobenzyl cyanide and cyclopropyl methyl ketone as main raw materials, first p-chlorobenzyl cyanide is halogenated at the benzyl position, then under the alkaline conditions of potassium hydroxide and cyclopropyl methyl ketone, Darzen reaction obtains epoxide, and " one pot method " cyanohydrolysis, deacidification obtain target product under the acidic conditions of sulfuric acid.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, in particular to a synthesis method of tebuconazole. Background Art

[0002] Tebuconazole, a highly effective, broad-spectrum, low-toxic triazole fungicide developed by Bayer in Germany, is widely used globally, offering protective, curative, and eradicative properties. It effectively controls diseases caused by species such as Erysiphe, Puccinia, Pyricularia, and Septoria, including powdery mildew, root rot, smut, and various rust diseases in cereal crops. Tebuconazole offers significant economic and social benefits, necessitating the development, production, and optimization of its synthesis process.

[0003] The synthesis methods reported in the literature so far all use pentacyclyl and 1,2,4-triazole as raw materials to synthesize tebuconazole. Huang Xinhui et al. reported on "Synthesis of a new fungicide tebuconazole" (Anhui Agricultural Science, 2007, 35 (1), 144-192) which disclosed a method for synthesizing tebuconazole. The method used cyclohexanol as solvent, heated to 150 ° C for 20 hours, and the tebuconazole yield was 53.8%. Gao Renjun also reported on "Synthesis of tebuconazole and its control effect on wheat stripe blight" (Master's thesis of China Agricultural University, 2002). In the research paper, it was reported that n-butanol was used as solvent, potassium hydroxide was used as catalyst, and the temperature was kept at 133 ° C for 4 hours, and the tebuconazole yield was 79%. Zhang Zhixing et al. also reported on "Synthesis of tebuconazole and its control effect on wheat stripe blight" (Master's thesis of China Agricultural University, 2002). "Study on the Synthesis of the Fungicide Tebuconazole" (Pesticide Science and Management, 2004, 25 (5), 23-25), under the conditions of certain solvents, catalysts and potassium carbonate, CO2 gas was slowly introduced and refluxed, and the yield of tebuconazole was about 83%; in these synthesis methods, the yield and content of tebuconazole were both low, and further optimization and improvement were needed; for example, in the synthesis method reported in Chinese patent CN109705048, in the solvent diethylene glycol monomethyl ether, pentacyclic oxide and 1,2,4-triazole were heated and kept warm in the inorganic base potassium hydroxide to react, and tebuconazole was obtained after post-treatment. Both of them use pentacyclic oxide as the raw material, and pentanone needs to be prepared and separated first to obtain pentacyclic oxide. The process route is long and the raw material cost is high.

[0004] Therefore, seeking an economical, environmentally friendly, green and efficient method for synthesizing tebuconazole remains a hot topic in research in this field. Summary of the Invention

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

[0006] The present invention solves the above-mentioned technical problem in the following way: a method for synthesizing tebuconazole, which comprises the following steps:

[0007] Step 1: Add 1,2,4-triazole and dichloromethane to a pressure autoclave, add a base, heat to 70-80°C, and keep warm for 5-6 hours to react. The base is sodium hydroxide or potassium hydroxide.

[0008] Step 2: After the reaction is completed, the temperature is cooled to room temperature, and the filtrate is filtered and concentrated to obtain chloromethyltriazole;

[0009] Step 3: In a reaction flask, under nitrogen protection, add a solvent, magnesium chips or zinc powder, and a small amount of initiator iodine. The solvent is a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran, or toluene. Then, dropwise add a mixed solution of chloromethyltriazole and pentanone. After the addition is complete, heat the mixture to react at 20-30° C. for 2-3 hours.

[0010] Step 4: After the reaction is completed, dilute acid is added to neutralize the mixture. After standing for phase separation and concentration of the organic phase, tebuconazole is obtained. The synthetic process is as follows:

[0011] .

[0012] On the basis of the above technical solution, the present invention can also be improved as follows.

[0013] Furthermore, the molar ratio of the pentanone to the chloromethyltriazole is 1.0:1.0-1.1.

[0014] The beneficial effects of the present invention are as follows: the present invention provides a method for synthesizing tebuconazole, which has the following advantages:

[0015] Compared with the traditional method for synthesizing tebuconazole, the present method for synthesizing tebuconazole does not require the prior preparation and separation of pentacyclic oxide, and avoids the use of methylating reagents such as dimethyl sulfate. 1,2,4-triazole and dichloromethane are first reacted to obtain chloromethyltriazole, and then pentanone and chloromethyltriazole are prepared in a one-pot Grignard reaction and added to obtain tebuconazole, which can effectively improve processing efficiency and the safety of the processing process.

[0016] 2. Compared with traditional synthesis methods, the process route is clean and green, which reduces environmental pressure. In addition, the reaction conditions are simple and the yield is high, making it suitable for industrial scale-up production.

[0017] The above description is only an overview of the technical solution of the present invention. In order to more clearly understand the technical means of the present invention and implement it according to the contents of the description, the following is a detailed description of the preferred embodiments of the present invention. The specific implementation methods of the present invention are given in detail in the following examples. DETAILED DESCRIPTION

[0018] The principles and features of the present invention are described below. The examples provided are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The following paragraphs describe the present invention in more detail by way of example. The advantages and features of the present invention will become more apparent from the following description and claims.

[0019] Example 1: Step 1, add 16.7g of 1,2,4-triazole and 100.0g of dichloromethane solvent to the autoclave, add 9.7g of sodium hydroxide, heat to 70-80°C and keep the temperature to react for 5-6 hours;

[0020] Step 2: After the reaction is complete, the mixture is cooled to room temperature, filtered, and the filtrate is concentrated to obtain chloromethyltriazole, which is directly used in the next reaction;

[0021] Step 3: In a three-necked flask, under nitrogen protection, add a mixed solvent of 50.0 g tetrahydrofuran and 50.0 g toluene, 6.1 g magnesium chips, and dissolve the above-obtained chloromethyltriazole and 50.0 g (0.22 mol) pentanone in 50.0 g tetrahydrofuran. Slowly add the mixture dropwise to the flask, controlling the temperature at 20-30°C. After the addition is complete, keep the mixture warm for 2-3 hours.

[0022] Step 4: After the reaction is completed, 5% dilute hydrochloric acid is added dropwise for neutralization, and the mixture is allowed to stand for phase separation. The organic phase is concentrated to obtain 63.8 g of tebuconazole product with a purity of 98.2% and a yield of 92.6%.

[0023] GC-MS: 307 (M+);

[0024] 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).

[0025] Example 2: Step 1, add 16.7g of 1,2,4-triazole and 100.0g of dichloromethane solvent to the autoclave, add 9.7g of sodium hydroxide, heat to 70-80°C and keep the temperature to react for 5-6 hours;

[0026] Step 3: After the reaction is complete, the mixture is cooled to room temperature, filtered, and the filtrate is concentrated to obtain chloromethyltriazole, which is directly used in the next reaction;

[0027] Step 3: In a three-necked flask, under nitrogen protection, add a mixed solvent of 50.0 g tetrahydrofuran and 50.0 g toluene, and 16.4 g zinc powder. Dissolve the above-obtained chloromethyltriazole and 50.0 g (0.22 mol) pentanone in 50.0 g tetrahydrofuran, and slowly add the mixture dropwise to the flask. Control the temperature at 20-30°C. After the addition is complete, keep the mixture warm for 2-3 hours.

[0028] Step 4: After the reaction is completed, 5% dilute hydrochloric acid is added dropwise for neutralization, and the mixture is allowed to stand for phase separation. The organic phase is concentrated to obtain 62.6 g of tebuconazole product with a purity of 98.6% and a yield of 91.2%.

[0029] GC-MS: 307 (M+);

[0030] 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).

[0031] Example 3: Step 1, add 16.7g of 1,2,4-triazole and 100.0g of dichloromethane solvent to the autoclave, add 9.7g of sodium hydroxide, heat to 70-80°C and keep the temperature to react for 5-6 hours;

[0032] Step 2: After the reaction is complete, the mixture is cooled to room temperature, filtered, and the filtrate is concentrated to obtain chloromethyltriazole, which is directly used in the next reaction;

[0033] Step 3: In a three-necked flask, under nitrogen protection, add a mixed solvent of 50.0g 2-methyltetrahydrofuran, 50.0g toluene, and 6.1g magnesium chips. Dissolve the above-obtained chloromethyltriazole and 50.0g (0.22mol) pentanone in 50.0g 2-methyltetrahydrofuran and slowly add dropwise to the flask. Control the temperature at 20-30°C. After addition, keep warm for 2-3 hours.

[0034] Step 4: After the reaction is completed, 5% dilute hydrochloric acid is added dropwise for neutralization, and the mixture is allowed to stand for phase separation. The organic phase is concentrated to obtain 63.9 g of tebuconazole product with a purity of 98.3% and a yield of 92.8%.

[0035] GC-MS: 307 (M+);

[0036] 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).

[0037] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any ordinary technician in this industry can smoothly implement the present invention as described above. However, any equivalent changes, modifications and evolutions made by technicians familiar with this profession without departing from the scope of the technical solution of the present invention using the technical content disclosed above are all 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 are still within the scope of protection of the technical solution of the present invention.

Claims

1. A method for synthesizing tebuconazole, characterized in that: Its synthesis method comprises the following steps: Step 1: Add 1,2,4-triazole and dichloromethane to a pressure autoclave, add a base, heat to 70-80°C, and keep warm for 5-6 hours to react. The base is sodium hydroxide or potassium hydroxide. Step 2: After the reaction is completed, the temperature is cooled to room temperature, and the filtrate is filtered and concentrated to obtain chloromethyltriazole; Step 3: In a reaction flask, under nitrogen protection, add a solvent, magnesium chips or zinc powder, and a small amount of initiator iodine. The solvent is a mixture of one or more of tetrahydrofuran, 2-methyltetrahydrofuran, or toluene. Then, dropwise add a mixed solution of chloromethyltriazole and pentanone. After the addition is complete, heat the mixture to react at 20-30° C. for 2-3 hours. Step 4: After the reaction is completed, dilute acid is added to neutralize the mixture. After standing for phase separation and concentration of the organic phase, tebuconazole is obtained. The synthetic process is as follows: 。 2. The method for synthesizing tebuconazole according to claim 1, wherein: The molar ratio of the pentanone to the chloromethyltriazole is 1.0:1.0-1.1.

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