Synthesis method of meconazole
By combining acetylation and epoxidation reactions, the synthesis process of chlorofluranocrinazole is simplified, and the problems of complex steps of existing methods and difficult to obtain raw materials are solved, and low-cost and efficient production of chlorofluranocrinazole is achieved, which is suitable for industrialization application.
Patent Information
- Application Number
- CN202411220694.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-02
- Publication Date
- 2024-12-20
AI Technical Summary
The existing synthesis method of chloroflurancazole has complex steps, the reaction raw materials are not easy to obtain, and the reaction conditions are harsh, resulting in high costs and environmental pollution.
The aryl format reagent was prepared with 2-bromo-5-fluorotoluene and reacted with bromoacetone. After ring-opening substitution and etherification reaction, chlorofluoroprostazole was obtained, and two-step reactions of acetylation and epoxidation were combined. Simplified process flow.
It reduces the cost of chloroflurancazole synthesis, improves economic and environmental friendliness, simplifies reaction steps, improves atomic utilization, and is suitable for large-scale industrial production.
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Figure CN119161308A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of intermediate preparation, in particular to the field of IPCC07C45, and more specifically to a method for synthesizing clofothiazolinone. Background Art
[0002] As the first isopropyl alcohol triazole fungicide, clofoclofen (CAS No.: 1417782-03-6) makes up for the shortcomings of traditional triazole fungicides, such as increasing drug resistance and high ecological and environmental risks. It has broad spectrum, high efficiency, systemic, eradication and protection effects, especially outstanding biological activity against a variety of fungal diseases that are difficult to control, and can significantly enhance the prevention and control of more than 60 kinds of crop diseases. It not only has higher biological activity, but also has good environmental characteristics, low toxicity to mammals, bees, etc., and high safety. It has become an effective alternative to traditional triazole fungicides and has broad application prospects.
[0003] Zhang Xiaoguang, Wang Lun, Mao Mingzhen. Review of the synthesis of clofoconazole [J]. Pesticides, 2019, 58(7): 475-477. A synthetic route is disclosed: 2-bromo-5-fluoro-trifluorotoluene is used as the starting material to obtain the target product through etherification, acylation, epoxidation and ring-opening substitution in four steps, with a total yield of up to 92%; Zhang Zhigang, Zhang Kuizuo, Zheng Xiaodi, et al. Review of the synthesis of clofoconazole [J]. Modern Pesticides, 2019, 18(4): 24-26. Another synthetic route is disclosed: 4-fluoro-2-trifluoromethylacetophenone and 4-chlorophenol are used as starting materials to obtain the original drug of clofoconazole through substitution, epoxidation and ring-opening in three steps under alkaline conditions, with a total yield of up to 75%. The above-mentioned synthetic methods have complicated synthetic steps or the raw materials are not easy to obtain and the reaction conditions are harsh. Summary of the invention
[0004] The present invention provides a method for synthesizing clofoconazole, wherein 2-bromo-5-fluoro-trifluorotoluene is used as a starting material to first prepare an aromatic Grignard reagent, which is then reacted with bromoacetone, and then subjected to ring-opening substitution and etherification reactions in sequence to obtain clofoconazole. The synthesis route is shown in Formula 1:
[0005]
[0006] The synthesis method of chlorfenapyr comprises the following steps:
[0007] Step 1: 2-bromo-5-fluoro-trifluorotoluene is prepared into an aromatic Grignard reagent, which is reacted with bromoacetone, and then post-treated to obtain an intermediate product, 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane;
[0008] Step 2: 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane and 1,2,4-triazole undergo a ring-opening substitution reaction, followed by post-treatment to obtain an intermediate product, 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol;
[0009] Step 3: 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and p-chlorophenol are subjected to etherification reaction and then post-treated to obtain the product.
[0010] The preparation method of the aryl Grignard reagent in step 1 comprises: adding magnesium to tetrahydrofuran, replacing nitrogen protection, and obtaining a mixture; diluting 2-bromo-5-fluoro-trifluorotoluene with tetrahydrofuran, and then dropwise adding the mixture to react to obtain the obtained product.
[0011] The temperature was controlled at 20-30° C. during the dropwise addition, and the mixture was stirred for 1-3 hours after the dropwise addition.
[0012] The molar ratio of magnesium, 2-bromo-5-fluoro-trifluorotoluene and bromoacetone is 1:(0.5-0.7):(0.6-0.9).
[0013] Preferably, the molar ratio of magnesium, 2-bromo-5-fluoro-trifluorotoluene and bromoacetone is 1:(0.6-0.7):(0.7-0.9).
[0014] The reaction with bromoacetone in step 1 specifically comprises: cooling the aromatic Grignard reagent to 0-5° C. for standby use, dissolving bromoacetone in a solvent, and then dropwise adding the dissolved bromoacetone into the cooled aromatic Grignard reagent to perform a nucleophilic addition reaction to obtain a crude product.
[0015] Preferably, the reaction with bromoacetone in step 1 specifically comprises: cooling the aromatic Grignard reagent to 0-5° C. for standby use, dissolving bromoacetone in toluene, and then dropwise adding the cooled aromatic Grignard reagent to perform a nucleophilic addition reaction to obtain a crude product.
[0016] The present application has found that 2-bromo-5-fluorobenzotrifluoride is prepared into an aromatic Grignard reagent, which then undergoes a nucleophilic addition reaction with bromoacetone and further undergoes a ring closure to directly obtain 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, thereby combining the two-step acetylation and epoxidation reactions in the existing synthesis method into a one-step reaction, thereby reducing the cost of synthesizing clofothiazolinone.
[0017] The temperature of the nucleophilic addition reaction is 5-10° C. and the time is 1-3 h.
[0018] The post-treatment in step 1 specifically includes: adding the crude product to an aqueous solution of ammonium chloride, allowing the phases to stand to separate, obtaining an organic phase, and performing reduced pressure distillation to obtain an intermediate product, 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane.
[0019] The ammonium chloride aqueous solution is a 5-30wt% ammonium chloride aqueous solution.
[0020] The molar ratio of the 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane to 1,2,4-triazole is 1:(1.1-1.5).
[0021] Preferably, the molar ratio of 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane to 1,2,4-triazole is 1:(1.1-1.3).
[0022] The molar ratio of the 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol to p-chlorophenol is 1:(1.1-1.5).
[0023] Preferably, the molar ratio of 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol to p-chlorophenol is 1:(1.1-1.3).
[0024] The post-treatment in step 2 specifically includes: distilling off methanol under reduced pressure, adding solvent A and solvent B in sequence for heating and liquid separation, cooling the organic phase to room temperature for crystallization, filtering, and drying to obtain the product.
[0025] Preferably, the solvent A is water, the solvent B is an organic solvent, and the volume ratio of water to the organic solvent is 1:(1.5-3.5).
[0026] The reaction temperature in step 2 is reflux temperature, and the reaction time is 8-12 hours.
[0027] The post-treatment in step 3 specifically includes: cooling the reaction liquid to 30-50° C., adding water and stirring, standing for phase separation, discarding the aqueous phase, adding an inorganic alkali aqueous solution and stirring, standing for phase separation, cooling the organic phase to room temperature for crystallization, suction filtering, and drying to obtain the product.
[0028] In step 3, the reaction temperature is 80-120° C. and the reaction time is 3-6 hours.
[0029] Beneficial Effects
[0030] 1. In the present application, 2-bromo-5-fluorobenzotrifluoride is prepared into an aromatic Grignard reagent, which is then subjected to a nucleophilic addition reaction with bromoacetone and further undergoes a ring closure to directly obtain 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, thereby combining the two-step acetylation and epoxidation reactions in the existing synthesis method into a one-step reaction, thereby reducing the cost of synthesizing clofothiazolin.
[0031] 2. The starting materials of the present application are cheap, easily available, low in toxicity and low in pollution, which ensures the economy and environmental friendliness of the synthetic route.
[0032] 3. The reaction conditions of this application are mild and can be applied to industrial large-scale production.
[0033] 4. The post-processing of the present application is simple, and the comprehensive yield of chlorfenapyr is more than 65%.
[0034] 5. This application reduces the reaction time and improves the atomic utilization rate. BRIEF DESCRIPTION OF THE DRAWINGS
[0035] Figure 1 This is the H NMR spectrum of chlorpyrifos prepared in step 3 of Example 1. DETAILED DESCRIPTION
[0036] Example 1
[0037] A synthetic method of chlorfenapyr comprises the following steps:
[0038] Step 1: As shown in Formula 2, 2-bromo-5-fluoro-trifluorotoluene is prepared into an aromatic Grignard reagent, which is reacted with bromoacetone, and then post-treated to obtain an intermediate product, 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane;
[0039] Step 2: As shown in Formula 3, 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane and 1,2,4-triazole undergo a ring-opening substitution reaction, followed by post-treatment to obtain an intermediate product, 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol;
[0040] Step 3: As shown in Formula 4, 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and p-chlorophenol are subjected to etherification reaction and then post-treated to obtain the product.
[0041]
[0042] Step 1 is specifically as follows: at room temperature (25°C), add 15.0g magnesium chips to 200mL tetrahydrofuran, replace nitrogen protection, dilute 100.0g 2-bromo-5-fluorobenzotrifluoride with 200mL tetrahydrofuran, slowly dropwise add to the reaction, control the temperature to 25°C, stir for 2h, and control no 2-bromo-5-fluorobenzotrifluoride residue in the gas phase. The reaction temperature is cooled to 3°C, 67.6g bromoacetone is dissolved in 100mL toluene, slowly dropwise add to the reaction, control the temperature to 8°C, stir for 2h, and control the reaction in the gas phase to be complete. After the reaction is complete, slowly add 100mL 10wt% ammonium chloride aqueous solution, stand for phase separation, and evaporate the organic phase under reduced pressure to remove the solvent to obtain 78.8g of yellow oil.
[0043] Step 2 is specifically as follows: at room temperature (25°C), 8.3g of 1,2,4-triazole and 10.4g of potassium carbonate are added to 100mL of methanol in sequence, stirred at room temperature for 0.5h, 22g of 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane is added, and the temperature is raised to reflux for reaction. After 8h, HPLC detected that there was no 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)-2-methyl-oxirane, the reaction was completed, methanol was evaporated under reduced pressure, 50mL of water and 100mL of toluene were added in sequence, heated to 50°C for separation, the organic phase was cooled to room temperature for crystallization, a white solid was obtained by suction filtration, and 23.9g of a white solid was obtained by drying.
[0044] Step 3 is specifically as follows: at room temperature (25°C), 20g of 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol, 9.8g of p-chlorophenol, and 4.2g of sodium hydroxide are added to 100mL of xylene in sequence, and the temperature is raised to 100°C for stirring and reaction. After 4h, HPLC detected that there was no 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol, and the reaction was completed. The reaction solution was cooled to 50°C, 100mL of water was added and stirred, and the phases were allowed to stand for separation. The aqueous phase was discarded, 20mL of 10wt% sodium hydroxide aqueous solution was added and stirred, and the phases were allowed to stand for separation. The organic phase was cooled to room temperature for crystallization, and a white solid was obtained by suction filtration, and 24.9g of a white solid was obtained by drying.
[0045] Performance testing methods and data
[0046] 1. Calculate the yield of the product of steps 1-3 and record it in Table 1.
[0047] 2. The chlorfenapyr prepared in step 3 was characterized by nuclear magnetic resonance spectroscopy. Figure 1 As shown, 1H NMR (400 MHz, Chloroform-d) δ8.02 (s, 1H), 7.89 (s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.37 (d, J = 2.7 Hz, 1H), 7.36-7.31 (m, 2H), 7.02 (dd, J = 8.9, 2.7 Hz, 1H), 6.97-6.92 (m, 2H), 4.65 (d, J = 14.2 Hz, 1H), 4.45 (d, J = 14.2 Hz, 1H), 1.63 (s, 3H), which proved the successful synthesis of chlorfenapyr.
[0048] Table 1
[0049] Yield % Step 1 87.0 Step 2 82.6 Step 3 90.5
Claims
1. A method for synthesizing chlorpyrifos, It is characterized in that Using 2-bromo-5-fluoro-trifluorotoluene as the starting material, an aromatic Grignard reagent is first prepared and then reacted with bromoacetone, and then a ring-opening substitution and an etherification reaction are performed in sequence to obtain chlorfluanidazole. The synthetic route is shown in Formula 1:
2. The method for synthesizing cyfluthrin according to claim 1, It is characterized in that The following steps are involved: Step 1: 2-bromo-5-fluoro-trifluorotoluene is prepared into an aromatic Grignard reagent, which is reacted with bromoacetone, and then post-treated to obtain an intermediate product, 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane; Step 2: 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane and 1,2,4-triazole undergo a ring-opening substitution reaction, followed by post-treatment to obtain an intermediate product, 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol; Step 3: 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and p-chlorophenol are subjected to etherification reaction and then post-treated to obtain the product.
3. The method for synthesizing chlorfenapyr according to claim 2, It is characterized in that The preparation method of the aryl Grignard reagent in step 1 comprises: adding magnesium to tetrahydrofuran, replacing nitrogen protection, and obtaining a mixture; diluting 2-bromo-5-fluoro-trifluorotoluene with tetrahydrofuran, and then dropwise adding the mixture to react to obtain the obtained product.
4. The method for synthesizing cyfluthrin according to claim 3, It is characterized in that The temperature was controlled at 20-30° C. during the dropwise addition, and the mixture was stirred for 1-3 hours after the dropwise addition.
5. The method for synthesizing cyfluthrin according to claim 3 or 4, It is characterized in that The molar ratio of magnesium, 2-bromo-5-fluoro-trifluorotoluene and bromoacetone is 1:(0.5-0.7):(0.6-0.9).
6. The method for synthesizing cyfluthrin according to claim 5, It is characterized in that The reaction with bromoacetone in step 1 specifically comprises: cooling the aromatic Grignard reagent to 0-5° C. for standby use, dissolving bromoacetone in a solvent, and then dropwise adding the dissolved bromoacetone into the cooled aromatic Grignard reagent to perform a nucleophilic addition reaction to obtain a crude product.
7. The method for synthesizing cyfluthrin according to claim 6, It is characterized in that The temperature of the nucleophilic addition reaction is 5-10° C. and the time is 1-3 h.
8. The method for synthesizing cyfluthrin according to claim 7, It is characterized in that The post-treatment in step 1 specifically includes: adding the crude product to an aqueous solution of ammonium chloride, allowing the phases to stand to separate, obtaining an organic phase, and performing reduced pressure distillation to obtain an intermediate product, 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane.
9. The method for synthesizing cyfluthrin according to claim 2 or 8, It is characterized in that The molar ratio of 1-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-oxirane to 1,2,4-triazole is 1: (1.1-1.5)。 10. The method for synthesizing cyfluthrin according to claim 2 or 8, It is characterized in that The molar ratio of 2-(4-fluoro-2-(trifluoromethyl)phenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol to p-chlorophenol is 1: (1.1-1.5)。