Process for the preparation of propiconazole intermediates

Abstract

The application discloses a preparation method of propiconazole intermediate, which comprises the following steps: adding water, sodium bromate, an organic solvent, 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane and azobisisobutyronitrile into a reaction bottle in sequence, stirring and heating to 30-100 DEG C, dropping sodium bisulfite solution, keeping the reaction temperature for 1-4 hours after dropping, and obtaining the propiconazole intermediate 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane through post-treatment after the reaction is completed. The method adopts a catalytic bromination system of sodium bromate+ sodium bisulfite+ azobisisobutyronitrile, the catalytic bromination system not only greatly accelerates the speed of the bromination reaction, but also greatly improves the conversion rate of the bromination reaction, so that a higher reaction yield is obtained, the product purity is also higher, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of fungicide intermediate preparation technology, specifically relating to a method for preparing a propiconazole intermediate. Background Technology

[0002] Propiconazole is a triazole fungicide developed by Syngenta. It belongs to the sterol methylation inhibitor class and is a systemic fungicide with protective and curative effects. It can be absorbed by roots, stems, and leaves and can be quickly translocated upwards within the plant to control diseases caused by ascomycetes, basidiomycetes, and deuteromycetes. It is particularly effective against wheat take-all, powdery mildew, rust, and root rot, rice basilosis, and banana leaf spot.

[0003] The conventional synthetic route for propiconazole is as follows: starting with 2,4-dichloroacetophenone and 1,2-pentanediol, a cyclization reaction is first performed to obtain the first intermediate 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane, followed by a bromination reaction to obtain the second intermediate 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane, which is then condensed with triazole to obtain propiconazole [see references 1-4]. The specific synthetic route is as follows: .

[0004] The problems with the existing technology for the second step of the above synthetic route, namely the bromination reaction, are as follows: (1) The intermediate 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane is an unstable substance. Bromination with liquid bromine is prone to reversible reaction, producing monobrominated and dibrominated derivatives of 2,4-dichloroacetophenone, resulting in a low conversion rate of the bromination reaction, which is not suitable for large-scale industrial production. (2) Existing technologies basically use liquid bromine as the brominating agent. On the one hand, liquid bromine is highly volatile, unsafe to use, and difficult to measure. On the other hand, the bromination reaction of liquid bromine is slow, and the bromination tail gas produced is not easy to treat, causing serious environmental pollution.

[0005] Reference 1: Chinese patent document CN101323612A, published on December 17, 2008.

[0006] Reference 2: Chinese patent document CN101781290A, published on July 21, 2010.

[0007] Reference 3: Chinese patent document CN102225935A, published on October 26, 2011.

[0008] Reference 4: Chinese patent document CN113444077A, published on September 28, 2021. Summary of the Invention

[0009] The purpose of this invention is to solve the above-mentioned problems and provide a method for preparing propiconazole intermediates that is not only highly safe and less polluting to the environment, but also has a fast reaction rate and a high reaction yield.

[0010] The technical solution for achieving the objective of this invention is: a method for preparing the propiconazole intermediate 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane, characterized by the following steps: ① Add water, sodium bromate (brominating agent), organic solvent, 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane, and azobisisobutyronitrile (catalyst) sequentially into a reaction flask, stir and heat to 30-100℃, add sodium bisulfite solution dropwise, and maintain the reaction temperature for 1-4 hours after the addition is complete.

[0011] ② After the reaction is complete, the reaction system is cooled to room temperature (15-25℃, the same below), the pH of the reaction system is adjusted to neutral, and the layers are allowed to separate. The organic layer is washed with water and the solvent is removed by vacuum distillation to obtain the propiconazole intermediate 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane.

[0012] The above steps In this context, the organic solvent is dichloroethane, acetonitrile, tetrahydrofuran, or toluene, preferably dichloroethane or acetonitrile, and more preferably dichloroethane.

[0013] In step ① above, the reaction temperature is 50–80°C.

[0014] In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to sodium bromate is 1:2 to 1:3, preferably 1:2 to 1:2.2.

[0015] In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to azobisisobutyronitrile is 1:0.01 to 1:0.1, preferably 1:0.03 to 1:0.08.

[0016] In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to sodium bisulfite is 1:5 to 1:7, preferably 1:5 to 1:5.5.

[0017] The positive effects of this invention are as follows: The method of this invention adopts a catalytic bromination system of sodium bromate + sodium bisulfite + azobisisobutyronitrile. This catalytic bromination system not only greatly accelerates the bromination reaction of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane, but also greatly improves the conversion rate of the bromination reaction of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane, thereby obtaining a high reaction yield and a high product purity, which is suitable for large-scale industrial production. Detailed Implementation

[0018] (Example 1) The specific method for preparing the propiconazole intermediate 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane in this embodiment is as follows: Add 300g of water, 92.87g of sodium bromate (0.615mol), 300g of dichloroethane, 82.5g of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane (0.3mol), and 1.97g of azobisisobutyronitrile (0.012mol) to the reaction flask in sequence. Stir and heat to 70±2℃, then add 497.25g of 32wt% sodium bisulfite solution (1.53mol) dropwise over about 1 hour. After the addition is complete, maintain the temperature at 70±2℃ for 2 hours.

[0019] After the reaction was completed, the reaction system was cooled to room temperature, and 30 wt% sodium hydroxide aqueous solution was added dropwise to adjust the pH of the reaction system to 7.0. After standing and separating the layers, the organic layer was washed with water, and the solvent was removed by vacuum distillation to obtain 101.2 g of pale yellow liquid 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane, with a yield of 95.3% and a GC purity of 98.6%.

[0020] (Examples 2-3) The preparation methods of propiconazole intermediates in each embodiment are basically the same as those in Example 1, except for the organic solvent and reaction temperature, as detailed in Table 1.

[0021] Table 1 Example 1 Example 2 Example 3 organic solvents dichloroethane Acetonitrile Tetrahydrofuran reaction temperature 70±2℃ 70±2℃ 60±2℃ product 101.2g 99.9g 90.9g yield 95.3% 94.1% 85.6% purity 98.6% 97.5% 95.2% .

[0022] (Examples 4 to 8) The preparation methods of each embodiment are basically the same as those of Example 1, and the differences are shown in Table 2.

[0023] Table 2 Example 1 Example 4 Example 5 Example 6 Example 7 Example 8 Sodium bromate 92.87g, 0.615mol 92.87g, 0.615mol 92.87g, 0.615mol 99.67g, 0.66mol 99.67g, 0.66mol 99.67g, 0.66mol Azobisisobutyronitrile 1.97g, 0.012mol 0.985g, 0.006mol 3.94g, 0.024mol 1.97g, 0.012mol 0.985g, 0.006mol 3.94g, 0.024mol 32wt% sodium bisulfite solution 497.25g, 1.53mol 497.25g, 1.53mol 497.25g, 1.53mol 536.25g, 1.65mol 536.25g, 1.65mol 536.25g, 1.65mol product 101.2g 95.8g 102.2g 101.9g 98.3g 103.1g yield 95.3% 90.2% 96.2% 96.0% 92.6% 97.1% purity 98.6% 97.2% 98.7% 98.8% 97.9% 99.0% .

[0024] (Comparative Example 1) The difference between this comparative example and Example 1 is that azobisisobutyronitrile was not added in step ①. As a result, the target product 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane was not detected in the reaction system after 2h, 5h and 8h of reaction.

[0025] (Comparative Example 2) The difference between this comparative example and Example 1 is that sodium bisulfite solution was not added in step ①. As a result, the target product 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane was not detected in the reaction system after 2h, 5h and 8h of reaction.

Claims

1. A method for preparing a propiconazole intermediate, characterized in that... It includes the following steps: ① Add water, sodium bromate (brominating agent), organic solvent, 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane and azobisisobutyronitrile (catalyst) sequentially into a reaction flask, stir and heat to 30-100℃, add sodium bisulfite solution dropwise, and keep the reaction at the same temperature for 1-4 hours after the addition is complete. ② After the reaction is complete, the reaction system is cooled to room temperature, the pH of the reaction system is adjusted to neutral, and the layers are allowed to separate. The organic layer is washed with water and the solvent is removed by vacuum distillation to obtain the propiconazole intermediate 2-(2,4-dichlorophenyl)-2-bromomethyl-4-propyl-1,3-dioxolane.

2. The method for preparing the propiconazole intermediate according to claim 1, characterized in that: In step ① above, the organic solvent is dichloroethane, acetonitrile, tetrahydrofuran, or toluene.

3. The method for preparing the propiconazole intermediate according to claim 2, characterized in that: In step ① above, the organic solvent is dichloroethane or acetonitrile.

4. The method for preparing the propiconazole intermediate according to any one of claims 1 to 3, characterized in that: In step ① above, the reaction temperature is 50–80°C.

5. The method for preparing the propiconazole intermediate according to any one of claims 1 to 3, characterized in that: In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to sodium bromate is 1:2 to 1:

3.

6. The method for preparing the propiconazole intermediate according to claim 5, characterized in that: In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to sodium bromate is 1:2 to 1:2.

2.

7. The method for preparing the propiconazole intermediate according to any one of claims 1 to 3, characterized in that: In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to azobisisobutyronitrile is 1:0.01 to 1:0.

1.

8. The method for preparing the propiconazole intermediate according to claim 7, characterized in that: In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to azobisisobutyronitrile is 1:0.03 to 1:0.

08.

9. The method for preparing the propiconazole intermediate according to any one of claims 1 to 3, characterized in that: In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to sodium bisulfite is 1:5 to 1:

7.

10. The method for preparing the propiconazole intermediate according to claim 9, characterized in that: In step ① above, the molar ratio of 2-(2,4-dichlorophenyl)-2-methyl-4-propyl-1,3-dioxolane to sodium bisulfite is 1:5 to 1:5.5.