An improved method for the synthesis process of the pesticide Oxazosulfyl

Abstract

The present invention provides an improved method for preparing Oxazosulfyl, which comprises reacting 3-ethylsulfonylpyridine-2-carboxylic acid, 2-amino-4-(trifluoromethyl) mercaptophenol and anhydrous zinc chloride in a pressure reactor to obtain Oxazosulfyl. The process route of the present invention is short and the operation is simple, which is suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly to an improved method for synthesizing the pesticide Oxazosulfyl. Background Art

[0002] Oxazosulfyl, molecular formula: C 15 H 11 F3N2 O9S2, relative molecular mass: 420.38, CAS No.: 1616678-32-0, chemical name: 2-[3-(ethylsulfonyl)-2-pyridinyl]-5-[(trifluoromethyl)sulfonyl]benzoxazole, English name: {2-[3-(ethylsulfonyl)-2-pyridinyl]-5-[(trifluoromethyl)sulfonyl]benzoxazole}. This product is a new insecticide developed by Sumitomo Chemical Co., Ltd. of Japan, with the trade name ALLESTM. This variety is a new type of benzoxazole insecticide containing an ethylsulfonylpyridine structure, mainly used for controlling rice pests and diseases.

[0003] The literature (Xu Xinhua, Review of the Synthesis Method of Insecticide Oxazosulfyl, Anhui Chemical Industry, Vol. 45, No. 6, December 2019) reviewed the synthesis methods of this product, mainly including the following three synthetic routes:

[0004] Route 1: Using 3-ethylthiophene-2-carboxylic acid as the raw material, the target product is prepared through three-step reactions.

[0005]

[0006] Among them, triphenylphosphine is highly toxic, not easy to store, and prone to strong reactions with oxidants. Hydrogen peroxide is an easily made drug reagent. Finally, the target product is prepared through an oxidation reaction. In the oxidation process, the mercapto group is not completely oxidized, and it is easy to cause the oxidation of the heterocyclic N, resulting in low purity of Oxazosulfyl. The overall route is long, the yield is low, and the quality is not high, which is not conducive to industrial production.

[0007] Route 2: Using 3-ethylsulfonylpyridine-2-carboxylic acid as the raw material, the target product is prepared through three-step reactions..

[0008]

[0009] Among them, in the first-step reaction, thionyl chloride is used to acylate 3-ethylsulfonylpyridine-2-carboxylic acid. The acylation reaction is one of the typical reactions in the production processes of 18 key hazardous chemicals, and its operation safety and environmental protection drawbacks are relatively obvious. The acylation product then undergoes an amidation reaction with 2-amino-4-(trifluoromethylsulfonyl)phenol, and finally, it is cyclized with p-toluenesulfonamide to obtain Oxazosulfyl. The process route is long, the operation is cumbersome, and a large amount of waste gas and waste liquid are generated, which is not conducive to environmental protection.

[0010] Route 3: Using 3-chloropyridine-2-carboxaldehyde as the raw material, the target product is obtained through two-step reactions.

[0011]

[0012] Among them, 3-chloropyridine-2-carboxaldehyde has poor stability, and the aldehyde group is easily oxidized, which is not conducive to long-term storage and large-scale production. Summary of the Invention

[0013] The purpose of the present invention is to provide an improved process for the efficient synthesis of Oxazosulfyl using 3-ethylsulfonylpyridine-2-carboxylic acid as the raw material.

[0014] Specifically, the present invention provides a method for directly preparing Oxazosulfyl from 3-ethylsulfonylpyridine-2-carboxylic acid as the starting material through one-step reaction, with a conversion rate greater than 75%. It includes reacting 3-sulfonylpyridine-2-carboxylic acid and the compound shown in Formula I in an organic solvent under the conditions of zinc chloride, heating, and sealed tube to obtain Oxazosulfyl shown in Formula II. The reaction formula is as follows:

[0015]

[0016] Through the screening of different catalytic conditions, the present invention unexpectedly discovers that 3-ethylsulfonylpyridine-2-carboxylic acid and 2-amino-4-(trifluoromethyl)sulfonic acid phenol can directly undergo a cyclization reaction under the catalysis of anhydrous zinc chloride in a sealed tube reaction. The product is single, with few impurities, the reaction conditions are relatively mild, and the temperature is controllable.

[0017] In the above Oxazosulfyl preparation method, the molar ratio of 3-ethylsulfonylpyridine-2-carboxylic acid, 2-amino-4-(trifluoromethyl)sulfonic acid phenol, and zinc chloride is 1:0.8 - 1:0.1 - 0.6.

[0018] Serial number Equivalent Yield % 1 0.1 72.2 2 0.2 87.3 3 0.3 82.3 4 0.4 75.8 5 0.5 71.4 6 0.6 66.1

[0019] Note: Other conditions are that the molar ratio of 3-ethylsulfonylpyridine-2-carboxylic acid and 2-amino-4-(trifluoromethyl)sulfonic acid phenol is 1:0.95, the solvent is 1,4-dioxane, the reaction is carried out in a sealed tube, and the reaction temperature is 70°C.

[0020] The results show that the molar yield of Oxazosulfyl can reach 87.3% with 0.2 equivalents of zinc chloride, and there is no further catalytic effect with increasing equivalents.

[0021] In the above-mentioned method for preparing Oxazosulfyl, the organic solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, toluene and acetone, preferably 1,4-dioxane and toluene.

[0022] Serial number Solvent Temperature (°C) Reaction time (h) Yield % 1 Tetrahydrofuran 60 24 63.1 2 1,4-Dioxane 80 4 87.3 3 Toluene 80 6 84.2 4 Acetone 50 20 59.5

[0023] Note: Other conditions are: the molar ratio of 3-ethylsulfonylpyridine-2-carboxylic acid, 2-amino-4-(trifluoromethyl)sulfonylphenol and zinc chloride is 1:0.95:0:2, and the reaction is carried out in a sealed tube.

[0024] Studies have shown that the yields of 1,4-dioxane and toluene are relatively high, reaching more than 85%. The reaction time of tetrahydrofuran and acetone is long and the yield is low. Considering that acetone is a drug-making reagent, it is inconvenient to use and manage.

[0025] In the above-mentioned method for preparing Oxazosulfyl, the reaction temperature is selected from 50 to 90°C, preferably 60 to 80°C.

[0026] Serial number Temperature (°C) Reaction time (h) Yield % 1 50 12 75.2 2 60 6 82.9 3 70 4 87.3 4 80 4 83.3 5 90 3 85.4

[0027] Note: Other conditions are that the molar ratio of 3-ethanesulfonylpyridine-2-carboxylic acid, 2-amino-4-(trifluoromethyl)sulfonylphenol and zinc chloride is 1:0.95:0:2, and the solvent is 1,4-dioxane.

[0028] Studies have shown that with 1,4-dioxane as solvent, the reaction can be carried out at 50-90°C with a sealed tube. The reaction time is longer at lower temperatures, and the reaction effect is best at about 70°C. As the reaction temperature is further increased, there is no significant effect on the yield. The higher the temperature, the higher the energy consumption, preferably 60-80°C.

[0029] The beneficial effects of the Oxazosulfyl preparation method provided by the present invention are:

[0030] 1) Using 3-ethylsulfonylpyridine-2-carboxylic acid as the starting material, the target product is obtained by a one-step reaction under the conditions of anhydrous zinc chloride, heating and sealing, with a yield of more than 85%;

[0031] 2) The reaction system does not involve other organic catalysts, the reaction system is simple, and the purity of the obtained product can reach more than 98% without recrystallization;

[0032] 3) The reaction system does not involve ultra-high temperature reactions, and no waste acid or waste gas is generated during the post-treatment process, which is beneficial to environmental protection. Description of the Drawings

[0033] Figure 1 : MS diagram of Compound II

[0034] Figure 2 : of Compound II 1 HNMR spectrum

[0035] Figure 3 : HPLC purity inspection chart of Compound II Detailed Implementation Modes

[0036] The following specific implementation modes are for detailed description of the present invention. The examples are only for more detailed specific description and do not limit the present invention in any form.

[0037]

[0038] Example 1

[0039] At room temperature, 3-ethylsulfonylpyridine-2-carboxylic acid (5.0 g, 23.2 mmol), 2-amino-4-(trifluoromethyl)sulfonylphenol (5.3 g, 22.0 mmol), 1,4-dioxane (50 mL) were added to a reaction kettle, and then anhydrous zinc chloride (0.63 g, 4.64 mmol) was added. The mixture was heated to 70 °C and sealed for reaction. After about 4 h, the reaction was completed. The reaction system was cooled to room temperature, and the pH was adjusted to near neutral with 1 M sodium hydroxide. Then 100 ml of ethyl acetate was added for extraction. After liquid separation, the organic phase was washed successively with saturated sodium chloride aqueous solution and water. The ethyl acetate layer was further dried with sodium sulfate, filtered, and concentrated to obtain the target product (8.1 g, 19.2 mmol, molar yield about 87.3%), and the HPLC purity was 99.8%.

[0040] MS(ESI): [M+H] + = 421.3

[0041] 1 HNMR(500M, d-DMSO): δ(ppm): 1.1352~1.1387(t, 3H, CH3), 4.0137~4.0782(q, 2H, CH2), 6.9862~8.8232(m, 6H, Ar-H)

[0042] Example 2

[0043] At room temperature, 3-ethylsulfonylpyridine-2-carboxylic acid (5.0 g, 23.2 mmol), 2-amino-4-(trifluoromethyl)sulfonylphenol (5.3 g, 22.0 mmol), 1,4-dioxane (50 mL) were added to a reaction kettle, and then anhydrous zinc chloride (1.26 g, 9.28 mmol) was added. The mixture was heated to 70 °C, sealed for reaction, and the reaction was completed in about 4 h. The reaction system was cooled to room temperature, the pH was adjusted to near neutral with 1 M sodium hydroxide, then 100 ml of ethyl acetate was added for extraction, and the layers were separated. The organic phase was washed successively with saturated sodium chloride aqueous solution and water, and the ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to obtain the target product (7.0 g, 16.7 mmol, molar yield about 75.8%), and the HPLC purity was 98.6%.

[0044] Example 3

[0045] At room temperature, 3-ethylsulfonylpyridine-2-carboxylic acid (5.0 g, 23.2 mmol), 2-amino-4-(trifluoromethyl)sulfonylphenol (4.5 g, 18.6 mmol), tetrahydrofuran (50 mL) were added to a reaction kettle, and then anhydrous zinc chloride (0.63 g, 4.64 mmol) was added. The mixture was heated to 50 °C, sealed for reaction, and the reaction was completed in about 24 h. The reaction system was cooled to room temperature, the pH was adjusted to near neutral with 1 M sodium hydroxide, then 100 ml of dichloromethane was added for extraction, and the layers were separated. The organic phase was washed successively with saturated sodium chloride aqueous solution and water, and the dichloromethane layer was dried over sodium sulfate, filtered, and concentrated to obtain the target product (4.9 g, 11.7 mmol, molar yield about 63.1%), and the HPLC purity was 97.6%.

[0046] Example 4

[0047] At room temperature, 3-ethylsulfonylpyridine-2-carboxylic acid (5.0 g, 23.2 mmol), 2-amino-4-(trifluoromethyl)sulfonylphenol (4.5 g, 18.6 mmol), toluene (50 mL) were added to a reaction kettle, and then anhydrous zinc chloride (0.63 g, 4.64 mmol) was added. The mixture was heated to 90 °C, sealed for reaction, and the reaction was completed in about 6 h. The reaction system was cooled to room temperature, the pH was adjusted to near neutral with 1 M sodium hydroxide, and then the layers were separated. The organic phase was washed successively with saturated sodium chloride aqueous solution and water, and the toluene layer was dried over sodium sulfate, filtered, and concentrated to obtain the target product (6.6 g, 15.7 mmol, molar yield about 84.2%), and the HPLC purity was 98.3%.

[0048] Example 5

[0049] At room temperature, 3-ethylsulfonylpyridine-2-carboxylic acid (5.0 g, 23.2 mmol), 2-amino-4-(trifluoromethyl)sulfonylphenol (5.3 g, 22.0 mmol), 1,4-dioxane (60 mL) were added to a reaction kettle, and then anhydrous zinc chloride (0.63 g, 4.64 mmol) was added. The mixture was heated to 50 °C, sealed and reacted for about 12 h until the reaction was completed. The reaction system was cooled to room temperature, the pH was adjusted to near neutral with 1 M sodium hydroxide, then 100 ml of ethyl acetate was added for extraction, and the layers were separated. The organic phase was washed successively with saturated sodium chloride aqueous solution and water, and the ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to obtain the target product (6.9 g, 16.5 mmol, molar yield about 75.2%), and the HPLC purity was 98.1%.

[0050] Example 6

[0051] At room temperature, 3-ethylsulfonylpyridine-2-carboxylic acid (5.0 g, 23.2 mmol), 2-amino-4-(trifluoromethyl)sulfonylphenol (5.3 g, 22.0 mmol), 1,4-dioxane (60 mL) were added to a reaction kettle, and then anhydrous zinc chloride (0.63 g, 4.64 mmol) was added. The mixture was heated to 90 °C, sealed and reacted for about 3 h until the reaction was completed. The reaction system was cooled to room temperature, the pH was adjusted to near neutral with 1 M sodium hydroxide, then 100 ml of ethyl acetate was added for extraction, and the layers were separated. The organic phase was washed successively with saturated sodium chloride aqueous solution and water, and the ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to obtain the target product (7.9 g, 18.8 mmol, molar yield about 85.4%), and the HPLC purity was 98.7%.

Claims

1. A method for preparing Oxazosulfyl, characterized in that: The compound shown in Formula I and 2-amino-4-(trifluoromethyl)sulfonylphenol are heated and subjected to a sealed-tube reaction in an organic solvent under the action of anhydrous zinc chloride to obtain Oxazosulfyl shown in Formula II. The reaction formula is as follows: ； The organic solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, toluene, and acetone, and the heating temperature is selected from 50~90°C.

2. The preparation method according to claim 1, characterized in that: The organic solvent is selected from 1,4-dioxane and toluene.

3. The preparation method according to claim 2, characterized in that: The heating temperature is selected from 60~80°C.

4. The preparation method according to claim 1, characterized in that: The molar ratio of 3-ethylsulfonylpyridine-2-carboxylic acid, 2-amino-4-(trifluoromethyl)sulfonylphenol, and anhydrous zinc chloride is 1:0.8~1:0.1~0.

6.

5. The preparation method according to claim 4, wherein: The molar ratio of 3-ethylsulfonylpyridine-2-carboxylic acid, 2-amino-4-(trifluoromethyl)sulfonylphenol, and anhydrous zinc chloride is 1:0.9:0.2~0.3.

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