Pesticide Oxazosulfyl synthesis process improvement method

Abstract

The invention provides an improved preparation method of Oxazosulfyl. The improved preparation method of Oxazosulfyl comprises the following step: enabling 3-ethylsulfonyl pyridine-2-formic acid, 2-amino-4-(trifluoromethyl) mercaptophenol and anhydrous zinc chloride to react in a pressure reaction kettle, so as to obtain Oxazosulfyl. The method is short in process route, simple to operate and suitable for industrial production.

Description

Technical Field

[0001] The invention relates to the field of drug synthesis, and in particular to an improved method for the synthesis process of the pesticide Oxazosulfyl. Background Art

[0002] Oxazosulfyl, molecular formula: C 15 H 11 F 3 N 2 O 9 S 2 , relative molecular mass: 420.38, CAS number: 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 type of insecticide developed by Sumitomo Chemical Co., Ltd. of Japan, with the trade name ALLESTM. This variety is a new type of benzoxazole insecticide containing ethylsulfonylpyridine structure, mainly used for the prevention and control of rice diseases and insect pests.

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

[0004] Route 1: Using 3-ethylthiopyridine-2-carboxylic acid as raw material, the target product is prepared through three steps of reaction.

[0005]

[0006] Among them, triphenylphosphine is highly toxic, difficult to store, and easily reacts strongly with oxidants. Hydrogen peroxide is an easy-to-prepare poison reagent. Finally, the target product is prepared through an oxidation reaction. The oxidation process has incomplete oxidation of the sulfhydryl group and is easy to cause oxidation of the heterocyclic N, resulting in low purity of Oxazosulfyl. The overall route is long, the yield is low, the quality is not high, and it 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 steps of reaction.

[0008]

[0009] Among them, the first step is to use thionyl chloride to acylate 3-ethylsulfonylpyridine-2-carboxylic acid. The acylation reaction is one of the typical reactions in the production process of 18 key hazardous chemicals, and the operational safety and environmental protection disadvantages are relatively obvious. The acylation product is then reacted with 2-amino-4-(trifluoromethylsulfonyl)phenol for amidation, and finally 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 raw material, the target product is obtained by two-step reaction.

[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 efficiently synthesizing Oxazosulfyl by using 3-ethylsulfonylpyridine-2-carboxylic acid as a raw material.

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

[0015]

[0016] Through screening of different catalytic conditions, the present invention unexpectedly discovered that 3-ethanesulfonylpyridine-2-carboxylic acid and 2-amino-4-(trifluoromethyl)sulfonylphenol can directly undergo a cyclization reaction by conducting a sealed tube reaction under the catalysis of anhydrous zinc chloride, and the product is single, with few impurities, mild reaction conditions, and controllable temperature.

[0017] In the above-mentioned method for preparing Oxazosulfyl, the molar ratio of 3-ethylsulfonylpyridine-2-carboxylic acid, 2-amino-4-(trifluoromethyl)sulfonic acid phenol and zinc chloride is 1:0.8 to 1:0.1 to 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: the molar ratio of 3-ethanesulfonylpyridine-2-carboxylic acid to 2-amino-4-(trifluoromethyl)sulfonylphenol is 1:0.95, the solvent is 1,4-dioxane, the tube is sealed, 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 Solvents Temperature(℃) 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(℃) 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 reaction, and no waste acid or waste gas is generated during the post-treatment process, which is beneficial to environmental protection. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 :MS pattern of compound II

[0034] Figure 2 :Compound II 1 HNMR spectrum

[0035] Figure 3 : HPLC purity test chart of compound II DETAILED DESCRIPTION

[0036] The following specific implementation methods are intended to illustrate the present invention in detail. The examples are only used for more detailed specific descriptions and are not intended to 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)sulfonic acid phenol (5.3 g, 22.0 mmol), 1,4-dioxane (50 mL) were added to the reaction kettle, and then anhydrous zinc chloride (0.63 g, 4.64 mmol) was added, and the mixture was heated to 70°C, and the reaction was sealed for about 4 hours until the reaction was completed. The reaction system was cooled to room temperature, and the pH was adjusted to near neutral with 1M sodium hydroxide, and then 100 ml of ethyl acetate was added for extraction, and the organic phase was washed with saturated sodium chloride aqueous solution and water in turn. The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated to obtain the target product (8.1 g, 19.2 mmol, molar yield of about 87.3%), with a HPLC purity of 99.8%.

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

[0041] 1 HNMR (500M, d-DMSO): δ (ppm): 1.1352~1.1387 (t, 3H, CH 3 ),4.0137~4.0782(q,2H,CH 2 ),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)sulfonic acid phenol (5.3 g, 22.0 mmol), 1,4-dioxane (50 mL) were added to the reaction kettle, and then anhydrous zinc chloride (1.26 g, 9.28 mmol) was added, and the mixture was heated to 70°C, and the reaction was sealed for about 4 hours until the reaction was completed. The reaction system was cooled to room temperature, and the pH was adjusted to near neutral with 1M sodium hydroxide, and then 100 ml of ethyl acetate was added for extraction, and the organic phase was washed with saturated sodium chloride aqueous solution and water in turn. 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 of about 75.8%), with an HPLC purity of 98.6%.

[0044] Example 3

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

[0046] Example 4

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

[0048] Example 5

[0049] At room temperature, 3-ethylsulfonylpyridine-2-carboxylic acid (5.0 g, 23.2 mmol), 2-amino-4-(trifluoromethyl)sulfonic acid phenol (5.3 g, 22.0 mmol), 1,4-dioxane (60 mL) were added to the reaction kettle, and then anhydrous zinc chloride (0.63 g, 4.64 mmol) was added, and the mixture was heated to 50°C, and the reaction was sealed for about 12 hours until the reaction was completed. The reaction system was cooled to room temperature, and the pH was adjusted to near neutral with 1M sodium hydroxide, and then 100 ml of ethyl acetate was added for extraction, and the organic phase was washed with saturated sodium chloride aqueous solution and water in turn. 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 of about 75.2%), with an HPLC purity of 98.1%.

[0050] Example 6

[0051] At room temperature, 3-ethylsulfonylpyridine-2-carboxylic acid (5.0 g, 23.2 mmol), 2-amino-4-(trifluoromethyl)sulfonic acid phenol (5.3 g, 22.0 mmol), 1,4-dioxane (60 mL) were added to the reaction kettle, and then anhydrous zinc chloride (0.63 g, 4.64 mmol) was added, and the mixture was heated to 90°C, and the reaction was sealed for about 3 hours until the reaction was completed. The reaction system was cooled to room temperature, and the pH was adjusted to near neutral with 1M sodium hydroxide, and then 100 ml of ethyl acetate was added for extraction, and the organic phase was washed with saturated sodium chloride aqueous solution and water in turn. 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 of about 85.4%), with a HPLC purity of 98.7%.

Claims

1. A method for preparing Oxazosulfyl, characterized in that: The compound of formula I and 2-amino-4-(trifluoromethyl)sulfonic acid phenol are heated in an organic solvent under the action of anhydrous zinc chloride and sealed to react to obtain Oxazosulfyl of 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. The temperature is selected from 50 to 90°C.

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

3. The preparation method according to claim 2, characterized in that: The temperature is selected from 60 to 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 zinc chloride is 1:0.8 to 1:0.1 to 0.

6.

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

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