Preparation method of 2-chloro-3-methyl-4-methylsulfonyl benzoate

Abstract

The invention discloses a preparation method of a compound as shown in 2-chloro-3-methyl-4-methylsulfonyl benzoate (formula (1)), which comprises the following steps: dissolving a compound as shown in formula (3) 2-chloro-3-methyl-4-methylsulfonyl benzoic acid in an alcohol reaction solvent, and then adding thionyl chloride to prepare the compound as shown in formula (1), the synthesis route is as follows: # imgabs0 #, wherein the definition of R is as defined in the specification.

Description

Technical Field

[0001] The invention belongs to the field of pesticide intermediate synthesis, and specifically relates to a method for preparing 2-chloro-3-methyl-4-methylsulfonyl benzoate. Background Art

[0002] 2-Chloro-3-methyl-4-methylsulfonylbenzoate is an important pesticide and pharmaceutical intermediate, which is mainly used in cymbalta, furansulfuron, triazosulfuron, etc. Cymbalta, furansulfuron, triazosulfuron, etc. are all benzoylcyclohexanedione herbicides, which are inhibitors of hydroxyphenylpyruvate dioxygenase (HPPD). They are highly active, have a long control period, and are used in small amounts. They are mainly used to control annual and perennial broadleaf weeds in rice and grain fields, and can be used before and after germination.

[0003] 2-Chloro-3-methyl-4-methylsulfonylbenzoate is an important fine chemical intermediate for synthesizing the above-mentioned benzoylcyclohexanedione herbicides. The existing technology for preparing 2-chloro-3-methyl-4-methylsulfonylbenzoate mainly includes the following methods:

[0004] (1) In patent CN104292137A and journal Yu Yu, Su Jianyu, Dong Yuanhai, et al. Synthesis of cornfield herbicide tampronone [J]. Pesticides, 2017, 56(5): 326-327, concentrated sulfuric acid or p-toluenesulfonic acid is used as an acid catalyst to make dried 2-chloro-3-methyl-4-methylsulfonylbenzoic acid undergo a long-term reflux reaction in methanol solvent to prepare methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate. The reaction mechanism is as follows:

[0005]

[0006] (2) Patents CN104292137A, CN108409616A, WO2000021924A, DE19846792, WO2000107422A, CN1146548C, CN1269800C, CN1269800C, JP5005852 and the master's thesis "Yu Yu. Synthesis of Novel Herbicide Cyclosulfone and Pesticide Spirotetramat [D]. Wuhan University of Technology, 2018" use a methanol solution of hydrochloric acid or introduce hydrogen chloride gas into the methanol solution of the reaction system to esterify the dried 2-chloro-3-methyl-4-methylsulfonylbenzoic acid with methanol to obtain methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate. The reaction mechanism is as follows:

[0007]

[0008] (3) In patent CN108409616A, 2-chloro-3-methyl-4-methylsulfonylbenzoic acid (formula (3)) is first reacted with thionyl chloride to generate an acyl chloride intermediate, and then methanol is added for esterification to obtain 2-chloro-3-methyl-4-methylsulfonylbenzoic acid methyl ester. However, it is found that a small amount of chloride ions will be generated during the reaction of thionyl chloride and carboxylic acid, and the chloride ions will replace the hydrogen ions on the methyl group to generate chloride impurities. After the intermediate chloride impurities react with methanol, the impurities of formula (7) are generated. The impurities of formula (7) directly affect the quality of the product (formula (2)). Moreover, the compound of formula (7) has similar properties to the product and is difficult to be cleaned by conventional methods, so the obtained product is difficult to meet market requirements. The reaction mechanism is as follows:

[0009]

[0010] Although the above three methods can obtain methyl 2-chloro-3-methyl-4-methylsulfonylbenzoate, they all have their own disadvantages: method (1) requires the use of a large amount of sulfuric acid or p-toluenesulfonic acid, the reaction time is as long as dozens of hours, and the conversion is not complete. There is always about 5% of the raw material 2-chloro-3-methyl-4-methylsulfonylbenzoic acid present, and the yield is low. For example, the journal "Yu Yu, Su Jianyu, Dong Yuanhai, et al. Synthesis of cornfield herbicide cyclosulfone [J]. Pesticides, 2017, 56 (5): 326-327" has a yield of only 81.3%; method (2 ) can make the reaction completely converted, but the hydrochloric acid gas is introduced into the methanol solution, the highest content is about 30%, and it needs to be stored at a low temperature of about minus 10 degrees. It is easy to decompose at room temperature, resulting in the high price of methanol hydrochloric acid solution; during the reaction, it is necessary to continuously introduce hydrogen chloride gas until 2-chloro-3-methyl-4-methylsulfonylbenzoic acid is completely converted, but the amount of hydrogen chloride gas introduced cannot be controlled during this process. Excessive hydrogen chloride gas discharged into the tail gas system will cause serious damage to the reaction equipment, operators and the environment. In method (3), first react with thionyl chloride to form acyl chloride and then react with methanol to form methyl ester. Although this method can completely convert, the reaction process is time-consuming, and when thionyl chloride is used for acylation, 2%-3% of the compound of formula (7) will be generated. In addition, the impurity compound of formula (7) will also affect the purity and yield of the next product formula (2), and its structural formula is as follows:

[0011]

[0012] The applicant has provided a new preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoate through continuous experimental exploration and optimization. This method overcomes various shortcomings existing in the prior art, is time-saving, simple to operate, low in cost, high in yield and more suitable for industrial production. Summary of the invention

[0013] In view of the technical defects in the prior art for preparing 2-chloro-3-methyl-4-methylsulfonyl benzoate, the present invention provides a method for preparing 2-chloro-3-methyl-4-methylsulfonyl benzoate which is simpler to synthesize, safer and more reliable, simple to operate, has a high conversion rate, is low-cost and more environmentally friendly.

[0014] In order to achieve the above object, the present invention provides a one-pot preparation method of 2-chloro-3-methyl-4-methylsulfonylbenzoate represented by formula (1), which comprises: contacting and reacting a compound represented by formula (3) with thionyl chloride in the presence of an alcohol solvent, and the synthesis route is as follows:

[0015]

[0016] Wherein, R is a C1-C6 alkyl group.

[0017] Beneficial effects of the present invention:

[0018] 1. Overcoming the problem of high cost of producing the compound of formula (I) in the prior art, the production process adopts a one-pot process with high product yield and low cost;

[0019] 2. The preparation method of the present invention can completely overcome the problem in the prior art that the compound of formula (3) reacts with thionyl chloride to produce an impurity compound of formula (7) with a large content and is difficult to purify.

[0020] 3. The preparation method of the present invention can produce 2-chloro-3-methyl-4-methylsulfonylbenzoate with high purity, and can overcome the generation of the impurity compound of formula (7), thereby improving the yield and enhancing the competitive advantage of the product. Specific embodiments

[0021] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Unless otherwise expressly stated, throughout the specification and claims, the term "including" or its variations such as "comprising" or "including" will be understood to include the stated components or steps, without excluding other material components or steps.

[0022] In addition, in order to better illustrate the present invention, numerous specific details are given in the following detailed description.

[0023] Those skilled in the art will appreciate that the present invention can be implemented without certain specific details. In some embodiments, raw materials, methods, means, etc. that are well known to those skilled in the art are not described in detail in order to highlight the main purpose of the present invention.

[0024] In the present invention, C n -C m The subscripts n and m in each case indicate the number of carbon atoms in the group. For example, C1-C6 indicates that it contains 1 to 6 carbon atoms. The alkyl group appearing in the definition of the substituent may be straight-chain or branched, such as methyl, ethyl, n-propyl, n-butyl, but is not limited thereto.

[0025] Specifically, the present invention provides a method for preparing a compound represented by 2-chloro-3-methyl-4-methylsulfonylbenzoate (Formula (1)), comprising the following steps: 2-chloro-3-methyl-4-methylsulfonylbenzoic acid (Formula (3)) is contacted with thionyl chloride in an alcohol solvent to obtain the compound represented by 2-chloro-3-methyl-4-methylsulfonylbenzoate (Formula (1)). The synthesis route is as follows: Wherein R is a C1-C6 alkyl group.

[0026] Preferably, 2-chloro-3-methyl-4-methylsulfonylbenzoic acid (Formula (3)) is dissolved in an alcohol solvent, heated to the reaction temperature, and thionyl chloride is slowly added dropwise. After the addition is completed, the reaction is carried out by keeping the temperature. The reaction time after the addition is completed is 1-10 hours, preferably 2-6 hours. The time for slowly adding thionyl chloride dropwise is 1-6 hours, preferably 2-5 hours. Experimental studies have shown that when thionyl chloride is added dropwise too quickly, it preferentially decomposes at high temperatures to produce a large amount of gas, which is dangerous; and the intermediate state generated by thionyl chloride and alcohol is accelerated to make it unable to react with carboxylic acid, thereby reducing the reaction yield.

[0027] Preferably, the alcohol solvent described in the above preparation method is preferably one or more of anhydrous methanol, anhydrous ethanol, anhydrous propanol and anhydrous butanol, and the amount of the alcohol solvent used is 2-6 times the weight of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid (Formula (3)), preferably 2-3 times.

[0028] Preferably, in the above preparation method, the molar ratio of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid to thionyl chloride is 1:1.05-1.45, preferably 1:1.1-1.2.

[0029] Preferably, in the above preparation method, the reaction temperature is 40-90°C, preferably 50-80°C.

[0030] The raw material compound of formula (3) used in the preparation method of the present invention can be prepared with reference to patents WO2000021924A and CN108409616A:

[0031]

[0032] Example

[0033] The present invention is further described below in conjunction with the examples. The raw materials used in the reaction can be prepared according to the prior art or purchased from the market.

[0034] Example 1

[0035] In a 500ml four-necked reaction bottle equipped with a thermometer, a reflux condenser and a stirring paddle, add 49.74g (0.2mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid and 148.8g of anhydrous methanol, stir and dissolve, then heat up, control the temperature between 55-60°C, slowly dropwise add 26.17g (0.22mol) of thionyl chloride solution within 2-3 hours, and reflux for 4.0-5.0h after the dropwise addition. After the reaction is completed, add water for quenching, and stand for stratification. The organic phase is concentrated to obtain 51.88g of light yellow solid, with a content of 96.98% and a yield of 95.76%. No impurity compound (7) is detected.

[0036] The NMR data of its products are characterized as follows:

[0037] 1H NMR (500MHz, CDCl3) δ8.07(d,J=8.3Hz,1H),7.66(d,J=8.2Hz,1H),3.98(s,3H),3.13(s,3H),2.82(s,3H).

[0038] Example 2

[0039] In a 500ml four-necked reaction bottle equipped with a thermometer, a reflux condenser and a stirring paddle, add 49.74g (0.2mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid and 148.8g of anhydrous methanol, stir and dissolve, then heat up, control the temperature between 55-60°C, dropwise add 26.17g (0.22mol) of thionyl chloride solution within 0.5 hours, and reflux for 4.0-5.0h after the addition is complete. After the reaction is completed, add water for quenching, and stand for stratification. The organic phase is concentrated to obtain 51.06g of light yellow solid, with a content of 92.64% and a yield of 90.27%. No impurity compound (7) was detected.

[0040] Example 3

[0041] In a 500ml four-necked reaction bottle equipped with a thermometer, a reflux condenser and a stirring paddle, add 49.74g (0.2mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid and 148.8g of anhydrous methanol, stir and dissolve, then heat up, control the temperature between 55-60°C, slowly drop 28.55g (0.24mol) of thionyl chloride solution within 2-3 hours, and reflux for 4.0-5.0h after the dropwise addition. After the reaction is completed, add water for quenching, and stand for stratification. The organic phase is concentrated to obtain 52.31g of light yellow solid, with a content of 96.01% and a yield of 95.59%. No impurity compound (7) was detected.

[0042] Example 4

[0043] In a 500ml four-necked reaction bottle equipped with a thermometer, a reflux condenser and a stirring paddle, add 49.74g (0.2mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid and 148.8g of anhydrous ethanol, stir and dissolve, then heat up, control the temperature between 65-70°C, slowly drop 26.17g (0.22mol) of thionyl chloride solution within 2-3 hours, and keep the temperature for 4.0-5.0h after the dropwise addition. After the reaction is completed, add water for quenching, and stand for stratification. The organic phase is concentrated to obtain 55.04g of light yellow solid, with a content of 95.29% and a yield of 94.76%. No impurity compound (7) was detected.

[0044] Example 5

[0045] In a 500ml four-necked reaction bottle equipped with a thermometer, a reflux condenser and a stirring paddle, add 49.74g (0.2mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid and 148.8g of anhydrous isopropanol, stir and dissolve, then heat up, control the temperature between 65-70°C, slowly drop 26.17g (0.22mol) of thionyl chloride solution within 2-3 hours, and reflux for 4.0-5.0h after the dropwise addition. After the reaction is completed, add water for quenching, and stand for stratification. The organic phase is concentrated to obtain 57.78g of light yellow solid, with a content of 95.43% and a yield of 94.82%. No impurity compound (7) is detected.

[0046] Comparative Example

[0047] Comparative Example 1

[0048] In a 500ml four-necked reaction flask equipped with a thermometer, a dehydrator, a reflux condenser and a stirring paddle, 49.74g (0.2mol) of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid, 198.4g of anhydrous methanol and 9.95g of p-toluenesulfonic acid were added and refluxed for 60h. After the reaction was completed, methanol was removed under reduced pressure to obtain 49.57g of a light yellow solid with a content of 91.43% and a yield of 86.26%.

[0049] Comparative Example 2

[0050] In a 500ml four-mouth reaction bottle with a thermometer, a dehydrator, a reflux condenser and a stirring paddle, add 49.74g (0.2mol) 2-chloro-3-methyl-4-methylsulfonylbenzoic acid and 97.12g (0.8mol) thionyl chloride solution. After the addition is complete, keep warm for 1.0-2.0h, take a sample for control, and remove the excess thionyl chloride solution under reduced pressure after the reaction is completed. Then slowly add 148.8g of anhydrous methanol, and after the addition is complete, reflux for 2.0-3.0h. After the reaction is completed, add water for quenching and let stand for stratification. The organic phase is concentrated to obtain 51.36g of light yellow solid, with a content of 92.23% and a yield of 90.16%. The content of the impurity compound formula (7) detected is 2.53%.

[0051] Compared with the methods of the prior art, the method of the present invention can obtain a compound of formula (1) with higher purity and yield. In a preferred embodiment, the purity of the compound of formula (1) obtained by the method of the present invention can reach about 95%, and the yield can reach more than 94%. The method of the present invention has the advantages of safe operation, simple operation and low cost, and overcomes the generation of the impurity compound formula (7), reducing the difficulty of post-processing.

[0052] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing a compound represented by 2-chloro-3-methyl-4-methylsulfonylbenzoate (Formula (1)), characterized in that: The method comprises the following steps: 2-chloro-3-methyl-4-methylsulfonylbenzoic acid (Formula (3)) is contacted with thionyl chloride in an alcohol solvent to react to obtain a compound represented by 2-chloro-3-methyl-4-methylsulfonylbenzoate (Formula (1)). The synthesis route is as follows: Wherein R is a C1-C6 alkyl group.

2. The preparation method according to claim 1, characterized in that The alcohol solvent is preferably one of anhydrous methanol, anhydrous ethanol, anhydrous propanol and anhydrous butanol. The amount of the alcohol solvent is 2-6 times the weight of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid (Formula (3)), preferably 2-3 times.

3. The preparation method according to claim 1, characterized in that: The molar ratio of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid (Formula (3)) to thionyl chloride is 1:1.05-1.45, preferably 1:1.1-1.

2.

4. The preparation method according to claim 1, characterized in that: The reaction temperature is 40-90°C, preferably 50-80°C.

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