阅读说明：本技术 一种2-氯-3-烷氧基甲基-4-甲磺酰基苯甲酸的制备方法 (Preparation method of 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid ) 是由 赵东江 罗正 伍斌 丁慧 黄超群 于 2019-10-10 设计创作，主要内容包括：本发明涉及一种2-氯-3-烷氧基甲基-4-甲磺酰基苯甲酸的制备方法,所述方法包括以下步骤：原料2-氯-3-溴甲基-4-甲磺酰基苯甲酸甲酯在碱性物质存在下于三级醇溶剂中发生酯解反应得到2-氯-3-溴甲基-4-甲磺酰基苯甲酸盐；2-氯-3-溴甲基-4-甲磺酰基苯甲酸盐在碱性物质存在下与醇反应或者将2-氯-3-溴甲基-4-甲磺酰基苯甲酸盐与碱金属醇盐反应,得到所述2-氯-3-烷氧基甲基-4-甲磺酰基苯甲酸。本发明提供的制备方法以三级醇为溶剂,原料在碱性物质存在下发生酯解反应,降低了杂质的含量,目标化合物的收率和品质得到了大幅的提升,为最终合成高品质环磺酮和呋喃磺草酮原药提供了保障。(The invention relates to a preparation method of 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid, which comprises the following steps: carrying out an esterification reaction on a raw material of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate in a tertiary alcohol solvent in the presence of an alkaline substance to obtain 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate; reacting 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with an alcohol in the presence of a basic substance or reacting 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with an alkali metal alkoxide to obtain the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid. According to the preparation method provided by the invention, tertiary alcohol is used as a solvent, the raw materials are subjected to an esterification reaction in the presence of an alkaline substance, the content of impurities is reduced, the yield and the quality of a target compound are greatly improved, and a guarantee is provided for the final synthesis of high-quality crude drugs of tembotrione and benzofuranone.)

1. A preparation method of 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid is characterized by comprising the following steps:

(1) carrying out an esterification reaction on a raw material of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate in a tertiary alcohol solvent in the presence of an alkaline substance to obtain 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate;

(2) reacting 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with an alcohol in the presence of a basic substance or reacting 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with an alkali metal alkoxide to obtain the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid.

2. The method according to claim 1, wherein the tertiary alcohol in step (1) is any one or a combination of at least two of t-butanol, t-amyl alcohol or 2-methyl-2-amyl alcohol, preferably t-butanol;

preferably, in the step (1), the amount of the tertiary alcohol solvent is 700-3500 mL relative to 1mol of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester.

3. The production method according to claim 1 or 2, wherein the molar ratio of the methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the basic substance in the step (1) is 1 (1 to 1.1);

preferably, the alkaline substance in the step (1) is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, metallic sodium or metallic potassium, preferably sodium hydroxide;

preferably, the mass concentration of the sodium hydroxide is 30-96%;

preferably, the mass concentration of the potassium hydroxide is 30-96%.

4. The method according to any one of claims 1 to 3, wherein the temperature of the esterification reaction in step (1) is 25 to 40 ℃;

preferably, the time of the esterification reaction in the step (1) is 5-12 h.

5. The production method according to any one of claims 1 to 4, wherein the alcohol in step (2) is 2,2, 2-trifluoroethanol or 2-tetrahydrofuromethane;

preferably, the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the alcohol in the step (2) is 1 (1.05-1.35).

6. The production method according to any one of claims 1 to 5, wherein the basic substance in the step (2) is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride and potassium hydride;

preferably, the mass concentration of the sodium hydroxide is 30-96%;

preferably, the mass concentration of the potassium hydroxide is 30-96%;

preferably, the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the alkaline substance in the step (2) is 1 (1.2-1.5).

7. The process according to any one of claims 1 to 6, wherein the molar ratio of the 2-chloro-3-bromomethyl-4-methanesulfonyl benzoate salt to the alkali metal alkoxide in the step (2) is 1 (1.2 to 1.5);

preferably, the alkali metal alkoxide in the step (2) is obtained by reacting an alcohol and an alkali metal;

preferably, the alkali metal is metallic sodium or metallic potassium;

preferably, in the step (2), when the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate reacts with the alcohol in the presence of the alkaline substance, the alkaline substance and the alcohol are added into the reaction solvent, and then the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate is added;

preferably, the step (2) of reacting the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate with the alkali metal alkoxide is carried out in a sequence of adding the alkali metal alkoxide to the solvent and then adding the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate.

8. The process according to any one of claims 1 to 7, wherein the solvent used in step (2) is any one or a combination of at least two of acetonitrile, DMF, DMSO or THF;

preferably, in the step (2), the amount of the solvent is 700-3500 mL relative to 1mol of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate;

preferably, the 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid is obtained by acidification after the reaction in the step (2) is completed;

preferably, the acid used for the acidification is hydrochloric acid;

preferably, the pH value of the acidified reaction system is 2-3.

9. The method according to any one of claims 1 to 8, wherein the reaction temperature in the step (2) is-5 to 15 ℃;

preferably, the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate in the step (2) is added to the reaction system in the step (2) in batches, and the total adding time of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate is 1-3 h;

preferably, the reaction time in the step (2) is 3-6 h.

10. The method of any one of claims 1 to 9, comprising the steps of:

(1) carrying out an esterification reaction on a raw material 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate in a tertiary alcohol solvent in the presence of an alkaline substance, and reacting for 5-12 h at 25-40 ℃ to obtain 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate, wherein the dosage of the tertiary alcohol solvent is 700-3500 mL relative to 1mol of the 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate, and the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate to the alkaline substance is 1 (1-1.1);

(2) reacting 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate with an alcohol in the presence of an alkaline substance, or reacting 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate with alkali metal alkoxide, the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the alcohol is 1: (1.05 to 1.35), the molar ratio of the alkali substance to the alkali substance is 1: (1.2-1.5), wherein the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the alkali metal alkoxide is 1: (1.2-1.5) reacting for 3-6 h at-5-15 ℃, and performing desolventizing, water diluting, acidifying, filtering and drying to obtain the 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid.

Technical Field

The invention belongs to the field of synthesis of fine chemical intermediates, and relates to a preparation method of 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid, in particular to a preparation method of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid and 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid.

Background

P-hydroxyphenylpyruvate dioxygenase (HPPD) is one of the most important herbicide action targets at present, HPPD inhibitor herbicides account for 18 types of herbicides worldwide, the sales account for 5.8% of the global herbicide market, and the agents are well known for broad spectrum, high efficiency and slow resistance development. HPPD inhibitor herbicides have the same mechanism of action, but are not structurally fully related, being triketones, pyrazolones and isoxazolones. Tembotrione (Tembotrione) and benzofuranone (Tefuryltrione) are HPPD-series triketone herbicides having the following structural formula:

the tembotrione is independently developed by Bayer companies in 2007, is higher in activity than mesotrione, is safe to crops, is mainly used for preventing and controlling weeds in corn fields, and has a wide weeding spectrum; fusulcotrione was jointly developed by Bayer, HOKKO (North Xing Japan) and Zen-Noh (International trade company of Japan Agrimony), and was marketed in Japan in 2008, and Fusulcotrione was mainly used for paddy field weed control. The compound annual growth rate between 2009 and 2014 of the tembotrione is as high as 51.6 percent, and the compound annual growth rate between 2009 and 2014 of the furansulcotrione is as high as 20.1 percent, and moreover, the patents of the two medicaments will expire in 9 months of 2019, and the patents will meet the opportunity of a round of development.

The compound 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid is a key intermediate of the series of compounds, and the structural formula is as follows:

CN105601548A, CN104292137A, US6376429, CN1364160A, CN1323292A, etc. all disclose a method for preparing 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid by using 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester as a raw material and reacting with corresponding alcohol or directly with corresponding sodium alkoxide under the action of alkali to obtain a target product methyl ester, and further saponifying to obtain the 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid, wherein the reaction formula is as follows:

wherein, R is a tembotrione intermediate when R is trifluoroethyl, and is a furansulcotrione intermediate when R is 2-tetrahydrofuryl methyl.

Although the target compound can be obtained by the above method, the purity of the obtained product is poor, and the impurity 2-chloro-3-methoxymethyl-4-methylsulfonylbenzoic acid is relatively large. The percentage of the impurities is greatly different due to different substrates, when R is trifluoroethyl, the percentage of the impurities is about 3-5%, and when R is 2-tetrahydrofuryl methyl, the percentage of the impurities is 8-12%. The impurities are generated by the byproduct methanol due to ester base breakage or ester exchange in the raw materials in an alkaline environment, the methanol further reacts with benzyl bromide groups in the raw materials, the impurities are similar to target compounds in structure and property and are not easy to remove, corresponding new impurities are derived in subsequent reactions, and finally the quality of the original drugs of the tembotrions and the fursulcotrione is seriously influenced.

With the improvement of the pesticide management system in China and the connection between the pesticide management system and the international standard, higher requirements are put forward on the quality of pesticide products, relevant laws and regulations are provided for the management of pesticide impurities, and the research on the generation mechanism of the impurities and the research on control means are particularly important. In order to obtain high-quality raw materials of the tembotrione and the furanone, a new preparation method of the 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid is urgently needed, so that the content of impurities is reduced, and the purity of a target product is improved.

Disclosure of Invention

In order to solve the technical problems, the invention provides the preparation method of the 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid, which effectively avoids the generation of the impurity 2-chloro-3-methoxymethyl-4-methylsulfonylbenzoic acid and provides guarantee for the subsequent preparation of high-quality crude drugs of the tembotrione and the furansulcotrione.

In order to achieve the purpose, the invention adopts the following technical scheme:

a preparation method of 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid comprises the following steps:

(1) carrying out an esterification reaction on a raw material of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate in a tertiary alcohol solvent in the presence of an alkaline substance to obtain 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate;

the reaction process in this step can be represented by the following reaction formula:

wherein M represents an alkali metal.

(2) Reacting 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with an alcohol in the presence of a basic substance or reacting 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate with an alkali metal alkoxide to obtain the 2-chloro-3-alkoxymethyl-4-methanesulfonylbenzoic acid.

The reaction process in this step can be represented by the following reaction formula:

wherein M represents an alkali metal, and R represents 2,2, 2-trifluoroethyl or 2-tetrahydrofurylmethyl.

According to the method, ester bonds of raw materials are broken under the action of alkali in an esterification link, methoxy groups are removed from molecules, and then 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate is obtained, and the salt is further subjected to condensation reaction with corresponding alcohol or sodium alkoxide to prepare a target compound. The method removes the methoxyl group before etherification, effectively avoids the generation of impurity 2-chloro-3-methoxymethyl-4-methylsulfonyl benzoic acid in the subsequent etherification reaction, and greatly improves the yield and quality of the target compound.

The alkaline hydrolysis of the ester is a conventional reaction, but the molecular structure of the raw material 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate used in the invention has an active group benzyl bromide which is sensitive to alkali, the conventional ester hydrolysis means is not feasible in the invention, the benzyl bromide group can participate in the reaction to generate a large amount of benzyl alcohol and benzyl ether compounds, and the structural formula is as follows:

the reaction is carried out in a special solvent system, namely a tertiary alcohol solvent, so that the activity of the benzyl bromide can be well reduced, and the purity of the alkaline hydrolysis link product is high.

As a preferred technical scheme of the invention, the tertiary alcohol in the step (1) is any one or a combination of at least two of tert-butyl alcohol, tert-amyl alcohol or 2-methyl-2-amyl alcohol, and is preferably tert-butyl alcohol.

Preferably, in the step (1), the amount of the tertiary alcohol solvent is 700-3500 mL relative to 1mol of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester, and may be 700mL, 1000mL, 1500mL, 2000mL, 2500mL, 3000mL or 3500mL, for example.

In a preferred embodiment of the present invention, the molar ratio of the raw material to the basic substance in step (1) is 1 (1 to 1.1), and may be, for example, 1:1, 1:1.02, 1:1.05, 1:1.08, or 1: 1.1.

Preferably, in the step (1), the basic substance is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, potassium hydride, sodium metal or potassium metal, and is preferably sodium hydroxide.

Preferably, the sodium hydroxide is used by first preparing an aqueous sodium hydroxide solution, and the mass concentration of the sodium hydroxide is 30 to 96%, for example, 30%, 40%, 50%, 60%, 70%, 85% or 96%.

Preferably, the potassium hydroxide is used by first preparing an aqueous solution of sodium hydroxide, and the mass concentration of potassium hydroxide is 30 to 96%, for example, 30%, 40%, 50%, 60%, 70%, 85% or 96%.

As a preferable technical scheme of the invention, the temperature of the esterification reaction in the step (1) is 25-40 ℃, for example, 25 ℃, 30 ℃, 35 ℃ or 40 ℃.

Preferably, the time of the esterification reaction in the step (1) is 5-12 h, for example, 5h, 8h, 10h or 12 h.

As a preferable technical scheme of the invention, the alcohol in the step (2) is 2,2, 2-trifluoroethanol or 2-tetrahydrofurfuryl alcohol.

Preferably, the molar ratio of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to alcohol in step (2) is 1 (1.05-1.35), and may be, for example, 1:1.05, 1:1.15, 1:1.25, or 1: 1.35.

In a preferred embodiment of the present invention, in the step (2), the basic substance is any one of sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride and potassium hydride.

Preferably, the sodium hydroxide is used by first preparing an aqueous sodium hydroxide solution, and the mass concentration of the sodium hydroxide is 30 to 96%, for example, 30%, 40%, 50%, 60%, 70%, 85% or 96%.

Preferably, the potassium hydroxide is used by first preparing an aqueous solution of sodium hydroxide, and the mass concentration of potassium hydroxide is 30 to 96%, for example, 30%, 40%, 50%, 60%, 70%, 85% or 96%.

Preferably, the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the basic substance in step (2) is 1 (1.2-1.5), and may be, for example, 1:1.2, 1:1.3, 1:1.4 or 1: 1.5.

In a preferred embodiment of the present invention, the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the alkali metal alkoxide in step (2) is 1 (1.2 to 1.5), and may be, for example, 1:1.2, 1:1.3, 1:1.4 or 1: 1.5.

Preferably, the alkali metal alkoxide in step (2) is obtained by reacting an alcohol with an alkali metal.

Preferably, the alkali metal is metallic sodium or metallic potassium.

In the present invention, when the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate salt in the step (2) is reacted with an alcohol in the presence of an alkaline substance, the alkaline substance and the alcohol are added to the reaction solvent first, and then the 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate salt is added.

In the present invention, in the step (2), the reaction of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate with the alkali metal alkoxide is carried out in the order of adding the alkali metal alkoxide to the solvent and then adding the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate.

In the invention, the feeding sequence in the step (2) is unchangeable, and if the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate is firstly put into a solvent and a mixed solution of an alkaline substance and alcohol or sodium or potassium alkoxide is dripped for reaction, the benzyl alcohol impurities and the double-joint impurities are greatly increased.

As a preferred embodiment of the present invention, the solvent used in step (2) is any one or a combination of at least two of acetonitrile, DMF, DMSO or THF.

Preferably, the solvent is used in the amount of 700 to 3500mL, for example, 700mL, 1000mL, 1500mL, 2000mL, 2500mL, 3000mL or 3500mL, relative to 1mol of 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate in the step (2).

As a preferred embodiment of the present invention, the temperature of the reaction in the step (2) is-5 to 15 ℃, and may be-5 ℃, 0 ℃, 5 ℃, 10 ℃ or 15 ℃, for example.

Preferably, the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate in the step (2) is added to the reaction system in the step (2) in batches, and the total addition time of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate is 1-3 h, such as 1h, 1.5h, 2h, 2.5h or 3 h;

preferably, the reaction time in the step (2) is 3-6 h, for example, 3h, 4h, 5h or 6 h.

Preferably, the 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid is obtained by acidification after the reaction in step (2) is completed.

Preferably, the acid used for the acidification is hydrochloric acid.

Preferably, the pH of the acidified reaction system is 2-3, and may be, for example, 2, 2.1, 2.3, 2.4, 2.5, 2.7, or 3.

As a preferred technical scheme of the invention, the preparation method comprises the following steps:

(1) carrying out an esterification reaction on a raw material 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate in a tertiary alcohol solvent in the presence of an alkaline substance, and reacting for 5-12 h at 25-40 ℃ to obtain 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate, wherein the dosage of the tertiary alcohol solvent is 700-3500 mL relative to 1mol of the raw material, and the molar ratio of the raw material to the alkaline substance is 1 (1-1.1);

(2) reacting 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate with an alcohol in the presence of an alkaline substance, the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the alcohol is 1: (1.05-1.35) and the molar ratio of the alkaline substance to the alkaline substance is 1: (1.2 to 1.5), or reacting 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate with alkali metal alkoxide, the molar ratio of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate to the alkali metal alkoxide is 1: (1.2-1.5) reacting for 3-6 h at-5-15 ℃, and performing desolventizing, water diluting, acidifying, filtering and drying to obtain the 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid.

The recitation of numerical ranges herein includes not only the above-recited numerical values, but also any numerical values between any of the above-recited numerical ranges not recited, and for the sake of brevity and clarity, the present invention is not intended to be exhaustive of the specific numerical values encompassed within the range.

Compared with the prior art, the invention has at least the following beneficial effects:

the method takes tertiary alcohol as a solvent, the raw materials are subjected to an esterification reaction in the presence of an alkaline substance, and methoxyl groups are cut off from a molecular structure, so that the generation of a main impurity 2-chloro-3-methoxymethyl-4-methylsulfonylbenzoic acid in the prior art is avoided, the quality of an intermediate and the yield of the reaction are fundamentally improved, and the product 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate in the step has a normalized ratio up to 98.3% in a liquid chromatogram;

the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate is continuously subjected to etherification reaction to generate a target compound, the highest yield of the two-step reaction of the method can reach 93.8%, the highest content of HPLC (high performance liquid chromatography) detection can reach 98.7%, the yield and the quality of the target compound are greatly improved, and a guarantee is provided for the final synthesis of high-quality raw drugs of tembotrione and benzofuranone.

Detailed Description

For the purpose of facilitating an understanding of the present invention, the present invention will now be described by way of examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

The preparation of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be referred to the methods described in CN105601548, CN104292137, US6376429, CN1146548 or CN 1323292. In the following examples, methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate was prepared in a purity of 98% by HPLC with reference to the preparation method provided in CN 105601548.

Example 1

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 200mL of tert-butyl alcohol into a reaction bottle, starting stirring, dripping 8.8g of sodium hydroxide (48%, 0.105mol) into the reaction bottle at room temperature, controlling the kettle temperature to be 25 ℃ after the sodium hydroxide is uniformly dispersed, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98%, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 25 ℃, and reacting for 7 hours. After the reaction is finished, controlling the normalized content of the sodium salt of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid to be 98.2% in the liquid chromatogram, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 50mL of trifluoroethanol into a reaction kettle, starting stirring, adding 5.2g of sodium hydride (60 percent, 0.13mol) at room temperature, stirring until the sodium hydride is completely dissolved, removing the solution to obtain a trifluoroethanol sodium alkoxide solid, and sealing for later use.

Adding 200mL of THF into sodium trifluoroethoxide, stirring and dissolving, controlling the kettle temperature at 5 ℃, adding the sodium 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (98.2%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 3h, and keeping the temperature for reaction for 3h after the addition is finished. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 2, 32.9g of product is obtained after filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification obtains that the content of the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid is 98.7 percent, and the two-step reaction yield is 93.8 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 2

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 200mL of tert-amyl alcohol into a reaction bottle, starting stirring, dripping 8.8g of sodium hydroxide (48%, 0.105mol) into the reaction bottle at room temperature, controlling the kettle temperature to be 25 ℃ after the sodium hydroxide is uniformly dispersed, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98%, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 25 ℃, and reacting for 7 hours. After the reaction is finished, controlling the normalized content of the sodium salt of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid to be 97.8% in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 50mL of trifluoroethanol into a reaction kettle, starting stirring, adding 2.8g of metal sodium (99%, 0.12mol) at room temperature, stirring until the metal sodium is completely dissolved, removing the solution to obtain trifluoroethanol sodium alkoxide solid, and sealing for later use.

Adding 70mL of DMSO (dimethyl sulfoxide) into sodium trifluoroethoxide, stirring and dissolving, controlling the kettle temperature at-5 ℃, adding the sodium 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (97.8%, 0.1mol) prepared in the step (1) into a reaction bottle for eight times, wherein the total feeding time is 2h, and carrying out heat preservation reaction for 5h after the addition is finished. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 2, 33.3g of a product is obtained by filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification obtains that the content of the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid is 96.7 percent, and the two-step reaction yield is 92.4 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 3

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 70mL of tert-butyl alcohol into a reaction bottle, starting stirring, dripping 14g of sodium hydroxide (30 percent, 0.105mol) into the reaction bottle at room temperature, controlling the kettle temperature to be 30 ℃ after the sodium hydroxide is uniformly dispersed, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98 percent, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 30 ℃ and reacting for 12 hours. After the reaction is finished, controlling the normalized content of the sodium salt of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid to be 92.5% in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

160ml DMMF, 11.6g trifluoroethanol (99 percent, 0.115mol) and 17.3g sodium hydroxide solution (30 percent, 0.13mol) are added into a reaction kettle, stirring is started, the kettle temperature is controlled at 5 ℃, 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid sodium salt (92.5 percent, 0.1mol) prepared in the step (1) is added into a reaction bottle in eight times, the total adding time is 2 hours, and the reaction is carried out for 4 hours under the condition of heat preservation after the adding. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 3, then 30.7g of a product is obtained by filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification obtains that the content of the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid is 95.8 percent, and the two-step reaction yield is 84.4 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 4

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 200mL of tert-butyl alcohol into a reaction bottle, starting stirring, dripping 4.6g of sodium hydroxide (96 percent, 0.11mol) into the reaction bottle at room temperature, controlling the kettle temperature to be 40 ℃ after the sodium hydroxide is uniformly dispersed, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98 percent, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 40 ℃ and reacting for 5 hours. After the reaction is finished, controlling the normalized content of the sodium salt of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid to be 96.4 percent in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 130mL of DMF, 10.6g of trifluoroethanol (99%, 0.105mol) and 14.1g of potassium tert-butoxide (95%, 0.12mol) into a reaction kettle, starting stirring, controlling the kettle temperature at 10 ℃, adding the sodium 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (96.4%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total addition time is 3 hours, and after the addition, keeping the temperature and reacting for 4 hours. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 2, 32.5g of product is obtained after filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification is carried out to obtain the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid with the content of 98.0 percent and the two-step reaction yield of 91.4 percent calculated by 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 5

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

350mL of tert-butyl alcohol is added into a reaction bottle, stirring is started, 6.9g of potassium hydroxide (85%, 0.105mol) is dripped into the tert-butyl alcohol at room temperature, after the potassium hydroxide is uniformly dispersed, the kettle temperature is controlled at 25 ℃, 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98%, 0.1mol) is poured into the kettle for alkaline hydrolysis reaction, slight heat is released in the reaction process, the kettle temperature is controlled at 25 ℃, and the reaction is carried out for 7 hours. After the reaction is finished, controlling the normalized content of the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid potassium salt to be 98.3% in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 150mL of trifluoroethanol into a reaction kettle, starting stirring, adding 20g of potassium hydride (30 percent and 0.15mol) at room temperature, stirring until the potassium hydride is completely dissolved, removing the solution to obtain trifluoroethanol potassium alcoholate solid, and sealing for later use.

Adding 200mL of THF into potassium trifluoroethoxide, stirring and dissolving, controlling the kettle temperature at 5 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl potassium benzoate (98.3%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 3h, and keeping the temperature for reaction for 3h after the addition is finished. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 2, 33.0g of product is obtained after filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification obtains that the content of the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid is 98.2 percent, and the two-step reaction yield is 93.5 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 6

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

350mL of tert-butyl alcohol is added into a reaction bottle, stirring is started, 6.6g of potassium hydroxide (85%, 0.1mol) is dripped into the tert-butyl alcohol at room temperature, after the potassium hydroxide is uniformly dispersed, 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98%, 0.1mol) is poured into the kettle at 25 ℃ for alkaline hydrolysis reaction, slight heat is released in the reaction process, the kettle temperature is controlled at 25 ℃, and the reaction is carried out for 7 hours. After the reaction is finished, controlling the normalized content of the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid potassium salt to be 97.3% in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 70ml of DMF, 12.6g of trifluoroethanol (99 percent, 0.125mol) and 26.1g of potassium hydroxide solution (30 percent, 0.14mol) into a reaction kettle, starting stirring, controlling the kettle temperature to be 5 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl potassium benzoate (97.3 percent, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 2 hours, and after the addition, carrying out heat preservation reaction for 4 hours. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 2, 32.4g of product is obtained by filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification is carried out to obtain the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid with the content of 96.0 percent and the two-step reaction yield of 89.3 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 7

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 200mL of tert-butyl alcohol into a reaction bottle, starting stirring, dripping 10.3g of sodium tert-butoxide (98 percent, 0.105mol) into the reaction bottle at room temperature, controlling the kettle temperature to be 25 ℃ after the sodium tert-butoxide is uniformly dispersed, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98 percent, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 25 ℃ and reacting for 6 hours. After the reaction is finished, controlling the normalized content of the sodium salt of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid to be 98.3 percent in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 130mL of THF, 10.6g of trifluoroethanol (99%, 0.105mol) and 11.8g of sodium tert-butoxide (98%, 0.12mol) into a reaction kettle, starting stirring, controlling the kettle temperature at 10 ℃, adding the sodium 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (98.3%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total addition time is 3 hours, and after the addition, keeping the temperature and reacting for 4 hours. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 2, 32.8g of product is obtained after filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification obtains that the content of the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid is 97.8 percent, and the two-step reaction yield is 92.7 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 8

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 200mL of tert-butyl alcohol into a reaction bottle, starting stirring, dripping 12.4g of potassium tert-butoxide (95%, 0.105mol) into the reaction bottle at room temperature, controlling the kettle temperature to be 25 ℃ after the potassium tert-butoxide is uniformly dispersed, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98%, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 25 ℃ and reacting for 6 hours. After the reaction is finished, controlling the normalized content of the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid potassium salt to be 98.0% in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 100mL of trifluoroethanol into a reaction kettle, starting stirring, adding 5.5g of metal potassium (99%, 0.14mol) at room temperature, stirring until the metal potassium is completely dissolved, desolventizing to obtain trifluoroethanol potassium alcoholate solid, and sealing for later use.

Adding 130mL of acetonitrile into potassium trifluoroethanol alkoxide, stirring and dissolving, controlling the kettle temperature at 15 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl potassium benzoate (98.0%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 1h, and carrying out heat preservation reaction for 6h after the addition is finished. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 3, filtering, leaching with water, and drying to obtain 32.6g of a product, and quantitatively obtaining the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid with the content of 98.2% by HPLC (high performance liquid chromatography), wherein the two-step reaction yield is 91.9% by using 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate.

Example 9

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 200mL of 2-methyl-2-pentanol into a reaction bottle, starting stirring, dripping 4.2g of sodium hydride (60 percent, 0.105mol) into the reaction bottle at room temperature, controlling the kettle temperature to be 25 ℃ after the sodium hydride is completely dissolved, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98 percent, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 25 ℃ and reacting for 6 hours. After the reaction is finished, controlling the normalized content of the sodium salt of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid to be 97.8% in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 200mL of DMF, 11.6g of trifluoroethanol (99%, 0.115mol) and 5.4g of sodium hydroxide (96%, 0.13mol) into a reaction kettle, starting stirring, controlling the kettle temperature at 5 ℃, adding the sodium salt of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid (97.8%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total addition time is 3 hours, and keeping the temperature for reaction for 6 hours after the addition is finished. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 3, 32.4g of product is obtained by filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification is carried out to obtain the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid with the content of 96.5 percent and the two-step reaction yield of 89.7 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 10

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 50mL of tertiary amyl alcohol and 150mL of tertiary butyl alcohol into a reaction bottle, starting stirring, dripping 14.0g of potassium hydride (30 percent, 0.105mol) into the reaction bottle at room temperature, controlling the kettle temperature to be 25 ℃ after the potassium hydride is completely dissolved, pouring 34.8g of methyl 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (98 percent, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 25 ℃ and reacting for 6 hours. After the reaction is finished, controlling the normalized content of the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid potassium salt to be 98.2% in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid, the main reaction process can be represented by the following reaction equation:

adding 200mL of DMF, 13.6g of trifluoroethanol (99%, 0.135mol) and 9.9g of potassium hydroxide (85%, 0.15mol) into a reaction kettle, starting stirring, controlling the kettle temperature at 5 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl potassium benzoate (98.2%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total adding time is 3 hours, and after the addition, keeping the temperature and reacting for 5 hours. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 3, 32.5g of product is obtained by filtering, water leaching and drying, and the HPLC (high performance liquid chromatography) quantification obtains that the content of the target compound 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonyl benzoic acid is 97.1 percent, and the two-step reaction yield is 91.1 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 11

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 200mL of tert-butyl alcohol into a reaction bottle, starting stirring, adding 2.4g of metal sodium (99%, 0.105mol) at room temperature, controlling the kettle temperature to be 25 ℃ after the metal sodium is completely dissolved, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98%, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 25 ℃, and reacting for 6 hours. After the reaction is finished, controlling the normalized content of the sodium salt of the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid to be 98.3 percent in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 130mL of THF, 10.8g of 2-tetrahydrofuryl methanol (99 percent, 0.105mol) and 11.8g of sodium tert-butoxide (98 percent, 0.12mol) into a reaction kettle, starting stirring, controlling the kettle temperature at 10 ℃, adding the sodium 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate (98.3 percent, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total addition time is 3 hours, and after the addition, carrying out heat preservation reaction for 4 hours. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 3, filtering, leaching with water, and drying to obtain 33.0g of a product, wherein the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid is obtained quantitatively by HPLC, the content is 96.6%, and the two-step reaction yield is 91.4% by using 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester.

Example 12

(1) The preparation of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoate can be represented by the following reaction equation:

adding 200mL of tert-butyl alcohol into a reaction bottle, starting stirring, adding 4.1g of metal potassium (99%, 0.105mol) at room temperature, controlling the kettle temperature to be 25 ℃ after the metal potassium is completely dissolved, pouring 34.8g of 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate (98%, 0.1mol) into the kettle for alkaline hydrolysis reaction, slightly releasing heat in the reaction process, controlling the kettle temperature to be 25 ℃, and reacting for 6 hours. After the reaction is finished, controlling the normalized content of the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid potassium salt to be 98.1% in liquid chromatography, and directly using the negative pressure to remove the solvent for the subsequent etherification reaction.

(2) The preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 130mL of DMF, 10.8g of 2-tetrahydrofuryl alcohol (99 percent, 0.105mol) and 14.1g of potassium tert-butoxide (95 percent, 0.12mol) into a reaction kettle, starting stirring, controlling the kettle temperature at 10 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl potassium benzoate (98.1 percent, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total addition time is 3 hours, and after the addition, carrying out heat preservation reaction for 4 hours. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 3, filtering, leaching with water, and drying to obtain 33.0g of a product, wherein the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid is obtained quantitatively by HPLC, the content is 96.8%, and the two-step reaction yield is 91.8% by using 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester.

Example 13

(1) The same procedure as described in example 1 was repeated to give 98.2% sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

(2) the preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 200mL of DMF, 11.8g of 2-tetrahydrofuryl alcohol (99%, 0.115mol) and 5.4g of sodium hydroxide (96%, 0.13mol) into a reaction kettle, starting stirring, controlling the kettle temperature at 5 ℃, adding the sodium salt of 2-chloro-3-bromomethyl-4-methylsulfonyl benzoate (98.2%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total addition time is 3 hours, and after the addition is finished, carrying out heat preservation reaction for 6 hours. After the reaction is finished, negative pressure desolventizing is carried out, 120mL of water is added into the kettle residue, concentrated hydrochloric acid is dropwise added after stirring and dissolving to acidify the pH value of the system to 3, 32.6g of a product is obtained by filtering, water leaching and drying, the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonyl benzoic acid is quantitatively obtained by HPLC, the content is 95.3%, and the two-step reaction yield is 89.1% by taking 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid as a basis.

Example 14

(1) The same procedure as described in example 1 was repeated to give 98.2% sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

(2) the preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 200ml of DMF, 11.8g of 2-tetrahydrofuryl alcohol (99 percent, 0.115mol) and 8.6g of potassium hydroxide (85 percent, 0.13mol) into a reaction kettle, starting stirring, controlling the kettle temperature to be 5 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid sodium salt (98.2 percent, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 3 hours, and after the addition, carrying out heat preservation reaction for 5 hours. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 3, filtering, washing with water, and drying to obtain 32.6g of a product, wherein the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonyl benzoic acid is 95.9% by HPLC (high performance liquid chromatography) quantification, and the two-step reaction yield is 89.8% by using 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 15

(1) The same procedure as described in example 1 was repeated to give 98.2% sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

(2) the preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

160ml DMMF, 11.8g of 2-tetrahydrofuran methanol (99 percent, 0.115mol) and 17.3g of sodium hydroxide solution (30 percent, 0.13mol) are added into a reaction kettle, stirring is started, the kettle temperature is controlled at 5 ℃, the sodium salt of 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid (98.2 percent, 0.1mol) prepared in the step (1) is added into a reaction bottle in eight times, the total feeding time is 2 hours, and the reaction is carried out for 4 hours after the addition is finished. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 3, filtering, washing with water, and drying to obtain 32.6g of a product, wherein the HPLC (high performance liquid chromatography) quantificationally obtains that the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonyl benzoic acid is 94.6 percent, and the two-step reaction yield is 88.4 percent based on 2-chloro-3-bromomethyl-4-methylsulfonyl methyl benzoate.

Example 16

(1) The same procedure as described in example 1 was repeated to give 98.2% sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

(2) the preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 70ml of DMF, 12.9g of 2-tetrahydrofuran methanol (99 percent, 0.125mol) and 26.1g of potassium hydroxide solution (30 percent, 0.14mol) into a reaction kettle, starting stirring, controlling the kettle temperature to be 5 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid sodium salt (98.2 percent, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 2 hours, and after the addition, carrying out heat preservation reaction for 4 hours. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 2, filtering, leaching with water, and drying to obtain 32.6g of a product, wherein the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid is 94.8% by HPLC (high performance liquid chromatography) quantification, and the two-step reaction yield is 88.8% by 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester.

Example 17

(1) The same procedure as described in example 1 was repeated to give 98.2% sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

(2) the preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 50mL of 2-tetrahydrofuran methanol into a reaction kettle, starting stirring, adding 5.2g of sodium hydride (60 percent, 0.13mol) at room temperature, stirring until the sodium hydride is completely dissolved, desolventizing under negative pressure by a high vacuum oil pump to obtain 2-tetrahydrofuran methanol sodium alkoxide solid, and sealing for later use.

Adding 200mL of THF into 2-tetrahydrofuran methanol sodium alcoholate, stirring and dissolving, controlling the temperature of a kettle to be 5 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid sodium salt (98.2%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 3h, and carrying out heat preservation reaction for 3h after the addition. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 3, filtering, leaching with water, and drying to obtain 33.1g of a product, wherein the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid is obtained quantitatively by HPLC, the content is 97.5%, and the two-step reaction yield is 92.5% based on 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester.

Example 18

(1) The same procedure as described in example 1 was repeated to give 98.2% sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

(2) the preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 150mL of 2-tetrahydrofuran methanol into a reaction kettle, starting stirring, adding 20g of potassium hydride (30 percent and 0.15mol) at room temperature, stirring until the potassium hydride is completely dissolved, carrying out negative pressure desolventization by a high vacuum oil pump to obtain 2-tetrahydrofuran methanol potassium alcoholate solid, and sealing for later use.

Adding 200mL of THF into 2-tetrahydrofuran methanol potassium alcoholate, stirring and dissolving, controlling the temperature of a kettle to be 5 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid sodium salt (98.2%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 3h, and carrying out heat preservation reaction for 3h after the addition. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 3, filtering, leaching with water, and drying to obtain 33.1g of a product, wherein the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid is obtained quantitatively by HPLC, the content is 97.0%, and the two-step reaction yield is 92.2% based on 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester.

Example 19

(1) The same procedure as described in example 1 was repeated to give 98.2% sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

(2) the preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 50mL of 2-tetrahydrofuran methanol into a reaction kettle, starting stirring, adding 2.8g of metal sodium (99 percent, 0.12mol) at room temperature, stirring until the metal sodium is completely dissolved, desolventizing under negative pressure by a high vacuum oil pump to obtain 2-tetrahydrofuran methanol sodium alkoxide solid, and sealing for later use.

Adding 70mL of DMSO (dimethyl sulfoxide) into 2-tetrahydrofuran methanol sodium alcoholate, stirring and dissolving, controlling the temperature of a kettle to be-5 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid sodium salt (98.2%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 2 hours, and carrying out heat preservation reaction for 5 hours after the addition. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 3, filtering, leaching with water, and drying to obtain 33.4g of a product, wherein the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonyl benzoic acid is 95.5% by HPLC (high performance liquid chromatography) quantification, and the two-step reaction yield is 91.5% by using 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid methyl ester.

Example 20

(1) The same procedure as described in example 1 was repeated to give 98.2% sodium 2-chloro-3-bromomethyl-4-methanesulfonylbenzoate;

(2) the preparation of 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, the main reaction sequence, can be represented by the following reaction equation:

adding 100mL of 2-tetrahydrofuran methanol into a reaction kettle, starting stirring, adding 5.5g of metal potassium (99 percent, 0.14mol) at room temperature, stirring until the metal potassium is completely dissolved, desolventizing under negative pressure by a high vacuum oil pump to obtain 2-tetrahydrofuran methanol potassium alcoholate solid, and sealing for later use.

Adding 130mL of acetonitrile into 2-tetrahydrofuran methanol potassium alcoholate, stirring and dissolving, controlling the temperature of a kettle to be 15 ℃, adding the 2-chloro-3-bromomethyl-4-methylsulfonyl benzoic acid sodium salt (98.2%, 0.1mol) prepared in the step (1) into a reaction bottle in eight times, wherein the total feeding time is 1h, and carrying out heat preservation reaction for 6h after the addition. After the reaction is finished, carrying out negative pressure desolventizing, adding 120mL of water into the kettle residue, stirring and dissolving, dropwise adding concentrated hydrochloric acid to acidify the pH value of the system to 2, filtering, leaching with water, and drying to obtain 32.6g of a product, wherein the content of the target compound 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid is obtained quantitatively by HPLC, the content is 97.0%, and the two-step reaction yield is 90.8% based on 2-chloro-3-bromomethyl-4-methylsulfonylbenzoic acid methyl ester.

The applicants state that the present invention is illustrated by the above examples to the preparation of 2-chloro-3-alkoxymethyl-4-methylsulfonylbenzoic acid, in particular 2-chloro-3- (2,2, 2-trifluoroethoxy) methyl-4-methylsulfonylbenzoic acid and 2-chloro-3- [ (RS) -tetrahydrofuran-2-ylmethoxymethyl ] -4-methylsulfonylbenzoic acid, but the present invention is not limited to the above detailed procedures, i.e. it is not meant that the present invention must rely on the above detailed procedures to be practiced. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.