Synthesis method of 3-(difluoromethylsulfonyl) benzoic acid compound

Abstract

The invention provides a synthesis method of a 3-(difluoromethylsulfonyl) benzoic acid compound, and belongs to the technical field of organic synthesis. Comprising the following steps: (1) reacting an m-aminobenzoic acid compound with xanthate to prepare an intermediate 1; (2) carrying out esterification reaction on the intermediate 1 and methanol to prepare an intermediate 2; (3) reacting the intermediate 2 with difluoro haloacetate to prepare an intermediate 3; (4) generating an intermediate 4 from the intermediate 3 under the oxidation action of an oxidizing agent; and (5) carrying out ester hydrolysis reaction on the intermediate 4 under the action of alkali to obtain the product. The synthesis method is simple, mild in condition, relatively high in product yield, free of expensive metal catalyst, low in cost, easy to realize industrial application, economical, efficient and wide in application prospect.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of organic synthesis, in particular to a synthesis method of 3-(difluoromethylsulfonyl) benzoic acid compounds. BACKGROUND

[0002] Organic fluorine compounds have very important roles in medicine, pesticides, new materials and life science. The physical and chemical properties and biological properties of organic compounds can be changed by introducing fluorine atoms into the organic compounds, so in recent years, the methods and means for efficiently introducing fluorine into molecules have attracted high attention from synthetic chemists. Organic fluorine compounds have very important applications in the medicine industry, and about 15-20% of the new drugs on the market are organic fluorine compounds every year. Among all the fluorine-containing groups, the difluoromethyl methylene is relatively special, the hydrogen atoms in the difluoromethyl have weak acidity, can form hydrogen bonds with the electron-rich system in biological macromolecules, and are conducive to the combination of drugs and receptors, so as to improve the activity of the drugs or lead compounds.

[0003] The synthesis of difluoromethyl aromatic compounds is one of the current research hotspots. With the increasing attention to sustainable development and human health, green chemistry with characteristics such as high efficiency, low pollution and atom economy has attracted widespread attention, so the efficient and green synthesis method of difluoromethyl aromatic compounds has attracted much attention.

[0004] The traditional synthesis method of 3-(difluoromethylsulfonyl) benzoic acid compounds is relatively more steps, cumbersome, the total yield is not high, or an expensive metal catalyst needs to be used, and the cost is too high.

[0005] Therefore, developing an economical and efficient synthesis method of 3-(difluoromethylsulfonyl) benzoic acid compounds will have broad application prospects. SUMMARY

[0006] The purpose of the application is to provide a synthesis method of 3-(difluoromethylsulfonyl) benzoic acid compounds, which is simple, has mild conditions, has a relatively high product yield, does not need to use an expensive metal catalyst, has low cost, is easy to realize industrial application, is economical and efficient, and has broad application prospects.

[0007] The technical scheme of the application is as follows:

[0008] The application provides a 3-(difluoromethylsulfonyl) benzoic acid compound, and the structural formula of the 3-(difluoromethylsulfonyl) benzoic acid compound is as shown in formula I:

[0009] ;

[0010] Formula I;

[0011] wherein R1, R2, R3, R4=H, C n H 2n+1 or OC n H 2n+1 , F, Cl or Br; n=1 or 2.

[0012] The application further provides a synthesis method of the 3-(difluoromethylsulfonyl)benzoic acid compound, comprising the following steps:

[0013] (1) reacting the m-aminobenzoic acid compound with xanthate to prepare an intermediate 1;

[0014] (2) esterifying the intermediate 1 with alcohol to prepare an intermediate 2;

[0015] (3) difluoromethylating the intermediate 2 with difluoro halogenated acetate to prepare an intermediate 3;

[0016] (4) generating the intermediate 4 under the oxidation of an oxidant;

[0017] (5) hydrolyzing the intermediate 4 under the action of a base to prepare a product.

[0018] As a further improvement of the application, the molar ratio of the m-aminobenzoic acid compound to xanthate in step (1) is 1:1-1.5, and the m-aminobenzoic acid compound has a structural formula as shown in formula II:

[0019] ;

[0020] formula II;

[0021] wherein R1, R2, R3, R4=H, C n H 2n+1 or OC n H 2n+1 , F, Cl or Br; n=1 or 2, and the xanthate is at least one of potassium ethyl xanthate, sodium ethyl xanthate and potassium butyl xanthate.

[0022] As a further improvement of the application, the temperature of the reaction in step (1) is 40-50°C, and the time is 1-3h.

[0023] As a further improvement of the application, a catalyst sulfuric acid is added to the esterification reaction in step (2), and the molar ratio of the intermediate 1 to sulfuric acid is 1:0.8-1.2.

[0024] As a further improvement of the application, the temperature of the esterification reaction in step (2) is 75-85°C, and the time is 2-4h.

[0025] As a further improvement of the present invention, the molar ratio of intermediate 2 to difluorohaloacetate in step (3) is 1:0.9-1.2, and the difluorohaloacetate is at least one of sodium difluorochloroacetate, sodium difluorobromoacetate, and potassium difluorobromoacetate.

[0026] As a further improvement of the present invention, the reaction temperature in step (3) is 85-95°C and the time is 0.5-1.5h.

[0027] As a further improvement of the present invention, the molar ratio of intermediate 3 to oxidant in step (4) is 1:2.4-2.6, and the oxidant is m-chloroperoxybenzoic acid or hydrogen peroxide.

[0028] As a further improvement of the present invention, the oxidation reaction temperature in step (4) is 40-50°C and the time is 14-18h.

[0029] As a further improvement of the present invention, the hydrolysis reaction in step (5) is carried out at room temperature for 1-3 hours, and the molar ratio of intermediate 4 to base is 1:1-1.2.

[0030] The present invention has the following beneficial effects:

[0031] The method for preparing 3-(difluoromethanesulfonyl)benzoic acid compounds involved in this invention has high availability of raw materials: This invention uses m-aminobenzoic acid compounds as starting materials. These compounds have simple structures, are widely available commercially, or can be efficiently synthesized through known routes. Therefore, the cost of raw materials and supply risks are greatly reduced. Compared with those routes that require rare or complex intermediates, the raw material supply chain of this invention is more stable and the process is more scalable.

[0032] The present invention relates to a method for preparing 3-(difluoromethanesulfonyl)benzoic acid compounds, and optimizes the difluoromethylating reagent: The present invention avoids the use of monochlorodifluoromethane (CHClF2) as a difluoromethylating reagent, as this gas has a high vapor pressure, is highly hazardous to operation, and is subject to strict environmental regulations; The present invention uses a stable solid difluorohaloacetate as a difluoromethylating reagent, which makes the reaction conditions milder and more controllable, significantly improves the safety of operation, and the difluorohaloacetate can efficiently generate a difluoromethyl source in the reaction, resulting in better reaction selectivity and fewer impurities.

[0033] The present invention relates to a method for preparing 3-(difluoromethanesulfonyl)benzoic acid compounds, with optimized oxidizing reagents: The present invention utilizes the traditionally used Oxone® (tri-salt system, typically...) Instead, m-CPBA (m-chloroperoxybenzoic acid) is used for oxidation. The advantages of this approach include:

[0034] (1) Higher yield: m-CPBA is an organic soluble peracid with a well-defined oxygen transfer mechanism (“butterfly mechanism”) and good stereoselectivity. m-CPBA can provide better and more reliable yields than Oxone.

[0035] (2) Equivalent reduction: Compared with Oxone, under the optimized conditions of this invention, the amount of m-CPBA can be significantly reduced, thereby reducing reagent costs. Although Oxone itself is inexpensive, it often requires a large amount or a complex buffer system when used.

[0036] (3) Mild reaction and good selectivity: m-CPBA reacts well in organic solvents and can achieve highly selective oxidation under appropriate conditions. Oxone is strongly acidic in aqueous solution, and this acidic environment may cause side reactions or decomposition of acid-sensitive substrates.

[0037] The present invention relates to a method for preparing 3-(difluoromethanesulfonyl)benzoic acid compounds, with mild reaction conditions: the synthesis of similar compounds in the prior art often requires high temperatures (up to 280 °C) to achieve an effective reaction, while the reaction of the present invention only requires about 90 °C and the reaction time is about 1 hour, which greatly reduces energy consumption and improves reaction safety.

[0038] The present invention relates to a method for preparing 3-(difluoromethanesulfonyl)benzoic acid compounds, and the protection of the carboxylic acid functional group: The present invention adds a step in the key intermediate: converting the carboxylic acid (–COOH) into an ester (–COOR) protecting group. This protection strategy has the following advantages:

[0039] (1) Suppressing side reactions: Unprotected carboxylic acids may participate in side reactions (such as lactone formation, elimination, rearrangement, etc.) in subsequent reactions (such as difluoromethylation, oxidation, etc.), while protection to ester can significantly reduce these undesirable pathways.

[0040] (2) Improved selectivity: Ester protection reduces the polarity and acid interference of the carboxylic acid itself, making the substrate more focused on the target reaction in subsequent steps.

[0041] The method for preparing 3-(difluoromethanesulfonyl)benzoic acid compounds disclosed in this invention has the advantages of easy preparation and storage of difluoromethylating reagents, high reaction selectivity, good functional group compatibility, wide substrate applicability, and environmental friendliness.

[0042] This invention relates to a method for preparing 3-(difluoromethanesulfonyl)benzoic acid compounds, using m-aminobenzoic acid compounds as raw materials and difluorohaloacetate as difluoromethylating reagents. This method offers advantages such as ease of preparation and storage, a simple reaction system, and mild reaction conditions. Simultaneously, it enables precise control of the reaction, improves reaction yield, reduces side reactions, and shortens reaction time, obtaining 3-(difluoromethanesulfonyl)benzoic acid compounds in an energy-saving, environmentally friendly, efficient, and safe manner.

[0043] This invention relates to a method for preparing 3-(difluoromethanesulfonyl)benzoic acid compounds, which exhibits high reaction selectivity and yield. The obtained 3-(difluoromethanesulfonyl)benzoic acid compounds belong to the class of fluorinated aromatic carboxylic acids and are commonly used as intermediates in organic synthesis, applicable to the synthesis of pharmaceuticals, functional materials, and other molecules. The difluoromethanesulfonyl group (-SO2CHF2) and carboxyl group (-COOH) in their structure endow them with high reactivity, while the introduction of fluorine atoms can regulate the compound's physicochemical properties such as lipophilicity and stability. Therefore, this invention has significant application value and socio-economic benefits. Attached Figure Description

[0044] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0045] Figure 1 FNMR of 3-((difluoromethyl)sulfonyl)-4-methylbenzoic acid prepared in this invention;

[0046] Figure 2 The ¹H NMR of 3-((difluoromethyl)sulfonyl)-4-methylbenzoic acid prepared in this invention;

[0047] Figure 3 The chromatogram of 3-((difluoromethyl)sulfonyl)-4-methylbenzoic acid was obtained by using a YMC-Triart C18 (4.6 mm × 250 mm, 5.0 μm) column from Japan. Detailed Implementation

[0048] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0049] Example 1:

[0050] A method for preparing a 3-(difluoromethanesulfonyl)benzoic acid compound, the synthetic route of which is as follows:

[0051] ;

[0052] In this context, compounds 1, 2, 3, and 4 represent intermediates obtained from the first to fourth steps of the reaction, respectively, and compound 5 represents the final product 3-((difluoromethyl)sulfonyl)-4-methylbenzoic acid.

[0053] Includes the following steps:

[0054] 1) Preparation of Compound 1

[0055] The specific procedure is as follows: Add 1.50 L of water and 0.6 L of hydrochloric acid to a 10 L reaction flask, control the temperature at 0-10℃, then add 150.00 g of 3-amino-4-methylbenzoic acid. Then, under nitrogen protection at 0-5℃, add an aqueous solution of sodium nitrite prepared from 71.89 g of sodium nitrite and 1.50 L of water dropwise to the reaction flask. After the addition is complete, react for 20 min. Then, add the resulting reaction solution to a mixture of 347.06 g of sodium carbonate, 1.50 L of aqueous solution, and 190.87 g of potassium ethyl xanthate, heat to 45℃ and react for 2 h. Cool to 0℃, adjust the pH to 4, filter and collect the precipitated solid. Dissolve the obtained solid in ethanol, then add to a solution containing 222.69 g of sodium carbonate. In a potassium hydroxide aqueous solution prepared by mixing 0.75 L of potassium hydroxide and 0.75 L of water, the reaction was carried out at 80 °C for 1 h. The temperature was then lowered to 10 °C, the pH was adjusted to 4, and a solid precipitated. The solid was collected and washed with 0.3 L of water. The resulting solid was then dissolved in 0.75 L of dichloromethane and 1.5 L of methanol. The mixture was separated, and the organic phase was concentrated and mixed with silica gel at 1.2 times the amount of the crude product. The column was lined with silica gel at 5 times the amount of the crude product. The product was eluent with dichloromethane:methanol = 100:0-50:1. The fraction was concentrated at 45 °C to obtain 70 g of solid compound 1.

[0056] Step 1 yield: 40-50% by mass; 35-45% by molar yield. Storage requirements for compound 1: Store under nitrogen protection.

[0057] 2) Preparation of Compound 2

[0058] The specific operation is as follows: 70g of solid compound 1 obtained in step 1) and 1.05L of methanol are added to a 2L reaction flask. Under the condition of controlling the temperature at 10-30℃, 40.81g of sulfuric acid is added dropwise. After the addition is completed, the reaction is carried out at 80℃ for 3 hours. The resulting reaction solution is extracted twice with 1.05L of dichloromethane. The organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated at 45℃ to obtain 75g of oily compound 2.

[0059] Step 2 mass yield: 100-110%; molar yield: 95-100%; storage requirements for compound 2: store at room temperature.

[0060] 3) Preparation of compound 3

[0061] The specific operation is as follows: 62.74 g of sodium difluorochloroacetate and 65.43 g of sodium carbonate were dissolved in 1.05 LDMF. After nitrogen purging three times, 75.0 g of compound 2 obtained in step 2) was added dropwise to this solution. After the addition was completed, the reaction was carried out under nitrogen protection at 90°C for 1 h. Then the reaction was cooled to room temperature, the reaction solution was added to water, and ethyl acetate was added for extraction several times. The organic phases were combined, washed with brine, separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated at 45°C to obtain 14 g of oily compound 3.

[0062] Step 3: Mass yield: 15-20%; Molar yield: 10-20%; Storage requirements for compound 3: Store at room temperature.

[0063] 4) Preparation of compound 4

[0064] The specific operation is as follows: Dissolve 14.0 g of compound 3 obtained in step 3) in 280 mL of chloroform, cool to 0℃, and then control the temperature to 10-20℃. Add 30.6 g of 85wt% m-CPBA (m-chloroperoxybenzoic acid) solution in batches to this mixture. After the addition is completed and the temperature is restored to room temperature, heat to 45℃ and react for 16 h. Then cool the reaction solution to 0-10℃, quench the excess m-CPBA with 140 mL of saturated sodium sulfite aqueous solution, stir for 30 min, filter the quenched reaction system, separate the filtrate, extract with dichloromethane, adjust the pH of the organic phase to 8-9 with 140 mL of saturated sodium carbonate aqueous solution, and then extract with 100 mL of dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, wash with dichloromethane, and then concentrate the filtrate at 47℃ to obtain 8.00 g of solid compound 4.

[0065] Step 4: Mass yield: 50-60%; Molar yield: 45-55%; Storage requirements for compound 4: Store at room temperature.

[0066] 5) Preparation of compound 5

[0067] The specific operation is as follows: Dissolve 8.00 g of compound 4 obtained in step 4) in 80.0 mL of tetrahydrofuran and 80.0 mL of water, add 1.40 g of lithium hydroxide monohydrate, react at room temperature for 2 h, concentrate the reaction solution at 45 °C, adjust the pH to 4 with hydrochloric acid, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase at 45 °C to obtain 7.00 g of compound 5, which is the target product 3-((difluoromethyl)sulfonyl)benzoic acid compound.

[0068] Step 5: Mass yield: 85-95%; Molar yield: 85-95%; Storage requirements for compound 5: Store at room temperature.

[0069] Among them, the FNMR of compound 5 obtained in Example 1 is as follows: Figure 1 As shown; HNMR as Figure 2 As shown. Based on the NMR fluorine spectrum and NMR 1H spectrum data, as well as the reactant structure and reaction mechanism, the structure of compound 5 can be deduced as follows. .

[0070] Figure 3 The chromatogram of compound 5 obtained in Example 1 was obtained by detecting a YMC-Triart C18 (4.6 mm × 250 mm, 5.0 μm) column.

[0071] High performance liquid chromatograph model: Agilent 1100.

[0072] Solvent: Acetonitrile-water (80:20)

[0073] Test solution: Take an appropriate amount of compound 5 obtained in Example 1, dissolve it in solvent and dilute it quantitatively to prepare a solution containing about 0.5 mg per 1 ml.

[0074] The column was packed with octadecylsilane-bonded silica gel (YMC-Triart C18, 4.6 mm × 250 mm, 5 μm or equivalent performance). A gradient elution was performed using 0.05% trifluoroacetic acid aqueous solution as mobile phase A and methanol as mobile phase B. The flow rate was 0.8 mL / min; the column temperature was 25 °C; the detection wavelength was 210 nm; and the injection volume was 5 μl. The gradient elution program was as follows: 0–15 min, mobile phase B volume ratio increased from 50% to 75%; 15–20 min, mobile phase B volume ratio increased from 75% to 90%; 20–30 min, mobile phase B volume ratio was maintained at 90% equilibrium; 30–31 min, mobile phase B volume ratio decreased from 90% to 50%; and 31–36 min, mobile phase B volume ratio was maintained at 50% equilibrium.

[0075] Depend on Figure 3It can be seen that the main peak retention time is 6.235 min, the peak area is 1.89485e4 mAU*s, and the peak area ratio is 97.2138%. There are a total of 8 impurity peaks, all of which have a peak area ratio of less than 2%, and 7 of them have a ratio of less than 0.5%, indicating that the overall purity is high.

[0076] Example 2:

[0077] A method for preparing a 3-(difluoromethanesulfonyl)benzoic acid compound, the synthetic route of which is as follows:

[0078] ;

[0079] In this context, compounds 1, 2, 3, and 4 represent intermediates obtained from the first to fourth steps of the reaction, respectively, and compound 5 represents the final product 3-((difluoromethyl)sulfonyl)-5-ethylbenzoic acid.

[0080] Includes the following steps:

[0081] 1) Preparation of Compound 1

[0082] The specific procedure is as follows: Add 1.65 L of water and 0.66 L of hydrochloric acid to a 10 L reaction flask, maintain the temperature at 0-10℃, then add 165.00 g of 3-amino-5-ethylbenzoic acid. Then, under nitrogen protection at 0-5℃, add dropwise an aqueous solution of sodium nitrite prepared from 72.45 g of sodium nitrite and 1.65 L of water to the reaction flask. After the addition is complete, react for 20 min. Then, add the resulting reaction solution to a mixture of 349.8 g of sodium carbonate, 1.65 L of aqueous solution, and 158.5 g of sodium ethyl xanthate, heat to 40℃ and react for 3 h. Cool to 0℃, adjust the pH to 4, filter and collect the precipitated solid. Dissolve the obtained solid in ethanol, then add it to a mixture of 224.44 g of potassium hydroxide and 0.825 g of sodium ethyl xanthate. In a potassium hydroxide aqueous solution prepared with L of water, the reaction was carried out at 80℃ for 1 h; the temperature was lowered to 10℃, the pH was adjusted to 4, and a solid precipitated. The solid was collected and washed with 0.33 L of water. The resulting solid was then dissolved in 1.65 L of dichloromethane and 1.65 L of methanol, separated, and the organic phase was concentrated and mixed with silica gel. The sample was then passed through a column with 1.2 times the amount of the crude product mixed with silica gel. The column was lined with 5 times the amount of the crude product. The product was eluent with dichloromethane:methanol = 100:0-50:1. The fraction was concentrated at 45℃ to obtain 77 g of solid compound 1.

[0083] Step 1) Mass yield: 40-50%; Molar yield: 35-45%. Storage requirements for compound 1: Store under nitrogen protection.

[0084] 2) Preparation of Compound 2

[0085] The specific operation is as follows: 77g of solid compound 1 obtained in step 1) and 1.15L of methanol are added to a 2L reaction flask. Under the condition of controlling the temperature at 10-30℃, 41.44g of sulfuric acid is added dropwise. After the addition is completed, the reaction is carried out at 70℃ for 4 hours. The resulting reaction solution is extracted twice with 1.15L of dichloromethane. The organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated at 45℃ to obtain 82g of oily compound 2.

[0086] Step 2) Mass yield: 100-110%; Molar yield: 95-100%; Storage requirements for compound 2: Store at room temperature.

[0087] 3) Preparation of compound 3

[0088] The specific operation is as follows: 82.24 g of sodium difluorobromoacetate and 66.43 g of sodium carbonate were dissolved in 1.23 L of DMF. After nitrogen purging three times, 82.0 g of compound 2 obtained in step 2) was added dropwise to this solution. After the addition was completed, the reaction was carried out under nitrogen protection at 80℃ for 1 h. Then the reaction was cooled to room temperature, the reaction solution was added to water, and ethyl acetate was added for extraction several times. The organic phases were combined, washed with brine, separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated at 45℃ to obtain 15.5 g of oily compound 3.

[0089] Step 3) Mass yield: 15-20%; Molar yield: 10-20%; Storage requirements for compound 3: Store at room temperature.

[0090] 4) Preparation of compound 4

[0091] The specific operation is as follows: Dissolve 15.5 g of compound 3 obtained in step 3) in 310 mL of chloroform, cool to 0℃, and then control the temperature to 10-20℃. Add 31.95 g of 85 wt% m-CPBA (m-chloroperoxybenzoic acid) solution in batches to this mixture. After the addition is completed and the temperature is restored to room temperature, heat to 40℃ and react for 18 h. Then cool the reaction solution to 0-10℃, quench the excess m-CPBA with 155 mL of saturated sodium sulfite aqueous solution, stir for 30 min, filter the quenched reaction system, separate the filtrate, extract with dichloromethane, adjust the pH of the organic phase to 8-9 with 155 mL of saturated sodium carbonate aqueous solution, and then extract with 111 mL of dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, wash with dichloromethane, and then concentrate the filtrate at 47℃ to obtain 9 g of solid compound 4.

[0092] Step 4) Mass yield: 50-60%; Molar yield: 45-55%; Storage requirements for compound 4: Store at room temperature.

[0093] 5) Preparation of compound 5

[0094] The specific operation is as follows: Dissolve 9 g of compound 4 obtained in step 4) in 90 mL of tetrahydrofuran and 90 mL of water, add 1.42 g of sodium hydroxide, react at room temperature for 2 h, concentrate the reaction solution at 45 °C, adjust the pH to 4 with hydrochloric acid, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase at 45 °C to obtain 7.8 g of compound 5, which is the target product 3-((difluoromethyl)sulfonyl)-5-ethylbenzoic acid.

[0095] Step 5) Mass yield: 85-95%; Molar yield: 85-95%; Storage requirements for compound 5: Store at room temperature.

[0096] Example 3:

[0097] A method for preparing a 3-(difluoromethanesulfonyl)benzoic acid compound, the synthetic route of which is as follows:

[0098] ;

[0099] Among them, compounds 1, 2, 3 and 4 represent intermediates obtained from the first to the fourth steps of the reaction, respectively, and compound 5 represents the final product 3-((difluoromethyl)sulfonyl)-6-methoxybenzoic acid.

[0100] Includes the following steps:

[0101] 1) Preparation of Compound 1

[0102] The specific procedure is as follows: Add 1.67 L of water and 0.67 L of hydrochloric acid to a 10 L reaction flask, maintain the temperature at 0-10℃, then add 167.16 g of 3-amino-6-methoxybenzoic acid. Then, under nitrogen protection at 0-5℃, add an aqueous solution of sodium nitrite prepared from 72.45 g of sodium nitrite and 1.67 L of water dropwise, allowing the reaction to proceed for 20 min after the addition is complete. Next, add the resulting reaction solution to a mixture of 349.7 g of sodium carbonate, 1.67 L of aqueous solution, and 226 g of potassium butyl xanthate, and heat to 50℃ for 1 h. Cool to 0℃, adjust the pH to 4, filter and collect the precipitated solid. Dissolve the solid in ethanol, then add it to a mixture of 224.4 g of potassium hydroxide and 0.84 g of hydrochloric acid. In a potassium hydroxide aqueous solution prepared with L of water, the reaction was carried out at 90℃ for 1 h; the temperature was lowered to 10℃, the pH was adjusted to 4, and a solid precipitated. The solid was collected and washed with 0.3 L of water. The resulting solid was then dissolved in 1.67 L of dichloromethane and 0.17 L of methanol, separated, and the organic phase was concentrated and mixed with silica gel. The sample was then passed through a column with 1.2 times the amount of the crude product mixed with silica gel. The column was lined with 5 times the amount of the crude product. The product was eluent with dichloromethane:methanol = 100:0-50:1. The fraction was concentrated at 45℃ to obtain 78.5 g of solid compound 1.

[0103] Step 1) Mass yield: 40-50%; Molar yield: 35-45%. Storage requirements for compound 1: Store under nitrogen protection.

[0104] 2) Preparation of Compound 2

[0105] The specific operation is as follows: 78.5g of solid compound 1 obtained in step 1) and 1.18 L of methanol are added to a 5L reaction flask. Under the condition of temperature control at 10-30℃, 41.8 g of sulfuric acid is added dropwise. After the addition is completed, the reaction is carried out at 90℃ for 2 h. The resulting reaction solution is extracted twice with 1.18 L of dichloromethane. The organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated at 45℃ to obtain 83.2g of oily compound 2.

[0106] Step 2) Mass yield: 100-110%; Molar yield: 95-100%; Storage requirements for compound 2: Store at room temperature.

[0107] 3) Preparation of compound 3

[0108] The specific operation is as follows: 90.26 g of potassium difluorobromoacetate and 66.75 g of sodium carbonate were dissolved in 1.25 LDMF. After nitrogen purging three times, 83.2 g of compound 2 obtained in step 2) was added dropwise to this solution. After the addition was completed, the reaction was carried out under nitrogen protection at 100℃ for 1 h. Then the reaction was cooled to room temperature, and the reaction solution was added to water. Ethyl acetate was added and extracted several times. The organic phases were combined, washed with brine, separated, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated at 45℃ to obtain 15.7 g of oily compound 3.

[0109] Step 3) Mass yield: 15-20%; Molar yield: 10-20%; Storage requirements for compound 3: Store at room temperature.

[0110] 4) Preparation of compound 4

[0111] The specific operation is as follows: Dissolve 15.7 g of compound 3 obtained in step 3) in 314 mL of chloroform, cool to 0℃, and then control the temperature to 10-20℃. Add 32.10 g of 85wt% m-CPBA (m-chloroperoxybenzoic acid) solution in batches to this mixture. After the addition is completed and the temperature is restored to room temperature, heat to 50℃ and react for 14 h. Then cool the reaction solution to 0-10℃, quench the excess m-CPBA with 157 mL of saturated sodium sulfite aqueous solution, stir for 30 min, filter the quenched reaction system, separate the filtrate, extract with 110 mL of dichloromethane, adjust the pH of the organic phase to 8-9 with 110 mL of saturated sodium carbonate aqueous solution, and then extract with dichloromethane. Dry the organic phase with anhydrous sodium sulfate, filter, wash with dichloromethane, and then concentrate the filtrate at 47℃ to obtain 9 g of solid compound 4.

[0112] Step 4): Mass yield: 50-60%; Molar yield: 45-55%; Storage requirements for compound 4: Store at room temperature.

[0113] 5) Preparation of compound 5

[0114] The specific operation is as follows: Dissolve 9 g of compound 4 obtained in step 4) in 90 mL of tetrahydrofuran and 90 mL of water, add 1.98 g of potassium hydroxide, react at room temperature for 2 h, concentrate the reaction solution at 45 °C, adjust the pH to 4 with hydrochloric acid, extract with ethyl acetate, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the organic phase at 45 °C to obtain 8 g of compound 5, namely the target product 3-((difluoromethyl)sulfonyl)-6-methoxybenzoic acid.

[0115] Step 5) Mass yield: 85-95%; Molar yield: 85-95%; Storage requirements for compound 5: Store at room temperature.

[0116] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing 3-(difluoromethanesulfonyl)benzoic acid compounds, characterized in that, The structural formula of the 3-(difluoromethanesulfonyl)benzoic acid compounds is shown in Formula I: ； Formula I; Where R1, R2, R3, R4 = H, C n H 2n+1 or OC n H 2n+1 F, Cl or Br; n=1 or 2; The preparation method includes the following steps: (1) React m-aminobenzoic acid compounds with xanthate to prepare intermediate 1; (2) Intermediate 1 is esterified with an alcohol to obtain intermediate 2; (3) Intermediate 2 is reacted with difluorohaloacetate by difluoromethylation to obtain intermediate 3; (4) Intermediate 3 is oxidized by an oxidizing agent to generate intermediate 4; (5) The intermediate 4 is subjected to ester hydrolysis under the action of alkali to obtain the product.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of the m-aminobenzoic acid compound to xanthate in step (1) is 1:1-1.5, and the structural formula of the m-aminobenzoic acid compound is shown in Formula II: ； Formula II; Where R1, R2, R3, R4 = H, C n H 2n+1 or OC n H 2n+1 F, Cl or Br; n=1 or 2, wherein the xanthate is at least one of potassium ethyl xanthate, sodium ethyl xanthate, and potassium butyl xanthate.

3. The synthesis method according to claim 1, characterized in that, The reaction in step (1) is carried out at a temperature of 40-50℃ for 1-3 hours.

4. The synthesis method according to claim 1, characterized in that, In step (2), sulfuric acid was added as a catalyst for the esterification reaction, and the molar ratio of intermediate 1 to sulfuric acid was 1:0.8-1.

2.

5. The synthesis method according to claim 1, characterized in that, The esterification reaction in step (2) is carried out at a temperature of 75-85℃ for 2-4 hours.

6. The synthesis method according to claim 1, characterized in that, In step (3), the molar ratio of intermediate 2 to difluorohaloacetate is 1:0.9-1.2, and the difluorohaloacetate is at least one of sodium difluorochloroacetate, sodium difluorobromoacetate, and potassium difluorobromoacetate.

7. The synthesis method according to claim 1, characterized in that, The reaction in step (3) is carried out at a temperature of 85-95℃ for 0.5-1.5h.

8. The synthesis method according to claim 1, characterized in that, In step (4), the molar ratio of intermediate 3 to oxidant is 1:2.4-2.6, and the oxidant is m-chloroperoxybenzoic acid or hydrogen peroxide.

9. The synthesis method according to claim 1, characterized in that, The oxidation reaction in step (4) is carried out at a temperature of 40-50℃ for 14-18 hours.

10. The synthesis method according to claim 1, characterized in that, The hydrolysis reaction in step (5) is carried out at room temperature for 1-3 hours, and the molar ratio of intermediate 4 to base is 1:1-1.2.

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