Preparation method of 4-methylsulfonyl phenylacetic acid
Through the reaction of p-fluorobromobenzene and sodium methanesulfonate and the participation of copper catalyst, 4-methanesulfonylphenylacetic acid was prepared, which solved the problems of difficult synthesis and low product yield in the prior art, and achieved an efficient and environmentally friendly preparation process.
Patent Information
- Application Number
- CN202411789729.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-06
- Publication Date
- 2025-04-15
AI Technical Summary
The existing synthesis route of 4-methanesulfonylphenylacetic acid has problems such as difficult operation, low product yield and environmental pollution.
Using para-fluorobromobenzene as the starting material, 4-methanesulfonylbromobenzene is produced by aryl nucleophilic substitution reaction with sodium methanesulfonate, and substitution reaction is carried out with malonate in the presence of a copper catalyst and ligand, followed by hydrolysis to obtain 4-methanesulfonylphenylacetic acid.
The preparation of 4-methanesulfonylphenylacetic acid with mild reaction, high product yield (up to 90%) and high purity (up to 99%) was achieved, avoiding high temperature conditions and environmental pollution.
Smart Images
Figure BDA0005175029330000021 
Figure BDA0005175029330000022 
Figure BDA0005175029330000023
Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing 4-methylsulfonylphenylacetic acid, and belongs to the technical field of drug intermediate synthesis. Background Art
[0002] 4-Methylsulfonylphenylacetic acid is an important intermediate of various drugs, such as an intermediate of a new generation of cyclooxygenase-2 (COX-2) inhibitors and the like, and is also a key intermediate for the synthesis of etoricoxib, and has a wide range of application prospects. At present, the synthesis of 4-methylsulfonylphenylacetic acid mainly includes using ethyl 4-mercaptophenylacetate as a starting material, and generating the target product 4-methylsulfonylphenylacetic acid through methylation, oxidation and hydrolysis. The main disadvantage of this route is that the methylating agent (such as iodomethane, dimethyl sulfate, etc.) is highly toxic, and the oxidizing agent (such as mCPBA) is prone to explosion hazard during post-treatment. There are also some methods that use 4-methylsulfonylacetophenone as a starting material, synthesize 2-(4-(methylsulfonyl)phenyl)-1-morpholinoethanethiol through the Wilgerodt-Kindler reaction, and then obtain the target product 4-methylsulfonylphenylacetic acid through a hydrolysis reaction. The main disadvantages of this process route are that it usually requires high temperature (above 130°C) and a reaction time of more than 10 hours. The reaction is difficult to control and the product yield is low, which is not conducive to industrial production. There is also a synthetic route that uses 4-methylthioacetophenone as a raw material, and obtains 4-methylsulfonylphenylacetic acid through WilgerodtKindler reaction, hydrolysis reaction, and potassium persulfate oxidation. This route also has problems with reaction temperature and time, low product yield, and the reaction is not easy to operate. The starting material 4-methylthioacetophenone is expensive and in short supply in the market, which is not conducive to industrial production. It also produces hydrogen sulfide gas, etc., which pollutes the environment. Summary of the invention
[0003] The present invention aims at the defects existing in the above prior art and provides a method for preparing 4-methylsulfonylphenylacetic acid, in order to solve the problems that the existing reaction route is difficult to operate and has a low product yield.
[0004] The object of the present invention is achieved by the following technical scheme: a method for preparing 4-methylsulfonylphenylacetic acid, the method comprising the following steps:
[0005] A. Using p-fluorobromobenzene, a compound of formula II, as a starting material, subjecting p-fluorobromobenzene, a compound of formula II, to an aromatic nucleophilic substitution reaction with sodium methanesulfonate to obtain 4-methylsulfonylbromobenzene, a compound of formula III;
[0006]
[0007] B. In the presence of an alkaline substance, a copper catalyst and a ligand, a substitution reaction is carried out between the compound of formula III, 4-methylsulfonyl bromobenzene, and a malonic ester in an inert organic solvent to obtain a compound of formula IV;
[0008]
[0009] R in the compound of formula IV is selected from a C1-C4 alkyl group;
[0010] C. hydrolyzing the compound of formula IV in the presence of an acid or a base to obtain the product compound of formula I, 4-methylsulfonylphenylacetic acid;
[0011]
[0012] The present invention reselects and designs the starting raw materials, takes 4-methylsulfonyl bromobenzene as a substrate, and first performs an aromatic substitution reaction with sodium methanesulfonate to obtain 4-methylsulfonyl bromobenzene. More importantly, by using a copper catalyst and a ligand as the catalyst system of the second step reaction, the methylene group in the malonic acid ester can be activated and attack the bromine group of 4-methylsulfonyl bromobenzene. The intermediate obtained only needs to be subsequently hydrolyzed to obtain the corresponding final product. The reaction is mild and does not require high temperature conditions. It has the advantages of good reaction operability. The synthetic route of the present invention can better avoid the generation of impurities, and the product yield and purity can be effectively improved. The yield reaches more than 90%, and the purity reaches more than 99%. At the same time, the reaction process of the present invention does not produce hydrogen sulfide gas to cause environmental pollution, and is environmentally friendly. Preferably, the malonic acid ester in the above step B is preferably selected from diethyl malonate, dimethyl malonate, dipropyl malonate, and diisopropyl malonate; and R in the compound of formula IV is selected from methyl, ethyl, propyl or isopropyl.
[0013] In the above-mentioned preparation method of 4-methylsulfonylphenylacetic acid, as a preference, the copper catalyst is selected from a copper salt catalyst and / or a cuprous salt catalyst. By using a copper salt or a cuprous salt as the main catalytic system and promoting the methylene activity in the malonic ester, it is more conducive to the substitution reaction, and the reaction can be reacted under milder conditions without the need for high temperature conditions, which is more conducive to simplifying the operation. As a further preference, the copper salt catalyst is selected from one or more of copper trifluoromethanesulfonate, copper chloride, copper bromide, copper acetate and copper sulfate; the cuprous salt catalyst is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride and cuprous trifluoromethanesulfonate. The above-mentioned copper salt or cuprous salt not only has a better promotion of the reaction, but also the raw materials used are easy to obtain, which is conducive to reducing production costs.
[0014] In the above-mentioned method for preparing 4-methylsulfonylphenylacetic acid, the ligand in step B is preferably a substance that can form a complex with the copper catalyst, such as an amide ligand, which can be a monoamide or a diamide. Phenolic ligands, carboxylic acid ligands and proline ligands can also be used, which can better cooperate with the copper catalyst to activate the methylene group in the malonic ester and better attack the bromine on the benzene ring, thereby having high reaction efficiency and the obtained intermediate product also has the effect of high yield and high purity. Preferably, the ligand is selected from one or more of oxalyl diamide, oxalic acid monoamide, monoamide oxalate, (n,n-di-2,4,6-trimethoxyphenyl)-oxalic acid-diamide, N,N′-di(o-methylphenyl) oxalic acid diamide, n-(2,6-dimethylphenyl) oxalic acid monoamide, n-phenyl oxalic acid monoamide, N,N′-di(m-chlorophenyl) oxalic acid diamide, phenol, 2-pyridinecarboxylic acid, o-phenylphenol, 2-hydroxybenzaldehyde vinyl acetal, 2-thiophenecarboxylic acid, benzothiophene-2-carboxylic acid, L-proline and trans-4-hydroxy-L-proline.
[0015] In the above-mentioned preparation method of 4-methylsulfonylphenylacetic acid, preferably, the alkaline substance in step B is selected from an inorganic base or an organic base, and the inorganic base is selected from one or more of alkali metal carbonates, alkali metal phosphates, alkali metal halides, alkali metal hydroxides and alkali metal hydrides; the organic base is selected from one or more of triethylamine (TEA), dimethylisopropylamine (DIEA), 1,8-diazabicycloundec-7-ene (DBU), pyridine and pyrrole. The reaction is carried out under alkaline conditions, which can neutralize the small molecular hydrogen bromide of the product during the reaction process, so that the reaction can be better carried out in the positive direction, improve the efficiency and conversion rate of the reaction, and better ensure the yield quality of the intermediate product.
[0016] In the above-mentioned preparation method of 4-methylsulfonylphenylacetic acid, the inert organic solvent will not participate in the reaction during the reaction, which can make the reaction more gentle and uniform. It is best to use a highly polar organic solvent, which is conducive to better reaction. Preferably, the inert organic solvent in step B is selected from a sulfoxide solvent or an amide solvent; the temperature of the substitution reaction is 80°C to 110°C. The sulfoxide solvent here is selected from dimethyl sulfoxide, thionyl chloride, etc., and the amide solvent is selected from DMF, N,N-dimethylacetamide, etc.
[0017] In the above-mentioned method for preparing 4-methylsulfonylphenylacetic acid, preferably, the amount of each raw material involved in the reaction in step B can be fed according to the corresponding molar equivalent in the chemical field. In order to better improve the utilization rate of raw materials and reduce waste, it is best to make the molar ratio of the compound of formula III 4-methylsulfonyl bromobenzene: malonate: copper catalyst: ligand: alkaline substance in step B be 1: 1.0-1.3: 0.01-0.03: 0.02-0.04: 1.0-2.0. It can better promote the reaction and ensure the yield and purity of the intermediate product.
[0018] In the above-mentioned method for preparing 4-methylsulfonylphenylacetic acid, preferably, the hydrolysis reaction in step C is carried out in a mixed solvent of an alcohol solvent and water, and the temperature of the hydrolysis reaction is 50° C. to 90° C. The alcohol solvent here is preferably a lower alcohol solvent such as methanol, ethanol, propanol, isopropanol, etc.
[0019] In the above-mentioned method for preparing 4-methylsulfonylphenylacetic acid, preferably, the acid in step C is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid; and the base is selected from one or more of sodium hydroxide, potassium hydroxide or lithium hydroxide.
[0020] In the above-mentioned preparation method of 4-methylsulfonylphenylacetic acid, preferably, the amount of each raw material in step A can be based on the corresponding molar equivalent. In order to better reduce the waste of raw materials and improve the utilization rate of raw materials, it is best to make the molar ratio of p-fluorobromobenzene to sodium methanesulfonate in step A be 1:1.1-1.3.
[0021] In the preparation method of the above-mentioned 4-methylsulfonylphenylacetic acid of the present invention, the aryl substitution reaction described in step A is carried out in a sulfoxide solvent II, and the temperature of the aryl nucleophilic substitution reaction is 70°C to 95°C. Carrying out in a sulfoxide solvent can make the reaction proceed mildly, such as dimethyl sulfoxide, thionyl chloride and other solvents. The amount of the solvent can be selected according to actual needs. Furthermore, it is best to carry out the aryl substitution reaction under the condition of 82°C to 90°C. The above-mentioned sulfoxide solvent I and sulfoxide solvent II of the present invention are only for better description, and do not limit the selection of the sulfoxide solvent, and can be a selection of solvents such as dimethyl sulfoxide and thionyl chloride.
[0022] In the above-mentioned method for preparing 4-methylsulfonylphenylacetic acid, in order to better illustrate the reaction process in step C, it is preferred that the molar ratio of the compound of formula IV: the base in step C is 1:1.0-2.5; the molar ratio of the compound of formula IV: the acid is 1:1.01.0-2.5. The volume ratio of the alcohol solvent to water in step C can also be further set to 1:0.5-1.2.
[0023] The chemical reaction equation of the preparation method of the above-mentioned 4-methylsulfonylphenylacetic acid of the present invention is as follows:
[0024]
[0025] In summary, compared with the prior art, the present invention has the following advantages:
[0026] 1. The synthetic route of the present invention has a mild reaction, does not require high temperature conditions, can better avoid products with impurities, and can effectively improve the yield and purity of the product, with the yield reaching more than 90% and the purity reaching more than 99%.
[0027] 2. In the reaction process of the present invention, the copper catalyst, ligand and base are used, so the reaction can be carried out mildly, and the hydrogen sulfide gas will not be produced to cause environmental pollution, which is environmentally friendly. DETAILED DESCRIPTION
[0028] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.
[0029] Example 1
[0030] Synthesis of Formula III Compound 4-Bromobenzylsulfone
[0031]
[0032] In a 3000mL clean reaction bottle, 175.00g (1.0mol) of p-fluorobromobenzene and 141.83g (1.20mol) of sodium methanesulfonate were added, and then 1000mL of dimethyl sulfoxide was added. The temperature was controlled at 90°C and the reaction was carried out for 6 hours. After TLC detection confirmed that the raw materials had reacted completely, the reaction was over, the reaction solution was cooled to room temperature, 1000mL of ethyl acetate and 1000mL of water were added for extraction, and the organic phase (ethyl acetate phase) was collected and washed with 500mL of water. The collected organic phase was concentrated under reduced pressure to recover the solvent to dryness to obtain 231.81g (0.986mol) of 4-bromobenzyl sulfone with a yield of 98.6% and a purity of 99.2%.
[0033] Embodiment 2:
[0034] Synthesis of diethyl 2-(4-methylsulfonylphenyl)malonate (R in the compound of formula IV is ethyl)
[0035]
[0036] To a 2000mL clean reaction bottle, 230.00g (0.98mol) of 4-bromobenzylsulfone prepared in Example 1 and 1000mL of dimethyl sulfoxide were added, stirred to dissolve, 188.36g (1.18mol) of diethyl malonate was added, 478.95g (1.47mol) of cesium carbonate was added, 1.90g (0.01mol) of cuprous iodide and 2.46g (0.02mol) of 2-pyridinecarboxylic acid were added, and the vacuum nitrogen was replaced three times. After heating to 90°C for 9 hours, TLC detection confirmed that the raw material reaction was complete and the reaction result was 90%. The reaction solution was cooled to room temperature, insoluble matter was removed by filtration, and the mixture was rinsed with 250 mL of dimethyl sulfoxide. The filtrate was collected and transferred to another reactor. 6250 mL of water and 6250 mL of ethyl acetate were added to the filtrate in sequence, and stirred for extraction. The mixture was allowed to stand for stratification, and the organic phase (ethyl acetate phase) was collected. The collected organic phase was washed with water twice, each time with 1000 mL of water. The collected organic phase was concentrated under reduced pressure to recover the solvent ethyl acetate, and 305.30 g (0.97 mol) of diethyl 2-(4-methylsulfonylphenyl)malonate was obtained with a yield of 99.0% and a purity of 99.2%.
[0037] Embodiment 3:
[0038] Synthesis of 4-Methanesulfonylphenylacetic acid
[0039]
[0040] 305.30 g (0.97 mol) of diethyl 2-(4-methylsulfonylphenyl)malonate prepared in Example 2 was added to a 3000 mL clean reaction bottle, 1000 mL of isopropanol and 1000 mL of water were added, and 108.85 g (1.94 mol) of potassium hydroxide was slowly added. After the addition was completed, the temperature was raised to 80° C. and the reaction was carried out for 8 hours. TLC detection was used to confirm that the raw material reaction was complete. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove isopropanol, and the residue was added to the mixture. 1000 mL of water was added and stirred for 15 min. Then, the pH value of the system was adjusted to 1-2 with concentrated hydrochloric acid, filtered, the filter cake was rinsed with 500 mL of water, and dried to obtain a crude 4-methylsulfonylphenylacetic acid. 1250 mL of n-heptane was added to the crude product and heated to 80° C. for slurrying for 4 h. Then, the temperature was lowered to room temperature and kept warm for 2 hours, filtered, rinsed with n-heptane, and the obtained wet product was dried to obtain 190.67 g (0.89 mol) of dry 4-methylsulfonylphenylacetic acid with a yield of 91.8% and a purity of 99.4%.
[0041] Example 4
[0042] In a 2000mL clean reaction bottle, 175.00g (1.0mol) of p-fluorobromobenzene and 135.70g (1.15mol) of sodium methanesulfonate were added, and then 900mL of dimethyl sulfoxide was added. The temperature was controlled at 70°C and the reaction was carried out for 7 hours. After TLC detection confirmed that the raw materials had reacted completely, the reaction was over, the reaction solution was cooled to room temperature, 800mL of ethyl acetate and 800mL of water were added for extraction, and the mixture was allowed to stand for stratification. The organic phase (ethyl acetate phase) was collected and washed with 500mL of water. The collected organic phase was concentrated under reduced pressure to recover the solvent to dryness to obtain 228.04g (0.97mol) of 4-bromobenzyl sulfone with a yield of 97.0% and a purity of 99.3%.
[0043] Add 228 g (0.97 mol) of 4-bromobenzyl sulfone obtained above and 900 mL of dimethyl sulfoxide to a 2000 mL clean reaction bottle, stir to dissolve, add 189.00 g (1.18 mol) of diethyl malonate, continue to add 137.80 g (1.3 mol) of sodium carbonate, add 2.13 g (0.01 mol) of cuprous trifluoromethanesulfonate and 2.62 g (0.02 mol) of trans-4-hydroxy-L-proline, evacuate and replace with nitrogen three times, start heating to 80 ° C ~ 85 ° C and react for 8 hours, TLC detection confirms that the raw material reaction The reaction was complete and the reaction was over. The reaction solution was cooled to room temperature, insoluble matter was removed by filtration, and the solution was rinsed with 250 mL of dimethyl sulfoxide. The filtrate was collected and placed in another reactor. 6000 mL of water and 6000 mL of ethyl acetate were added to the filtrate in sequence, and the mixture was stirred and extracted. The mixture was allowed to stand for stratification. The organic phase (ethyl acetate phase) was collected and washed with water twice, each time with 800 mL of water. The collected organic phase was concentrated under reduced pressure to recover the solvent ethyl acetate to obtain 289.62 g (0.92 mol) of diethyl 2-(4-methylsulfonylphenyl)malonate as an intermediate with a yield of 95.0% and a purity of 99.3%.
[0044] To a 3000 mL clean reaction bottle, add 289.60 g (0.92 mol) of the above-obtained diethyl 2-(4-methylsulfonylphenyl)malonate, add 1000 mL of ethanol and 1000 mL of water, and then slowly add 60.00 g (1.5 mol) of sodium hydroxide. After the addition is completed, the temperature is raised to 70° C. to 75° C. and the reaction is carried out for 6 hours. TLC detection is used to confirm that the raw material reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove ethanol, and 10 00mL water was added and stirred for 15min, then the pH value of the system was adjusted to 1-2 with concentrated hydrochloric acid, filtered, the filter cake was rinsed with 500mL water, and dried to obtain a crude 4-methylsulfonylphenylacetic acid product. 1200mL of n-heptane was added to the crude product and heated to 80°C for slurrying for 4h. Then, the temperature was slowly lowered to room temperature and kept warm for 2 hours, filtered, rinsed with n-heptane, and the obtained wet product was dried to obtain 190.66g (0.89mol) of dry 4-methylsulfonylphenylacetic acid with a yield of 96.7% and a purity of 99.5%.
[0045] Example 5
[0046] In a 2000mL clean reaction bottle, 175.00g (1.0mol) of p-fluorobromobenzene and 153.40g (1.3mol) of sodium methanesulfonate were added, and then 900mL of dimethyl sulfoxide was added. The temperature was controlled at 75°C and the reaction was carried out for 6 hours. After TLC detection confirmed that the raw materials had reacted completely, the reaction was over, and the reaction solution was cooled to room temperature. 900mL of ethyl acetate and 900mL of water were added for extraction. The mixture was allowed to stand for stratification, and the organic phase (ethyl acetate phase) was collected and washed with 400mL of water. The collected organic phase was concentrated under reduced pressure to recover the solvent to dryness to obtain 226.50g (0.964mol) of 4-bromobenzyl sulfone with a yield of 96.4% and a purity of 99.2%.
[0047] Add 199.83 g (0.85 mol) of the above-obtained 4-bromobenzylsulfone and 800 mL of DMF solvent to a 2000 mL clean reaction bottle, stir to dissolve, add 150.40 g (0.94 mol) of diethyl malonate, continue to add 23.50 g (0.98 mol) of sodium hydride, add 1.79 g (0.009 mol) of copper acetate and 2.30 g (0.018 mol) of 2-thiophenecarboxylic acid, evacuate and replace with nitrogen three times, start heating to 85°C to 90°C, react for 6 hours, and TLC detection confirms that the raw material reaction is complete After the reaction is completed, the reaction solution is cooled to room temperature, the insoluble matter is filtered out, and the mixture is rinsed with 200 mL of DMF solvent. The filtrate is collected and placed in another reactor. 6500 mL of water and 6500 mL of ethyl acetate are added to the filtrate in sequence, and the mixture is stirred and extracted. The mixture is allowed to stand for stratification, and the organic phase (ethyl acetate phase) is collected. The collected organic phase is washed with water twice, each time with 1000 mL of water. The collected organic phase is concentrated under reduced pressure to recover the solvent ethyl acetate, and 253.04 g (0.80 mol) of diethyl 2-(4-methylsulfonylphenyl)malonate is obtained with a yield of 94.7% and a purity of 99.5%.
[0048] To a 3000 mL clean reaction bottle, add 253.04 g (0.80 mol) of diethyl 2-(4-methylsulfonylphenyl)malonate obtained above, add 1000 mL of methanol and 1000 mL of water, and then slowly add 135.00 g of concentrated hydrochloric acid. After the addition is completed, the temperature is raised to 50° C. to 55° C. and the reaction is carried out for 6 hours. TLC detection is used to confirm that the raw material reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove methanol, and 1 The reaction mixture was stirred with 1000 mL of water for 15 min, filtered, the filter cake was rinsed with 500 mL of water, and dried to obtain a crude 4-methylsulfonylphenylacetic acid product. The crude 4-methylsulfonylphenylacetic acid product was added with 1200 mL of n-heptane and heated to 80° C. for slurrying for 4 h. Then, the temperature was slowly lowered to room temperature for insulation for 2 hours, filtered, rinsed with n-heptane, and the obtained wet product was dried to obtain 156.39 g (0.73 mol) of dry 4-methylsulfonylphenylacetic acid with a yield of 91.3% and a purity of 99.2%.
[0049] Example 6
[0050] In a 2000mL clean reaction bottle, 175.00g (1.0mol) of p-fluorobromobenzene and 129.80g (1.1mol) of sodium methanesulfonate were added, and then 1100mL of dimethyl sulfoxide was added. The temperature was controlled at 85°C and the reaction was carried out for 5 hours. After TLC detection confirmed that the raw materials had reacted completely, the reaction was over, and the reaction solution was cooled to room temperature. 1000mL of ethyl acetate and 1000mL of water were added for extraction. The mixture was allowed to stand for stratification, and the organic phase (ethyl acetate phase) was collected and washed with 600mL of water. The collected organic phase was concentrated under reduced pressure to recover the solvent to dryness to obtain 225.6g (0.96mol) of 4-bromobenzyl sulfone with a yield of 96.0% and a purity of 99.1%.
[0051] Add 225.6 g (0.96 mol) of the above-obtained 4-bromobenzylsulfone and 900 mL of N,N-dimethylacetamide solvent to a 2000 mL clean reaction bottle, stir to dissolve, add 163.2 g (1.02 mol) of diethyl malonate, continue to add 251.00 g (1.65 mol) of 1,8-diazabicycloundec-7-ene (DBU), add 3.39 g (0.017 mol) of copper acetate and 1.58 g (0.018 mol) of oxalyl diamide, evacuate and replace with nitrogen three times, start heating to 80°C to 85°C, react for 5 hours, T LC detection confirmed that the raw materials reacted completely and the reaction was over. The reaction solution was cooled to room temperature, filtered to remove insoluble matter, rinsed with 250 mL of DMF solvent, and the filtrate was collected. 6100 mL of water and 6100 mL of ethyl acetate were added to the filtrate in sequence, stirred and extracted, and allowed to stand for stratification. The organic phase (ethyl acetate phase) was collected and washed with water twice, each time with 900 mL of water. The collected organic phase was concentrated under reduced pressure to recover the solvent ethyl acetate to obtain 279.14 g (0.89 mol) of diethyl 2-(4-methylsulfonylphenyl)malonate as an intermediate with a yield of 92.5% and a purity of 99.4%.
[0052] To a 3000 mL clean reaction bottle, add 279.14 g (0.89 mol) of diethyl 2-(4-methylsulfonylphenyl)malonate obtained above, add 800 mL of ethanol and 800 mL of water, and then slowly add 150.00 g of concentrated hydrochloric acid. After the addition is completed, the temperature is raised to 75° C. to 80° C. and the reaction is carried out for 6 hours. TLC detection is used to confirm that the raw material reaction is complete. After the reaction is completed, the reaction solution is concentrated under reduced pressure to remove ethanol, and 10 The reaction mixture was stirred with 100 mL of water for 15 min, filtered, the filter cake was rinsed with 500 mL of water, and dried to obtain a crude 4-methylsulfonylphenylacetic acid product. The crude 4-methylsulfonylphenylacetic acid product was added with 1100 mL of n-hexane and heated to 85° C. for slurrying for 4 h. Then, the temperature was slowly lowered to room temperature for insulation for 2 hours, filtered, rinsed with n-hexane, and the obtained wet product was dried to obtain 179.95 g (0.84 mol) of dry 4-methylsulfonylphenylacetic acid with a yield of 94.4% and a purity of 99.1%.
[0053] Example 7
[0054] Synthesis of diethyl 2-(4-methylsulfonylphenyl)malonate (R in the compound of formula IV is ethyl)
[0055]
[0056] To a 2000mL clean reaction bottle, 230.00g (0.98mol) of 4-bromobenzylsulfone prepared in Example 1 and 1000mL of dimethyl sulfoxide were added, stirred and dissolved, 188.36g (1.18mol) of diethyl malonate, 478.95g (1.47mol) of cesium carbonate, 1.94g (0.02mol) of cuprous chloride and 2.59g (0.03mol) of oxalyl diamide were added, and the atmosphere was evacuated and replaced with nitrogen three times. After heating to 75°C for 8 hours, TLC detection confirmed that the raw material reaction was complete and the reaction result was 98.8%. The reaction solution was cooled to room temperature, insoluble matter was removed by filtration, and the mixture was rinsed with 250 mL of dimethyl sulfoxide. The filtrate was collected and transferred to another reactor. 6300 mL of water and 6300 mL of ethyl acetate were added to the filtrate in sequence, and the mixture was stirred and extracted. The mixture was allowed to stand for stratification, and the organic phase (ethyl acetate phase) was collected. The collected organic phase was washed with water twice, each time with 900 mL of water. The collected organic phase was concentrated under reduced pressure to recover the solvent ethyl acetate, and 295.9 g (0.94 mol) of diethyl 2-(4-methylsulfonylphenyl)malonate was obtained with a yield of 96.2% and a purity of 99.1%.
[0057] The copper catalyst cuprous chloride in this embodiment can be replaced by any other copper catalyst (cuprous bromide or cuprous trifluoromethanesulfonate), which can also make the yield of the intermediate product 2-(4-methylsulfonylphenyl) diethyl malonate reach more than 95% and the purity reach more than 99%.
[0058] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.
[0059] Although the present invention has been described in detail and some specific embodiments have been cited, it is obvious to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the present invention.
Claims
1. A method for preparing 4-methylsulfonylphenylacetic acid, characterized in that: The method comprises the following steps: A. Using p-fluorobromobenzene, a compound of formula II, as a starting material, subjecting p-fluorobromobenzene, a compound of formula II, to an aromatic nucleophilic substitution reaction with sodium methanesulfonate to obtain 4-methylsulfonylbromobenzene, a compound of formula III; B. In the presence of an alkaline substance, a copper catalyst and a ligand, a substitution reaction is carried out between the compound of formula III, 4-methylsulfonyl bromobenzene, and a malonic ester in an inert organic solvent to obtain a compound of formula IV; R in the compound of formula IV is selected from a C1-C4 alkyl group; C. hydrolyzing the compound of formula IV in the presence of an acid or a base to obtain the product compound of formula I, 4-methylsulfonylphenylacetic acid; 2. The method for preparing 4-methylsulfonylphenylacetic acid according to claim 1, characterized in that: The malonate in step B is selected from diethyl malonate, dimethyl malonate, dipropyl malonate, and diisopropyl malonate; and R in the compound of formula IV is selected from methyl, ethyl, propyl, or isopropyl.
3. The method for preparing 4-methylsulfonylphenylacetic acid according to claim 1, characterized in that: The copper catalyst in step B is selected from a copper salt catalyst and / or a cuprous salt catalyst.
4. The method for preparing 4-methylsulfonylphenylacetic acid according to claim 3, characterized in that: The copper salt catalyst is selected from one or more of copper trifluoromethanesulfonate, copper chloride, copper bromide, copper acetate and copper sulfate; the cuprous salt catalyst is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride and cuprous trifluoromethanesulfonate.
5. The method for preparing 4-methylsulfonylphenylacetic acid according to claim 3, characterized in that: The ligand in step B is selected from one or more of oxalyl diamide, oxalic acid monoamide, monoamide oxalate, (n,n-di-2,4,6-trimethoxyphenyl)-oxalic acid-diamide, N,N′-di(o-methylphenyl)oxalic acid diamide, n-(2,6-dimethylphenyl)oxalic acid monoamide, n-phenyl oxalic acid monoamide, N,N′-di(m-chlorophenyl)oxalic acid diamide, phenol, 2-pyridinecarboxylic acid, o-phenylphenol, 2-hydroxybenzaldehyde vinyl acetal, 2-thiophenecarboxylic acid, benzothiophene-2-carboxylic acid, L-proline and trans-4-hydroxy-L-proline.
6. The method for preparing 4-methylsulfonylphenylacetic acid according to any one of claims 1 to 5, characterized in that: The alkaline substance in step B is selected from an inorganic base or an organic base, the inorganic base is selected from one or more of alkali metal carbonates, alkali metal phosphates, alkali metal halides, alkali metal hydroxides and alkali metal hydrides; the organic base is selected from one or more of triethylamine, dimethylisopropylamine, 1,8-diazabicycloundec-7-ene, pyridine and pyrrole.
7. The method for preparing 4-methylsulfonylphenylacetic acid according to any one of claims 1 to 5, characterized in that: In step B, the inert organic solvent is selected from a sulfoxide solvent or an amide solvent, and the temperature of the substitution reaction is 80° C. to 110° C.
8. The method for preparing 4-methylsulfonylphenylacetic acid according to claim 7, characterized in that: In step B, the molar ratio of the compound of formula III, 4-methylsulfonyl bromobenzene: malonate: copper catalyst: ligand: alkaline substance is 1: 1.0-1.3: 0.01-0.03: 0.02-0.04: 1.0-2.
0.
9. The method for preparing 4-methylsulfonylphenylacetic acid according to any one of claims 1 to 5, characterized in that: The hydrolysis reaction in step C is carried out in a mixed solvent of an alcohol solvent and water, the acid is selected from one or more of hydrochloric acid, sulfuric acid and phosphoric acid; the base is selected from one or more of sodium hydroxide, potassium hydroxide or lithium hydroxide; the temperature of the hydrolysis reaction is 50°C to 90°C.
10. The method for preparing 4-methylsulfonylphenylacetic acid according to any one of claims 1 to 5, characterized in that: The aromatic nucleophilic substitution reaction in step A is carried out in a sulfoxide solvent 2, and the temperature of the aromatic nucleophilic substitution reaction is 70° C. to 95° C.