An industrial preparation method for 2-methylphenylacetic acid

Abstract

This invention relates to an industrial preparation method for 2-methylphenylacetic acid, comprising the following steps: under an inert solvent, 2-methylhalobenzene and malonate diester undergo a coupling reaction in the presence of a catalyst and base A to obtain compound one; compound one is hydrolyzed and decarboxylated under the presence of base B to prepare 2-methylphenylacetic acid; the chemical structural formula of compound one is: [formula missing], where R is a C1-C8 alkyl group. Compared with existing technologies, this invention uses inexpensive raw materials, is simple to operate, can react under normal pressure, has relatively mild conditions, is safe and environmentally friendly, and is easy to industrialize.

Description

Technical Field

[0001] This invention belongs to the field of organic intermediate synthesis technology, and relates to an industrial preparation method of 2-methylphenylacetic acid. Background Technology

[0002] 2-Methylphenylacetic acid (2-MPA) is an important organic synthesis intermediate widely used in pharmaceuticals, pesticides, materials, and fragrances. In the pharmaceutical field, 2-MPA is used to synthesize nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or antibiotic intermediates. Furthermore, the reduction of 2-MPA yields 2-methylphenylethanol, leading to a series of important pharmaceutical intermediates. In the pesticide field, 2-MPA is used to synthesize phenoxycarboxylic acid herbicides or derivatives of other plant growth regulators, such as azoxystrobin, pyraclostrobin, and difenoconazole, among other fungicides. In materials science, 2-MPA may participate in polymerization reactions to prepare functional polymers or liquid crystal materials. In the fragrance and flavor industry, phenylacetic acid itself has a honey-like sweet aroma, while methyl substitution can adjust its volatility and aroma characteristics, making it suitable for formulating long-lasting fragrances.

[0003] Currently, there are three main routes reported for the synthesis of 2-methylphenylacetic acid both domestically and internationally: Route 1 (Tetrahedron Letters, 2014, 55, 3802–3804) starts with o-xylene and proceeds through chlorination, cyano substitution, and hydrolysis to obtain 2-methylphenylacetic acid. This route has a long synthetic process, low yield, high pollution, and relatively dangerous reactions. Route 2 (CN114835542) also starts from o-xylene, first chlorinating it to obtain 2-methylbenzyl chloride, and then directly obtaining 2-methylphenylacetic acid via a carbonylation reaction. The carbonylation reaction in this route uses an expensive palladium catalyst and a special pressure reactor, resulting in high costs and making it unsuitable for industrial production. Route 3 (Journal of Organic Chemistry, 2011, 76, 8107–8112) starts with 2-bromotoluene, proceeds through butyllithium hydrogen-extracting and boron esterification to obtain 2-methylboronic acid, then couples it with ethyl bromoacetate to obtain ethyl 2-methylphenylacetic acid, and finally hydrolyzes it to obtain 2-methylphenylacetic acid. This route is lengthy, uses the hazardous reagent butyllithium, and employs expensive noble metal catalysts, resulting in high costs and making it unprofitable for industrial production. Therefore, there is an urgent need to develop a method for preparing 2-methylphenylacetic acid that uses inexpensive raw materials, is simple to operate, can react under normal pressure, has relatively mild conditions, is safe and environmentally friendly, and is easy to produce industrially. Summary of the Invention

[0004] The purpose of this invention is to provide an industrial preparation method for 2-methylphenylacetic acid that is economical, efficient, safe and environmentally friendly, with relatively mild reaction conditions and is easy to industrialize.

[0005] The objective of this invention can be achieved through the following technical solutions: An industrial method for preparing 2-methylphenylacetic acid includes the following steps: In an inert solvent, 2-methyl halobenzene and malonate diester undergo a coupling reaction in the presence of a catalyst and base A to give compound one; Compound 1 was hydrolyzed and decarboxylated in the presence of base B to prepare 2-methylphenylacetic acid; The chemical structural formula of compound one is as follows: , where R is a C1-C8 alkyl group.

[0006] The process flow of the above preparation method is as follows: .

[0007] Furthermore, the chemical structural formula of the 2-methylhalobenzene is as follows: Where X is Cl or Br; The chemical structural formula of the malonate diester is: .

[0008] Furthermore, R can be methyl, ethyl, isopropyl, or n-propyl.

[0009] Furthermore, the inert solvent is one or a combination of several selected from N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, and ester solvents. Ethanol or tert-butanol is preferred.

[0010] Further, the base A is one or a combination of several of the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, triethylamine, pyridine, diisopropylethylamine, 2-methylpyridine, DBU, and tetrabutylammonium hydroxide. Preferably, base A can be potassium carbonate or sodium ethoxide, etc. Additionally, the amount of base A added is 1 to 20 times the molar equivalent of the theoretical amount of compound A. Preferably, it is 1 to 5 times the molar equivalent.

[0011] Furthermore, the catalyst is a combination of a copper-based active ingredient and a ligand, wherein the copper-based active ingredient is one or a combination of several of the following: Cu powder, cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous thiocyanate, copper thiophene-2-carboxylate (I), copper acetate, copper sulfate, copper carbonate, copper chloride, copper bromide, copper oxide, copper acetylacetonate, and 8-hydroxyquinoline copper. The ligand is any one or a combination of compounds having the following structures: , or , Among them, R a R b R c R f Each is independently a C6-C14 aryl group that is optionally substituted, or a 5-6 heteroaryl group that is optionally substituted with 1-3 ring atoms independently selected from C, N, O and S, or a 5-7 heterocyclic alkyl group that is optionally substituted with 1-3 ring atoms independently selected from C, N, O and S. R d It is an optionally substituted C6-C14 aryl group, or an optionally substituted 5-6 membered heteroaryl group containing 1-3 independently selected ring atoms from C, N, O and S; R e It is an optionally substituted C6-C14 aryl group, or an optionally substituted 5-6 membered heteroaryl group containing 1-3 ring atoms independently selected from C, N, O and S, or an optionally substituted 5-7 membered heterocyclic alkyl group containing 1-3 ring atoms independently selected from C, N, O and S.

[0012] Furthermore, the ligand is selected from one or more of the following L1 to L12: , , , , , , , , , , , .

[0013] Furthermore, the amount of the copper-based active ingredient used is 0.1% to 3% of the theoretical molar amount of compound one; The amount of the ligand used is 0.1-3% of the theoretical molar amount of compound one.

[0014] Furthermore, the alkali B is one or a combination of several of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, and potassium phosphate, and the amount of alkali B added is 1 to 10 times the molar equivalent of the theoretical amount of compound B. Preferably, it is 1 to 5 times the molar equivalent.

[0015] Furthermore, the coupling reaction is carried out at a temperature of 50~120℃ for a time of 2~24h; The hydrolysis decarboxylation reaction is carried out at a temperature of 80-90℃ for 1-2 hours.

[0016] Compared with the prior art, the present invention has the following advantages: (1) Using 2-methylhalobenzene as raw material, 2-methylphenylacetic acid is synthesized by copper or copper compound / ligand catalysis under inert solvent and alkaline conditions. The whole process does not involve dangerous reactions and does not carry out experiments under high temperature and high pressure, thus avoiding a large safety risk.

[0017] (2) The raw materials are cheap and the operation is simple. No precious metal catalysts are used, which gives it a significant cost advantage.

[0018] (3) The catalyst dosage is small, the catalytic efficiency is high, the reaction yield is high, and the product purity is good.

[0019] (4) The reaction is carried out under normal pressure, and the reaction conditions are relatively mild, making it suitable for industrial production. Detailed Implementation

[0020] The present invention will now be described in detail with reference to specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the application.

[0022] As used herein, the terms "and / or," "or / and," and "and / or" encompass any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected using at least two conjunctions selected from "and / or," "or / and," and "and / or," it should be understood that, in this application, the technical solution undoubtedly includes solutions connected by "logical AND," and also undoubtedly includes solutions connected by "logical OR."

[0023] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0024] In this application, numerical ranges are referred to as continuous unless otherwise specified, and include the minimum and maximum values ​​of the range, as well as every value between the minimum and maximum values. Furthermore, when the range refers to integers, it includes every integer between the minimum and maximum values ​​of the range. Additionally, when multiple ranges are provided to describe a feature or characteristic, the ranges may be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges to which they are incorporated.

[0025] This document only specifically discloses some numerical ranges. However, any lower limit can be combined with any upper limit to form an unspecified range; and any lower limit can be combined with other lower limits to form an unspecified range, just as any upper limit can be combined with any other upper limit to form an unspecified range. Furthermore, each individually disclosed point or single value can itself serve as a lower or upper limit and be combined with any other point or single value or with other lower or upper limits to form an unspecified range.

[0026] Unless otherwise specified, the temperature parameters in this application may be either constant temperature processing or processing within a certain temperature range. The constant temperature processing allows temperature fluctuations within the precision range controlled by the instrument, such as ±5°C, ±4°C, ±3°C, ±2°C, or ±1°C.

[0027] In this document, the term "suitable" as used in phrases such as "suitable combination," "suitable method," and "any suitable method" refers to the ability to implement the technical solution of this application, solve the technical problem of this application, and achieve the expected technical effect of this application.

[0028] In this application, terms such as "further," "even further," and "particularly" are used to describe purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0029] In this application, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "optional" entries in a technical solution, unless otherwise specified, and there are no contradictions or mutual constraints, each "optional" entry shall be independent.

[0030] In the description of the application, "multiple" means at least two, such as two, three, etc., unless otherwise explicitly specified.

[0031] Unless otherwise specified, all preparations and tests described herein took place at 25°C.

[0032] The terms “comprising,” “including,” “containing,” “having,” “comprising,” or other variations thereof are intended to cover non-closed inclusion, and no distinction is made between these terms. The term “comprising” means that other steps and ingredients may be added without affecting the final result. The compositions and methods / processes of the present invention comprise, consist of, and substantially consist of the essential elements and limitations described herein, as well as any additional or optional ingredients, components, steps, or limitations described herein. No distinction is made between the terms “efficacy,” “performance,” “effect,” and “potency” herein.

[0033] Unless otherwise specified, all embodiments and optional embodiments of this application can be combined to form new technical solutions. Unless otherwise specified, all technical features and optional technical features of this application can be combined to form new technical solutions.

[0034] Unless otherwise specified, all steps of this application may be performed sequentially or randomly, but sequentially is preferred.

[0035] Example 1: Add 100g of 2-methylbromobenzene, 206g of diethyl malonate, 77.5g of tert-butanol, 1.7g of cuprous chloride, and 5.0g of ligand L1 to a 1L reaction flask. Purge the mixture with nitrogen three times, raise the temperature to 55℃, stir for 0.5h, add 84g of sodium ethoxide in portions, raise the temperature to 95℃, and react for 9h. The reaction is completed by HPLC.

[0036] The temperature was lowered to 85℃, and 108g of 25wt% sodium hydroxide solution was added dropwise. The mixture was stirred for 1 hour, and the reaction was confirmed by HPLC. The temperature was then lowered to approximately 27℃, and the pH was adjusted to 1-2 with concentrated hydrochloric acid. The product crystallized out, was filtered, washed with water, and dried to obtain 79g of product with a purity of 99.80%.

[0037] 1 HNMR (CDCl3): δ7.22-7.14 (m, 4H), 3.66 (s, 2H), 2.32 (s, 3H) Example 2: Add 74g of 2-methylchlorobenzene, 206g of diethyl malonate, 77.5g of tert-butanol, 1.7g of cuprous chloride, and 5.0g of ligand L1 to a 1L reaction flask. Purge the mixture with nitrogen three times, raise the temperature to 55℃, stir for 0.5h, add 84g of sodium ethoxide in portions, raise the temperature to 95℃, and react for 9h. The reaction is completed by HPLC.

[0038] The temperature was lowered to 85℃, and 108g of 25wt% sodium hydroxide solution was added dropwise. During the addition, ethanol and tert-butanol were distilled off under vacuum. The mixture was stirred at 85℃ for 1 hour, and the reaction was confirmed to be complete by HPLC. The temperature was then lowered to 27℃, and 300g of process water was added. The mixture was stirred for 0.5 hours, filtered, and the filtrate was extracted twice with 226g of dichloromethane. The pH of the aqueous phase was adjusted to 1-2 with concentrated hydrochloric acid, and the product crystallized out. The crystals were filtered, washed with water, and dried to obtain 57g of product with a purity of 99.10%.

[0039] 1 HNMR (CDCl3): δ7.22-7.14 (m, 4H), 3.66 (s, 2H), 2.32 (s, 3H) Example 3: Add 100g of 2-methylbromobenzene, 242g of diisopropyl malonate, 77.5g of tert-butanol, 1.7g of cuprous chloride, and 5.0g of ligand L1 to a 1L reaction flask. Purge the mixture three times with nitrogen, raise the temperature to 55℃, and stir for 0.5h. Add 84g of sodium ethoxide in portions, raise the temperature to 95℃, and react for 9h. HPLC analysis confirms the reaction is complete. Cool to 85℃, add 108g of 25wt% sodium hydroxide solution dropwise. During the dropwise addition, distill off ethanol and tert-butanol under vacuum. Continue stirring at 85℃ for 1h. HPLC analysis confirms the reaction is complete. Cool to 27℃, add 300g of process water, stir for 0.5h, filter, and extract the filtrate twice with 226g of dichloromethane. Adjust the pH of the aqueous phase to 1-2 with concentrated hydrochloric acid. The product crystallizes out, filters, washes with water, and dries to obtain 55g of product with a purity of 99.20%.

[0040] 1 HNMR (CDCl3): δ7.22-7.14 (m, 4H), 3.66 (s, 2H), 2.32 (s, 3H) Example 4: Add 74g of 2-methylchlorobenzene, 242g of diisopropyl malonate, 77.5g of tert-butanol, 1.7g of cuprous chloride, and 5.0g of ligand L1 to a 1L reaction flask. Purge the mixture with nitrogen three times, raise the temperature to 55℃, stir for 0.5h, add 84g of sodium ethoxide in portions, raise the temperature to 95℃, and react for 9h. The reaction is completed by HPLC.

[0041] The temperature was lowered to 85℃, and 108g of 25wt% sodium hydroxide solution was added dropwise. During the addition, ethanol and tert-butanol were distilled off under vacuum. The mixture was stirred at 85℃ for 1 hour, and the reaction was confirmed to be complete by HPLC. The temperature was then lowered to 27℃, and 300g of process water was added. The mixture was stirred for 0.5 hours, filtered, and the filtrate was extracted twice with 226g of dichloromethane. The pH of the aqueous phase was adjusted to 1-2 with concentrated hydrochloric acid, and the product crystallized out. The crystals were filtered, washed with water, and dried to obtain 51g of product with a purity of 99.50%.

[0042] 1 HNMR (CDCl3): δ7.22-7.14 (m, 4H), 3.66 (s, 2H), 2.32 (s, 3H) Example 5: Add 100g of 2-methylbromobenzene, 206g of diethyl malonate, 77.5g of ethanol, 1.7g of cuprous chloride, and 5.0g of ligand L1 to a 1L reaction flask. Purge the mixture with nitrogen three times, raise the temperature to 55℃, stir for 0.5h, add 84g of sodium ethoxide in portions, raise the temperature to 95℃, and react for 9h. The reaction is completed by HPLC.

[0043] The temperature was lowered to 85℃, and 108g of 25wt% sodium hydroxide solution was added dropwise. During the addition, ethanol and tert-butanol were distilled off under vacuum. The mixture was stirred at 85℃ for 1 hour, and the reaction was confirmed to be complete by HPLC. The temperature was then lowered to 27℃, and 300g of process water was added. The mixture was stirred for 0.5 hours, filtered, and the filtrate was extracted twice with 226g of dichloromethane. The pH of the aqueous phase was adjusted to 1-2 with concentrated hydrochloric acid, and the product crystallized out. The crystals were filtered, washed with water, and dried to obtain 64g of product with a purity of 98.20%.

[0044] 1 HNMR (CDCl3): δ7.22-7.14 (m, 4H), 3.66 (s, 2H), 2.32 (s, 3H) Example 6: Add 100g of 2-methylbromobenzene, 206g of diethyl malonate, 77.5g of ethanol, 1.7g of cuprous chloride, and 5.0g of ligand L1 to a 1L reaction flask. Purge the mixture with nitrogen three times, raise the temperature to 55℃, stir for 0.5h, add 170g of potassium carbonate in portions, raise the temperature to 95℃, and react for 9h. The reaction is completed by HPLC.

[0045] The temperature was lowered to 85℃, and 108g of 25wt% sodium hydroxide solution was added dropwise. During the addition, ethanol and tert-butanol were distilled off under vacuum. The mixture was stirred at 85℃ for 1 hour, and the reaction was confirmed to be complete by HPLC. The temperature was then lowered to 27℃, and 300g of process water was added. The mixture was stirred for 0.5 hours, filtered, and the filtrate was extracted twice with 226g of dichloromethane. The pH of the aqueous phase was adjusted to 1-2 with concentrated hydrochloric acid, and the product crystallized out. The crystals were filtered, washed with water, and dried to obtain 70g of product with a purity of 99.10%.

[0046] 1 HNMR (CDCl3): δ7.22-7.14 (m, 4H), 3.66 (s, 2H), 2.32 (s, 3H) Similarly, following the scheme of Example 1, the types of catalysts and ligands were adjusted, while all other conditions remained the same, to verify the compatibility and feasibility of different catalyst and ligand types. The specific results are shown in Table 1.

[0047] Table 1 Furthermore, this invention has found that when only copper-based active components are used (e.g., copper salts, copper powder, or a combination of copper salts and copper powder (or different copper salts)), i.e., without the addition of ligands to the catalyst, the entire reaction cannot proceed even under the same conditions as in Example 1, such as reflux reaction. This reflects the safety and operability of the reaction of this invention. In addition, compared to existing technologies (which require high temperature and high pressure to achieve good conversion rates), the catalyst has high catalytic efficiency, can be used for experiments at atmospheric pressure, and the reaction conditions are relatively mild, avoiding significant production safety risks.

[0048] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. An industrial method for preparing 2-methylphenylacetic acid, characterized in that, Includes the following steps: In an inert solvent, 2-methyl halobenzene and malonate diester undergo a coupling reaction in the presence of a catalyst and base A to give compound one; Compound 1 was hydrolyzed and decarboxylated in the presence of base B to prepare 2-methylphenylacetic acid; The chemical structural formula of compound one is as follows: , where R is a C1-C8 alkyl group.

2. The industrial preparation method of 2-methylphenylacetic acid according to claim 1, characterized in that, The chemical structural formula of the 2-methylhalobenzene is: Where X is Cl or Br; The chemical structural formula of the malonate diester is: 。 3. The industrial preparation method of 2-methylphenylacetic acid according to claim 1, characterized in that, R is methyl, ethyl, isopropyl, or n-propyl.

4. The industrial preparation method of 2-methylphenylacetic acid according to claim 1, characterized in that, The inert solvent is one or a combination of several of the following: N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, toluene, acetonitrile, alcohol solvents, ether solvents, ketone solvents, and ester solvents.

5. The industrial preparation method of 2-methylphenylacetic acid according to claim 1, characterized in that, The base A is one or a combination of several of the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, triethylamine, pyridine, diisopropylethylamine, 2-methylpyridine, DBU, and tetrabutylammonium hydroxide, and its addition amount is 1 to 20 times the molar equivalent of the theoretical yield of compound A.

6. The industrial preparation method of 2-methylphenylacetic acid according to claim 1, characterized in that, The catalyst is a combination of a copper-based active ingredient and a ligand, wherein the copper-based active ingredient is one or a combination of several of the following: Cu powder, cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous thiocyanate, copper thiophene-2-carboxylate (I), copper acetate, copper sulfate, copper carbonate, copper chloride, copper bromide, copper oxide, copper acetylacetonate, and 8-hydroxyquinoline copper. The ligand is any one or a combination of compounds having the following structures: , or , Among them, R a R b R c R f Each is independently a C6-C14 aryl group that is optionally substituted, or a 5-6 heteroaryl group that is optionally substituted with 1-3 ring atoms independently selected from C, N, O and S, or a 5-7 heterocyclic alkyl group that is optionally substituted with 1-3 ring atoms independently selected from C, N, O and S. R d It is an optionally substituted C6-C14 aryl group, or an optionally substituted 5-6 membered heteroaryl group containing 1-3 independently selected ring atoms from C, N, O and S; R e It is an optionally substituted C6-C14 aryl group, or an optionally substituted 5-6 membered heteroaryl group containing 1-3 ring atoms independently selected from C, N, O and S, or an optionally substituted 5-7 membered heterocyclic alkyl group containing 1-3 ring atoms independently selected from C, N, O and S.

7. The industrial preparation method of 2-methylphenylacetic acid according to claim 6, characterized in that, The ligand is selected from one or more of the following L1 to L12: 、 、 、 、 、 、 、 、 、 、 、 。 8. The industrial preparation method of 2-methylphenylacetic acid according to claim 6, characterized in that, The amount of the copper-based active ingredient used is 0.1-3% of the theoretical molar amount of compound one. The amount of the ligand used is 0.1-3% of the theoretical molar amount of compound one.

9. The industrial preparation method of 2-methylphenylacetic acid according to claim 1, characterized in that, The base B is one or a combination of several of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, and potassium phosphate, and its amount is 1 to 10 times the molar equivalent of the theoretical amount of compound B.

10. The industrial preparation method of 2-methylphenylacetic acid according to claim 1, characterized in that, The coupling reaction is carried out at a temperature of 50~120℃ for 2~24h. The hydrolysis decarboxylation reaction is carried out at a temperature of 80-90℃ for 1-2 hours.

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