Synthetic Methods and Pharmaceutical Applications of 4-Acetyl-2-methylbenzoic acid

4-Acetyl-2-methylbenzoic acid is a benzoic acid derivative that appears as a white to yellow solid powder under ambient conditions. It exhibits weak acidity and good chemical stability. This compound is insoluble in water and low-polarity ether solvents but soluble in dimethyl sulfoxide (DMSO) and N,N-dimethylformamide (DMF). 4-Acetyl-2-methylbenzoic acid can be prepared from o-bromotoluene via Friedel–Crafts acylation followed by carbonylation. Primarily used as a pharmaceutical intermediate, 4-acetyl-2-methylbenzoic acid is applied in the synthesis of fungicides and insecticides.

Figure1: Picture of 4-Acetyl-2-methylbenzoic acid

Synthetic Methods

Method 1

A reported synthesis of 4-acetyl-2-methylbenzoic acid starts with 4‑amino‑3‑methylbenzoic acid. Through diazotization and a Sandmeyer reaction, compound 2 is obtained. Compound 2 is then converted to compound 3 via acyl chlorination using a chlorinating agent. Under basic conditions, compound 3 undergoes nucleophilic substitution at the acyl carbon with a malonate ester to yield compound 4. Decarboxylation of compound 4 gives compound 5, which finally undergoes carbonylation in the presence of a catalyst, ligand, and a gas‑generating system to produce 4‑acetyl‑2‑methylbenzoic acid. This synthetic route employs inexpensive and readily available starting materials, offers safe and controllable reaction conditions, significantly reduces production costs, and ensures high product yield. Thus, 4-acetyl-2-methylbenzoic acid can be efficiently synthesized on a large industrial scale using this method. [1]

Method 2

A patented preparation of 4-acetyl-2-methylbenzoic acid utilizes low‑cost, readily available intermediates of citalopram, such as 5‑carboxyphthalide or 5‑chloroformylphthalide, as starting materials. These are first condensed with a malonate ester (e.g., isopropylidene malonate, dimethyl malonate, or diethyl malonate), followed by decarboxylation to introduce a formyl group at the 5‑position. Subsequent direct hydrogenation yields 2‑methyl‑4‑acetylbenzoic acid. This reported method avoids the lengthy steps of the original process and eliminates the need for highly toxic carbon monoxide or cyanide compounds. With commercially accessible starting materials, mild reaction conditions, and simple operations, 4-acetyl-2-methylbenzoic acid can be readily scaled up for industrial production. [2]

Esterification Reaction

Researchers have reported an esterification method for 4-acetyl-2-methylbenzoic acid, comprising the following steps: S1 –An acylation reagent is added to a solution of 2‑fluorotoluene to carry out an acylation reaction, yielding 4‑fluoro‑3‑methylacetophenone. S2 –4‑Fluoro‑3‑methylacetophenone is dissolved, followed by the addition of a cyanating reagent to perform a cyanation reaction, giving 3‑methyl‑4‑cyanophenone. S3 – An acid is added to 3‑methyl‑4‑cyanophenone to conduct a hydrolysis reaction, affording 2‑methyl‑4‑acetylbenzoic acid. S4 – Methanol is added to 4‑acetyl‑2‑methylbenzoic acid to carry out an esterification reaction, producing methyl 2‑methyl‑4‑acetylbenzoate. The method described in this invention is simple to operate, provides high reaction yields, employs readily available reagents and equipment, and incurs low costs, making it highly feasible for practical application. [3]

Pharmaceutical Applications

Synthesis of the Insecticide Fluxametamide

Studies have reported that 4-Acetyl-2-methylbenzoic acid can be used to synthesize the target compound fluxametamide. Starting from 3,5‑dichlorobromobenzene, Grignard reaction followed by treatment with methyl trifluoroacetate yields 3',5'‑dichloro‑2,2,2‑trifluoroacetophenone. Catalyzed by sodium laurate, 4-Acetyl-2-methylbenzoic acid condenses with 3',5'‑dichloro‑2,2,2‑trifluoroacetophenone, undergoes dehydration, and then cyclizes with hydroxylamine hydrochloride to afford the key intermediate 4‑[5‑(3,5‑dichlorophenyl)‑5‑trifluoromethyl‑4,5‑dihydroisoxazol‑3‑yl]‑2‑methylbenzoic acid. This key intermediate is subsequently converted via acyl chlorination and ammonolysis to 4‑[5‑(3,5‑dichlorophenyl)‑5‑trifluoromethyl‑4,5‑dihydroisoxazol‑3‑yl]‑2‑methylbenzamide, which finally reacts with trimethyl orthoformate and methoxyamine hydrochloride to give the target product fluxametamide. The structure of the product was confirmed by ¹H‑NMR. This process is simple, economical, and operates under mild conditions, demonstrating promising potential for industrial application. [4]

Synthesis of the Insecticide Fluralaner

Fluralaner has attracted widespread attention in the industry due to its high insecticidal activity, unique mode of action, and absence of cross‑resistance. Fluralaner is constructed from three intermediate fragments: 4-Acetyl-2-methylbenzoic acid, 3,5‑dichloro‑2,2,2‑trifluoroacetophenone, and 2‑amino‑N‑(2,2,2‑trifluoroethyl)acetamide hydrochloride. Catalyzed by triethylamine, 2‑methyl‑4‑acetylbenzoic acid condenses with 3,5‑dichloro‑2,2,2‑trifluoroacetophenone, followed by dehydration to form the α,β‑unsaturated compound 4‑(3‑(3,5‑dichlorophenyl)‑4,4,4‑trifluoro‑3‑oxobut‑1‑en‑1‑yl)‑2‑methylbenzoic acid. This compound undergoes cyclization with hydroxylamine to yield the isoxazoline product 4‑[5‑(3,5‑dichlorophenyl)‑5‑trifluoromethyl‑4,5‑dihydro‑3‑isoxazolyl]‑2‑methylbenzoic acid. Finally, this isoxazoline intermediate undergoes amide condensation with 2‑amino‑N‑(2,2,2‑trifluoroethyl)acetamide hydrochloride to afford the target product fluralaner. [5]

Reference

[1] Chen, L., Wen, J., Zhou, L., et al. A synthesis method for 2?methyl?4?acetylbenzoic acid: CN 202410610419.2 [P].

[2] Zhang, L., et al. A new method for preparing 2?methyl?4?acetylbenzoic acid and its derivatives: CN 202211308709.9 [P].

[3] Mao, X., Yang, C., He, X., et al. A synthesis method for methyl 2?methyl?4?acetylbenzoate: CN 201811570802.0 [P].

[4] Li, N., Zhu, Q., Liu, R., et al. Study on the synthesis process of the isoxazoline insecticide fluxametamide [J]. World Pesticides, 2023, 45(1): 37?42.

[5] Yao, M. Synthesis of the insecticides fluralaner and fluxametamide [D]. Master’s Thesis, Wuhan Institute of Technology, 2023.

You may like