Chemical Properties
White to brown crystal powde
Uses
A building block which is used in preparation of anthranilic acids possessing antibacterial activity. 4-bromo-2-methylbenzoic acid could be used to synthesis 4-chloro-3'-(2-cyclopentyl-1-oxoisoindolin-5-yl)biphenyl-3-carboxylic acid through Suzuki couplings[1].
Application
4-Bromo-2-methylbenzoic acid serves as a key synthetic building block for active pharmaceutical ingredients and can be used for:
(1) Preparation of NHE inhibitors. Following chlorosulphonic acid chlorosulphonation, reduction and methylation, this compound yields 4-bromo-2-methyl-5-(methylsulphonyl)benzoic acid methyl ester [2].
(2) Preparation of 5α-reductase inhibitors. When this compound is used as a starting material in a Friedel–Crafts acylation reaction with diphenyl ether, it yields the key intermediate (4-bromo-2-methylphenyl)(4-phenoxyphenyl)methan [3].
(3) Preparation of anti-folate drugs. This compound can be used in a Pd⁰-catalysed Buchwald–Hartwig amination reaction, followed by NBS bromination and condensation with L-glutamic acid diethyl ester, to yield the key N-methylamino lactam intermediate 18 [4].
Synthesis
General procedure for the synthesis of 2-methyl-4-bromobenzoic acid from 4-bromo-2-methylbenzonitrile: 4-bromo-2-methylbenzonitrile (1 mmol) was suspended in water (49 mL) and potassium hydroxide (50 mmol) was added. The reaction mixture was stirred overnight under reflux conditions. Upon completion of the reaction, it was cooled to room temperature and the basic aqueous solution was washed with ethyl acetate (3 x 15 mL) to remove unreacted material. Subsequently, the aqueous phase was acidified to pH < 2 with 6 M hydrochloric acid and the acidified aqueous phase was extracted with ethyl acetate (3 x 15 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the white solid product 2-methyl-4-bromobenzoic acid. Yield: 60%. Thin Layer Chromatography (TLC) analysis (unfolding agent: dichloromethane/methanol = 9:1): Rf = 0.46. melting point: 182 °C. 1H-NMR (300 MHz, CD3OD) δ (ppm): 7.80 (d, J = 8.4 Hz, 1H, H-6), 7.48 (s, 1H, H-3), 7.42 (d, J = 8.4 Hz, 1H, H- 5), 2.56 (s, H- 5), 2.56 (s, H- 5), 2.56 (s, H- 5). 5), 2.56 (s, 3H, CH3).
References
[1] Shyama Sidique. “Orally Active Metabotropic Glutamate Subtype 2 Receptor Positive Allosteric Modulators: Structure–Activity Relationships and Assessment in a Rat Model of Nicotine Dependence.” Journal of Medicinal Chemistry 55 22 (2012): 9434–9445.
[2] Baumgarth, M., Beier, N., & Gericke, R. (1997). (2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ Antiporter Inhibitors†.
Journal of Medicinal Chemistry,
40 13, 2017–2034.
https://doi.org/10.1021/jm960768n[3] Salem, O. I. A., Frotscher, M., Scherer, C. (2005). Novel 5α-Reductase Inhibitors: Synthesis, Structure−Activity Studies, and Pharmacokinetic Profile of Phenoxybenzoylphenyl Acetic Acids.
Journal of Medicinal Chemistry,
49 2, 748–759.
https://doi.org/10.1021/jm050728w[4] Rosowsky, A., Forsch, R. A., Wright, J. E. (2004). Synthesis and in Vitro Antifolate Activity of Rotationally Restricted Aminopterin and Methotrexate Analogues.
Journal of Medicinal Chemistry,
47 27, 6958–6963.
https://doi.org/10.1021/jm040122s
