Uses
2-Methyl-4-nitrobenzoic acid is used as a reagent to synthesize amino-1H-pyrazole amide derivatives, compounds that act as Raf kinase inhibitors in melanoma cells. 2-Methyl-4-nitrobenzoic acid is also used as a reagent to synthesize fluorogenic substrates, compounds that can be used for activity imaging within living cells.
Synthesis
The general procedure for the synthesis of 2-methyl-4-nitrobenzoic acid from 4-nitrophthalic acid is as follows: in a 50 mL three-necked round-bottomed flask equipped with a magnetic stirrer and reflux condenser, 4-nitrophthalic acid (0.15 g, 1 mmol), N-hydroxyphthalimide (NHPI, 0.05 g, 0.3 mmol), 40% nitric acid (1.26 g, 8 mmol), cobalt chloride hexahydrate (CoCl2-6H2O, 7.1 mg, 0.03 mmol), manganese acetate tetrahydrate (Mn(OA)), and cobalt chloride hexahydrate (CoCl2-6H2O). , 8 mmol), cobalt chloride hexahydrate (CoCl2-6H2O, 7.1 mg, 0.03 mmol), manganese acetate tetrahydrate (Mn(OAc)2-4H2O, 7.1 mg, 0.03 mmol), and phase transfer catalyst (0.04 mmol). The reaction mixture was heated to reflux at atmospheric pressure for 12 hours. After completion of the reaction, it was cooled to room temperature and washed with 10 mL of water. The aqueous phase was extracted with ethyl acetate (3 x 5 mL), the organic phases were combined and dried over anhydrous sodium sulfate. Ethyl acetate was removed from the organic phase by rotary evaporation and the crude product was quantified by HPLC analysis based on an internal standard (2,4-dinitrotoluene). The crude product was recrystallized by ethanol/water (3:1) to afford white acicular crystals of 2-methyl-4-nitrobenzoic acid (0.13 g, 72% yield) with melting point 151-152°C. IR (KBr) ν/cm-1 : 1702 (C=O).1H NMR (CDCl3, 500 MHz) δ: 2.79 (s, 3H, CH3), 8.13- 8.17 (m, 2H, Ar-H), 8.21 (d, 1H, J=6.8Hz, Ar-H). The by-product 4-nitrophthalic acid was separated by column chromatography (ethyl acetate/hexane, 1:5) to give light-colored acicular crystals with a melting point of 163°C. IR (KBr) ν/cm-1 : 1730, 1677 (C=O).1H NMR (CDCl3, 500MHz) δ: 7.86 (d, J=8.6Hz, 1H, Ar-H), 8.36 ( dd, J1=8.6Hz, J2=2.0Hz, 1H, Ar-H), 8.42 (d, J=2.0Hz, 1H, Ar-H).
References
[1] Chemical Papers, 2015, vol. 69, # 4, p. 580 - 585
[2] Patent: CN106995374, 2017, A. Location in patent: Paragraph 0043; 0044; 0045; 0046; 0047; 0048; 0049-0057
[3] Journal of Organic Chemistry, 2018, vol. 83, # 15, p. 8092 - 8103
[4] Patent: CN105777565, 2016, A. Location in patent: Paragraph 0006
