4-Methoxy-1H-indole-2-carboxylic acid

4-Methoxy-1H-indole-2-carboxylic acid can be used as a precursor to prepare 4-methoxy-1H-indole-2-carboxamide via treatment with thionyl chloride in dry tetrahydrofuran, followed by reaction with ammonia[6].

Methyl 4-methoxy-2-indolecarboxylate (4 g, 19.49 mmol, 1 eq) was added to an aqueous solution of sodium hydroxide (2M, 98 mL, 0.20 mmol, 10 eq). The suspension was stirred and heated until the reaction mixture was uniform, and then the mixture was refluxed for 30 minutes with heating. The mixture solution was acidified, and the resulting precipitate was extracted three times with ethyl acetate (100 mL). The extracts were combined, washed with water, dried over magnesium sulfate, and concentrated to give a white solid of 4-methoxy-1H-indole-2-carboxylic acid (3.71 g, yield 99 per cent).

[1] Journal of Medicinal Chemistry,  2004,  vol. 47,  # 25,  p. 6270 - 6282
[2] Patent: EP1533299,  2005,  A1. Location in patent: Page/Page column 8
[3] Journal of Medicinal Chemistry,  1998,  vol. 41,  # 19,  p. 3624 - 3634
[4] Patent: WO2008/60621,  2008,  A2. Location in patent: Page/Page column 118
[5] Bioorganic and Medicinal Chemistry Letters,  2000,  vol. 10,  # 5,  p. 483 - 486
[6] Spadoni, G., Balsamini, C., Bedini, A., Diamantini, G., Giacomo, B. D., Tontini, A., Tarzia, G., Mor, M., Plazzi, P. V., Rivara, S., Nonno, R., Pannacci, M., Lucini, V., Fraschini, F., Stankov, B. M. (1998). 2-[N-Acylamino(C₁−C₃)alkyl]indoles as MT₁ Melatonin Receptor Partial Agonists, Antagonists, and Putative Inverse Agonists. Journal of Medicinal Chemistry, 41(19), 3624–3634. https://doi.org/10.1021/jm970721h