Synthesis
General procedure for the synthesis of 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylic acid from methyl 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylate:
a) Hydrolysis reaction: 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylic acid methyl ester (2.00 g, 7.47 mmol) was dissolved in a mixture of 50 mL of water and 50 mL of methanol containing KOH (2.0 g, 36 mmol), and the reaction was carried out at reflux for 2 hours. Upon completion of the reaction, the methanol was removed by evaporation, and the residue was diluted with water to twice the original volume and washed with ethyl acetate. The aqueous layer was acidified with aqueous NaHSO4 to pH < 7. The precipitate precipitated was collected by filtration, washed with water and dried to give 1.85 g (98% yield) of the target product 3-amino-5-(4-chlorophenyl)thiophene-2-carboxylic acid. The product was characterized by 1H NMR (DMSO-d6): δ 7.62 (m, 2H), 7.48 (m, 2H), 6.96 (s, 1H).
References
[1] Patent: WO2007/11284, 2007, A1. Location in patent: Page/Page column 22-23
[2] Patent: WO2007/11285, 2007, A1. Location in patent: Page/Page column 19
[3] Patent: WO2007/11286, 2007, A1. Location in patent: Page/Page column 20
[4] Patent: WO2005/66163, 2005, A2. Location in patent: Page/Page column 109
[5] European Journal of Medicinal Chemistry, 2013, vol. 65, p. 223 - 231
