Synthesis
Step 1: Synthesis of methyl 3-methylthiophene-2-carboxylate: 3-methylthiophene-2-carboxylic acid (15 g, 105 mmol, 1.0 eq.) was dissolved in methanol (150 mL) and concentrated sulfuric acid (7.5 mL) was added slowly and dropwise. The reaction mixture was heated to reflux for 12 hours. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed sequentially with water (2 x 50 mL), saturated aqueous sodium bicarbonate solution (2 x 50 mL) and brine (50 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford 20 g (97% yield) of methyl 3-methylthiophene-2-carboxylate as an oil. The product was confirmed by 1H NMR (400 MHz, CDCl3): δ 7.38 (d, J=5.0 Hz, 1H), 6.91 (d, J=5.0 Hz, 1H), 3.85 (s, 3H), 2.55 (s, 3H); ESI-MS m/z 157 ([M+H]+).
References
[1] Patent: WO2012/56478, 2012, A1. Location in patent: Page/Page column 75-76
[2] Patent: WO2007/124546, 2007, A1. Location in patent: Page/Page column 58
[3] Patent: WO2014/64131, 2014, A2. Location in patent: Page/Page column 114; 115
[4] Patent: WO2014/76104, 2014, A1. Location in patent: Page/Page column 79-80
[5] Journal of Medicinal Chemistry, 1995, vol. 38, # 24, p. 4806 - 4820
