Synthesis
Example 2 Step 1. Preparation of 2-amino-3-methoxybenzaldehyde: Iron powder (40 g) was slowly added to a stirred mixed solution of 3-methoxy-2-nitrobenzaldehyde (70 g, 386 mmol) in acetic acid (100 mL) and absolute ethanol (400 mL). The reaction mixture was cooled with an ice bath and concentrated hydrochloric acid (1 mL) was added dropwise. The reaction was exothermic and after the reaction temperature stabilized, it was heated to reflux. After about 20 minutes of reaction, the completion of the reaction was confirmed based on LCMS analysis. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and concentrated to a brown syrupy consistency. The residue was dissolved in ethyl acetate (500 mL) and water (200 mL) and alkalized with 6 M NaOH solution to pH about 50. The mixture was filtered through diatomaceous earth to separate the organic and aqueous layers. The organic layer was washed sequentially with saturated NaHCO3 solution (2 x 100 mL), water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and evaporated to give a dark amber colored oily substance. The oily material was dried under vacuum to obtain 2-amino-3-methoxybenzaldehyde with 95% purity and 64% yield (37.2 g, 246 mmol).
References
[1] Inorganic Chemistry, 2011, vol. 50, # 21, p. 10966 - 10973
[2] Patent: WO2007/117607, 2007, A2. Location in patent: Page/Page column 306
[3] Journal of Medicinal Chemistry, 2007, vol. 50, # 15, p. 3515 - 3527
[4] Patent: WO2016/53794, 2016, A1. Location in patent: Page/Page column 63; 64
[5] Journal of the Chemical Society, 1925, vol. 127, p. 876,877
