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11th March 2012 @ 07:32
This synthesis is based off one put forth by Son et al. (p. 17), and is summarised below: [b]Conclusion:[/b] methyl 3-formamidothiophene-2-carboxylate was recovered along with starting material with a combined mass of 0.057 g. [b]Reaction start time: 11am 07/03/2012[/b] Ethyl-3-aminothiophene-2-carboxylate (0.376 g, 2.39 mmol, 1 equiv.) was dissolved in formamide (1 mL, 25.15 mmol, ~10 equiv.) and heated to 180 °C. TLC at +6.5 hr showed some new products being formed. [b]TLC (10% ethyl acetate/hexane): + 6.5 hr, visualised with UV/vanillin[/b] [data]1948[/data] Reaction was cooled to rt and left for 36 hr. The mixture was filtered, with no solid product recovered. The mixture was extracted once with ethyl acetate (10mL) and the organic layer was washed twice with water (10mL) and twice with brine (10mL) before being dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to yield 0.057 g red solid, and 1H-NMR was taken, revealing a mixture of starting material and a product consistent with the following structure: methyl 3-formamidothiophene-2-carboxylate [b]1H-NMR:[/b] This red soild was purified by column chromatography using 60% ethyl acetate/hexane as the eluent. Three fractions were collected: Fraction 1: 0.037 g 1H-NMR showed this to be mostly starting material [b]1H-NMR:[/b][data]2241[/data][data]2243[/data] Fraction 2: 0.004 g 1H-NMR revealed this to be methyl 3-formamidothiophene-2-carboxylate. [b]1H-NMR:[/b][data]2245[/data][data]2247[/data] Fraction 3: 0.056 g 1H-NMR revealed this to be a mixture of solvents and a very small amount of methyl 3-formamidothiophene-2-carboxylate. [b]1H-NMR:[/b][data]2249[/data][data]2251[/data] An accurate yield was not obtained due to a column that did not give good separation, and due to the low crude yield. [b]Risk Assessment: (paper copy signed)[/b] [data]2024[/data] [b]References:[/b] Son, J.B.; Jung, S. H.; Choi, W.I.; Jung, Y.H.; Choi, J.Y.; Song, J.Y.; Lee, K.H.; Lee, J.C.; Kim, E.Y.; Ahn, Y.G.; Kim, M.S.; Choi, HG.; Sim, T.B.; Ham, Y.J.; Park, D.; Kim, H.; Kim, D. (Hanmi Holdings Co., Ltd., S. Korea; Korea Institute of Science and Technology; Catholic University Industry Academic Cooperation Foundation). Preparation of thienopyrimidine derivatives for use as protein kinase inhibitors. World Intellectual Property Organisation 2011093684 A2, 2011; SciFinder Scholar AN 2011:971406 (accessed 3/2/2012).
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