Synthesis
Example 4 Synthesis of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide: 2,4-dichloro-5-methoxyaniline (5.00 g, 26 mmol) was mixed with cyanoacetic acid (2.28 g, 26.8 mmol) at 50 °C. Tetrahydrofuran was added to the mixture until complete dissolution. Subsequently, the solution was heated to reflux and 1,3-diisopropylcarbodiimide (4.2 mL, 26.8 mmol) was added slowly and dropwise. After 30 minutes of reaction, the reaction mixture was cooled to about 15 °C in an ice bath. The solid product formed was collected by filtration and washed with tetrahydrofuran. The filtrate was slowly poured into water and stirred for 30 minutes. The white solid product was collected by filtration again, washed with water and dissolved in 500 mL of ethyl acetate. The resulting solution was dried over anhydrous sodium sulfate and subsequently concentrated under vacuum to afford 5.9 g (88% yield) of the target compound 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide as a white solid with a melting point of 180-181 °C.1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 4.02 (s, 2H) 7.58 (s, 1H), 7.66 (s, 1H), 10.00 (s, 1H); mass spectra (electrospray ionization) m/z 257.0, 259.0 ([M-H]-). Elemental analysis (C10H8Cl2N2O2) calculated values: C, 46.36; H, 3.11; N, 10.81. measured values: C, 46.25; H, 3.10; N, 10.85.
References
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 26, p. 7868 - 7876
[2] Patent: US2005/43537, 2005, A1. Location in patent: Page/Page column 3; 6
[3] Patent: WO2006/47262, 2006, A1. Location in patent: Page/Page column 13-14
[4] Letters in Drug Design and Discovery, 2011, vol. 8, # 1, p. 9 - 13
