Synthesis
General procedure for the synthesis of 2-chlorothiazole-5-carbonitrile using 2-amino-5-cyano thiazole as starting material: 3.4 g (27 mmol) of 2-amino-5-cyano thiazole (Example 43) was homogeneously dispersed in 100 mL of acetonitrile with 5.1 g (30 mmol) of copper chloride dihydrate. Under vigorous stirring conditions, 5.7 mL of an acetonitrile solution of isoamyl nitrite was slowly added dropwise over a period of 30 minutes, and the reaction was continued for 10 hours after completion of the dropwise addition. After completion of the reaction, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate and filtered to remove insoluble impurities. The organic phase was concentrated and purified by column chromatography to give 2.6 g of the target product (67% yield) as a liquid. The liquid precipitated needle-like crystals upon standing, with a melting point of 54-57 °C. 13C NMR (CDCl3, ppm) data were as follows: 108.16, 110.41, 150.59, 157.36; mass spectrometry (EI) showed the molecular ion peak m/z of 144.1 (M+).
References
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6363 - 6372
[2] Patent: EP2039686, 2009, A1. Location in patent: Page/Page column 32-33
[3] Patent: US2010/87448, 2010, A1. Location in patent: Page/Page column 22
[4] Patent: US2004/23978, 2004, A1. Location in patent: Page/Page column 13
[5] Patent: US2004/23980, 2004, A1. Location in patent: Page/Page column 13
