Synthesis
The general procedure for the synthesis of methyl 2-chloro-4-cyanobenzoate from methyl 2-chloro-4-aminobenzoate and cuprous cyanide was as follows: methyl 2-chloro-4-aminobenzoate (4.7 g, 25 mmol) was dissolved in water (12 mL) and concentrated hydrochloric acid (12 mL) was added. The mixture was sonicated to form a fine suspension and subsequently cooled to 0°C. A solution of sodium nitrite (1.91 g, 27.7 mmol) in water (15 mL) was added slowly and dropwise while maintaining the reaction temperature at 0-5 °C. The mixture was stirred at 0-5 °C for 15 min and then neutralized by addition of solid sodium bicarbonate. Subsequently, the resulting solution was added to a solution of water (25 mL) containing cuprous cyanide (2.79 g, 31 mmol) and potassium cyanide (4.0 g, 61 mmol) at 75 °C. The reaction mixture was stirred at 75 °C for 45 min, cooled to room temperature and extracted twice with toluene. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by fast column chromatography on silica gel (eluent 20% ethyl acetate/80% petroleum ether) to give a light orange solid, which was identified as methyl 2-chloro-4-cyanobenzoate in a yield of 2.61 g and 53%.
References
[1] Patent: EP1512687, 2005, A1. Location in patent: Page/Page column 9-10
[2] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 8124 - 8134
