Synthesis
Step b) Synthesis of 2-chloro-3-nitrobenzamide from intermediate 2-chloro-3-nitrobenzonitrile: Sufficiently dried 2-chloro-3-nitrobenzamide (83 g, 0.413 mol) was added to a refluxing solution containing a dehydrating agent. The mixture was kept at reflux temperature for 4 hours and the reaction was subsequently continued at room temperature for 16 hours. Upon completion of the reaction, the reaction mixture was quenched with ice water and 400 ml of water was added to facilitate phase separation. The aqueous phase was discarded and the organic phase was washed sequentially with water and brine and then dried with anhydrous Na2SO4. The dried organic phase was filtered and concentrated to afford the target product 2-chloro-3-nitrobenzonitrile (74.4 g, 99% yield). The product was characterized by 1H NMR (300 MHz, DMSO-d6): δ 7.76 (t, J = 7.93 Hz, 1H), 8.27 (dd, J = 7.93, 1.47 Hz, 1H), 8.36 (dd, J = 8.22, 1.47 Hz, 1H).
Preparation of the *dehydrating agent trimethylmethylsilyl polyphosphate: in 1 liter of anhydrous dichloromethane, P2O5 (254 g, 1.79 mol) was added and stirred under reflux conditions. Hexamethyldisiloxane (330 ml, 1.54 mol) was slowly added through a dropping funnel over a period of 1 h. Care was taken to control the rate of addition to cope with the exothermic reaction. After the addition was completed, the reaction mixture continued to be stirred at reflux temperature for 1 hour.
References
[1] Patent: WO2008/18827, 2008, A1. Location in patent: Page/Page column 29-30
[2] Patent: US6344459, 2002, B1. Location in patent: Page column 68
[3] Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5464 - 5474
[4] Journal of Heterocyclic Chemistry, 2009, vol. 46, # 5, p. 936 - 948
