Synthesis
General procedure for the synthesis of 2-amino-6-chloronicotinamide (Inter.3) from 2-amino-6-chloronicotinic acid (Inter.2): Thionyl chloride (3.3 eq.) was added drop-wise to an anhydrous THF solution of 0.3 M 2-amino-6-chloronicotinic acid (1 eq.) under inert atmosphere. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was concentrated in vacuum to give a crude yellow solid residue. The crude solid was dissolved in THF in the same volume as the initial reaction volume and concentrated again under vacuum to give a yellow solid residue. After repeating this dissolution and concentration process once, the residue was dissolved in THF (prepared as a 0.3 M solution) and ammonia was passed into the solution for 1 hour. The resulting precipitate was removed by filtration and the filtrate was concentrated under vacuum to give a yellow precipitate. The precipitate was ground in water at 50 °C and subsequently dried to afford the target compound 2-amino-6-chloronicotinamide (92% yield, 93% purity). The product was analyzed by LC-MS, m/z (ESP): 172 [M + H]+, retention time (R/T) = 3.19 min. The purity of the product met the requirements for use and no further purification was required.
References
[1] Patent: US2009/99174, 2009, A1
[2] Patent: WO2007/60404, 2007, A1. Location in patent: Page/Page column 57-58
[3] Patent: WO2008/23161, 2008, A1. Location in patent: Page/Page column 100
[4] Patent: WO2014/205593, 2014, A1. Location in patent: Page/Page column 59
[5] Patent: US2003/187026, 2003, A1
