Preparation of Niclosamide

Niclosamide was synthesized industrially by first chlorinating salicylic acid in chlorobenzene to yield 5-chlorosalicylic acid (I). Control of the amount of chlorine introduced is essential at this step, because an excess halogen leads to the formation of 3,5-dichlorosalicylic acid in addition to (I). When (I) is heated with 2-chloro-4-nitroaniline (II) in chlorobenzene (102— 104°C) in the presence of phosphorus oxychloride, niclosamide (III) is obtained [7]. 

Another alternate synthetic method for the manufacturing of niclosamide is reported [1], Phosphorus trichloride (PC13) is slowly introduced into a boiling xylene solution containing 5-chlorosalicylic acid and 2-chloro-4-nitroaniline in equimolar ratio and the heating continued for 3 h. Crystals of niclosamide separate on cooling and are recrystallized from ethanol [7,8], van Tonder et al. [9] prepared and characterized three crystal forms of niclosamide namely the anhydrate and the two monohydrates. 

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