5-Chlorosalicylic acid 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. 

A method was described for the determination of niclosamide in simulated gastric and intestinal media using spectrophotometry at 386 nm [55], The method obeyed Lambert-Beer s law at 2-16 pg niclosamide/mL. Alkaline hydolysis of niclosamide gave two products, 5-chlorosalicylic acid and 2-chloro-4-nitroaniline. Niclosamide appeared to be stable in simulated gastric and intestinal media. 

The stability of niclosamide was studied in simulated gastric and intestinal juices, with and without enzymes, after incubation at 37°C. The remaining intact drug and its degradation products (2-chloro-4-nitroaniline and 5-chlorosalicylic acid) were extracted with chloroform/methanol (5 1) and determined by TLC and HPLC. The drug was stable in these media for at least 6 h [68]. 

Niclosamide Niclosamide, 2, 5-dichloro-4 nitrosaicylanilide (38.1.34), is made by reacting 5-chlorosalicylic acid with 2-chloro-4-nitroaniline in the presence of phosphorus trichloride [38-40]. 

The interaction between 5-chlorosalicylic acid and 2-chloro-4-nitro aniline in the presence of xylene, phosphorous tri-chloride and heating results into the formation of niclosamide with the elimination of one mole of water. 

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