Research On Synthesis And Crystallization Process Of Nitazoxanide

Nitazoxanide is a novel broad-spectrum intestinal antiparasitic drug, the spectrum of activity of nitazoxanide is effective against a wide range of intestinal protozoa and a lot of common helminthes, it is widely used in medical field. The yield and purity of nitazoxanide is low at home and abroad because of the reaction steps is more and the product colour is poor, it is unfavorable to industrial production, and there is no crystallization process research system, directly affect the quality of the product and economic benefits. Based on the above problems, in the paper, we systematically studied the synthesis and crystallization process of nitazoxanide.Nitazoxanide was synthesized through amidation from 2-amino-5-nitrothiazole and acetylsalicylic acid at the presence of P₂O₅ as dehydrant. The optimal conditions were as follows: n(acetylsalicylic acid): n(2-amino-5-nitrothiazole): n(P₂O₅) = 1.2:1.0:2.5, in DMF at 90℃for 2.0 h. The yield can be higher than 75.1%. Nitazoxanide was synthesized through amidation from 2-amino-5-nitrothiazole and acetylsalicylic acid in the presence of triethylamine as acid acceptor and N, N-dimethylform amide as catalyst. The optimal conditions were as follows: the temperature of acyl chloride is 70℃, the molar ratio of acetylsalicylic acid to SOCl2 is 1.0:1.3, the molar ratio of 2-amino-5-nitrothiazole to acetylsalicylic acid is 1.0:1.4, the reaction time of amidation is 2.5 h. Under such optimal reaction conditions, the yield can reach 76. 8%.The saturated and supersaturated characteristics of nitazoxanide in DMF, DMSO, methanol and acetone at different temperatures were investigated by using the laser detection technique, the crystallization metastable zone width of nitazoxanide was obtained at different temperatures in the above four solvents, drawn the curve of solubility, super solubility and the metastable zone width. The results indicated that the solubility, super solubility and the metastable zone width of nitazoxanide raise with increasing temperature. The solubility of nitazoxanide in the above solvents decreased in the order DMF > DMSO > methanol > acetone. The metastable zone width of nitazoxanide relations as follows: acetone < DMSO < methanol < DMF. Investigate the affect of cooling rate and stiring rate on metastable zone of nitazoxanide.The decolorization of nitazoxanide by activated carbon was studied, based on experiments, the equation was obtained to compute pigment concent ration by absorbance, and adsorption isotherm was established. The optimal conditions were as follows: 20℃, 2.0h, 5% amount of activated carbon and the stirring rate is 120r/min. Under the optimal reaction conditions, the decolorization rate could be 90.2%, the yield is 97.1%. Purify nitazoxanide by cooling crystallization method, select DMF for solvent, The optimal conditions were as follows: reactant ratio of product and solvent is 1.0:1.7, starting temperature is 60℃, stirring rate is 120r/min, cooling rate is 5℃/h, and the final cooling temperature is 25℃, the yield is 57.9%, the purity can reach 92.8%.