Synthesis Of Voriconazole And Determination Of Organic Residual Solvent Produced In Synthesis Technology

Voriconazole, triazole antifungal agent, is one of fluconazole derivatives, with the characteristics of broad spectrum antifungal and strong antifungal efficiency. This medicine was developed by American Pfizer, and was listed at first in U.S.A. in 2002. It is mainly used for treating the acute or chronic deep fungal infection on clinic.WTO statistics show that there are about more than 270 kinds of fungi can cause human disease. It is varied that the form expression of causing the disease, the shallow fungi can infringe the hair, the nail or the toenail and smooth skin, and the deep fungi can attack each organ and system such as heart , liver, spleen, lung, kidney, brain, blood, intestines and stomach skeleton etc.. The prognosis is serious and death rate is high. Especially, various reasons can cause fungal infection to organism patient who has low resistance easy to take place, for instance use the hormone wide-sprctrum antibiotic immune inhibitor for a long time, and burn, organ transplant , AIDS people, etc.. Therefore the fungal infection caused the great attention of the clinical medical personnels all over the world. The research for antifungal medicine has become hot field.It is reported that there are four routes of the synthetic route of voriconazole .But the four routes have been patented in China. Under the Zn/I₂ , with 6-(1-bromo-ethyl)-4-chloro-5-fluorpyridine andl-(2,4-difluoro-phenyl)-2-(lH-l,2,4-triazole-l-yl)ethyl-ketoxime condensation, then hydrogenation separation and the product was obtained. This route is short, high yield and the reaction condition was mildness.In the synthetic process of raw material drugs, selecting solvent play an important role because solvent can impact yield, crystalline form, purity, and dissolvability of drugs. However, residual solvent not only no therapeutic effectiveness, but also can impact the security of product so that it is necessary to study it. Residual solvent in drugs is that organic solvent used in synthetic process of raw material drug, accessories and preparation of pharmaceutics but not completely removed. According to the toxicity and hazard to environment, organic solvent is divided four classes which are avoiding usage, limited usage, low toxicity and toxic data shortage by ICH. Benzene, tetrachloromethane and 1,2-dichloroethane etc. were listed poisonous compounds by EHC and IRIS. In order to prevent the hazard caused by long contact chemicals, physical acceptable level was carried out by some organization such as IPCS, EPA and FDA.In the present paper, synthesis technology and physicochemical property of voriconazole, test method of organic residual components produced during synthesis procedure were studied. Organic residual components were determined using Static Headspace Gas Chromatography Method(DM-624 Copillary Column: 30m x0.53mmx3.0//m, stationary phase: 6% biscyanopropyl — 94 % poly cyanopropylphenyl siloxane, flame ionization detectorC FID), temperature programming). The results indicated that the content of : methanol<0.04%, acetone=0.01%, isopropanol=0.26%. No ethanol, dichloromethane, ethyl acetate, tetrahydrofuran and glycol diemthyl ether was detected.