Improvement On Production Process Of Voriconazole Intermediates

Voriconazole is a second generation of three azole antifungal drugs,which is obtained by modifying early antifungal drug fluconazole and first listed in the United States in 2002.In this paper,the synthesis process of a key intermediate of voriconazole,named(2R,3S/2S,3R)-3-(4-chloro-5–fluoroprrimidin-6-l-)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-tria zol-1-yl)butan-2-ol hydrochloride was studied.This paper analyzed the existing routes of voriconazole.Through comparing the reaction type,raw material,environmental protection,yield and industrialization of different routes,we selected an economical and environmentally friendly route,which was suitable for industrial production.The target product was synthesized and its structure was determined by NMR.The main research is as follows.First: the solvent dosage,reaction temperature,reaction time and other conditions of every steps were studied.The optimal process conditions of high yield and low cost were selected.Second: post-processing of cyclization reaction was improved.(1)Replaced hydrochloric acid with acetic acid,the product was easy to crystallization.Boiling point of acetic acid was high and easy to remain,which was not conducive to crystallization.(2)The product was extracted with ethyl acetate and acetone mixture for several times reported in the literature.The process was trivial and not conducive to industrial production In this paper,the product was dissolved in ethyl acetate,the hydrochloride was filtrated,the filtrate was concentrated and crystallized in low temperature.The improved process was easy to operate,and not need to be extracted for many times.Third: As literature reported,reformatsky reaction chose iodine as catalyst,which was difficult to control.The product purity of product was low,and the yield was not high.This paper chose trimethylchlorosilane and zinc chloride as mixed catalyst to optimize the process.The impurities were reduced obviously,the yield was increased to more than 40% and the purity was reached to 98%.