Research On Racemization Of Industrial Waste Dexvoriconazole (2S, 3R)

The development of circulation economy is great importance of constructing environmental friendly society and realizing sustainable development in China.Resource recycle is central to circulation economy,which suggests the significance of recycling industrial wastes.Voriconazole,as a fluconazole derivative,is a novel second-generation triazole antifungal agent developed by Pfizer.Voriconazole has mainly been prescribed for clinical treatment of acute or chronic deep fungal infection owing to its broad spectrum,vigorous antifungal efficacy and favorable security.With the rapid increase in demand of antifungal agent,there is no doubt that voriconazole will occupy a lion’s share in future market.For voriconazole racemer,only(-)voriconazole showed antifungal efficacy.For voriconazole production on the industrial scale,voriconazole racemer was initially synthesized and then(-)voriconazole was resolved and purified,and side product of(+)voriconazole was considered as industrial wastes for further treatment.Accordingly,in this paper,voriconazole racemer including(-)(+)voriconazole(50:50)provided by Changzhou Qihui pharmacy company,was used to carry out conversion of(+)voriconazole into(-)form.Initially,voriconazole racemer was resolved by L-camphorsulfonic acid;Then,the conversion process of(+)voriconazole into(-)form catalyzed by acid and base was optimized.The main contents of this dissertation are as follows:Initially,(-)voriconazole was resolved and purified from voriconazole racemer(50:50)by L-camphorsulfonic acid and the process was optimized.Result showed that,with solvent ratio of acetone:methanol 2:1,voriconazole racemer:L-camphorsulfonic acid 1:1,complexing reaction temperature 50℃ and 40%(w/v)sodium hydroxide in hydrolysis,final yield of(-)voriconazole was 39%from 50%in voriconazole racemer.Effects of sulfuric acid on conversion of(+)voriconazole into(-)form was investigated and affecting factor was optimized.Results indicated that,with reaction temperature 60℃ and reaction time 90 minutes,final conversion yield of(+)voriconazole into(-)form was 32%.By using sodium ethoxide as catalyst and glycol as solvent,the conversion of(+)voriconazole into intermediate 4-ethyl-5-fluoropyrimidine and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone was optimized.Results showed that,reaction temperature and time was 70℃ and 10hours,respectively,these two intermediates were obtained in great amounts,which were used as reactant to synthesize voriconazole racemer.It was suggested that recycling of(+)voriconazole waste is being feasible on large scale.In this paper,the separation of voriconazole racemer and conversion of(+)voriconazole into(-)form was investigated.The(+)voriconazole was converted into(-)form and intermediate by sulfuric acid and sodium ethoxide,respectively.A new method was provided for the utilization of the waste(+)voriconazole.