| Invasive fungal disease is one of the most serious fungal infections.In recent years,the incidence and drug resistance rates have increased significantly,and the mortality rate is extremely high(39%-100%).Drugs for the treatment of invasive mycosis mainly include polyene antifungals,echinocandin antifungals and triazole antifungals.Among them,triazoles are more widely used.Isavuconazolium sulfate is a novel triazole antifungal drug mainly used for the treatment of invasive aspergillosis and mucormycosis.The antifungal drug was jointly developed by Astellas Pharma and Basella Pharma.On March 6,2015,it was approved by the US FDA to be marketed under the trade name Cresemba.In October of the same year,the European Commission also granted its marketing authorization.And it was granted fast track approval and orphan drug status at the time of review.The research contents of this subject are as follows:1.Using unreported starting materials,design and complete the docking of isavuconazole and the hydrophilic side chain,and also the subsequent salt formation reaction,and successfully synthesize isavu-conazolium sulfate.This route starts with(2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazol-1-yl)butane Thioamide and4-(2-bromoacetyl)benzonitrile were used as starting materials,and the compound 6 in the form of quaternary ammonium salt was obtained through the reaction of ring closure and nucleophilic substitution,and then anion exchanged into onium sulfate.2.Through the control of the material ratio,the utilization rate of high-cost raw materials is effectively improved in the synthesis process of isavuconazole,the waste of high-cost raw materials is avoided,and the cost is controlled.At the same time,the liquid chromatography purity of isavuconazole reaches 98%;In the synthesis of the hydrophilic side chain,through the screening of the system,temperature and feeding method,the most suitable conditions for this step reaction are finally determined,so that the liquid chromatography purity of the hydrophilic side chain can reach 95%;In the synthesis of isavuconazole and the hydrophilic side chain docking,when screening the system and catalyst,the antagonistic relationship between the thermal stability of the hydrophilic side chain and the reaction temperature was solved,and the bimodal phenomenon in the liquid chromatography was analyzed.The reaction conditions were re-screened,and finally passed through the column during salt formation,and the purity of the reaction product was increased to more than 99%.So far the yield is 80%.3.Through the analysis of the anion exchange of quaternary ammonium salts,three salt-forming routes are designed,which are:1.first deprotection,then exchange anions for hydroxide,and finally exchange sulfuric acid for hydrogen sulfate;2.first treat resin with sulfuric acid resin,and then exchange the anion for hydrogen sulfate,and then deprotection group;3.directly exchange the anion for hydroxide with weakly basic anion exchange resin,and then simultaneously deprotection group and exchange anion with sulfuric acid.By comparing the three routes,the most suitable route for later industrialization was screened out and optimized.The dosage of weakly basic ion exchange resin and the ion exchange time were optimized,and the conditions that were relatively more suitable for industrialization were selected.At the same time,the deprotection group reaction was further optimized,and the reaction conversion rate was improved by adjusting the amount of sulfuric acid,so that the liquid chromatography purity of the final product isavu-conazolium sulfate reached more than 97%,and the final total yield was 60%. |
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