The Study And Process Optimization Of New Route Of Isaconazole

Isavuconazole is an anti-fungal drug developed by Basella Pharmaceuticals and Astellas.In 2013 and 2014 the partners won orphan drug designation in the US for isavuconazonium as the treatment for invasive aspergillosis,mucormycosis,and invasive candidiasis.On March 6,2015,FDA granted approval of isavuconazonium sulfate(trade name:Cresemba)after receiving priority review,then the drug was marketed in the USA.On October 15,2015,European Medicines Agency also approved Isavuconazole.In 2017 Basilea licensed rights to Pfizer to sell in most of Europe and a few other countries.The main topic of this project includes:1.A new route was designed and actualized to synthesize Isavuconazole.In this new route,ethyl 2-cyanoacetate and 4-acetylbenzonitrile were utilized as the starting materials and eleven steps such as ester exchange reaction,condensation reaction,methyl ation reaction,and Corey-Chaykovsky epoxidation reaction were included.2.To optimize the conditions for the asymmetric methylation reaction,Evans chiral auxiliary was introduced to control the stereoselectivity by steric effect.Results demonstrated that the proportion between the two configurations of the product was determined to be 9.3:1.In addition,the configuration of asymmetric epoxy compounds was well controlled through the Corey-Chaykovsky reaction.The synthesis process of the key intermediates in this route were optimized to make it more applicable for industrial applications.3.The synthetic route to Isavuconazole through epoxy ring-opening reaction using the intermediate of effluconazole as the raw material was also explored.Nucleophiles including Grignard reagents,copper magnesium reagents,and copper lithium reagents were tried as to react with the corresponding epoxy compounds,but unfortunately none of them could yield the target products.While,new methods of synthesizing 4-(2-bromoacetyl)benzonitrile and 4-(2-bromothiazol-4-yl)benzonitrile were researched during the process.