Study On Synthesis Of Isaconazole Sulfate

Isaconazole Sulfate is a new generation of triazole antifungal drugs used to treat invasive mucormycosis and invasive aspergillosis.In the approval stage,it was granted orphan drug qualifications.In 2015,it was successively approved by the FDA and the European Commission to be listed under the trade name Cresemba.Compared with other antifungal drugs,the drug has the advantages of good oral bioavailability,high safety,stable pharmacokinetic parameters and so on,so the study of the drug is of great significance.The research contents of this topic include:1.We designed and tried a new synthesis method of Isaconazole,using 4-acetylbenzonitrile as a raw material,through a bromination reaction,thiocyanate substitution,thiazole ring cyclization three-step reaction to obtain intermediate 4-(2-bromothiazol-4-yl)benzonitrile.It was then prepared into organolithium reagents and Grignard reagents,and undergoesed a ring-opening reaction with epoxide intermediates,and was optimized by adding reagents such as HMPA,CuI,and magnesium chloride.2.Based on the route reported in US6300353,a new attempt was made in two steps of the reaction,using R-methyl lactate as the raw material,undergoing nucleophilic substitution of morpholine,hydroxytetrahydropyranation,Grignard reaction,Wittig reaction,double bond hydroxylation,hydroxyl deprotection,hydroxyl dehydration ring,cyano nucleophilic ring opening,a total of 8 steps to synthesize the target compound.3.With reference to several literature methods,the synthesis of the hydrophilic side chain of Isaconazole was completed.Using 2-chloronicotinic acid as the raw material,after the Boc on the carboxyl group,methylamine substitution,and carbonyl reduction,successive substitution reactions with ethyl 1-chloroethylacetate and Boc sarcosine,a total of four steps of successful synthesis of Isaconazole hydrophilic side chain.We had optimized the process for each step in the route:In the synthesis of t-Butyl 2-(N-methylamino)nicotinate,it was changed to normal temperature and pressure reaction,which reduced the operation risk;In the reduction of carbonyl compounds,LiAlH4 was replaced with a cheaper and safer combination of sodium borohydride and Lewis acid.