Synthesis Of Itraconazole And The Key Intermediate Of Iclaprim

Itraconazole is an antifungal drug developed by Johnson&Johnson,which was widely used clinically to treat invasive fungal infection caused by Aspergillus and Candida.4-[[4-(4-Hydroxyphenyl)piperazin-1-yl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one(1)was the key intermediate of itraconazole.In the article,we reported its novel synthesis method:1 was prepared via condensation of phenyl4-[[4-(4-hydroxyphenyl)piperazin-1-yl]phenyl]carbamate(6)and N2-sec-butylformohydrazide(2).The secondary butyl was introduced before building the triazole ring,which avoided the butylation with low yield after triazole-ring formation.Besides,the phenolic hydroxyl of compound 6 didn't need to be protected,so that the de-protection by strong acid was deleted in the following reaction.The intermediate 2 was obtained by acylation of hydrazine hydrate with ethyl formate,condensation with butanone,and reduction by sodium borohydride.Intermediate 6 was prepared by acylation of 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine with phenyl chloroformate.The main improvements were made as the followings:The mixed solvent IPA:H2O=10:1 was used in the reduction reaction,so that the amount of sodium borohydride was reduced from 0.85 equiv in literature to 0.5 equiv,and the product was purified by vacuum distillation instead of column chromatography in literature.In the acylation with phenyl chloroformate,the bis-phase syntem(dichloromethane/water)was used as the solvent,and sodium bicarbonate was used as base.The reaction proceeded in two-phase so that the formation of bis-acylated impurity was avoided.Itraconazole was obtained by substitution of 1 with cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmcthyl)-1,3-dioxolanyl-4]methyl mesylate.The purity of itraconazole obtained was over 99.53%,which complied with the provisions of the United States Pharmacopoeia.Iclaprim,a dihydrofolate reductase inhibitor developed by MotifBio,had been completed phase III clinical trail on the treatment of acute bacterial skin and skin structure infections(ABSSSI)in the United States.It was expected to submit the new drug application in 2018.In the second part of this article,the synthesis of iclaprim in the literature was reviewed and the synthesis of the key intermediate 2-cyclopropyl-7,8-dimethoxy-2H-benzopyran-5-carbaldehyde(14)was investigated:1-cyclopropyl-3-(trimethylsilyl)propyl-2-yn-1-ol(10)was prepared via the acetylation of 1,2-bis(trimethylsilyl)ethyne with cyclopropanecarbonyl chloride and reduction with sodium borohydride.Compound 14 was prepared via Mitsunobu reaction between 10 and 3,4-dimethoxy-5-hydroxybenzaldehyde(11),followed by the removal of trimethylsilyl with potassium carbonate and cyclization.Meanwhile,Compound 11 was prepared from vanillin via bromination,hydrolysis,and methylation.The main improvements were made as the followings:In the bromination,the amount of acetic acid(as the solvent)was reduced from 8 ml/g in the literature to 5 ml/g,and by the improvement for the work-up,the yield was increased from 69%(reported in the literature)to 91.6%.In the hydrolysis,the reaction time was shortened from 24 h to 17 h by increasing the concentration of the aqueous sodium hydroxide solution.The product was purified by recrystallization instead of the column chromatography in the literature.In the methylation,the dimethylated impurities was reduced by adjusting the reaction temperature and the ratio of dimethylsulfate and the product was obtained by simple work-up,avoiding column chromatography in literature.In the reduction reaction,the expensive cesium chloride heptahydrate was replaced with acetic acid.