Synthesis Of Acyclic Nucleotide Analogs As Tenofovir Prodrugs

Tenofovir is an adenine acyclic nucleotide analogue,which can effectively inhibit the replication of hepatitis B virus(HBV).Due to its low oral bioavailability,poor cell permeability,and high nephrotoxicity,tenofovir is usually used as a prodrug to improve efficacy and reduce nephrotoxicity.Tenofovir exalidex(CMX157)and tenofovir alafenamide(TAF)are two new type of tenofovir prodrugs for the treatment of chronic hepatitis B.CMX157 and TAF have the advantages of high drug safety and low nephrotoxicity.Therefore,the future market is broad.Based on the literature,a new synthetic route of tenofovir exalidex was designed and optimized in this paper.The synthetic route was following: In presence of potassium hydroxide,1-bromo-3-chloropropane was reacted with hexadecanol through Williamson reaction to give 1-chloro-3-hexadecyloxpropane(compound 7).The target product tenofovir exalidex was obtained from compound 7 and tenofovir(compound 2)under the reaction of tetrabutylammonium hydroxide.Based on the literature,the synthetic routes of tenofovir alafenamide in the literature was optimized as following: Tenofovir was reacted with phenol to give(R)-9-[2-[(phenoxyphosphinyl)methoxy]propyl]adenine(compound 8)through esterification in presence of N,N’-dicyclohexylcarbodiimide(DCC).The compound 8 was reacted with sodium hydroxide to obtain the sodium salt of the compound 8(compound8a).Compound 8a was chlorinated to corresponding phosphonochloridate,and tenofovir alafenamide(compound 10a)and its diastereomers was obtained from the phosphonochloridate and L-alanine isopropyl ester.After chemical resolution,tenofovir alafenamide was reacted with fumaric acid to obtain tenofovir alafenamide fumarate.According to the analyses of the experimental conditions and results,the new synthetic process of tenofovir exalidex and tenofovir alafenamide has the advantages of low cost,less pollution,no hrash reaction conditions,high yield and is suitable for industrial preparation.The chemical structures of the target products and intermediates compounds were confirmed by NMR,IR and so on.