Study On The Synthesis Of Tenofovir Disoproxil And The New Crystal Form Of The Salts

Acyclic nucleoside antiviral drugs have been become a group of the remarkable medicines in the pharmaceutical market at home and abroad in recent years. Not only do they have low toxicity, low tolerability and broad-spectrum anti-DNA virus activity, but aslo they have a strong effacicy against resistant strains. So they play an important role in the field of antiviral therapy. Much attention has been paid to the development of this class of antiviral drugs recently.Tenofovir, as one of the novel acyclic nucleoside antiviral drugs, has a srong inhibitory effect on HIV and HBV. It can be also used by patients who are resistant to lamivudine. In addition, tenofovir has a good drug tolerance to the patients of HIV. Because of its low oral bioavailability, the development of the prodrugs of tenofovir and their crystalline salt has been become the main research hotspot in recent years.This thesis work includes three aspects as the following:(1) 9-(2-hydroxypropyl) adenine was synthesized by the reaction of ring-opening condensation with adenine and 1,2-propylidene carbonate. (R)-9-[2-(diethylphosphon-omethoxy)propyl]adenine was synthesized by condensation with 9-(2-hydroxy-propyl)adenine and diethyl[[(p-Toluenesulfonyl)oxy]methyl]phosphonate. Tenofovir was prepared by deesterification and hydration with (R)-9-[2-(Diethylphosphono-methoxy)propyl]adenine. The traditional process has been improved in order to increasing the yield of tenofovir. The products of each step were characterized by IR and 1HNMR.(2) Tenofovir disoproxil was prepared by the reaction of condensation with tenofovir and chloromethyl isopropyl carbonate. Tenofovir disoproxil fumarate was prepared by the combination of tenofovir disoproxil and fumaric acid (mole ratio 1:1). The tenofovir disoproxil fumarate was characterized by IR,1HNMR,13CNMR and DSC.(3) In order to increasing the oral bioavailability of tenofovir and more convenient for preparation and oral medication. In this paper, a series of salt forms were synthesized by reacting tenofovir disoproxil with organic acids, such as maleic acid, tartaric acid, ascorbic acid, D-camphor-10-sulfonic acid, L-alanine, taurine, L-aspartic acid, L-(-)-malic acid, succinic acid, fructose acid, citric acid, benzoic acid, phosphoric acid, hydrochloric acid, sulfuric acid tenofovir disoproxil. They were characterized by IR and screened by morphologic observation. Then the selection was characterizd by DSC,1NMR and XRD. And then the crystallinity was calculated. This research lays a foundation on the in-depth research and development of the anti-viral applications of the compounds.