Studies On Scale Up Synthesis Of O-iso-propyl-5'-H-phosphonate Of D4T And It's Properties And Studies On Novel Synthesis Of D4T 5'-H-phosphonate Diesters

Some d4T-5'-hydrogen phosphonates are promising drugs for curing AIDS because of their much higher activity of anti-HIV and, meanwhile, lower cytotoxicity compare to d4T and other anti-HIV drugs now employed. Studies from Prokrovsky, A. G et al. have shown that O-iso-propyl-5'-H-phosphonate of d4T has much higher activity of anti-HIV and, meanwhile, lower cytotoxicity compares to d4T. According to the excellent results in the pre-clinic trail it's a promising drug for curing AIDS. Thus, it is of great importance to study the synthesis of this species of compounds and to study the enlarged laboratory synthesis of O-iso-propyl-5'-H-phosphonate of d4T and it's properties.After considering the stock cost, reaction conditions, yields, and separation of product, we chose to employ an efficient and economical one-pot synthesis method giving reasonable yields to prepare O-iso-propyl-5'-H-phosphonate of d4T by using a phosphorus trichloride/alcohol system, which is originated from our lab. The reaction pathway is suggested according to the resembling Abuzov reaction mechanism. We have optimized the reaction conditions and product separation. And that the reaction is well under controlled when subjected to enlarged scale preparation of O-iso-propyl-5 '-H-phosphonate of d4T.Further more, we have studied the physical properties of O-iso-propyl-5'-H-phosphonate of d4T. And combined NMR, IR and ESI-MS with other means of detection, we have identified the structure of O-iso-propyl-5 '-H-phosphonate of d4T.We have also studied it's stability. When subjected to water it decomposed in about half a month. But while water is deprived of from where the compound is stored, it can stand 60℃for more than 10 days.In this dissertation we also described the discovery and studies on a novel method to synthesize d4T-5'-hydrogen phosphonates . By using 2-chloro-1,3-dimethylimidazolinium Chloride ( DMC ) as the condensing reagent, a series of d4T-5' -hydrogen phosphonates had been synthesized. First d4T and phosphorous acid ( H₃PO₃ ) were dissolved in dried pyridine, then DMC in dried CH₂Cl₂ was slowly dropped to the above solution at room temperature under nitrogen atmosphere with stirring. A few minutes later, the correspondent alcohol ROH was added to the above mixture and then DMC in dried CH₂Cl₂ was added to the above mixture dropwise at room temperature. The reaction finished in a few minutes. Studies showed that the reaction processed on favorably at room temperature; Further more, the correspondent alcohol ROH can not only be n- and iso- alcohol but can also be tert-alcohol. In short, the method to synthesize d4T-5'-hydrogen phosphonates was prompt, easy to be managed, and can be carried out under mild condition.