Synthesis And Biological Active Study Of Triazole Modified Spiro, Fused And Medium-sized Nucleosides

Nucleoside analogues are the primary means of man against the virus, they make use of preventing replication of viral DNA to achieve therapeutic effect. The existing structure of nucleoside antiviral drugs in viral DNA makes them simple and selective difference between normal human DNA, leading to toxic side effects. Structure discovery and development of novel modified nucleosides is aimed to improve the selectivity of the effective means of anti-virus,recently the study of conformational restriced nucleosides and acyclic nucleosides attract more attention by pharmaceutical chemist, Through the ring system to restrict the conformation of nucleotides can enhance nucleoside selectivity between the enzymes in the biological, and open-loop structure with broad-spectrum nucleoside and antiviral activity. This paper studies is on the basis of our group, we design and sythesis two 4'-azido nucleoside conformational restrictions and two triazole and middle ring modified nucleosides. the last compounds were characterized by 1H NMR and 13C NMR. The evalution of bioactivity about these copounds are carried out.In the first part of the thesis, the synthesis process of 4'-Azido bicyclothymidine and 4'-Azido spirocyclicthymidine are elaborated.Starting from thymidine, the convertion from 5'-hydroxy group to 5'-iodo group by mistunobu reaction, the elimination by sodium methylate to 4',5'-olefinethymidine, then the electrophilic addition by iodine monochloride and sodium azide to 4'-Azido-5'-iodothymidine. then the peracid oxiadation of 5'-iodo were eliminated by mCPBA and sodium methylate to the key imidiate conpund. Then we started from the key conpund, in one line, we protected the 5'-hydroxy group by TrCl, and introduced propargyl in the 3'-hydroxy group by ultrasonoscope, and to our surprise, the cyclization were reacted in the meantime, then the thymine were converted to 5-methylcytosine. In the other line, we protected all the hydroxyl with TBS, selectively deprotecting 5'-TBS, introduced propargyl in the 5'-hydroxy group by ultrasonoscope. and the cyclization were also reacted in the meantime, the thymine were converted to 5-methylcytosine later. We designed and synthesized the 4'-Azido bicyclothymidine and 4'-Azido spirocyclicthymidine containing triazole, and the basic group were converted, and the question in the process were analysised and discussed.In the second part of the thesis, the synthesis of the 2'-Azido-2',3'-seco middle ring uradine and 3'-Azido-2',3'-seco middle ring uradine were elaborated. Started from uridine, after a sequence of protecting 5'-hydroxyl by TrCl, the oxidation and reduction by sodium periodate and sodium borohydride were handled, then mesthlation of 2',3'-dihydroxy gaved che key imidate conpund. Then we started from the key conpund, in one line, the 5'-O-trityl-2',O2- anhydro- 2',3'-secouridine were synthesized by lithium azide, then the 2', O2-anhydro ring were opened by 1 N sodium hydroxide, the propargyl were introduced in the 2'-hydroxyl by ultrasonoscope, then the cyclization were reacted in toluene at reflux, then the uracil were converted to cytosine. In the other line,5'-O-trityl-2',O2-anhydro-3'-O-mesyl- 2',3'-secouridine were synthesized by DBU, then we synthesized the 5'-O-tryty1-2', O2-anhydro-3'-benzoxy-2',3'-secouridine by potassium benzoate, then the 2', O2-anhydro ring were opened and azido were introduced in the 2'position, then we introduce propargy1 in the 3'-hydroxy group by ultrasonoscope, next the cyclization were reacted in toluene at reflux, later we coverted uracil into cytosine. We designed and synthesized 2'-Azido-2',3'-seco middlering uridine and 3'-Azido-2'.3'-seco middlering uridine containing triazole, and we analysised and discussed the question in the process.