Synthesis Of Ribosyl-ribitol Intermediate And 4'-spiro Nucleosides Intermediates

This dissertation is divided into two parts. The first part deals with the synthesis of the ribosyl-ribitol intermediate, which is the most important part in the whole synthesis of the Hib vaccines. The second part deals with the synthesis of the 2′-3′-didehydro-3′-deoxy-4′-spirothymidine intermediates, and finally we have syntheses two compounds: 1-[5′-(O-2-bromoallyl)-2′,3′-didehydro -2′,3′-deoxy--β-D - ribofuranosyl]thymine, 1-[5′-(N-2-bromoallyl-N-tert-butyloxycarbonyl)amino -2′, 3′-didehydro -2′,3′-deoxy-β-D - ribofuranosyl]-3-benzylthymine. At last, the final products were fully characterized by HPLC-MS, 1H NMR.In part one, the background and the synthesis of the ribosyl-ribitol intermediate of the Hib vaccine have been introduced. Hib bacterium causes, mainly in children, meningitis, pneumonia, epiglottis and other diseases of the respiratory tract. And since the Hib conjugate vaccine which was the capsular polyribosyl ribitol phosphate (PRP) couples with specific virus protein has been discovered, the infection ratios among the enfant have been dramatically reduced. In this part, after reviewed many literatures, an short synthetic route of ribosyl-ribitol was chosen, of which the starting material was cheap and easy to get. The ribosyl-ribitol was got with a yield of 16% after 11 steps including protecting, deprotecting, reduction and coupling reactions. During these processes, the synthetic conditions were optimized and the total yield of the synthesis was improved.In part two, We Introducted the 1, 5- radical translocation/cyclization reactions, which is an efficient way for synthesis of cyclocompounds, especially spiro- compounds. Moreover, 4′-spironucleosides is an important kind of conformation restricted nucleosides. So far, little literatures were reported on the synthesis of 4′-spironucleosides by 1, 5- radical translocation/cyclization reactions. On the bases of our lab′s forepart research, an efficient and high-yielding synthetic route was evaluated for the preparation of 2′-3′-didehydro-3′-deoxy-4′-spirothymidine precursor. First, the d4T has been synthesized through 3 steps according literatures. Then, starting from d4T by a sequence of methylsulfonation, nucleophilic attraction of azido anion and allylation, and the title compounds were got with a good yield. This part of work is good foundation of synthesis of 2′-3′-didehydro-2′-3′-dideoxy-4′-spiro- nucleosides, and provides new methods of the modified nucleosides′synthesis.