Studies Of The Synthetic Methods For 5-deoxy-1,2,3-tri-o-acetyl-d-ribofuranoside

Tumor is severe disease to threaten human life. The anti-tumor agents, also called anti-cancer drugs, have the properties to kill the cancer cell in human body and developed very quickly in recent two decades. Nucleoside analogue is a kind of important anti-cancer chemotherapy agents, which include purine and pyrimidine derivatives. With more research on nucleotide agents, the process of nucleotide's metabolize and nucleotide's anti-cancer mechanism have been elucidated, which promote the development of the anti-tumor agents based on nucleotide. It need to be note that modification of nucleotide according to the principle of prodrug has become an important methodolgy in recent drug discovery.As the prodrug of fluorouracil, Capecitabine has been approved by FDA as a new oral anticancer agent. This agent has no cytotoxicity in vitro, but it could converted to active metabolite fluorouracil in vivo..Therefore, Capecitabine has good selectivity on cancer tissue with low toxicity and exhibit good efficacy and safety.In order to investigate the process for industry, two intermediate should be solved for their preparation. One is fluorouracil, the other is 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose. Considering the fluorouracil is commercial available due to its launched for many years, the synthesis of 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose become more important for the preparation of Capecitabine.The literature reported that the compound of 1,2,3-tri-O-acetyl-5-deoxy- D-ribofuranose could be synthesized with inosine or D-ribofuranose. In our studies, we tried these two different methods and finally choose the synthetic route with D-ribofuranose as starting material. This synthetic route includes the reaction of methlation, protection of diol, tosylation, reduction and finally acylation.In order to optimize the process as cheap and efficient synthetic way, we did several modifications as follows:(1) using cupric sulphate anhydrous as dehydration reagent in the reaction of protecting diol; (2) using tosyl as protecting group and simplifying the process of first three steps without purification; (3) using cation resin as catalyst in acylation; (4) purifying the final product with methanol and water recrystallation. Finally, 1,2,3-tri-O-acetyl-5-deoxy-D-ribofuranose was obtained and identified with 1H-NMR and IR.We also did further modification using the basic solution to remove tosyl group, while the traditional method had to utilize the expensive chemical reducing reagent. The patent has been filed to protect this new method and we believe that the further studies would be greatly helpful for the bulky production of Capecitabine.