Studies On The Synthesis Of Nucleoside Compound FUGA And Its Analogs

Hepatitis B virus(HBV) is one of the most important pathogens which severely do harm to human health worldwide. Suffering persons can result in diverse clinical manifestations, ranging from asymptomatic carriers to acute or chronic hepatitis and fulminant hepatitis. Some chronic hepatitis B patients can transform into cirrhosis, hepatocellar carcinoma and lead to death in the end. According to the statistical date of WHO, there are approximately 350million people who have infected HBV, more than 120 million of which are Chinese. HBV vaccine is widely used to prevent HBV diffusion, but can not change condition of patients which have infected HBV. Antiviral therapy of chronic HBV infection remains an important clinical problem because of lacking currently efficiency treatments. Now there are several methods to cure HBV in clinical, including anti-HBV replication, immunoregulating medicament, improving liver condition and anti-hepatic fibrosis. Now nucleosides and interferons are the major drugs applying in clinic. Interferons are limited in clinic because of high price and low effect. Nucleosides are one of the important biology molecule. As the central fabric of nucleoic acid, nucleosides participate in gene communication, replication and transcription. Nucloeside drugs are one of rapidly developing drugs and are provided with favorable anti-HBV. More and more people pay attention to nucleoside drugs, especially Lamivudine, Adefovir Dipivoxil are provided to anti-HBV. In addition, nucleoside drugs have favorable anti-tumor activity, such as FUDR, 5'-DFUR.Nucleoside drugs are widely applied in clinical, because of perfectable treatment effection and low price. It will be a major aspect of anti-HBV through new nucleoside synthesis or the structure modification.l-(5-Fluoruacil-l)-2,5-di-O-acetyl-p-D-glucofuranurono-6,3-lactone (FUGA)was synthesized by Ruta A. Paegle in 1978. Compared with the known preparation similar action, for example a widely used preparation fluorafur, FUGA has a more pronounced antitumor activity toward a wide range of strains of graded tumors mice and rats, such as leukemia P-388, adenocarcinoma755, Lewis lung carcinoma, melanoma Bi6, and so on. Furthermore, the proposed preparation is several times less toxic than fluorafur, and in addition it is less neurotoxic.We designed and improved the synthesis of FUGA analog and selected an optimized one from two routine. The FUGA was synthesized from 5-Fluoruacil and Glucurolactone by acetylation, Fridel Craft acylation. Then we got the important intermediate l-(5-Fluoruacil-l)-P-D-glucofuranurono-6,3-lactone and improved the yield by 4-Toluene sulfonic acid replacing HC1. The yield was improved and the time is shorter. Finally, we synthesized the target compound successfully. The routine is shorter time, the material is cheaper and may be applied in factories. The intermediate absolute configurations of FUGA and l-(5-Fluoruacil-l)-P-D-glucofurone had been established by single crystal X-ray crystallography. We believe that our work will provide the experiment and theory foundation for further investigation.