To Decitabine Synthesis

Decitabine (2'-Deoxy-5-azacytidine) is an efficient methylation inhibitor of DNA and used in the treatment of some other diseases. Some recent researches help the forword of therapeutic mechanism for the inhibition of DNA methyltransferase, that is it can undergo phosphorylation in human body.Decitabine was first synthesized in 1964 by a multistep procedure described by Pliml and Sorm. More recently, improved yields were obtained by a direct glycosylation procedure of silylated 5-azacytosine or via a total synthesis using glycosyl isocyanates as intermediates.This dissertation involves the study on the synthesis of Decitabine. Several methods to synthesize Decitabine were reviewed. And a modified route to prepare Decitabine was developed in this dissertation, which including the following steps:2-deoxyribose was acetylized with acetic anhydride and cross coupled with 5-azacytosine catalyzed by Lewis acids to get 1-(3,5-di-O-acetyl-2-deoxy-D-ribofuranosyl)-5-azacytosine, Decitabine was finally obtained by deprotection and recrystallization from methanol.Some effect factors of the C-N couple, such as the catalysts, the doseage of the catalysts, the solvent, workup method, etc, were discussed. Some optimized reaction conditions werer obtained as follows:the best yield of acetylization was 83% at 15℃; One-pot method was used for the protection of-NH2 and-OH when refluxing at 120℃, and the yield was about 95%; Anhydrous SnCl4 was found to be the best catalyst for reduction and the best dose equivalence was about 1.5, ethylene chloride was found to be the best solvent, 1-(3,5-di-O-acetyl-2-deoxy-D-ribofuranosyl)-5-azacytosine could be achieved in a yield of 65% under this condition. At last, Decitabine was obtained through deprotection by diethylamine or triethylamine in a yield of 51.1% and the overall yield was about 26.2%.A modified process for the synthesis of Decitabine was developed in this dissertation. This process has some advantages such as application of an inexpensive Lewis acid SnCl4 as catalyst and avoidance of tedious pretreatment and workup process. The results indicate this process was of practical value.