Study On The Synthesis Of Decitabine As The Important Anti-cancer Drug

Decitabine (Dacogen), an analogue of the natural nucleoside 2'-deoxycytidine, is a new important anti-cancer drug. It's chemical name is 4-amino-1-(2-deoxy-β-D-erythro-pentofuranosyl)-1,3,5-triazin-2-one. Decitabine is approved by Euro EMEA in April, 2006 and by the U. S. FDA in May, 2006. It is specifically indicated for the treatment of multiple types of myelodysplastic syndromes, including previously treated and untreated, de novo and secondary myelodysplastic syndromes (MDS), et al. Decitabine is designed to disrupt DNA synthesis. Although its special kind of mechanism attracts many researchers, few were reported about its complete synthesis process. Therefore, the research of preparation process of Decitabine was needed.Based on the references, the process for synthesis of Decitabine was studied in the first part of the dissertation, which was synthesized from 2-deoxy-D-ribose by acetylization with acetic anhydride, then glycosidated with protected 5-azacytosine under the catalysis of TMSOTf to obtain 1-(3,5-di-O-acetyl-D-ribofuranosyl)-5-azacytosine. After the deprotection in methanol with NH3, Decitabine was synthesized in total yield 34%. During the process research, we firstly obtained the single crystal of 1,3,4-tri-O-acetyl-2-deoxy-β-D-erythro-pentopyranose whose structure was characterized by the X-ray diffraction analysis. The optimum process parameters were discussed and determined as follows: 1,3,5-tri-O-acetyl-2-deoxyribose was synthesized in pyridine solvent, 2-deoxy-D-ribose : acetic anhydride=1 : 3.5, the reaction temperature was 20oC, the reaction time was 24 h, the optimal yield was 97%. 1-(3,5-di-O-acetyl-D-ribofuranosyl)-5-aza-cytosine was synthesized firstly in HMDS at the refluxing temperature in 2.5 h, then without separation reacted in 1,2-dichloroethane in 12 h at the room temperature, 1,3,5-tri-O-acetyl-2-de-oxyribose : 5-azacytosine : TMSOTf=1 : 1.5 : 2.3. Decitabine was synthesized in methanol solvent with NH3, then through the TLC method the isomers of Decitabine was separated with the developing solvent: V(EtOAc) : V(HCOOH) : V(H2O) : V(CH3OH)=65 : 5 : 5 : 30.The second part described the new designed process for Decitabine synthesis, which was synthesized from 2-deoxy-D-ribose and methanol by acetalation with the acid catalyst, and by substitution reaction to protect the ribose ring's hydroxy group, then glycosidated with protected 5-azacytosine with the catalyst TMSOTf to get 1-(3,5-di-O-benzoyl-2- deoxy-D-ribose)-5-azacytosine. After the deprotection in methanol with NH3, Decitabine was prepared in total yield 24%. This process firstly introduced solid acid catalyst to synthesized 1-methyl-2-deoxyribose, and the reactant ratio was 2-deoxy-D-ribose : H2SO4-SiO2=1 : 0.1(mass ratio). It was reacted in methanol solvent with 20oC for 30 min. Meanwhile, compared with the old process which was halogenated the anomeric carbon before glycosidation reaction, we introduced the catalyst of TMSOTf to carry out the glycosidation directly from 1-methyl-2-deoxy -D-ribose and 5-azacytosine, and successfully obtain the target product.