Synthesis Of 9-[(2-Chloro-Allyloxy) Methyl] Guanine And Eplerenone Intermediate Canrenone

PARTⅠAntiviral drug ganciclovir has been widely used in clinic. In the course of its manufacturing, some related substances(impurities) were unavoidedly introduced. The impurities can affect the quality of ganciclovir. In part one of this thesis, we designed one feasible synthetic route for the synthesis of 9-[(2-chloroallyloxy)methyl]guanine which is one of the impurities in ganciclovir. Thus the sample of 9-[(2-chloroallyloxy)methyl]guanine was provided and used as a standard sample for quality control of ganciclovir.2,3-dichloropropene was used as starting material. side chain 2-chloro-1--acetyloxymethyl-2-propylene was first prepared sequentially through substitution reaction of 2,3-dichloropropene with potassium acetate, hydrolysis with potassium hydroxide, chloromethylation of hydroxyl group and esterification with potassium acetate. Next, condensation of 2-chloro-1-acetoxymethyl-2-propylene with N2,9-diacetylguanine catalyzed by p-toluenesulfonic acid monohydrate in N,N-dimethylformamide followed by hydrolysis with aqueous sodium hydroxide solution offered target molecule 9-[(2-chloroallyloxy)methyl]guanine. PARTⅡEplerenone is a new selective aldosterone receptor antagonist for the treatment of hypertension. Because of its small side effects and that it can be used together with other drugs to treat hyportension, its market share increased steadily since 2002.In this part, we investigated the synthesis of canrenone, a key intermediate of eplerenone. Based on the reported reference papers, androst-4-en-3,17-dione was used as starting material for the synthesis of canrenone. First, unsaturated 3-ketonic group of androst-4-ene-3,17-dione was protected through enol etherification with ethanol in the presence of p-toluenesulfonic acid and triethyl orthoformate. Then 17-one was epoxidized with sulfur ylide reagent and subsequently chloranil-induced dehydrogenation. Finally, lactonization with diethyl malonate and subsequent de-ester provided the target molecule canrenone. A new and efficient synthetic route for canrenone was developed.