Synthesis Of Exemestane And Study On Its Spiro Derivative

Exemestane is an oral steroidal aromatase inhibitor with good tolerance,no cross-resistance and less side effects,which has been a first-line treatment drug of advanced breast cancer.In recent years,the sales of exemestane are keeping rising,the development of a new synthetic route for this drug with lower costs and ease of implementation has been a important subject.Themainworkof this thesis is presented as follows:(1)Efforts were made to design and develop a new synthetic route:firstly,3-ethoxy-3,5-dien-17-one was synthesized via enol etherification using triethyl orthoformate,4-androstene-3,17-dione and ethanol as starting materials,p-TSA as a catalyst.Secondly,a Mannich reaction was carried out with N-methylaniline and paraformaldehydetopreparethenewcompound6-(N-methyl-N-phenyl)-amino-methyl-4-androstene-3,17-dione,whichwasthen followedbyeleminationtopreparethekeyintermediate6-methylene-androst-4-ene-3,17-dione.Finally,exemestane was obtained via oxigenation of 6-methylene-androst-4-ene-3,17-dione.An overall yield of this route was about 43.6%,and the content was 99.92%(HPLC).All the intermediates and the product exemestane were characterized by ~1 H-NMR,~133 C-NMR,DEPT135,GC-MS,etc.(2)The spiro byproduct 4,6-dimer-4-ene-3,17-dione produced during the third step of the synthesis of exemestane was also investigated.We synthesised this spiro compound by a new method.Firstly,the compound was dissolved in ethanol,and followed by the addition into 36%of HCl at 0-5?,then the reaction mixture was stirred at 5-10?for 2h.The content of obtained product was about 60%(HPLC).Secondly,the product was also characterized by ~1 H-NMR,~133 C-NMR,DEPT135,single-crystal X-ray diffraction and HMBC.Furthermore,the antitumor activity of this spiro compound was measured by MTT assay,the results indicated that the compound significantly inhibited the growth of HepG2,MCF-7.It has great significance for the development of new steroidal anti-cancer drugs.