Synthesis Of Cilastatin Sodium And Its E-isomer

Cilastatin sodium functioning as an inhibitor of DHP- I can enhance the stability of Imipenem and maintain its effective antibiotic concentration in the kidney. Imipenem and Cilastatin sodium-Tienam developed by Merck Company in 1979 is the first launched cabapenem antibiotic. Tienam is a broad-spectrum antibiotic, whose high potency and p-lactamase stability made it warmly embraced and one of the highest appreciated antibiotics in the world.This dissertation focuses on the synthetic process of Cilastatin sodium and the synthetic method of its E-isomer.The synthesis of Cilastatin sodium started from ethyl acetoacetate and 1-bromo-5-chloropentane, through 3 steps to produce ethyl 7-chloro-2-oxoheptanoate; Ethyl 7-chloro-2-oxoheptanoate condensed with (S)-(+)-2,2-dimethylcyclopropane carboxamide (prepared from 2,2-dimethylpropane-l,3-diol through 8 steps) and underwent hydrolyzing, acidifying and then reacted with cyteine·HCl to produce Cilastatin sodium. The total yield of the 7 reactions was 32.2% (yield of literature: 28%).We have made impressive progress in that we discarded the arduous resin purification process so simplified the operation and effectively reduced the degradation of chemically unstable Cilastatin sodium. This process is unique to former methods. The purity of the final product was >98% (HPLC).The E-isomer can function as a reference to control the quality of Cilastatin sodium. We successfully synthesized it and controlled its content bellow 0.5% in the final product. The synthesis of this compound is innovative.The structure of Cilastatin sodium was confirmed by HPLC, ¹H-NMR, ¹³C-NMR, DEPT and MS etc.The structure of the E-isomer of Cilastatin sodium was confirmed by HPLC, LC-MS and NOSEY etc.