A Novel Method For The Synthesis Of Simeprevir Key Intermediates

(1R,2R)-dimethyl4-oxocyclopentane-1,2-dicarboxylate(CAS:35079-19-7) is the keyintermediate for synthesis of HCV inhibitor, Simeprevir. A novel method for the synthesis of keyintermediates for Simeprevir has been developed by using PLE (pig liver esterase) mediatedselective hydrolysis.The existing literature is through the application of PLE (pig liver esterase) selectivehydrolysis of racemic dimethyl4-oxocyclopentane-1,2-dicarboxylate,to afford (1R,2R)-dimethyl4-oxocyclopentane-1,2-dicarboxylate in last step. In this thesis, the application of PLE selectivehydrolysis of racemic dimethyl cyclohex-4-ene-1,2-dicarboxylate in early stage of the synthesis,gave rise to (1R,2R)-dimethyl cyclohex-4-ene-1,2-dicarboxylate. The ring opening of(1R,2R)-dimethyl cyclohex-4-ene-1,2-dicarboxylate by oxidized, followed by lactone formationand subsequent decarboxylation reaction, yielded (1R,2R)-dimethyl4-oxocyclopentane-1,2-dicarboxylate. The advantage of this method is to generate the chiralintermediate at the beginning, which can reduce reagent cost on racemic intermediates duringlate stage of the synthesis.In this thesis, some preliminary studies with the effect of buffer and substrate concentration onthe yield of PLE hydrolysis, which provided parameters for the subsequent optimization. Thisnovel method also extends the application scope of PLE for asymmetric hydrolysis.