Synthesis Of Pharmaceutical Intermediates By Carbonylation Reaction

The carbonylative ring expansion of strained heterocycles and the carbonylation of halogenated hydrocarbons are the important sections of carbonylation research.The research work in this dissertation is mainly focused on the application of transition metal-catalyzed carbonylation in the syntehsis of pharmaceutical intermediates,which includes the following two aspects:1.Utilizing cobalt-catalyzed carbonylative ring expansion of thietane for the synthesis of key intermediates of montelukast sodiumA mild and efficient method for carbonylation ring expansion of thietane under atmospheric CO conditions using Co₂（CO）₈ as pre-catalyst has been developed.γ-Thiolactones can be obtained in good yields.This method has been applied in the synthesis of key intermediate for anti-asthma drug montelukast sodium.In this protocol,Co₂（CO）₈ could be alternatively used as both pre-catalyst and CO surrogate,which enables the carbonylation proceeding under CO-free conditions.The mechanism of this carbonylation reaction was revealled by designed control experimetns and investigation with operando FT-IR and EPR spectroscopy.2.The application of palladium-catalyzed carbonylation in the synthesis of key intermediates of sitagliptinA new process for the synthesis of methyl（2,4,5-trifluorophenyl）acetate by Pd-catalyzed methoxycarbonylation of 2,4,5-trifluorobenzyl chloride under mild conditions has been developed.Three crticial points to the high coversion and chemoselectivity of this reaction with 0.02 mol%Pd-Xantphos catalyst loading lie in:i)the in-situ preparation of acid scavenger magnesium methoxide with magnesium and methanol;ii)the large excess of 2,4,5-trifluorobenzyl chloride to magnesium methoxide;iii)charging CO into the reaction system after adding all other reaction ingredient and retaining low CO pressure.