Study On Synthesis Of Novel Lead Compounds Of Methyl 3-Aminobicyclo [1.1.1] Pentane-1-Carboxylate Hydrochloride

Lead compounds are compounds that has unique structure has a certain activity or potential activity, explore the new derivatives from the lead compound is found effective ways and means of new drugs. Dicyclic hydrocarbons (bicyclo[1.1.1]pentane, bicyclo[2.2.2]octane etc.) compounds are a class of important physiological activity of bridge ring compounds in recent years discovered.This paper mainly study on the synthesis of methyl 3-amino-bicyclo[1.1.1]pentane-l-car-boxylate hydrochloride which was a novel lead compound. Using diethyl phenylmalonate as the starting materials, first by four lithium aluminum hydrogen reduction the ester base, the hydroxyl and p-toluene sulfonyl chloride esterification tosylate, and then cyclization with diethyl malonate, hydrolysis with potassium hydroxide, high temperature melting decarboxylation, esterification of concentrated sulfuric acid to give methyl 3-phenyl-cyclobutane carboxylate. It brominates by NBS and intramolecular nucleophlic substitution to give methyl 3-phenyl-bicyclo[1.1.0]butane-l-carboxylate. And then it introduces bridging by sodium trichloroacetate carbene insertion, dechlorination by tributyltin hydrogen, hydrolysis by sodium hydroxide, esterification by diazomethane to give methyl 3-phenyl-bicyclo[1.1.1]pentane carboxylate. The intermediates oxidation by sodium periodate, curtius rearrangement with DPPA, finally removal of Boc protection by the hydrogen chloride gas to give the final product, methyl 3-amino-bicyclo[1.1.1]pentane-1-carboxylate hydrochloride. The experimental results show that this method has the advantages of low cost, simple operation, high yield and purity. It is a synthetic method with a suitable for industrial production.The structures of the target compounds and intermediates were characterized by 1H NMR,13C NMR and LCMS. The every step of reaction conditions and synthetic methods were discussed as well.