合成路线1

A new synthesis of [14C]-labeled E-1040 with the label in the quinuclidine ring has been reported: The reduction of [14C]-labeled bromoacetic acid (I) with borane-dimethyl sulfide complex in ethyl ether gives 2-bromoethanol (II), which is condensed with piperidine-4-carboxamide (III) by means of K2CO3 and KI in refluxing isopropanol, yielding the [14C]-labeled 1-(2-hydroxyethyl)piperidine-4-carboxamide (IV). The reaction of (IV) with SOCl2 in refluxing acetonitrile affords the 1-(2-chloroethyl)piperidine-4-carbonitrile (V), which is cyclized by means of lithium diisopropylamide in THF, giving the quinuclidine (VI). The hydrolysis of (VI) with sulfuric acid gives [14C]-labeled quinuclidine-4-carboxamide (VII), which is finally condensed with the 3-chloromethylcephalosporin (VIII) by means of Na in acetone and a treatment with trifluoroacetic acid.