The reaction of 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-(methoxyimino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (I) with N-methyl-N-(trimethylsilyl)trifluoroacetamide and then with iodotrimethylsilane in dichloromethane gives the corresponding silylated 3-iodomethyl derivative (II), which is then treated with 4-carbamoylquinuclidine (III) in acetonitrile.
A new synthesis for [14C]-E-1040 has been described: The cyclization of [14C]-labeled potassium thiocyanate (I) with 2-(N-chlorocarboxamidino)-2-(methoxyimino)acetic acid (II) in methanol by means of triethylamine gives 2-(2-aminothiazol-4-yl)-2(Z)-(methoxyimino)acetic acid (III), which is treated with PCl5 in dichloromethane, yielding the corresponding acyl chloride (IV). Finally, this compound is condensed with 7-amino-3-(4-carbamoylquinuclidinio-1-ylmethyl)-3-cephem-4-carboxylate (V) by means of sodium acetate in dichloromethane.
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.