Thiadiazole (II) was synthesized from 3-aminoisoxazole (I) following a known procedure. Esterification of (II) to give (III) was carried out by treatment with MeOH and SOCl2. Subsequent oxidation of (III) employing I2 in DMSO provided keto ester (IV), which was converted into oxime (V) and then protected as the O-trityl derivative (VI). Basic hydrolysis of the methyl ester group yielded carboxylic acid (VII). Then, coupling of acid (VII) with aminocephalosporin (VIII) by means of POCl3 furnished the corresponding amide (IX).
Borane reduction of 3-tert-butylthiopyridine-2-carboxylic acid (X) provided alcohol (XI), which was chlorinated to (XII) with SOCl2 and subsequently displaced with N-Boc-2-mercaptoethylamine (XIII), yielding thioether (XIV). Acid deprotection of the tert-butyl groups of (XIV), followed by air oxidation in the presence of FeCl3, produced the dimeric disulfide (XV). This was reprotected with Boc2O to afford the biscarbamate (XVI). Disulfide (XVI) was reduced in situ with PPh3 to the corresponding thiol, which was coupled with the cephem mesylate (IX) to produce adduct (XVII). The title compound was finally obtained by cleavage of the protecting groups of (XVII) by means of trifluoroacetic acid.
Borane reduction of 3-tert-butylthiopyridine-2-carboxylic acid (X) provided alcohol (XI), which was chlorinated to (XII) with SOCl2 and subsequently displaced with N-Boc-2-mercaptoethylamine (XIII), yielding thioether (XIV). Acid deprotection of the tert-butyl groups of (XIV), followed by air oxidation in the presence of FeCl3, produced the dimeric disulfide (XV). This was acylated with the protected aspartate pentafluorophenyl ester (XVI) to afford the diamide (XVII). Disulfide (XVII) was reduced in situ with PPh3 to the corresponding thiol, which was coupled with the cephem mesylate (IX) to produce adduct (XVIII). The title compound was finally obtained by cleavage of the protecting groups of (XVIII) by means of trifluoroacetic acid.