The alkylation of ethyl 1,3-dithiane-2-carboxylate (I) with 1,5-dibromopentane (II) by means of NaH in DMF gives ethyl 2-(5-bromopentyl)-1,3-dithiane-2-carboxylate (III), which is treated with NBS in acetonitrile water to open the dithiane ring yielding ethyl 7-bromo-2-oxoheptanoate (IV). Hydrolysis of the ester group of (IV) with 50% HBr affords 7-bromo-2-oxoheptanoic acid (V), which is condensed with 2,2-dimethylcyclopropanecarboxamide (VI) in refluxing toluene giving 7-bromo-2-(2,2-dimethycyclopropanecarboxamido)-2-octenoic acid (VII). Finally, this compound is condensed with L-cysteine (VIII) by means of NaOH in water.
The condensation of 7-chloro-2-oxoheptanoic acid ethyl ester (I) with (S)-2,2-dimethylcyclopropanecarboxamide (II) by means of TsOH in refluxing toluene gives (S)-7-chloro-2-(2,2-dimethylcyclopropanecarboxamido)-2-heptenoic acid ethyl ester (III), which is hydrolyzed in aq. NaOH to yield the corresponding carboxylic acid (IV). Finally, this compound is condensed with (R)-cysteine (V) by means of NaOH in water to afford the target Cilastatino.