The intermediate dipeptide ester (V) was prepared as follows. Coupling between D-norleucine tert-butyl ester (I) and N-Boc-D-tryptophan (II) by means of EDC and HOBt provided the protected dipeptide (III). Subsequent acylation of the indole N with methyl chloroformate under phase-transfer conditions yielded the N-(methoxycarbonyl)indole derivative (IV). The N-Boc protecting group was then selectively removed from (IV) by treatment with trifluoroacetic acid at 0 C.
Benzyl ester (VII) was prepared by reaction of N-Boc-L-gamma-methylleucine (VI) with benzyl bromide in the presence of Cs2CO3. Subsequent N-Boc group cleavage in (VII) by means of HCl in dioxane furnished gamma-methylleucine benzyl ester (VIII). Amino ester (VIII) was converted into urea (X) by condensation with 2,6-dimethylpiperidine (IX) either in the presence of carbonyl diimidazole or diphosgene. Then, hydrogenolysis of the benzyl ester group of (X) in the presence of Pd/C led to the N-carbamoyl aminoacid (XI). Coupling of amino acid (XI) with dipeptide (V) in the presence of EDC and HOBt gave the tripeptide derivative (XII). The tert-butyl ester group of (XII) was then cleaved under acidic conditions, and the resultant carboxylic acid was finally converted to the corresponding sodium salt by treatment with NaHCO3.
In a related synthetic method, N-Boc-tryptophan (II) was coupled with benzyl alcohol using EDC and HOBt to produce the corresponding benzyl ester (XIII). Incorporation of the methoxycarbonyl group into the indole N (XIV) was accomplished by treatment of (XIII) with dimethyl carbonate in the presence of DMAP. The Boc protecting group of (XIV) was then removed under acidic conditions to afford amino ester (XV). The dipeptide derivative (XVI) was prepared by coupling of amino ester (XV) with the N-carbamoyl aminoacid (XI). After hydrogenolysis of the benzyl ester group of (XVI), acid (XVII) was coupled with norleucine benzyl ester (XVIII) yielding tripeptide (XIX). Further benzyl ester hydrogenolysis in (XIX) gave the corresponding carboxylic acid, which was finally converted into the title sodium salt.