C(OC(=O)NC(C(=O)N(CCN)CC(=O)NCC(C)(C1C=CC=CC=1)C)CC1NC=NC=1)C1C=CC=CC=1.[C:39]([O:43][C:44](=[O:49])[NH:45][CH2:46][CH2:47][NH2:48])([CH3:42])([CH3:41])[CH3:40].Br[CH2:51][C:52]([O:54][CH3:55])=[O:53].C(N(CC)CC)C.C(Cl)[Cl:64]>>[ClH:64].[CH3:55][O:54][C:52](=[O:53])[CH2:51][NH:48][CH2:47][CH2:46][NH:45][C:44]([O:43][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:49]Scheme 3 shows a method by which the compounds of the present invention can be prepared, by illustrating the synthesis of Example 6, [1-{(2-Amino-ethyl)-[(2-methyl-2-phenyl-propylcarbamoyl)-methyl]-carbamoyl}-2-(3H-imidazol-4-yl)-ethyl]-carbamic acid benzyl ester. Reaction of (2-aminoethyl) carbamic acid tert-butyl ester with methyl bromoacetate was carried out in methylene chloride in the presence of triethylamine as the base to give (2-tert-butoxycarbonylamino-ethylamino)-acetic acid methyl ester hydrochloride which was then coupled to Cbz-His(trityl) in methylene chloride/dimethylformamide with HATU and HOAt as coupling agents, and diisopropylethylamine as the base. The resulting product was saponified using sodium hydroxide, followed by coupling with β,β-dimethylphenethylamine in methylene chloride, with PyBOP as coupling agent, and diisopropylethylamine as the base. The trityl and Boc groups were removed by treatment with 95% aqueous TFA.
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