1) The condensation of benzyloxycarbonyl-L-alanine (I) with 2-(4-piperidyloxy)acetic acid ethyl ester (II) by means of pivaloyl chloride and triethylamine in ethyl acetate gives the protected alanyl-piperidine (III), which is deprotected by hydrogenation over Pd/C in ethanol to yield compound (IV). The condensation of (IV) with 4-cyanobenzoyl chloride (V) by means of triethylamine in toluene affords the corresponding benzoyl derivative (VI), which is finally treated with hydroxylamine in the same solvent.
Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) with DMSO and oxalyl chloride afforded the corresponding aldehyde (II). Subsequent pinacol dimerization by treatment with VCl3 and Zn gave diol (III) with a 98% diastereomeric purity. After protection of the hydroxyl groups of (III) as the [2-(trimethylsilyl) ethoxy]methyl (SEM) ethers upon treatment with SEMCl and diisopropyl ethylamine, (IV) was obtained, then the N-benzyloxycarbonyl groups were removed by hydrogenolysis in the presence of Pd/C. The resulting diamine (V) was cyclized with carbonyl diimidazole and pyridine to furnish the cyclic urea (VI). Alkylation with benzyl bromide (VII) and NaH provided the bisbenzylated compound, which was finally deprotected by treatment with HCl in MeOH-dioxan.
Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) gave aldehyde (II), which was subjected to a vanadium-mediated pinacol coupling to yield diol (III). Protection of the hydroxyl groups of (III) by reaction with [2-(trimethylsilyl)-ethoxy]methyl chloride (SEMCl) (IV) and DIEA in DMF provided trimethylsilyl)ethoxymethyl ether (V), whose N-benzyloxycarbonyl groups were removed by hydrogenolysis over Pd/C to afford diamine (VI). Finally, cyclization of diamine (VI) with carbonyldiimidazole produced the cyclic urea (VII).
Alkylation of diazepinone (VII) with m-nitrobenzyl bromide (VIII) in the presence of NaH gave the bis-nitrobenzyl derivative (IX). The silylethoxymethyl protecting groups of (IX) were then removed by means of HCl in dioxan to afford diol (X). The nitro groups of (X) were finally reduced by catalytic hydrogenation to the target diamino compound, which was finally converted to the bis-methanesulfonate salt.
Swern oxidation of N-(benzyloxycarbonyl)-(R)-phenylalaninol (I) with DMSO and oxalyl chloride afforded the corresponding aldehyde (II). Subsequent pinacol dimerization by treatment with VCl3 and Zn gave diol (III) with a 98% diastereomeric purity. After protection of the hydroxyl groups of (III) as the [2-(trimethylsilyl) ethoxy]methyl (SEM) ethers upon treatment with SEMCl and diisopropyl ethylamine, (IV) was obtained, then the N-benzyloxycarbonyl groups were removed by hydrogenolysis in the presence of Pd/C. The resulting diamine (V) was cyclized with carbonyl diimidazole and pyridine to furnish the cyclic urea (VI). Alkylation with benzyl bromide (VII) and NaH provided the bisbenzylated compound, which was subsequently deprotected by treatment with HCl in MeOH-dioxan to give (VIII) (1). The stereoselective hydroxyl inversion of the diol was then achieved Swern by oxidation to the ketol (IX), followed by reduction with NaBH4 in EtOH, and purification of the major isomer by column chromatography.