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.
Diol (I) was protected as the bis(methoxymethyl) ether (III) by reaction with methoxymethyl bromide (II) in the presence of diisopropyl ethylamine in DMF, and then, the carbobenzoxy groups of (III) were removed by hydrogenolysis in the presence of Pd/C to afford diamine (IV). Subsequent treatment of (IV) with carbonyl diimidazole (CDI) and pyridine provided the cyclic urea (V). Alkylation of (V) with m-iodobenzyl bromide (VI) in the presence of NaH in DMF provided the bis(iodobenzyl) diazepinone (VII). The title compound was then obtained by Suzuki coupling of (VII) with the protected pyrazolylboronic acid (VIII) in the presence of Pd(PPh3)4 and K2CO3 to furnish the bis(pyrazolylbenzyl) derivative (IX), followed by deprotection of the (trimethylsilyl)ethoxymethyl groups upon treatment with HCl in dioxan-methanol.
Diol (I) was protected as the bis(methoxymethyl) ether (III) by reaction with methoxymethyl bromide (II) in the presence of diisopropyl ethylamine in DMF, and then, the carbobenzoxy groups of (III) were removed by hydrogenolysis in the presence of Pd/C to afford diamine (IV). Subsequent treatment of (IV) with carbonyl diimidazole (CDI) and pyridine provided the cyclic urea (V). Monoalkylation of (V) with m-iodobenzyl bromide (VI) in the presence KOH and polyethylene glycol in toluene provided the (iodobenzyl)diazepinone (VII). Suzuki coupling of (VII) with the protected pyrazolylboronic acid (VIII) in the presence of Pd(PPh3)4 and K2CO3 afforded the (pyrazolylbenzyl) derivative (IX). Further alkylation of (IX) with m-nitrobenzyl bromide (X) and NaH gave (XI). After deprotection of the methoxymethyl and the (trimethylsilyl)ethoxymethyl groups of (XI) upon treatment with HCl in dioxan-methanol, the title compound was obtained by hydrogenation of the nitro group in the presence of Pd/C.
In an alternative method, the diamino ketal (XI) was subjected to reductive alkylation with m-nitrobenzaldehyde (XII) using sodium cyanoborohydride, sodium triacetoxyborohydride, or pyridine-borane complex as the reducing reagents to produce the bis-benzylamine (XIII). Cyclization of diamine (XIII) to urea (XIV) was accomplished by means of either phosgene or triphosgene in the presence of diisopropyl ethylamine. Subsequent ketal hydrolysis in (XIV) with methanesulfonic acid in MeOH yielded the dinitro precursor (X), which was finally reduced to the title compound by the same method as above.
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.
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.