新产品编号:1392669

Chemical Name: (4R,5S,6R,7R)-1,3,4,7-Tetrabenzyl-5,6-dihydroxyhexahydro-1,3-diazepin-2-one
项目整合开发状态: Biological Testing
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线: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).

合成路线: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.

合成路线: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.

合成路线: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.