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【结 构 式】

【分子编号】59260

【品名】(4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis(3-nitrobenzyl)-1,3-diazepan-2-one

【CA登记号】

【 分 子 式 】C33H32N4O7

【 分 子 量 】596.63984

【元素组成】C 66.43% H 5.41% N 9.39% O 18.77%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(X)

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.

3 Lam, P.Y.; Eyermann, C.J.; Hodge, C.N.; Jadhav, P.K.; DeLucca, G.V. (DuPont Pharmaceuticals Co.); Cyclic ureas and analogues useful as retroviral protease inhibitors. EP 0607334; EP 0686151; EP 0765873; JP 1995500324; JP 1996509700; US 5610294; WO 9307128; WO 9419329 .
1 Hodge, C.N.; et al.; Improved cyclic urea inhibitors of the HIV-1 protease: Synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Chem Biol 1996, 3, 4, 301.
2 Lam, P.Y.S.; et al.; Cyclic HIV protease inhibitors. Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996, 39, 18, 3514.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 19922 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis[[2-(trimethylsilyl)ethoxy]methoxy]-1,3-diazepan-2-one C31H50N2O5Si2 详情 详情
(VIII) 19636 1-(bromomethyl)-3-nitrobenzene 3958-57-4 C7H6BrNO2 详情 详情
(IX) 59259 (4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-nitrobenzyl)-5,6-bis{[2-(trimethylsilyl)ethoxy]methoxy}-1,3-diazepan-2-one C45H60N4O9Si2 详情 详情
(X) 59260 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis(3-nitrobenzyl)-1,3-diazepan-2-one C33H32N4O7 详情 详情

合成路线2

该中间体在本合成路线中的序号:(X)

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.

1 Confalone, P.N.; Smyser, T.E. (Bristol-Myers Squibb Co.); Method for preparing N,N'-disubstd. cyclic ureas. WO 9639393 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(X) 59260 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis(3-nitrobenzyl)-1,3-diazepan-2-one C33H32N4O7 详情 详情
(XI) 18091 (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenylethylamine; (1S)-1-[(4R,5R)-5-[(1S)-1-amino-2-phenylethyl]-2,2-dimethyl-1,3-dioxolan-4-yl]-2-phenyl-1-ethanamine C21H28N2O2 详情 详情
(XII) 12646 3-Nitrobenzaldehyde 99-61-6 C7H5NO3 详情 详情
(XIII) 59261 (1R)-1-((4S,5S)-2,2-dimethyl-5-{(1R)-1-[(3-nitrobenzyl)amino]-2-phenylethyl}-1,3-dioxolan-4-yl)-N-(3-nitrobenzyl)-2-phenyl-1-ethanamine; N-[(1R)-1-((4S,5S)-2,2-dimethyl-5-{(1R)-1-[(3-nitrobenzyl)amino]-2-phenylethyl}-1,3-dioxolan-4-yl)-2-phenylethyl]-N-(3-nitrobenzyl)amine C35H38N4O6 详情 详情
(XIV) 59262 (3aS,4R,8R,8aS)-4,8-dibenzyl-2,2-dimethyl-5,7-bis(3-nitrobenzyl)hexahydro-6H-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one C36H36N4O7 详情 详情
Extended Information