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【结 构 式】

【药物名称】

【化学名称】[4R-(4α,5α,6β,7β)]-1-(3-Aminobenzyl)-4,7-dibenzyl-5,6- dihydroxy-3-[3-[3(5)-pyrazolyl]benzyl]perhydro-1,3- diazepin-2-one

【CA登记号】

【 分 子 式 】C36H37N5O3

【 分 子 量 】587.72799

【开发单位】DuPont Pharm

【药理作用】ANTIINFECTIVE THERAPY,AIDS MEDICINES

合成路线1

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.

1 Han, Q.; Lam, P.Y.S.; Li, R.; Jadhav, P.K.; Chang, C.-H.; Ru, Y.; Cyclic HIV protease inhibitors: Design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency. J Med Chem 1998, 41, 12, 2019.
2 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 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 19618 benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-dihydroxy-5-phenylpentylcarbamate C34H36N2O6 详情 详情
(II) 19619 bromo(methoxy)methane; bromomethyl methyl ether 13057-17-5 C2H5BrO 详情 详情
(III) 19620 benzyl (1R,2S,3S,4R)-1-benzyl-4-[[(benzyloxy)carbonyl]amino]-2,3-bis(methoxymethoxy)-5-phenylpentylcarbamate C38H44N2O8 详情 详情
(IV) 19621 (2R,3S,4S,5R)-3,4-bis(methoxymethoxy)-1,6-diphenyl-2,5-hexanediamine; (1R,2S,3S,4R)-4-amino-1-benzyl-2,3-bis(methoxymethoxy)-5-phenylpentylamine C22H32N2O4 详情 详情
(V) 19622 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one C23H30N2O5 详情 详情
(VI) 19623 1-(bromomethyl)-3-iodobenzene 49617-83-6 C7H6BrI 详情 详情
(VII) 19633 (4R,5S,6S,7R)-4,7-dibenzyl-1-(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one C30H35IN2O5 详情 详情
(VIII) 19625 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-ylboronic acid C9H19BN2O3Si 详情 详情
(IX) 19635 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1-[3-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl)benzyl]-1,3-diazepan-2-one C39H52N4O6Si 详情 详情
(X) 19636 1-(bromomethyl)-3-nitrobenzene 3958-57-4 C7H6BrNO2 详情 详情
(XI) 19637 (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1-(3-nitrobenzyl)-3-[3-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl)benzyl]-1,3-diazepan-2-one C46H57N5O8Si 详情 详情
Extended Information