【结 构 式】 |
【药物名称】 【化学名称】 【CA登记号】 【 分 子 式 】C39H38N6O3 【 分 子 量 】638.77611 |
【开发单位】 【药理作用】0 |
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). 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.
【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) | 19624 | (4R,5S,6S,7R)-4,7-dibenzyl-1,3-bis(3-iodobenzyl)-5,6-bis(methoxymethoxy)-1,3-diazepan-2-one | C37H40I2N2O5 | 详情 | 详情 | |
(VIII) | 19625 | 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-ylboronic acid | C9H19BN2O3Si | 详情 | 详情 | |
(IX) | 19626 | (4R,5S,6S,7R)-4,7-dibenzyl-5,6-bis(methoxymethoxy)-1,3-bis[3-(1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazol-5-yl)benzyl]-1,3-diazepan-2-one | C55H74N6O7Si2 | 详情 | 详情 |