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【结 构 式】 
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【分子编号】19619 【品名】bromo(methoxy)methane; bromomethyl methyl ether 【CA登记号】13057-17-5 |
【 分 子 式 】C2H5BrO 【 分 子 量 】124.9651 【元素组成】C 19.22% H 4.03% Br 63.94% O 12.8% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of 2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole (I) with methoxymethyl bromide (II) in toluene gives the benzimidazolium bromide (III), which is condensed with 4-aminopiperidine-1-carboxylic acid ethyl ester (IV) in hot toluene to yield the adduct (V). Finally, this compound is treated first with BBr3 in dichloromethane and then with HBr or HCl at 110 C to provide the target Norastemizole.
| 【1】 Hong, Y.; Senanayake, C.H.; Bakale, R.P. (Sepracor Inc.); Methods for synthesizing 2-substd. imidazoles. EP 0977740; JP 2001520658; US 5817823; WO 9846571 . |
| 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) | 12043 | 1-(4-Fluorobenzyl-2-chlorobenzimidazol; 2-Chloro-1-(4-fluorobenzyl)-1H-benzimidazole; 1-(4-Fluorobenzyl)-2-chlorobenzimidazole | 84946-20-3 | C14H10ClFN2 | 详情 | 详情 |
| (II) | 19619 | bromo(methoxy)methane; bromomethyl methyl ether | 13057-17-5 | C2H5BrO | 详情 | 详情 |
| (III) | 61777 | 2-chloro-3-(4-fluorobenzyl)-1-(methoxymethyl)-3H-benzimidazol-1-ium | C16H15ClFN2O | 详情 | 详情 | |
| (IV) | 61778 | propyl 4-amino-1-piperidinecarboxylate | C9H18N2O2 | 详情 | 详情 | |
| (V) | 61779 | 3-(4-fluorobenzyl)-1-(methoxymethyl)-2-{[1-(propoxycarbonyl)-4-piperidinyl]amino}-3H-benzimidazol-1-ium bromide | C25H32BrFN4O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)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 |
合成路线3
该中间体在本合成路线中的序号：(II)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 |