|
【结 构 式】 
|
【药物名称】GGTI-2151 【化学名称】N-[4-(1H-Imidazol-4-ylmethylaminomethyl)-2-(1-naphthyl)benzoyl]-L-leucine 【CA登记号】 【 分 子 式 】C28H30N4O3 【 分 子 量 】470.5763 |
【开发单位】University of Pittsburgh (Originator), University of South Florida (Originator), Yale University (Originator) 【药理作用】Oncolytic Drugs, PHARMACOLOGICAL TOOLS, Geranylgeranyl Transferase Inhibitors, Inhibitors of Signal Transduction Pathways |
合成路线1
Suzuki coupling of methyl 2-bromo-4-nitrobenzoate (I) with 1-naphthylboronic acid (II) provided naphthyl benzoate ester (III). The nitro group of (III) was then reduced by hydrogenation over Pd/C yielding aniline (IV). Diazotization of (IV), followed by reaction with KI gave aryl iodide (V), and subsequent halogen displacement by KCN in the presence of palladium catalyst afforded nitrile (VI). After basic hydrolysis of the methyl ester of (VI), the resulting carboxylic acid (VII) was coupled to L-leucine methyl ester (VIII) using EDC and HOBt to yield amide (IX). Reduction of the nitrile group of (IX) with NaBH4 and CoCl2 gave the corresponding amine, which was isolated as the tert-butyl carbamate (X) upon treatment with Boc2O.
| 【1】 Vasudevan, A.; et al.; Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I. J Med Chem 1999, 42, 8, 1333. |
| 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) | 27702 | methyl 2-bromo-4-nitrobenzoate | C8H6BrNO4 | 详情 | 详情 | |
| (II) | 27703 | 1-naphthylboronic acid | 13922-41-3 | C10H9BO2 | 详情 | 详情 |
| (III) | 27704 | methyl 2-(1-naphthyl)-4-nitrobenzoate | C18H13NO4 | 详情 | 详情 | |
| (IV) | 27705 | methyl 4-amino-2-(1-naphthyl)benzoate | C18H15NO2 | 详情 | 详情 | |
| (V) | 27706 | methyl 4-iodo-2-(1-naphthyl)benzoate | C18H13IO2 | 详情 | 详情 | |
| (VI) | 27707 | methyl 4-cyano-2-(1-naphthyl)benzoate | C19H13NO2 | 详情 | 详情 | |
| (VII) | 27708 | 4-cyano-2-(1-naphthyl)benzoic acid | C18H11NO2 | 详情 | 详情 | |
| (VIII) | 27709 | methyl (2S)-2-amino-4-methylpentanoate | C7H15NO2 | 详情 | 详情 | |
| (IX) | 27710 | methyl (2S)-2-[[4-cyano-2-(1-naphthyl)benzoyl]amino]-4-methylpentanoate | C25H24N2O3 | 详情 | 详情 | |
| (X) | 27711 | methyl (2S)-2-[[4-[[(tert-butoxycarbonyl)amino]methyl]-2-(1-naphthyl)benzoyl]amino]-4-methylpentanoate | C30H36N2O5 | 详情 | 详情 |
合成路线2
Further acidic treatment of compund (X) regenerated the amine, which was condensed with the imidazole aldehyde (XI) in the presence of titanium isopropoxide as the water scavenger to give imine (XII). This was reduced to amine (XIII) using NaBH3CN. Finally, the title compound was obtained after acid cleavage of the trityl group of (XXXIII), followed by hydrolysis of the resulting ester (XIV).
| 【1】 Vasudevan, A.; et al.; Potent, highly selective, and non-thiol inhibitors of protein geranylgeranyltransferase-I. J Med Chem 1999, 42, 8, 1333. |
| 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) | 27711 | methyl (2S)-2-[[4-[[(tert-butoxycarbonyl)amino]methyl]-2-(1-naphthyl)benzoyl]amino]-4-methylpentanoate | C30H36N2O5 | 详情 | 详情 | |
| (XI) | 27712 | 1-trityl-1H-imidazole-4-carbaldehyde；1-Tritylimidazole-4-carboxaldehyde | 33016-47-6 | C23H18N2O | 详情 | 详情 |
| (XII) | 27713 | methyl (2S)-4-methyl-2-[[2-(1-naphthyl)-4-([[(E)-(1-trityl-1H-imidazol-4-yl)methylidene]amino]methyl)benzoyl]amino]pentanoate | C48H44N4O3 | 详情 | 详情 | |
| (XIII) | 27714 | methyl (2S)-4-methyl-2-[[2-(1-naphthyl)-4-([[(1-trityl-1H-imidazol-4-yl)methyl]amino]methyl)benzoyl]amino]pentanoate | C48H46N4O3 | 详情 | 详情 | |
| (XIV) | 27715 | methyl (2S)-2-[[4-[[(1H-imidazol-4-ylmethyl)amino]methyl]-2-(1-naphthyl)benzoyl]amino]-4-methylpentanoate | C29H32N4O3 | 详情 | 详情 |