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【结 构 式】 
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【药物名称】Danusertib, PHA-739358 【化学名称】N-[5-[2(R)-Methoxy-2-phenylacetyl]-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl]-4-(4-methylpiperazin-1-yl)benzamide 【CA登记号】827318-97-8 【 分 子 式 】C26H30N6O3 【 分 子 量 】474.5548 |
【开发单位】Nerviano Medical Sciences (IT). 【药理作用】Aurora Kinase Inhibitor, Oncolytic |
合成路线1
Protection of 3-amino-5-Boc-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (I) by treatment with ethyl chloroformate and DIEA gives the 1-ethoxycarbonyl derivative (II). After conversion of 4-(4-methylpiperazinyl)benzoic acid (III) to the corresponding acid chloride by means of oxalyl chloride and DMF, coupling with the amino heterocycle (II) furnishes the amide (IV). The N-Boc group of (IV) is then selectively deprotected under acidic conditions to give (V). Activation of (R)-α-methoxyphenylacetic acid (VI) with oxalyl choride and DMF gives the acid chloride (VII), which is coupled with the deprotected pyrrolopyrazole (V) to yield amide (VIII). Finally, the ethoxycarbonyl group of (VIII) is removed by treatment with Et3N in MeOH to provide the title compound (1, 2). Scheme 1.
| 【1】 Fancelli, D., Forte, B., Moll, J., Varasi, M., Vianello, P. (Pfizer Italia Srl). Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors. EP 1644376, US 2005032839, WO 2005005427. |
| 【2】 Fancelli, D., Moll, J., Varasi, M. et al. 1,4,5,6-Tetrahydropyrrolo[3,4-c]pyrazoles: Identification of a potent Aurora kinase inhibitor with a favorable antitumor kinase inhibition profile. J Med Chem 2006, 49(24): 7247-51. |
| 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) | 65715 | tert-Butyl 3-amino-4,6-dihydropyrrolo[3,4-C]pyrozole-5-carboxylate; 5-Boc-3-amino-4,6-dihydropyrrolo[3,4-c]pyrozole | 398491-59-3 | C10H16N4O2 | 详情 | 详情 |
| (II) | 65716 | Ethyl 5-(tert-butoxycarbonyl)-3-amino-4,6-dihydropyrrolo[3,4-c]pyrazole-1-carboxylate; 3-Amino-5-((tert-butoxy)carbonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester; 3-Amino-5-tert-butyloxycarbonyl-1-ethoxycarbonyl-4,6-dihydro-1H-pyrrolo[3,4-c]pyrazole | 398495-65-3 | C13H20N4O4 | 详情 | 详情 |
| (III) | 65717 | 4-(4-Methylpiperazino)benzoic acid; 4-(4-Methylpiperazin-1-yl)benzoic acid | 86620-62-4 | C12H16N2O2 | 详情 | 详情 |
| (IV) | 65718 | 1-Ethyl 5-(2-methyl-2-propanyl) 3-{[4-(4-methyl-1-piperazinyl)benzoyl]amino}-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate | 761443-69-0 | C25H34N6O5 | 详情 | 详情 |
| (V) | 65719 | Ethyl 3-{[4-(4-methyl-1-piperazinyl)benzoyl]amino}-5,6-dihydropyrrolo[3,4-c]pyrazole-1(4H)-carboxylate | 761443-50-9 | C20H26N6O3 | 详情 | 详情 |
| (VI) | 50060 | (2R)-2-methoxy-2-phenylethanoic acid | 3966-32-3 | C9H10O3 | 详情 | 详情 |
| (VII) | 16302 | (2R)-2-methoxy-2-phenylethanoyl chloride | C9H9ClO2 | 详情 | 详情 | |
| (VIII) | 65720 | C29H34N6O5 | 详情 | 详情 |