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【结 构 式】 
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【药物名称】PNU-103657 【化学名称】N-[2-[4-[N-(3-Isobutylpyridin-2-yl)-N-methylamino]piperidin-1-ylcarbonyl]-1H-indol-5-yl]methanesulfonamide 【CA登记号】179556-43-5 【 分 子 式 】C25H33N5O3S 【 分 子 量 】483.63746 |
【开发单位】Pfizer (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors |
合成路线1
Ethyl 5-nitroindole-2-carboxylate (I) was hydrogenated over Pd/C to give amino indole (II), which was condensed with methanesulfonyl chloride, affording sulfonamide (III). Subsequent hydrolysis of the ester group of (III) furnished the intermediate indolecarboxylic acid (IV).
| 【1】 Romero, D.L.; Thomas, R.C.; May, P.D.; Poel, T.-J. (Pharmacia Corp.); Alkyl substd. piperadinyl and piperazinyl anti-AIDS cpds.. EP 0797576; JP 1998510530; US 5866589; WO 9618628 . |
| 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) | 38163 | ethyl 5-nitro-1H-indole-2-carboxylate | 16732-57-3 | C11H10N2O4 | 详情 | 详情 |
| (II) | 38164 | ethyl 5-amino-1H-indole-2-carboxylate | C11H12N2O2 | 详情 | 详情 | |
| (III) | 38165 | ethyl 5-[(methylsulfonyl)amino]-1H-indole-2-carboxylate | C12H14N2O4S | 详情 | 详情 | |
| (IV) | 38166 | 5-[(methylsulfonyl)amino]-1H-indole-2-carboxylic acid | C10H10N2O4S | 详情 | 详情 |
合成路线2
Deprotonation of 2-bromopyridine (V) with LDA and subsequent quenching with dimethylformamide provided 2-bromo-3-formylpyridine (VI). Nucleophilic substitution of the bromine of (VI) with N-Boc-4-(methylamino)piperidine (VII) in diisopropylethylamine at 100 C in a sealed tube yielded aminopyridine derivative (VIII). Then, Wittig olefination of (VIII) with the ylide resulting from isopropyl triphenylphosphonium iodide and n-BuLi introduced the isobutenyl substituent giving (IX), and further catalytic hydrogenation furnished the isobutyl derivative (X). The Boc group of (X) was deprotected by treatment with HCl in dioxan to give piperidine (XI). Finally, coupling of (XI) with indolecarboxylic acid (IV) via activation with carbonyl diimidazole yielded the title carboxamide.
| 【1】 May, P.D.; Poel, T.J.; Genin, M.J.; et al.; Synthesis and structure-activity relationships of the (alkylamino)piperidine-containing BHAP class of non-nucleoside reverse transcriptase inhibitors: Effect of 3-alkypyridine ring substitution. J Med Chem 1999, 42, 20, 4140. |
| 【2】 Romero, D.L.; Thomas, R.C.; May, P.D.; Poel, T.-J. (Pharmacia Corp.); Alkyl substd. piperadinyl and piperazinyl anti-AIDS cpds.. EP 0797576; JP 1998510530; US 5866589; WO 9618628 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 38166 | 5-[(methylsulfonyl)amino]-1H-indole-2-carboxylic acid | C10H10N2O4S | 详情 | 详情 | |
| (V) | 29052 | 2-Bromopyridine；α-bromopyridine;α-bromoazine | 109-04-6 | C5H4BrN | 详情 | 详情 |
| (VI) | 38167 | 2-bromonicotinaldehyde | C6H4BrNO | 详情 | 详情 | |
| (VII) | 38168 | tert-butyl 4-(methylamino)-1-piperidinecarboxylate | C11H22N2O2 | 详情 | 详情 | |
| (VIII) | 38169 | tert-butyl 4-[(3-formyl-2-pyridinyl)(methyl)amino]-1-piperidinecarboxylate | C17H25N3O3 | 详情 | 详情 | |
| (IX) | 38170 | tert-butyl 4-[methyl[3-(2-methyl-1-propenyl)-2-pyridinyl]amino]-1-piperidinecarboxylate | C20H31N3O2 | 详情 | 详情 | |
| (X) | 38171 | tert-butyl 4-[(3-isobutyl-2-pyridinyl)(methyl)amino]-1-piperidinecarboxylate | C20H33N3O2 | 详情 | 详情 | |
| (XI) | 38172 | 3-isobutyl-N-methyl-N-(4-piperidinyl)-2-pyridinamine; N-(3-isobutyl-2-pyridinyl)-N-methyl-N-(4-piperidinyl)amine | C15H25N3 | 详情 | 详情 |