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【结 构 式】 
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【分子编号】58544 【品名】9-amino-3-ethyl-3,7-dihydro-6H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazin-6-one 【CA登记号】 |
【 分 子 式 】C10H10N6O 【 分 子 量 】230.22924 【元素组成】C 52.17% H 4.38% N 36.5% O 6.95% |
合成路线1
该中间体在本合成路线中的序号：(IIIa)Wittig reaction between 2-nitrobenzyltriphenylphosphonium bromide (I) and pyridine-4-carboxaldehyde (II) provided the olefin adduct (IIIa-b) as a mixture of geometric isomers. After, nitro group reduction employing SnCl2, the desired E-isomer (VII), was isolated from the reaction mixture by fractional crystallization. In an alternative approach to intermediate (VII), condensation between 2-nitrobenzaldehyde (IV) and 4-picoline (V) in refluxing acetic anhydride furnished the E-olefin (VI), which was subsequently reduced with SnCl2 to the desired aniline (VII). Acylation of amine (VII) with 4-methoxybenzenesulfonyl chloride (VIII) in pyridine gave sulfonamide (IX). Subsequent oxidation of the pyridine ring to the corresponding N-oxide (X) was accomplished by treatment with peracetic acid at 70 C. The sulfonamide N was finally acetylated in boiling acetic anhydride.
| 【1】 Matsuura, A.; Matsuda, M. (Nippon Shinyaku Co., Ltd.); Aminostilbazole derivs. and medicine. EP 0754682; WO 9527699 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IIIa) | 58544 | 9-amino-3-ethyl-3,7-dihydro-6H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazin-6-one | C10H10N6O | 详情 | 详情 | |
| (IIIb),(VI) | 58555 | 4-[(E)-2-(2-nitrophenyl)ethenyl]pyridine | C13H10N2O2 | 详情 | 详情 | |
| (I) | 58553 | (2-nitrobenzyl)(triphenyl)phosphonium bromide | C25H21BrNO2P | 详情 | 详情 | |
| (II) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (IV) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (V) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (VII) | 58556 | 2-[(E)-2-(4-pyridinyl)ethenyl]aniline; 2-[(E)-2-(4-pyridinyl)ethenyl]phenylamine | C13H12N2 | 详情 | 详情 | |
| (VIII) | 15719 | 4-methoxybenzenesulfonyl chloride | 98-68-0 | C7H7ClO3S | 详情 | 详情 |
| (IX) | 58557 | 4-methoxy-N-{2-[(E)-2-(4-pyridinyl)ethenyl]phenyl}benzenesulfonamide | C20H18N2O3S | 详情 | 详情 | |
| (X) | 58558 | 4-[(E)-2-(2-{[(4-methoxyphenyl)sulfonyl]amino}phenyl)ethenyl]-1-pyridiniumolate | C20H18N2O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The condensation between diethyl ethoxymethylenemalonate (I) and 5-amino-1-ethylpyrazole (II) afforded the enamino malonate (III). Cyclization of (III) upon heating at 255 C in diphenyl ether produced the pyrazolopyridine (IV). This was subsequently chlorinated to (V) in refluxing phosphoryl chloride. Alternatively, enamino malonate (III) was directly converted to the chloro pyrazolopyridine (V) by treatment with POCl3. Nitrile (VI) was prepared by displacement of the chloro group of (V) with cyanide in the presence of a phase-transfer catalyst. Cyclization of the cyano ester (VI) with hydrazine led to the pyrazolopyridopyridiazine tricyclic system (VII). Diazotization of amine (VII) generated the dioxo derivative (VIII), which was chlorinated with POCl3 to yield the dichloro derivative (IX). Selective displacement of the 6-chloro group of (IX) with the imidazole carboxamide (X) produced the imidazolyl derivative (XI).
| 【1】 Kim, S.; Wang, Y.; Yu, G.; Macor, J.; Chung, H.-J.; Humora, M.; Katipally, K. (Bristol-Myers Squibb Co.); Fused pyridopyridazine inhibitors of cGMP phosphodiesterase. EP 1165521; JP 2002540102; US 6316438; WO 0056719 . |
| 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) | 14088 | Diethyl ethoxymethylenemalonate; Diethyl 2-(ethoxymethylene)malonate | 87-13-8 | C10H16O5 | 详情 | 详情 |
| (II) | 40098 | 1-ethyl-1H-pyrazol-5-amine; 1-ethyl-1H-pyrazol-5-ylamine | 3528-58-3 | C5H9N3 | 详情 | 详情 |
| (III) | 40099 | diethyl 2-[[(1-ethyl-1H-pyrazol-5-yl)amino]methylene]malonate | C13H19N3O4 | 详情 | 详情 | |
| (IV) | 40100 | ethyl 1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate | C11H13N3O3 | 详情 | 详情 | |
| (V) | 58542 | ethyl 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate | C11H12ClN3O2 | 详情 | 详情 | |
| (VI) | 58543 | ethyl 4-cyano-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate | C12H12N4O2 | 详情 | 详情 | |
| (VII) | 58544 | 9-amino-3-ethyl-3,7-dihydro-6H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazin-6-one | C10H10N6O | 详情 | 详情 | |
| (VIII) | 58545 | 3-ethyl-7,8-dihydro-3H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazine-6,9-dione | C10H9N5O2 | 详情 | 详情 | |
| (IX) | 58546 | 6,9-dichloro-3-ethyl-3H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazine | C10H7Cl2N5 | 详情 | 详情 | |
| (X) | 58547 | N-methyl-1H-imidazole-4-carboxamide | C5H7N3O | 详情 | 详情 | |
| (XI) | 58548 | 1-(9-chloro-3-ethyl-3H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazin-6-yl)-N-methyl-1H-imidazole-4-carboxamide | C15H13ClN8O | 详情 | 详情 |