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【结 构 式】 
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【药物名称】T-2585.HCl 【化学名称】2-[4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]pyridin-2-yl]-4-(3-pyridyl)phthalazin-1(2H)-one hydrochloride 【CA登记号】186461-09-6, 186461-26-7 (free base) 【 分 子 式 】C34H31ClN4O5 【 分 子 量 】611.10297 |
【开发单位】Tanabe Seiyaku (Originator) 【药理作用】Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, Phosphodiesterase IV Inhibitors |
合成路线1
The reaction of 2-bromo-4,5-diethoxybenzaldehyde dimethylacetal (I) with 2-chloropyridine-4-carbaldehyde (II) by means of BuLi in THF gives the diarylcarbinol (III), which is cyclized with dimethyl fumarate (IV) by means of AcOH in refluxing toluene (or xylene) yielding the naphthalene-2,3-dicabroxylic ester (V). The reduction of (V) with NaBH4 in THF/methanol affords the bis(hydroxymethyl)naphthalene (VI), which is treated with hydrazine in refluxing water to give the 2-pyridylhydrazine derivative (VII). Finally, this compound is cyclized with 2-(3-pyridylcarbonyl)benzoic acid (VIII) by heating at 150 C in ethylene glycol.
| 【1】 Wada, K.; Nakata, A.; Naito, K.; Terakawa, Y.; Ikezawa, K.; Kikkawa, H.; Kuroda, T.; Sugahara, M.; Ohmachi, Y.; Ukita, T.; Novel, potent, and selective phosphodiesterase-4 inhibitors as antiasthmatic agents: Synthesis and biological activities of a series of 1-pyridylnaphthalene derivatives. J Med Chem 1999, 42, 6, 1088. |
| 【2】 Ukita, T.; Ikezawa, K.; Yamagata, S. (Tanabe Seiyaku Co., Ltd.); Naphthalene derivs., process for the preparation thereof, and pharmaceutical compsns. comprising them. CA 2178974; EP 0748805; JP 1997059255; US 6005106 . |
| 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) | 17202 | (2-bromo-4,5-diethoxyphenyl)(methoxy)methyl methyl ether; 1-bromo-2-(dimethoxymethyl)-4,5-diethoxybenzene | C13H19BrO4 | 详情 | 详情 | |
| (II) | 29234 | 2-chloroisonicotinaldehyde | C6H4ClNO | 详情 | 详情 | |
| (III) | 29235 | (2-chloro-4-pyridinyl)[2-(dimethoxymethyl)-4,5-diethoxyphenyl]methanol | C19H24ClNO5 | 详情 | 详情 | |
| (IV) | 17206 | dimethyl (Z)-2-butenedioate; Dimethyl Maleate | 23055-10-9 | C6H8O4 | 详情 | 详情 |
| (V) | 29236 | dimethyl 1-(2-chloro-4-pyridinyl)-6,7-diethoxy-2,3-naphthalenedicarboxylate | C23H22ClNO6 | 详情 | 详情 | |
| (VI) | 29237 | [1-(2-chloro-4-pyridinyl)-6,7-diethoxy-3-(hydroxymethyl)-2-naphthyl]methanol | C21H22ClNO4 | 详情 | 详情 | |
| (VII) | 29238 | [6,7-diethoxy-4-(2-hydrazino-4-pyridinyl)-3-(hydroxymethyl)-2-naphthyl]methanol | C21H25N3O4 | 详情 | 详情 | |
| (VIII) | 29239 | 2-(3-pyridinylcarbonyl)benzoic acid | C13H9NO3 | 详情 | 详情 |