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【结 构 式】 
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【分子编号】17202 【品名】(2-bromo-4,5-diethoxyphenyl)(methoxy)methyl methyl ether; 1-bromo-2-(dimethoxymethyl)-4,5-diethoxybenzene 【CA登记号】 |
【 分 子 式 】C13H19BrO4 【 分 子 量 】319.19546 【元素组成】C 48.92% H 6% Br 25.03% O 20.05% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 2-bromo-4,5-diethoxybenzaldehyde dimethyl ketal (I) with pyridine-4-carbaldehyde (II) by means of NaH in THF gives the expected addition product (III), which by treatment with acetic acid in refluxing toluene yields the isobenzofuran (IV) (unstable, not isolated compound) that is submitted immediately to a Diels-Alder cyclization with dimethyl maleate (V) to afford the epoxy-tetrahydronaphthalene (VI). The aromatization of (VI) with trifluoroacetic acid (TFA) in chloroform, or with BF3/ethyl ether in acetonitrile gives 6,7-diethoxy-1-(4-pyridyl)naphthalene-2,3-dicarboxylic acid dimethyl ester (VII). The oxidation of (VII) with m-chloroperbenzoic acid (MCPBA) in dichloromethane gives the corresponding N-oxide (VIII), which is isomerized to the pyridone (IX) by refluxing in acetic anhydride. The condensation of (IX) with 2-chloroethyl methyl ether (X) by means of NaH or Li in DMF affords the N-substituted pyridone (XI), which is finally reduced with NaBH4 in THF.
| 【1】 Graul, A.; Leeson, P.; Castañer, J.; T-440. Drugs Fut 1997, 22, 7, 729. |
| 【2】 Iwasaki, T.; Kondo, K.; Kuroda, T.; Moritani, Y.; Yamagata, S.; Sugiura, M.; Kikkawa, H.; Kaminuma, O.; Ikezawa, K.; Novel selective PDE IV inhibitors as antiasthmatic agents. Synthesis and biological activities of a series of 1-aryl-2,3-bis(hydroxymethyl)naphthalene lignans. J Med Chem 1996, 39, 14, 2696-704. |
| 【3】 Iwasaki, T.; Kondo, K.; Ikezawa, K.; Kikkawa, H.; Yamagata, S. (Tanabe Seiyaku Co., Ltd.); Naphthalene derivs. processes for preparing the same, and synthetic intermediates thereof. EP 0557016; JP 1993229987; US 5342941 . |
| 【4】 Iwasaki, T.; Kondo, K.; Ikesawa, I.; Yoshikawa, H.; Yamashina, S. (Tanabe Seiyaku Co., Ltd.); Antiasthma agent. JP 1995101861 . |
| 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) | 17203 | 4-Pyridinecarboxaldehyde; isonicotinaldehyde | 872-85-5 | C6H5NO | 详情 | 详情 |
| (III) | 17204 | [6-(dimethoxymethyl)-3,4-diethoxy-2,4-cyclohexadien-1-yl](4-pyridinyl)methanol | C19H27NO5 | 详情 | 详情 | |
| (IV) | 17205 | 6-ethoxy-1-(4-pyridinyl)-2-benzofuran-5-yl ethyl ether; 4-(5,6-diethoxy-2-benzofuran-1-yl)pyridine | C17H17NO3 | 详情 | 详情 | |
| (V) | 17206 | dimethyl (Z)-2-butenedioate; Dimethyl Maleate | 23055-10-9 | C6H8O4 | 详情 | 详情 |
| (VI) | 17207 | dimethyl 4,5-diethoxy-1-(4-pyridinyl)-11-oxatricyclo[6.2.1.0(2,7)]undeca-2,4,6-triene-9,10-dicarboxylate | C23H25NO7 | 详情 | 详情 | |
| (VII) | 17208 | dimethyl 6,7-diethoxy-1-(4-pyridinyl)-2,3-naphthalenedicarboxylate | C23H23NO6 | 详情 | 详情 | |
| (VIII) | 17209 | 4-[6,7-diethoxy-2,3-bis(methoxycarbonyl)-1-naphthyl]-1-pyridiniumolate | C23H23NO7 | 详情 | 详情 | |
| (IX) | 17210 | dimethyl 6,7-diethoxy-1-(2-oxo-1,2-dihydro-4-pyridinyl)-2,3-naphthalenedicarboxylate | C23H23NO7 | 详情 | 详情 | |
| (X) | 17211 | 1-Chloro-2-methoxyethane; 2-Chloroethyl methyl ether | 627-42-9 | C3H7ClO | 详情 | 详情 |
| (XI) | 17212 | dimethyl 6,7-diethoxy-1-[1-(2-methoxyethyl)-2-oxo-1,2-dihydro-4-pyridinyl]-2,3-naphthalenedicarboxylate | C26H29NO8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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 |