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【结 构 式】

【药物名称】T-440

【化学名称】4-[6,7-Diethoxy-2,3-bis(hydroxymethyl)naphthalen-1-yl]-1-(2-methoxyethyl)pyridin-2(1H)-one

【CA登记号】155043-84-8

【 分 子 式 】C24H29NO6

【 分 子 量 】427.50183

【开发单位】Tanabe Seiyaku (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Atopic Dermatitis, Agents for, Bronchodilators, DERMATOLOGIC DRUGS, RESPIRATORY DRUGS, Phosphodiesterase IV Inhibitors

合成路线1

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

An efficient N-alkylation process suitable for the large-scale synthesis of T-440 has been reported: Alkylation of the previously reported pyridone (I) with 2-methoxyethyl iodide (II) by means of LiH in hot DMF gives the N-alkylated pyridone (II) purified by crystallization. Finally, this compound is reduced with NaBH4 and MeOH in refluxing THF.

1 Sugahara, M.; et al.; An efficient synthesis of the anti-asthmatic agent T-440: A selective N-alkylation of 2-pyridone. Chem Pharm Bull 2000, 48, 4, 589.
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) 17210 dimethyl 6,7-diethoxy-1-(2-oxo-1,2-dihydro-4-pyridinyl)-2,3-naphthalenedicarboxylate C23H23NO7 详情 详情
(II) 47687 1-iodo-2-methoxyethane; 2-iodoethyl methyl ether C3H7IO 详情 详情
(III) 17212 dimethyl 6,7-diethoxy-1-[1-(2-methoxyethyl)-2-oxo-1,2-dihydro-4-pyridinyl]-2,3-naphthalenedicarboxylate C26H29NO8 详情 详情
Extended Information