T-440, -Drug Synthesis Database

【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 合成路线2

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.

参考文献中间体

【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.

参考文献中间体

【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	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