dimethyl (Z)-2-butenedioate; Dimethyl Maleate -Drug Synthesis Database

【结构式】

【分子编号】17206

【品名】dimethyl (Z)-2-butenedioate; Dimethyl Maleate

【CA登记号】23055-10-9

【分子式】C₆H₈O₄

【分子量】144.12712

【元素组成】C 50% H 5.59% O 44.4%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(LXIII)

The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl maleate (LXIII) gives the expected adduct (LXIV), which by thermal extrusion of CO2 yields the dihydronaphthodioxole (LXV). This compound is then converted to dihydroxycompound (X), which is finally cyclized by means of ZnCl2 to provide the target compound. The Diels-Alder cyclization of 5-(3,4,5-trimethoxyphenyl)-7H-pyrano[3,4-f][1,3]benzodioxol-7-one (I) with dimethyl fumarate (LXVI) gives the expected adduct (LXVII), which by hydrogenation with H2 over Pd/C yields the tricarboxylic acid derivative (LXVIII). The reaction of (LXVIII) with Pb(OAc)4 affords the acetoxy derivative (LXIX), which is selectively reduced with LiBEt3H providing the diol (LXI) with the wrong configuration at the secondary OH group. The treatment of (LXI) with aqueous acid isomerizes the secondary OH group to give the previously described (X) with the suitable configuration.

参考文献中间体

合成目标

【1】 Ward, R.S.; Synthesis of podophyllotoxin and related compounds. Synthesis 1992, 719.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(LXVLIII)	35016	(5R,6R,7R,8R)-6,7-bis(methoxycarbonyl)-8-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-5-carboxylic acid		C₂₅H₂₆O₁₁	详情	详情
(I)	34956	5-(3,4,5-trimethoxyphenyl)-7H-[1,3]dioxolo[4,5-g]isochromen-7-one		C₁₉H₁₆O₇	详情	详情
(X)	34965	methyl (5R,6R,7R,8R)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate		C₂₃H₂₆O₉	详情	详情
(LXI)	35011	methyl (5R,6R,7R,8S)-8-hydroxy-7-(hydroxymethyl)-5-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate		C₂₃H₂₆O₉	详情	详情
(LXIII)	17206	dimethyl (Z)-2-butenedioate; Dimethyl Maleate	23055-10-9	C₆H₈O₄	详情	详情
(LXIV)	35013	dimethyl (1S,11S,14R,15S)-13-oxo-11-(3,4,5-trimethoxyphenyl)-5,7,12-trioxatetracyclo[9.2.2.0(2,10).0(4,8)]pentadeca-2(10),3,8-triene-14,15-dicarboxylate		C₂₅H₂₄O₁₁	详情	详情
(LXV)	35014	dimethyl (5R,6R)-5-(3,4,5-trimethoxyphenyl)-5,6-dihydronaphtho[2,3-d][1,3]dioxole-6,7-dicarboxylate		C₂₄H₂₄O₉	详情	详情
(LXVI)	35018	dimethyl (E)-2-butenedioate	624-49-7	C₆H₈O₄	详情	详情
(LXVII)	35015	dimethyl (1R,11R,14S,15S)-13-oxo-11-(3,4,5-trimethoxyphenyl)-5,7,12-trioxatetracyclo[9.2.2.0(2,10).0(4,8)]pentadeca-2(10),3,8-triene-14,15-dicarboxylate		C₂₅H₂₄O₁₁	详情	详情
(LXIX)	35017	dimethyl (5S,6S,7R,8R)-5-(acetoxy)-8-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydronaphtho[2,3-d][1,3]dioxole-6,7-dicarboxylate		C₂₆H₂₈O₁₁	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

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

合成目标

【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3

该中间体在本合成路线中的序号：(IV)

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.

参考文献中间体

合成目标

【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

Extended Information