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【结 构 式】 
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【分子编号】10174 【品名】2,5-Dimethoxybenzaldehyde 【CA登记号】93-02-7 |
【 分 子 式 】C9H10O3 【 分 子 量 】166.1766 【元素组成】C 65.05% H 6.07% O 28.88% |
合成路线1
该中间体在本合成路线中的序号：(I)The synthesis of [14C]-labeled piritrexim has been described: The condensation of 2,5-dimethoxybenzaldehyde (I) with acetone in aqueous NaOH gives 4-(2,5-dimethoxyphenyl)-3-(E)-buten-2-one (II), which is hydrogenated with H2 over Pd/C in methanol to give 4-(2,5-dimethoxyphenyl)-2-butanone (III). The condensation of (III) with malononitrile (IV) by means of acetic acid-sodium acetate in refluxing toluene yields 2-cyano-5-(2,5-dimethoxyphenyl)-3-methyl-2-pentenenitrile (V), which is condensed with acetic acid diethoxymethyl ester (VI) at 105 C to afford the corresponding diethoxymethyl derivative (VII). The cyclization of (VII) with 32% HBr in acetic acid affords 2-bromo-5-(2,5-dimethoxybenzyl)-4-methylpyridine-3-carbonitrile (VIII), which is finally cyclized again with [14C]-labeled guanidine (IX) by means of NaH in refluxing tert-butyl alcohol.
| 【1】 Wisowaty, J.C.; Darnofall, M.E.; Hill, J.A.; Synthesis of carbon-14 labelled piritrexim - A potential anticancer agent. J Label Compd Radiopharm 1993, 33, 12, 1119. |
| 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) | 10174 | 2,5-Dimethoxybenzaldehyde | 93-02-7 | C9H10O3 | 详情 | 详情 |
| (II) | 10175 | (E)-4-(2,5-Dimethoxyphenyl)-3-buten-2-one | C12H14O3 | 详情 | 详情 | |
| (III) | 10176 | 4-(2,5-Dimethoxyphenyl)-2-butanone | C12H16O3 | 详情 | 详情 | |
| (IV) | 12061 | Malononitrile | 109-77-3 | C3H2N2 | 详情 | 详情 |
| (V) | 10177 | 2-[3-(2,5-Dimethoxyphenyl)-1-methylpropylidene]malononitrile | C15H16N2O2 | 详情 | 详情 | |
| (VI) | 17661 | Diethoxymethyl acetate | 14036-06-7 | C7H14O4 | 详情 | 详情 |
| (VII) | 10178 | 2-[2-(2,5-Dimethoxybenzyl)-3,3-diethoxy-1-methylpropylidene]malononitrile | C20H26N2O4 | 详情 | 详情 | |
| (VIII) | 10179 | 2-Bromo-5-(2,5-dimethoxybenzyl)-4-methylnicotinonitrile | C16H15BrN2O2 | 详情 | 详情 | |
| (IX) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (IX) | 44601 | guanidine | CH5N3 | 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 2,5-dimethoxybenzaldehyde (I) with ethyl acetoacetate (II) in a mixture of piperidine and glacial acetic acid in refluxing benzene gives ethyl alpha-acetyl-beta-(2,5-dimethoxyphenyl)acrylate (III), which is hydrogenated in a Parr low-pressure apparatus using 5% palladium on charcoal catalyst in ethyl acetate to yield ethyl alpha-acetyl-(2,5-dimethoxyphenyl)propionate (IV). The condensation of the propionate (IV) with 2,4.6-triaminopyrimidine in diphenylether at 195-230 C provides 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (VI). The key intermediate (VI) is converted to the 7-chloro compound (VII) by treatment with a 1:1 complex of N,N-dimethylformamide thionyl chloride, and finally (VII) is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield BW-301 U.
| 【1】 Grivsky, E.M.; et al.; Synthesis and antitumor activity of 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidine. J Med Chem 1980, 23, 3, 327-329. |
| 【2】 Sigel, C.W.; BW-301 U. Drugs Fut 1985, 10, 2, 108. |
| 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) | 10174 | 2,5-Dimethoxybenzaldehyde | 93-02-7 | C9H10O3 | 详情 | 详情 |
| (II) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (III) | 28975 | ethyl (Z)-2-acetyl-3-(2,5-dimethoxyphenyl)-2-propenoate | C15H18O5 | 详情 | 详情 | |
| (IV) | 28976 | ethyl 2-(2,5-dimethoxybenzyl)-3-oxobutanoate | C15H20O5 | 详情 | 详情 | |
| (V) | 28977 | 2,6-diamino-4-pyrimidinylamine | 1004-38-2 | C4H7N5 | 详情 | 详情 |
| (VI) | 28978 | 2,4-diamino-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-7(8H)-one | C17H19N5O3 | 详情 | 详情 | |
| (VII) | 28979 | 2-amino-7-chloro-6-(2,5-dimethoxybenzyl)-5-methylpyrido[2,3-d]pyrimidin-4-ylamine | C17H18ClN5O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The formylation of 1,4-dimethoxybenzene (I) with C6H11-Li, TMEDA and DMF gives 2,5-dimethoxybenzaldehyde (II), which is reduced with NaBH4 to the corresponding alcohol (III). The treatment of (III) with HBr affords the benzyl bromide (IV), which by reaction with PPh3 in hot toluene is converted into the phosphonium salt (V). The condensation of (V) with 5-formyl-2-hydroxybenzoic acid methyl ester (VI)(obtained by esterification of the corresponding acid (VII) with methanol and H2SO4) by means of LDA in THF affords the stilbene (VIII). Finally, this compound is reduced with H2 over Pd/C in ethyl acetate.
| 【1】 Kucerovy, A.; et al.; An efficient large-scale synthesis of methyl 5-[2-82,5-dimethoxyphenyl)ethyl]-2-hydroxybenzoate. Org Process Res Dev 1997, 1, 4, 287. |
| 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) | 21946 | 1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether | 150-78-7 | C8H10O2 | 详情 | 详情 |
| (II) | 10174 | 2,5-Dimethoxybenzaldehyde | 93-02-7 | C9H10O3 | 详情 | 详情 |
| (III) | 32353 | (2,5-dimethoxyphenyl)methanol | 33524-31-1 | C9H12O3 | 详情 | 详情 |
| (IV) | 32354 | 2-(bromomethyl)-4-methoxyphenyl methyl ether; 2-(bromomethyl)-1,4-dimethoxybenzene | C9H11BrO2 | 详情 | 详情 | |
| (V) | 32355 | (2,5-dimethoxybenzyl)(triphenyl)phosphonium bromide | C27H26BrO2P | 详情 | 详情 | |
| (VI) | 32356 | methyl 5-formyl-2-hydroxybenzoate | C9H8O4 | 详情 | 详情 | |
| (VII) | 32357 | 5-Formylsalicylic acid; 5-formyl-2-hydroxybenzoic acid | 616-76-2 | C8H6O4 | 详情 | 详情 |
| (VIII) | 32358 | methyl 5-[(E)-2-(2,5-dimethoxyphenyl)ethenyl]-2-hydroxybenzoate | C18H18O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Improved large scale synthesis: The formylation of 1,4-dimethoxybenzene (I) with C6H11-Li, TMEDA and DMF gives 2,5-dimethoxybenzaldehyde (II), which is reduced with NaBH4 in toluene/methanol to the corresponding alcohol (III). The treatment of (III) with PBr3 in ethyl acetate affords the benzyl bromide (IV), which by reaction with dimethyl phosphite (IX) and NaH in toluene is converted into the phosphonate (X). The condensation of (X) with 5-formyl-2-hydroxybenzoic acid methyl ester (VI)(obtained by esterification of the corresponding acid (VII) with methanol and H2SO4) by means of LiHMDS in THF affords the stilbene (VIII). Finally, this compound is reduced with H2 over Pd/C in ethyl acetate.
| 【1】 Kucerovy, A.; et al.; An efficient large-scale synthesis of methyl 5-[2-82,5-dimethoxyphenyl)ethyl]-2-hydroxybenzoate. Org Process Res Dev 1997, 1, 4, 287. |
| 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) | 21946 | 1,4-dimethoxybenzene; 4-methoxyphenyl methyl ether | 150-78-7 | C8H10O2 | 详情 | 详情 |
| (II) | 10174 | 2,5-Dimethoxybenzaldehyde | 93-02-7 | C9H10O3 | 详情 | 详情 |
| (III) | 32353 | (2,5-dimethoxyphenyl)methanol | 33524-31-1 | C9H12O3 | 详情 | 详情 |
| (IV) | 32354 | 2-(bromomethyl)-4-methoxyphenyl methyl ether; 2-(bromomethyl)-1,4-dimethoxybenzene | C9H11BrO2 | 详情 | 详情 | |
| (VI) | 32356 | methyl 5-formyl-2-hydroxybenzoate | C9H8O4 | 详情 | 详情 | |
| (VII) | 32357 | 5-Formylsalicylic acid; 5-formyl-2-hydroxybenzoic acid | 616-76-2 | C8H6O4 | 详情 | 详情 |
| (VIII) | 32358 | methyl 5-[(E)-2-(2,5-dimethoxyphenyl)ethenyl]-2-hydroxybenzoate | C18H18O5 | 详情 | 详情 | |
| (IX) | 32359 | dimethyl phosphonate | 868-85-9 | C2H7O3P | 详情 | 详情 |
| (X) | 32360 | dimethyl 2,5-dimethoxybenzylphosphonate | C11H17O5P | 详情 | 详情 |