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【结 构 式】 
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【分子编号】31028 【品名】5-nitro-2-benzofuran-1,3-dione 【CA登记号】5466-84-2 |
【 分 子 式 】C8H3NO5 【 分 子 量 】193.11556 【元素组成】C 49.76% H 1.57% N 7.25% O 41.42% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of L-glutamic acid diethyl ester (I) with 4-nitrophthalic anhydride (II) by means of DIEA in refluxing toluene gives the 4-nitrophthalimide (III), which is reduced with H2 over Pd/C to yield the 4-aminophthalimide (IV). The reduction of (IV) with Zn/HCl in ethanol affords a 3:1 mixture of the 5-aminoisoindolinone (V) and 6-aminoisoindolinone (VI) that is separated by chromatography. The desired isomer (V) is condensed with 9-(bromomethyl)-3-methylbenzo[f]quinazolin-1(2H)-one (VII) (obtained by bromination of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (VIII) with NBS) in DMF at 110?C to provide the precursor (IX). Finally, the ester groups of (IX) are hydrolyzed with NaOH in methanol.
| 【1】 Pendergast, W.; Dickerson, S.H.; Johnson, J.V.; Ferone, R. (GlaxoSmithKline plc); Pharmaceutically active benzoquinazoline cpds.. EP 0535034; EP 1199307; JP 1993507704; US 5405851; US 5663337; US 6306865; WO 9119700 . |
| 【2】 Pendergast, W.; et al.; Benzo[f]quinazoline inhibitors of thymidylate synthase: Methyleneamino-linked aroylglutamate derivatives. J Med Chem 1994, 37, 6, 838. |
| 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) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (II) | 31028 | 5-nitro-2-benzofuran-1,3-dione | 5466-84-2 | C8H3NO5 | 详情 | 详情 |
| (III) | 56649 | diethyl (2S)-2-(5-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C17H18N2O8 | 详情 | 详情 | |
| (IV) | 56650 | diethyl (2S)-2-(5-amino-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C17H20N2O6 | 详情 | 详情 | |
| (V) | 56651 | diethyl (2S)-2-(5-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C17H22N2O5 | 详情 | 详情 | |
| (VI) | 56652 | diethyl (2S)-2-(6-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C17H22N2O5 | 详情 | 详情 | |
| (VII) | 56653 | 9-(bromomethyl)-3-methylbenzo[f]quinazolin-1(2H)-one | C14H11BrN2O | 详情 | 详情 | |
| (VIII) | 56654 | 3,9-dimethylbenzo[f]quinazolin-1(2H)-one | C14H12N2O | 详情 | 详情 | |
| (IX) | 56655 | diethyl (2S)-2-(5-{[(3-methyl-1-oxo-1,2-dihydrobenzo[f]quinazolin-9-yl)methyl]amino}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C31H32N4O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Phthalimide (III) was prepared by condensation of 4-nitrophthalic anhydride (I) with 2,6-dimethylaniline (II) in refluxing AcOH. Reduction of the nitro group of (II) by transfer hydrogenation using cyclohexene and Pd/C provided the title aminophthalimide.
| 【1】 Vamecq, J.; Lambert, D.; Poupaert, J.H.; Masereel, B.; Stables, J.P.; Anticonvulsant activity and interactions with neuronal voltage-dependent sodium channel of analogues of ameltolide. J Med Chem 1998, 41, 18, 3307. |
合成路线3
该中间体在本合成路线中的序号：(IX)The esterification of 2-aminopropionic acid (I) with SOCl2 and methanol gives the methyl ester (II), whih is treated with benzaldehyde and TEA in dichloromethane yielding the benzylideneimine (III). The alkylation of (III) with N-(3-iodopropyl)phthalimide (IV) by means of LDA in THF affords the substituted pentanoate (V), which is treated with 1N HCl to give 2-amino-2-methyl-5-(phthalimido)pentanoic acid methyl ester (VI). The cyclization of (VI) by means of hydrazine and sodium methoxide in methanol yields the racemic 3-amino-3-methylpiperidin-2-one (VII), which is submitted to optical resolution with optically active binaphthyl phosphoric acid to afford 3(R)-amino-3-methy-piperidin-2-one (VIII). The reaction of (VIII) with 4-nitrophthalic anhydride (IX) in dioxane gives the amide (X), which is heated under vacuum to give the phthalimide (XI). The oxidation of (XI) with mCPBA in carbon tetrachloride yields the piperidinedione (XII), which is finally reduced at the nitro group by the usual methods.
| 【1】 Miyachi, H.; Koiso, Y.; Shirai, R.; Niwayama, S.; Liu, J.O.; Hashimoto, Y.; Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: Influence of substituents at the phthaloyl moiety on the activity and stereoselectivity. Chem Pharm Bull 1998, 46, 7, 1165. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 | |
| (I) | 31032 | alanine | 302-72-7 | C3H7NO2 | 详情 | 详情 |
| (II) | 25315 | methyl 2-aminopropanoate; Alanine, methyl ester | 7625-53-8 | C4H9NO2 | 详情 | 详情 |
| (III) | 31022 | methyl 2-[[(E)-benzylidene]amino]propanoate | C11H13NO2 | 详情 | 详情 | |
| (IV) | 31023 | 2-(3-iodopropyl)-1H-isoindole-1,3(2H)-dione | C11H10INO2 | 详情 | 详情 | |
| (V) | 31024 | methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methyl-2-[[(E)-benzylidene]amino]pentanoate | C22H22N2O4 | 详情 | 详情 | |
| (VI) | 31025 | methyl 2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpentanoate | C15H18N2O4 | 详情 | 详情 | |
| (VII) | 31026 | 3-amino-3-methyl-2-piperidinone | C6H12N2O | 详情 | 详情 | |
| (VIII) | 31027 | (3R)-3-amino-3-methyl-2-piperidinone | C6H12N2O | 详情 | 详情 | |
| (IX) | 31028 | 5-nitro-2-benzofuran-1,3-dione | 5466-84-2 | C8H3NO5 | 详情 | 详情 |
| (X) | 31029 | 2-([[(3R)-3-methyl-2-oxopiperidinyl]amino]carbonyl)-5-nitrobenzoic acid | C14H15N3O6 | 详情 | 详情 | |
| (XI) | 31030 | 2-[(3R)-3-methyl-2-oxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione | C14H13N3O5 | 详情 | 详情 | |
| (XII) | 31031 | 2-[(3R)-3-methyl-2,6-dioxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione | C14H11N3O6 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The esterification of 2-aminopropionic acid (I) with SOCl2 and methanol gives the methyl ester (II), whih is treated with benzaldehyde and TEA in dichloromethane yielding the benzylideneimine (III). The alkylation of (III) with N-(3-iodopropyl)phthalimide (IV) by means of LDA in THF affords the substituted pentanoate (V), which is treated with 1N HCl to give 2-amino-2-methyl-5-(phthalimido)pentanoic acid methyl ester (VI). The cyclization of (VI) by means of hydrazine and sodium methoxide in methanol yields the racemic 3-amino-3-methylpiperidin-2-one (VII), which is submitted to optical resolution with optically active binaphthyl phosphoric acid to afford 3(S)-amino-3-methylpiperidin-2-one (VIII). The reaction of (VIII) with 4-nitrophthalic anhydride (IX) in dioxane gives the amide (X), which is heated under vacuum to give the phthalimide (XI). The oxidation of (XI) with mCPBA in carbon tetrachloride yields the piperidinedione (XII), which is finally reduced at the nitro group by the usual methods.
| 【1】 Miyachi, H.; Koiso, Y.; Shirai, R.; Niwayama, S.; Liu, J.O.; Hashimoto, Y.; Tumor necrosis factor-alpha production enhancing activity of substituted 3'-methylthalidomide: Influence of substituents at the phthaloyl moiety on the activity and stereoselectivity. Chem Pharm Bull 1998, 46, 7, 1165. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 | |
| (I) | 31032 | alanine | 302-72-7 | C3H7NO2 | 详情 | 详情 |
| (II) | 25315 | methyl 2-aminopropanoate; Alanine, methyl ester | 7625-53-8 | C4H9NO2 | 详情 | 详情 |
| (III) | 31022 | methyl 2-[[(E)-benzylidene]amino]propanoate | C11H13NO2 | 详情 | 详情 | |
| (IV) | 31023 | 2-(3-iodopropyl)-1H-isoindole-1,3(2H)-dione | C11H10INO2 | 详情 | 详情 | |
| (V) | 31024 | methyl 5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methyl-2-[[(E)-benzylidene]amino]pentanoate | C22H22N2O4 | 详情 | 详情 | |
| (VI) | 31025 | methyl 2-amino-5-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-methylpentanoate | C15H18N2O4 | 详情 | 详情 | |
| (VII) | 31026 | 3-amino-3-methyl-2-piperidinone | C6H12N2O | 详情 | 详情 | |
| (VIII) | 31033 | (3S)-3-amino-3-methyl-2-piperidinone | C6H12N2O | 详情 | 详情 | |
| (IX) | 31028 | 5-nitro-2-benzofuran-1,3-dione | 5466-84-2 | C8H3NO5 | 详情 | 详情 |
| (X) | 31034 | 2-([[(3S)-3-methyl-2-oxopiperidinyl]amino]carbonyl)-5-nitrobenzoic acid | C14H15N3O6 | 详情 | 详情 | |
| (XI) | 31035 | 2-[(3S)-3-methyl-2-oxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione | C14H13N3O5 | 详情 | 详情 | |
| (XII) | 31036 | 2-[(3S)-3-methyl-2,6-dioxopiperidinyl]-5-nitro-1H-isoindole-1,3(2H)-dione | C14H11N3O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Condensation of 4-nitrophthalic anhydride (I) with O-benzyl hydroxylamine in refluxing toluene produced phthalimide (II). Catalytic transfer hydrogenation employing cyclohexene in the presence of Pd/C yielded 4-amino-N-hydroxyphthalimide (III), which was condensed with ethanesulfonyl chloride to give sulfonate (IV). Finally, acylation with acid chloride (V) furnished the title compound.
| 【1】 Kerrigan, J.E.; et al.; 6-Acylamino-2-[(alkylsulfonyl)oxy]-1H-isoindole-1,3-dione mechanism-based inhibitors of human leukocyte elastase. Bioorg Med Chem Lett 2000, 10, 1, 27. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14640 | O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene | 622-33-3 | C7H9NO | 详情 | 详情 | |
| (I) | 31028 | 5-nitro-2-benzofuran-1,3-dione | 5466-84-2 | C8H3NO5 | 详情 | 详情 |
| (II) | 38147 | 2-(benzyloxy)-5-nitro-1H-isoindole-1,3(2H)-dione | C15H10N2O5 | 详情 | 详情 | |
| (III) | 38148 | 5-amino-2-hydroxy-1H-isoindole-1,3(2H)-dione | C8H6N2O3 | 详情 | 详情 | |
| (IV) | 38149 | 5-amino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3(2H)-dione | C10H10N2O5S | 详情 | 详情 | |
| (V) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(V)Alkylation of 2-methoxy-5-nitrophenol (I) with cyclopentyl bromide (II) provides the cyclopentyl ether (III). Subsequent reduction of the nitro derivative (III) to aniline (IV) is effected by transfer hydrogenation in the presence of ammonium formate and Pd/C. Condensation of 3-(cyclopentyloxy)-4-methoxyaniline (IV) with 4-nitrophthalic anhydride (V) gives rise to phthalimide (VI). Reduction of imide (VI) by means of NaBH4 furnishes the amide alcohol (VII), which is further cyclized to isoindoline (VIII) under Mitsunobu conditions. Finally, transfer hydrogenation of nitro isoindoline (VIII) gives rise to the corresponding amine.
| 【1】 Park, J.S.; Moon, S.C.; Baik, K.U.; Cho, J.Y.; Yoo, E.S.; Byun, Y.S.; Park, M.H.; Synthesis and SAR studies for the inhibition of TNF-alpha production. Part 2. 2-[3-(Cyclopentyloxy)-4-methoxyphenyl]-substituted-1-isoindolinone derivatives. Arch Pharmacal Res 2002, 25, 2, 137. |
| 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) | 64272 | 2-methoxy-5-nitrophenol | C7H7NO4 | 详情 | 详情 | |
| (II) | 10972 | 1-Bromocyclopentane; Cyclopentyl bromide | 137-43-9 | C5H9Br | 详情 | 详情 |
| (III) | 64273 | cyclopentyl 2-methoxy-5-nitrophenyl ether; 2-(cyclopentyloxy)-1-methoxy-4-nitrobenzene | C12H15NO4 | 详情 | 详情 | |
| (IV) | 64274 | 3-(cyclopentyloxy)-4-methoxyphenylamine; 3-(cyclopentyloxy)-4-methoxyaniline | C12H17NO2 | 详情 | 详情 | |
| (V) | 31028 | 5-nitro-2-benzofuran-1,3-dione | 5466-84-2 | C8H3NO5 | 详情 | 详情 |
| (VI) | 64275 | 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-5-nitro-1H-isoindole-1,3(2H)-dione | C20H18N2O6 | 详情 | 详情 | |
| (VII) | 64276 | N-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-(hydroxymethyl)-5-nitrobenzamide | C20H22N2O6 | 详情 | 详情 | |
| (VIII) | 64277 | 2-[3-(cyclopentyloxy)-4-methoxyphenyl]-6-nitro-1-isoindolinone | C20H20N2O5 | 详情 | 详情 |