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【结 构 式】 
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【药物名称】Indobufen, K-3920, Ibustrin 【化学名称】(±)-2-[p-(1-Oxo-2-isoindolinyl)phenyl]butyric acid 【CA登记号】63610-08-2 【 分 子 式 】C18H17NO3 【 分 子 量 】295.34109 |
【开发单位】Pfizer (Originator) 【药理作用】Anticoagulants, Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS |
合成路线1
The reaction of phthalic anhydride (I) with ethyl p-amino-alpha-ethylphenylacetate (II) in refluxing acetic acid gives ethyl alpha-[4-(1,3-dioxo-2-isoindolinyl)phenyl]-n-butyrate (III), which is reduced with Zn in refluxing acetic acid to the isoindolinone (IV). Finally, this compound is hydrolyzed with K2CO3 in refluxing ethanol - water.
| 【1】 Giraldi, P.N.; et al.; Dérivés d'iso-indoline et procédé de leur préparation. DE 2154525; FR 2112480; JP 51068563; JP 52017463; NL 7115288 . |
| 【2】 Nannini, G.; et al.; New analgesic-antiinflammatory drugs. 1-oxo-2-substituted isoindoline derivatives. Arzneim-Forsch Drug Res 1973, 23, 8, 1090. |
| 【3】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109. |
| 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) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (II) | 33295 | ethyl 2-(4-aminophenyl)butanoate | C12H17NO2 | 详情 | 详情 | |
| (III) | 33296 | ethyl 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]butanoate | C20H19NO4 | 详情 | 详情 | |
| (IV) | 33297 | ethyl 2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]butanoate | C20H21NO3 | 详情 | 详情 |
合成路线2
The reaction of (II) with phthalide (V) at 280 C gives the isoindolinone (IV). Finally, this compound is hydrolyzed with K2CO3 in refluxing ethanol - water.
| 【1】 Giraldi, P.N.; et al.; Dérivés d'iso-indoline et procédé de leur préparation. DE 2154525; FR 2112480; JP 51068563; JP 52017463; NL 7115288 . |
| 【2】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109. |
合成路线3
The reaction of (II) with benzaldehyde (VI) in refluxing toluene gives ethyl p-benzylideneamino-alpha-methylphenylacetate (VII), which is reduced with H2 over PtO2 in ethanol to the N-benzyl derivative (VIII). The acylation of (VIII) with phosgene by means of pyridine in toluene yields the N-chlorocarbonyl compound (IX), which is then cyclized to the isoindolinone (IV) with AlCl3 in refluxing 1,2-dichloroethane. Finally, this compound is hydrolyzed with K2CO3 in refluxing ethanol - water.
| 【1】 Giraldi, P.N.; et al.; Verfahren zur Herstellung von Isoindolinderivaten. AT 325604B; CA 994785; CH 581106; JP 48057965; NL 7215830 . |
| 【2】 Nannini, G.; et al.; New analgesic-antiinflammatory drugs. 1-oxo-2-substituted isoindoline derivatives. Arzneim-Forsch Drug Res 1973, 23, 8, 1090. |
| 【3】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 33295 | ethyl 2-(4-aminophenyl)butanoate | C12H17NO2 | 详情 | 详情 | |
| (IV) | 33297 | ethyl 2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]butanoate | C20H21NO3 | 详情 | 详情 | |
| (VI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VII) | 33299 | ethyl 2-(4-[[(E)-benzylidene]amino]phenyl)butanoate | C19H21NO2 | 详情 | 详情 | |
| (VIII) | 33300 | ethyl 2-[4-(benzylamino)phenyl]butanoate | C19H23NO2 | 详情 | 详情 | |
| (IX) | 33301 | ethyl 2-[4-[benzyl(chlorocarbonyl)amino]phenyl]butanoate | C20H22ClNO3 | 详情 | 详情 |
合成路线4
By cyclization of phthalic aldehyde with p-amino-8-ethylphenylacetic acid (XI) in DMF at 100 C.
| 【1】 Giraldi, P.N.; et al.; Dérivés d'iso-indoline et procédé de leur préparation. DE 2154525; FR 2112480; JP 51068563; JP 52017463; NL 7115288 . |
| 【2】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109. |
合成路线5
The cyclization of (XI) with o-cyanobenzyl bromide (XII) in refluxing ethanol gives 1-imino-2-[p-[(alpha-ethyl)carboxymethyl]phenyl]isoindoline (XIII), which is finally hydrolyzed with K2CO3 in refluxing ethanol water.
| 【1】 Giraldi, P.N.; et al.; Dérivés d'iso-indoline et procédé de leur préparation. DE 2154525; FR 2112480; JP 51068563; JP 52017463; NL 7115288 . |
| 【2】 Nannini, G.; et al.; New analgesic-antiinflammatory drugs. 1-oxo-2-substituted isoindoline derivatives. Arzneim-Forsch Drug Res 1973, 23, 8, 1090. |
| 【3】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109. |
合成路线6
The reaction of benzaldehyde (VI) with p-amino-alpha-ethylphenylacetonitrile (XIV) in refluxing toluene gives p-benzylideneamino-alpha-ethylphenylacetonitrile (XV), which is reduced with H2 over PtO2 in ethanol yielding p-benzylamino-alpha-ethylphenylacetonitrile (XVI). The acylation of (XVI) with phosgene by means of pyridine in toluene affords the N-chlorocarbo-nyl compound (XVII), which is cyclized with AlCl3 in refluxing 1,2-dichloroethane to yield 1-oxo-2-[p-(alpha-ethyl-cyanomethyl)phenyl]isoindoline (XVIII). Finally, this compound is hydrolyzed with H2SO4 in refluxing water.
| 【1】 Giraldi, P.N.; et al.; Verfahren zur Herstellung von Isoindolinderivaten. AT 325604B; CA 994785; CH 581106; JP 48057965; NL 7215830 . |
| 【2】 de Angelis, L.; Castaner, J.; Indobufen. Drugs Fut 1979, 4, 2, 109. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (XIV) | 33305 | 2-(4-aminophenyl)butanenitrile | C10H12N2 | 详情 | 详情 | |
| (XV) | 33306 | 2-(4-[[(E)-benzylidene]amino]phenyl)butanenitrile | C17H16N2 | 详情 | 详情 | |
| (XVI) | 33307 | 2-[4-(benzylamino)phenyl]butanenitrile | C17H18N2 | 详情 | 详情 | |
| (XVII) | 33308 | 1-[benzyl(chlorocarbonyl)amino]-4-(1-cyanopropyl)benzene | C18H17ClN2O | 详情 | 详情 | |
| (XVIII) | 33309 | 2-[4-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]butanenitrile | C18H16N2O | 详情 | 详情 |