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【结 构 式】 
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【分子编号】21552 【品名】5-fluoro-1H-indole-2,3-dione 【CA登记号】443-69-6 |
【 分 子 式 】C8H4FNO2 【 分 子 量 】165.1237032 【元素组成】C 58.19% H 2.44% F 11.51% N 8.48% O 19.38% |
合成路线1
该中间体在本合成路线中的序号：(I)By cyclization of 5-fluoroisatin (I) with 4-(2-fluorophenyl)- propiophenone (II) by means of NaOH in refluxing ethanol - water.
| 【1】 Hesson, D.P. (DuPont Pharmaceuticals Co.); Phenylquinolinecarboxylic acids and derivatives as antitumor agents. AU 8430852; EP 0133244; JP 8542367; US 4680299 . |
| 【2】 Eastland, G. Jr.; Prous, J.; Castaner, J.; BREQUINAR SODIUM < Prop INNM >. Drugs Fut 1988, 13, 1, 13. |
合成路线2
该中间体在本合成路线中的序号：(VIII)Friedel-Crafts condensation of 2-fluorobiphenyl (I) with glutaric anhydride (II) in the presence of AlCl3 gave ketoacid (III). Reduction of the ketonic group of (III) with triethylsilane in trifluoroacetic acid afforded biphenylpentanoic acid (IV), which was cyclized to the benzosuberone derivative (V) using polyphosphoric acid. Ketone reduction of (IV) by means of triethylsilane and trifluoroacetic acid provided the benzocycloheptene (VI), which was further oxidized to the isomeric ketone (VII) with chromic acid. Finally, condensation of (VII) with 5-fluoroisatin (VIII) in the presence of KOH yielded the target tetracyclic system.
| 【1】 Suzuki, F.; Nakasato, Y.; Tsumuki, H.; Ohmori, K.; Nakajima, H.; Tamura, T.; Sato, S. (Kyowa Hakko Kogyo Co., Ltd.); Tetracyclic cpds.. US 5371225; WO 9322286 . |
| 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) | 31388 | 2-fluoro-1,1'-biphenyl | 321-60-8 | C12H9F | 详情 | 详情 |
| (II) | 15512 | Glutaric Anhydride; dihydro-2H-pyran-2,6(3H)-dione | 108-55-4 | C5H6O3 | 详情 | 详情 |
| (III) | 31389 | 5-(2'-fluoro[1,1'-biphenyl]-4-yl)-5-oxopentanoic acid | C17H15FO3 | 详情 | 详情 | |
| (IV) | 31390 | 5-(2'-fluoro[1,1'-biphenyl]-4-yl)pentanoic acid | C17H17FO2 | 详情 | 详情 | |
| (V) | 31391 | 3-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C17H15FO | 详情 | 详情 | |
| (VI) | 31392 | 2-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene | C17H17F | 详情 | 详情 | |
| (VII) | 31393 | 2-(2-fluorophenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C17H15FO | 详情 | 详情 | |
| (VIII) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)Keto ester (III) was prepared by Friedel-Crafts acylation of 2-fluorobiphenyl (I) with methyl glutaryl chloride (II). Subsequent Pfitzinger condensation of (III) with 5-fluoroisatin (IV) furnished the quinoline derivative (V). Chlorination of diacid (V) with SOCl2, followed by treatment with methanol produced selectively the mono-ester (VI). The remaining carboxyl group of (VI) was activated with SOCl2 in the presence of DMF, and subsequently coupled with n-octyl amine to generate amide (VII). The methyl ester group of (VII) was then hydrolyzed to acid (VIII), which was further subjected to intramolecular ring closure upon heating with triflic acid to afford the tetracyclic system (IX). Keto group reduction in (IX) to give (X) was accomplished by a two-step procedure with NaBH4 and then with HI and Ac2O.
| 【1】 Chujo, I.; et al.; Synthetic study on novel immunosuppressant KF20444. Bioorg Med Chem 2001, 9, 12, 3273. |
| 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) | 31388 | 2-fluoro-1,1'-biphenyl | 321-60-8 | C12H9F | 详情 | 详情 |
| (II) | 20650 | methyl 5-chloro-5-oxopentanoate; methyl-4-chloroformylbutyrate | 1501-26-4 | C6H9ClO3 | 详情 | 详情 |
| (III) | 56572 | methyl 5-(2'-fluoro[1,1'-biphenyl]-4-yl)-5-oxopentanoate | C18H17FO3 | 详情 | 详情 | |
| (IV) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
| (V) | 56573 | 3-(2-carboxyethyl)-6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-quinolinecarboxylic acid | C25H17F2NO4 | 详情 | 详情 | |
| (VI) | 56574 | 6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-3-(3-methoxy-3-oxopropyl)-4-quinolinecarboxylic acid | C26H19F2NO4 | 详情 | 详情 | |
| (VII) | 56575 | methyl 3-{6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-[(octylamino)carbonyl]-3-quinolinyl}propanoate | C34H36F2N2O3 | 详情 | 详情 | |
| (VIII) | 56576 | 3-{6-fluoro-2-(2'-fluoro[1,1'-biphenyl]-4-yl)-4-[(octylamino)carbonyl]-3-quinolinyl}propanoic acid | C33H34F2N2O3 | 详情 | 详情 | |
| (IX) | 56577 | 10-fluoro-3-(2-fluorophenyl)-N-octyl-5-oxo-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide | C33H32F2N2O2 | 详情 | 详情 | |
| (X) | 56578 | 10-fluoro-3-(2-fluorophenyl)-N-octyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]quinoline-8-carboxamide | C33H34F2N2O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The title quinolinecarboxylic acid was synthesized by Pfitzinger condensation of 5-fluoroisatin (I) with 1-(2',4'-dichlorobiphenyl-4-yl)ethanone (II) in the presence of KOH in aqueous EtOH.
| 【1】 Yu, X.Y.; et al.; Structure-activity relationship of biphenylquinoline analogs as inhbitors of S. aureus methionyl-TRNA synthetase. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 296. |
合成路线5
该中间体在本合成路线中的序号：(IX)5-Fluoroisatin (IX) is heated with neat hydrazine hydrate to produce 2-amino-5-fluorophenylacetic hydrazide (X), which, upon acidic treatment cyclizes to 5-fluorooxindole (XI). Subsequent condensation of oxindole (XI) with the formylpyrrole carboxamide (VIII) in the presence of piperidine in hot EtOH leads to the title compound. In an alternative procedure, oxindole (XI) is condensed with the formylpyrrole carboxylic acid (VI) giving (XII), which is further coupled with 2-(diethylamino)ethylamine (VII) in the presence of EDC/HOBt to yield the target carboxamide.
| 【1】 Sun, L.; Liang, C.; Shirazian, S.; Zhou, Y.; Miller, T.; Ciu, J.; Fukuda, J.Y.; Chu, J.-Y.; Nematalla, A.; Wang, X.; Chen, H.; Sistla, A.; Luu, T.C.; Tang, F.; Wei, J.; Tang, C.; Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine. J Med Chem 2003, 46, 7, 1116. |
| 【2】 Wei, C.C.; Miller, T.; Tang, P.C.; Nematalla, A.S.; Li, X.; Liang, C.; Shirazian, S.; Su, L.; Vojkovsky, T. (Sugen, Inc.); Pyrrole substd. 2-indolinone protein kinase inhibitors. EP 1255752; US 2002156292; US 6573293; WO 0160814 . |
| 【3】 Shenoy, N.; Sorasuchart, W. (Sugen, Inc.); Formulations for pharmaceutical agents ionizable as free acids or free bases. JP 2003514851; WO 0137820 . |
| 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) | 60382 | 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 253870-02-9 | C8H9NO3 | 详情 | 详情 |
| (VII) | 12420 | N-(2-Aminoethyl)-N,N-diethylamine; N,N-Diethylethylene-diamine; N(1),N(1)-Diethyl-1,2-ethanediamine | 100-36-7 | C6H16N2 | 详情 | 详情 |
| (VIII) | 63355 | N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxamide | 356068-86-5 | C14H23N3O2 | 详情 | 详情 |
| (IX) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
| (X) | 63356 | 2-(2-amino-5-fluorophenyl)acetohydrazide | 356068-89-8 | C8H10FN3O | 详情 | 详情 |
| (XI) | 60384 | 5-fluoro-1,3-dihydro-2H-indol-2-one | 56341-41-4 | C8H6FNO | 详情 | 详情 |
| (XII) | 60386 | 5-[(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 356068-93-4 | C16H13FN2O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(VI)Vilsmeier formylation of ethyl 2,4-dimethylindole-3-carboxylate (I) by means of POCl3 and DMF leads to aldehyde (II). Subsequent ester group hydrolysis in (II) under alkaline conditions furnishes acid (III), which is then coupled to N-(2-aminoethyl)pyrrolidine (IV) employing EDC/HOBt to afford the corresponding amide (V). Chemoselective reduction of the 3-carbonyl group of 5-fluoroisatin (VI) upon heating with hydrazine hydrate gives rise to 5-fluorooxindole (VII). Finally, condensation of (VII) with aldehyde (V) under Knoevenagel conditions provides the title compound
| 【1】 Wei, C.C.; Miller, T.; Tang, P.C.; Nematalla, A.S.; Li, X.; Liang, C.; Shirazian, S.; Su, L.; Vojkovsky, T. (Sugen, Inc.); Pyrrole substd. 2-indolinone protein kinase inhibitors. EP 1255752; US 2002156292; US 6573293; WO 0160814 . |
| 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) | 60380 | ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate | 2199-51-1 | C9H13NO2 | 详情 | 详情 |
| (II) | 60381 | ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate | 2199-59-9 | C10H13NO3 | 详情 | 详情 |
| (III) | 60382 | 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 253870-02-9 | C8H9NO3 | 详情 | 详情 |
| (IV) | 18161 | 2-(1-pyrrolidinyl)ethylamine; 2-(1-pyrrolidinyl)-1-ethanamine; 1-Pyrrolidineethanamine | 7154-73-6 | C6H14N2 | 详情 | 详情 |
| (V) | 60383 | 5-formyl-2,4-dimethyl-N-[2-(1-pyrrolidinyl)ethyl]-1H-pyrrole-3-carboxamide | C14H21N3O2 | 详情 | 详情 | |
| (VI) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
| (VII) | 60384 | 5-fluoro-1,3-dihydro-2H-indol-2-one | 56341-41-4 | C8H6FNO | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)5-Fluoroisatin (I) is alkylated with 4-methylbenzyl bromide (II) in the presence of NaH to afford the N-benzyl isatin derivative (III). Then, Knoevenagel condensation of isatin (III) with cyanoacetic acid (IV) by means of triethylamine in dioxane gives the indolinylidene adduct (V) as a mixture of E and Z isomers. Subsequent catalytic hydrogenation of (V) over Pd/C then furnishes the target compound
| 【1】 Da Settimo, F.; Primofiore, G.; Da Settimo, A.; La Motta, C.; Simorini, F.; Novellino, E.; Greco, G.; Lavecchia, A.; Boldrini, E.; Novel, highly potent aldose reductase inhibitors: Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives. J Med Chem 2003, 46, 8, 1419. |
| 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) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
| (II) | 24623 | 1-(bromomethyl)-4-methylbenzene | 104-81-4 | C8H9Br | 详情 | 详情 |
| (III) | 63451 | thieno[3,2-b]pyridin-7(4H)-one | C7H5NOS | 详情 | 详情 | |
| (IV) | 12591 | Cyanoacetic Acid; 2-Cyanoacetic acid | 372-09-8 | C3H3NO2 | 详情 | 详情 |
| (V) | 63542 | 2-cyano-2-[5-fluoro-1-(4-methylbenzyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetic acid | C19H13FN2O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)5-Fluoroisatin (I) is alkylated with 4-methylbenzyl bromide (II) in the presence of NaH to afford the N-benzyl isatin derivative (III). Then, Knoevenagel condensation of isatin (III) with isopropyl cyanoacetate (IV) by means of piperidine in isopropanol gives the indolinylidene adduct (V) as a mixture of E and Z isomers. Subsequent catalytic hydrogenation of (V) over Pd/C then furnishes the target compound
| 【1】 Da Settimo, F.; Primofiore, G.; Da Settimo, A.; La Motta, C.; Simorini, F.; Novellino, E.; Greco, G.; Lavecchia, A.; Boldrini, E.; Novel, highly potent aldose reductase inhibitors: Cyano(2-oxo-2,3-dihydroindol-3-yl)acetic acid derivatives. J Med Chem 2003, 46, 8, 1419. |
| 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) | 21552 | 5-fluoro-1H-indole-2,3-dione | 443-69-6 | C8H4FNO2 | 详情 | 详情 |
| (II) | 24623 | 1-(bromomethyl)-4-methylbenzene | 104-81-4 | C8H9Br | 详情 | 详情 |
| (III) | 63541 | 5-fluoro-1-(4-methylbenzyl)-1H-indole-2,3-dione | C16H12FNO2 | 详情 | 详情 | |
| (IV) | 63543 | isopropyl 2-cyanoacetate | C6H9NO2 | 详情 | 详情 | |
| (V) | 63544 | isopropyl 2-cyano-2-[5-fluoro-1-(4-methylbenzyl)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]acetate | C22H19FN2O3 | 详情 | 详情 |