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【结 构 式】 
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【分子编号】14098 【品名】2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin 【CA登记号】91-56-5 |
【 分 子 式 】C8H5NO2 【 分 子 量 】147.13324 【元素组成】C 65.31% H 3.43% N 9.52% O 21.75% |
合成路线1
该中间体在本合成路线中的序号：(I)Prepared by condensation of isatin (I) and indoxyl (II).
| 【1】 Mingzhu, M.; Bangyuan, Y.; Progress in indirubin treatment of chronic myelocytic leukemia. J Tradit Chin Med 1983, 3, 3, 245-8. |
| 【2】 Ru-yun, J.; Indirubin. Drugs Fut 1984, 9, 4, 266. |
合成路线2
该中间体在本合成路线中的序号：(V)By cyclocondensation of isatine (V) with cyclohexanone (II) and aqueous concentrated NH3 at 150 C in a pressure vessel to acridine-9-carboxamide (VI), followed by a Hoffman degradation with Br2 and sodium methoxide in methanol
| 【1】 Haslinger, B.; et al.; J Chem Listy 1957, 51, 5, 1906. |
| 【2】 Greenspan, S.; et al.; J Collect Czech Chem Commun 1958, 23, 10, 1319. |
| 【3】 Bielavsky, J.; Analogues of 9-amino-1,2,3,4-tetrahydroacridine. Coll Czech Chem Commun 1977, 42, 2802-7. |
| 【4】 Castaner, R.M.; Serradell, M.N.; Castaner, J.; Tacrine. Drugs Fut 1987, 12, 11, 1032. |
合成路线3
该中间体在本合成路线中的序号：(I)This compound can be prepared by two related ways: 1) The condensation of isatin (I) with methyl 3-phenylpropionate (II) by means of lithium diisopropylamide (LDA) in THF gives methyl alpha-benzyl-3 hydroxy-2-oxo-2,3-dihydro-1H-indole-3-acetate (III), which is reduced with LiAlH4 in THF to afford beta-benzylindole-3-ethanol (IV). The cyclization of (IV) with methyl propionylacetate (V) by means of boron trifluoride ethearate to toluene yields methyl 4-benzyl-1-ethyl 1,3,4,9 tetrahydropyrano[3,4-b]indole-1-acetate (VI), which is finally hydrolyzed with NaOH in refluxing ethanol. 2) The alkylation of methyl indole-3-acetate (VII) with benzyl chloride (VIII) by means of LDA o THF gives methyl alpha-benzylindole-3-acetate (IX), which is reduced with LiAlH4 in THF to the alcohol (IV), already obtained.
| 【1】 Gavin, G.; Katz, A.H.; Conway, K.M.; Asselin, A.A.; Demerson, C.A.; Guinoso, C.; Shah, V.; Mobilio, D.; Noureldin, R.; Humber, L.G.; Chau, T.T.; Jensen, N.P.; Schimid, J.; Shaw, C.-C.; Weichman, B.M.; Van Engen, D.; Synthesis and analgesic activity of pemedolac (cis. J Med Chem 1988, 31, 6, 1244. |
| 【2】 Katz, A.H.; Demerson, C.A.; Humber, L.G. (American Home Products Corp.); Substd. 1,3,4,9-tetrahydropyrano[3,4-b]indole-1-ac. EP 0238226; JP 1987221688; US 4670462; US 4775690 . |
| 【3】 Castaner, J.; Prous, J.; Pemedolac. Drugs Fut 1988, 13, 9, 834. |
| 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) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (II) | 23523 | methyl 3-phenylpropanoate | 103-25-3 | C10H12O2 | 详情 | 详情 |
| (III) | 23524 | methyl 2-(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-3-phenylpropanoate | C18H17NO4 | 详情 | 详情 | |
| (IV) | 23525 | 2-(1H-indol-3-yl)-3-phenyl-1-propanol | C17H17NO | 详情 | 详情 | |
| (V) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (VI) | 23527 | methyl 2-(4-benzyl-1-ethyl-1,3,4,9-tetrahydropyrano[3,4-b]indol-1-yl)acetate | C23H25NO3 | 详情 | 详情 | |
| (VII) | 23528 | 2-(1H-Indol-3-yl)acetic acid methyl ester | 1912-33-0 | C11H11NO2 | 详情 | 详情 |
| (VIII) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (IX) | 23529 | methyl 2-(1H-indol-3-yl)-3-phenylpropanoate | C18H17NO2 | 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 synthesis of [14C]-labeled tenidap sodium has been reported: The chlorination of [14C]-2,3-dihydro-1H-indole-2,3-dione (I) with sulfuryl chloride and triethylamine in hot acetonitrile gives the 5-chloro derivative (II), which is partially reduced by treatment with hydrazine hydrate in refluxing ethanol, followed by a treatment with KOH in the same refluxing solvent, to yield 5-chloro-2,3-dihydro-1H-indol-2-one (III). The reaction of (III) with chlorosulfonyl isocyanate (IV) in refluxing dichloromethane affords 5-chloro-2-oxo-2,3-dihydro-1H-indole-1-carboxamide (V), which is condensed with 2-thienylcarbonyl chloride (VI) by means of dimethylaminopyridine (DMAP) and triethylamine (TEA) in DMF, giving tenidap (VII). Finally, this compound is treated with NaHCO3 in hot acetone.
| 【1】 Hale, K.J.; Lennon, J.A.; Hobbs, C.J.; Javaid, M.H.; Manaviazar, S.; Asymmetric synthesis of the C17-C27 segment of the antineoplasticmacrolide bryostatin 1. J Label Compd Radiopharm 1995, 36, 8, 1359. |
| 【2】 Johnson, D.L.; Melvin, L.S.; Falkner, F.C.; Rusek, F.W.; Robinson, R.P.; Synthesis of C-14 isotopic isomers of tenidap - A novel antiinflammatory agent. J Label Compd Radiopharm 1996, 38, 3, 207. |
| 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) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (I) | 45196 | C8H5NO2 | 详情 | 详情 | ||
| (II) | 14099 | 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin | 17630-76-1 | C8H4ClNO2 | 详情 | 详情 |
| (II) | 45197 | C8H4ClNO2 | 详情 | 详情 | ||
| (III) | 14100 | 5-Chlorooxindole; 5-Chloro-1,3-dihydro-2H-indol-2-one | 17630-75-0 | C8H6ClNO | 详情 | 详情 |
| (III) | 45198 | C8H6ClNO | 详情 | 详情 | ||
| (IV) | 14101 | Chlorosulfonyl isocyanate | 1189-71-5 | CClNO3S | 详情 | 详情 |
| (V) | 14096 | 5-Chloro-2-oxo-1-indolinecarboxamide | C9H7ClN2O2 | 详情 | 详情 | |
| (V) | 45199 | C9H7ClN2O2 | 详情 | 详情 | ||
| (VI) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
| (VII) | 14104 | 5-Chloro-3-[(Z)-hydroxy(2-thienyl)methylidene]-2-oxo-1H-indole-1(2H)-carboxamide | C14H9ClN2O3S | 详情 | 详情 | |
| (VII) | 45200 | C14H9ClN2O3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)The condensation of methyl 2,3-diaminobenzoate (I) with isatin (II) in refluxing AcOH afforded a mixture of indoloquinoxaline-carboxylates (III) and (IV), which were separated by column chromatography. The desired 4-carboxylate isomer (III) was methylated at the indole N atom with CH3I in the presence of NaH to provide (V). The ester group of (V) was reduced to alcohol (VI) with LiAlH4 and then oxidized with activated MnO2 to yield aldehyde (VII). Subsequent condensation of (VII) with amine (VIII) in refluxing toluene in the presence of p-toluenesulfonic acid produced the corresponding imine (IX), which was finally reduced with NaBH4 in EtOH to the target amine, which was isolated as the hydrochloride salt.
| 【1】 Matsumoto, T.; Wada, H.; Migita, Y.; Hatayama, K.; Sekiguchi, Y. (Taisho Pharmaceutical Co., Ltd.); Indolo[2,3-b]quinoxaline derivs.. EP 0695754; JP 1995522993; WO 9424135 . |
| 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) | 18889 | methyl 2,3-diaminobenzoate | C8H10N2O2 | 详情 | 详情 | |
| (II) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (III) | 18891 | methyl 6H-indolo[2,3-b]quinoxaline-4-carboxylate | C16H11N3O2 | 详情 | 详情 | |
| (IV) | 18892 | methyl 6H-indolo[2,3-b]quinoxaline-1-carboxylate | C16H11N3O2 | 详情 | 详情 | |
| (V) | 18893 | methyl 6-methyl-6H-indolo[2,3-b]quinoxaline-4-carboxylate | C17H13N3O2 | 详情 | 详情 | |
| (VI) | 18894 | (6-methyl-6H-indolo[2,3-b]quinoxalin-4-yl)methanol | C16H13N3O | 详情 | 详情 | |
| (VII) | 18895 | 6-methyl-6H-indolo[2,3-b]quinoxaline-4-carbaldehyde | C16H11N3O | 详情 | 详情 | |
| (VIII) | 11770 | 2-Amino-2-methyl-1,3-propanediol | 115-69-5 | C4H11NO2 | 详情 | 详情 |
| (IX) | 18897 | 2-methyl-2-[[(Z)-(6-methyl-6H-indolo[2,3-b]quinoxalin-4-yl)methylidene]amino]-1,3-propanediol | C20H20N4O2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Condensation of isatin (I) with 2-methoxyacetophenone (II) in the presence of KOH afforded quinolinecarboxylic acid (III). Subsequent demethylation of the ether function of (III) with refluxing 57% HI gave (IV), which was then condensed with (S)-1-phenylpropyl amine (V) using DCC and HOBt to yield the title amide.
| 【1】 Giardina, G.A.M.; et al.; Discovery of a novel class of selective non-peptid. J Med Chem 1999, 42, 6, 1053. |
| 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) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (II) | 23641 | 2-methoxy-1-phenyl-1-ethanone | 4079-52-1 | C9H10O2 | 详情 | 详情 |
| (III) | 23642 | 3-methoxy-2-phenyl-4-quinolinecarboxylic acid | C17H13NO3 | 详情 | 详情 | |
| (IV) | 23643 | 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid | 485-89-2 | C16H11NO3 | 详情 | 详情 |
| (V) | 23644 | (1S)-1-phenylpropylamine; (1S)-1-phenyl-1-propanamine | 3789-59-1 | C9H13N | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The quinolinecarboxylic acid (III) was obtained by the Pfitzinger reaction of isatin (I) with 2-methoxyacetophenone (II) in ethanolic KOH at 80 C. Subsequent methyl ether cleavage in (III) using concentrated HI provided 3-hydroxy-2-phenylquinoline-4-carboxylic acid (IV). Coupling of acid (IV) with (S)-1-phenylpropylamine (V) by means of DCC and HOBt gave amide (VI). Ester (VIII) was then obtained by alkylation of the 3-hydroxy quinoline (VI) with ethyl bromoacetate (VII) in the presence of K2CO3 and KI. Finally, hydrolysis of the ethyl ester (VIII) with refluxing HCl afforded the corresponding carboxylic acid.
| 【1】 Giardina, G.A.M.; et al.; Discovery of a novel class of selective non-peptid. J Med Chem 1999, 42, 6, 1053. |
| 【2】 Giardina, G.A.M.; Grugni, M.; Raveglia, L.F.; Farino, C. (GlaxoSmithKline plc); Quinoline derivs.. EP 0876347; JP 2000501104; US 6277862; WO 9721680 . |
| 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) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (II) | 23641 | 2-methoxy-1-phenyl-1-ethanone | 4079-52-1 | C9H10O2 | 详情 | 详情 |
| (III) | 23642 | 3-methoxy-2-phenyl-4-quinolinecarboxylic acid | C17H13NO3 | 详情 | 详情 | |
| (IV) | 23643 | 3-hydroxy-2-phenyl-4-quinolinecarboxylic acid | 485-89-2 | C16H11NO3 | 详情 | 详情 |
| (V) | 23644 | (1S)-1-phenylpropylamine; (1S)-1-phenyl-1-propanamine | 3789-59-1 | C9H13N | 详情 | 详情 |
| (VI) | 58526 | 3-hydroxy-2-phenyl-N-[(1S)-1-phenylpropyl]-4-quinolinecarboxamide | C25H22N2O2 | 详情 | 详情 | |
| (VII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VIII) | 58527 | ethyl 2-{[2-phenyl-4-({[(1S)-1-phenylpropyl]amino}carbonyl)-3-quinolinyl]oxy}acetate | C29H28N2O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Triazinoindole thione (III) was obtained by condensation of isatin (I) with thiosemicarbazide (II). Subsequent S-alkylation of (III) with dipropylaminoethyl chloride (IV) furnished the title thioether derivative.
| 【1】 Pevear, D.C.; Nitz, T.J.; Seipel, M. (ViroPharma, Inc.); Methods for preventing and treating pestivirus infection and associated diseases. WO 9836752 . |
| 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) | 14098 | 2,3-Indolinedione; 1H-Indole-2,3-dione; Isatin | 91-56-5 | C8H5NO2 | 详情 | 详情 |
| (II) | 12954 | 1-Hydrazinecarbothioamide; Thiosemicarbazide | 79-19-6 | CH5N3S | 详情 | 详情 |
| (III) | 43357 | 2,5-dihydro-3H-[1,2,4]triazino[5,6-b]indole-3-thione | C9H6N4S | 详情 | 详情 | |
| (IV) | 20351 | N-(2-chloroethyl)-N-propyl-1-propanamine; N-(2-chloroethyl)-N,N-dipropylamine | C8H18ClN | 详情 | 详情 |