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【结 构 式】 
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【分子编号】60384 【品名】5-fluoro-1,3-dihydro-2H-indol-2-one 【CA登记号】56341-41-4 |
【 分 子 式 】C8H6FNO 【 分 子 量 】151.1401832 【元素组成】C 63.58% H 4% F 12.57% N 9.27% O 10.59% |
与该中间体有关的原料药合成路线共 6 条
合成路线1
该中间体在本合成路线中的序号：(XI)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2
该中间体在本合成路线中的序号：(VII)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3
该中间体在本合成路线中的序号：(II)In a related, scale-up procedure, 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (I) is condensed to 5-fluorooxindole (II) in the presence of pyrrolidine and AcOH to furnish adduct (III). This is then condensed with N-(2-aminoethyl)pyrrolidine (IV) in the presence of BOP to produce the target amide
| 【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) | 60382 | 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 253870-02-9 | C8H9NO3 | 详情 | 详情 |
| (II) | 60384 | 5-fluoro-1,3-dihydro-2H-indol-2-one | 56341-41-4 | C8H6FNO | 详情 | 详情 |
| (III) | 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 |
| (IV) | 18161 | 2-(1-pyrrolidinyl)ethylamine; 2-(1-pyrrolidinyl)-1-ethanamine; 1-Pyrrolidineethanamine | 7154-73-6 | C6H14N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：（IX)
| 【1】 Jin QW, Mnuragis MA, May PD. 2003. Process for preparing aminocarbonylpyrrolylmethylideneindolinones from indolinones, imidazolcarbonylpyrrolecarboxaldehydes, and amines. W0 2003070725 |
| 【2】 Manley JM, Kalman MJ, Conway BG, et al. 2003. Early amidation approach to 3-[(4-anudo)pyrrol-2-yl]-2-indolinones. J Org Cbem, 68(16):6447～6450 |
| 【3】 Wang JQ, Miller KD, Sledge GW, et aL. 2005. Synthesis of [18F] SU11248, a new potential PET tracer for imaging cancer tyrosine kinase. Bioorg Med Chem lett, 15(19): 4380～4384 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （IX) | 60384 | 5-fluoro-1,3-dihydro-2H-indol-2-one | 56341-41-4 | C8H6FNO | 详情 | 详情 |
| (I) | 11367 | 4-Methylene-2-oxetanone; Acetyl ketene | 674-82-8 | C4H4O2 | 详情 | 详情 |
| (II) | 66748 | N-(2-(diethylamino)ethyl)-3-oxobutanamide | C10H20N2O2 | 详情 | 详情 | |
| (III) | 27907 | Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate | 1694-31-1 | C8H14O3 | 详情 | 详情 |
| (IV) | 63353 | 1,1-dimethylethyl 2-(hydroxyimino)-3-oxobutanoate | 14352-65-9 | C8H13NO4 | 详情 | 详情 |
| (V) | 66749 | tert-butyl 4-((2-(diethylamino)ethyl)carbamoyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate | C18H31N3O3 | 详情 | 详情 | |
| (VI) | 66750 | N-(2-(diethylamino)ethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide | C13H23N3O | 详情 | 详情 | |
| (VII) | 17643 | (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride | 3724-43-4 | C3H7Cl2N | 详情 | 详情 |
| (VIII) | 66751 | N-((4-((2-(diethylamino)ethyl)carbamoyl)-3,5-dimethyl-1H-pyrrol-2-yl)methylene)-N-methylmethanaminium chloride | C16H29ClN4O | 详情 | 详情 | |
| (X) | 66752 | (Z)-N-[2-(Diethylamino)ethyl]-5-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide | 326914-13-0 | C22H27FN4O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(X）
| 【1】 Jin QW, Mnuragis MA, May PD. 2003. Process for preparing aminocarbonylpyrrolylmethylideneindolinones from indolinones, imidazolcarbonylpyrrolecarboxaldehydes, and amines. W0 2003070725 |
| 【2】 Manley JM, Kalman MJ, Conway BG, et al. 2003. Early amidation approach to 3-[(4-anudo)pyrrol-2-yl]-2-indolinones. J Org Cbem, 68(16):6447～6450 |
| 【3】 Sun L, Liang C, Shirazian S, et aL. 2003. Discovery of 5-[5-Fluoro-2-oxo-l,2-dihydroindol-(3Z)-ylidenemethyl}2,4一dimethyl-lH-pyrrole-3-carboxylic acid (2-diethylaminoethyl) amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem, 46(7): 1116～1119 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 63353 | 1,1-dimethylethyl 2-(hydroxyimino)-3-oxobutanoate | 14352-65-9 | C8H13NO4 | 详情 | 详情 |
| (VIII) | 14754 | ethylenediamine;1,2-Diaminoethane;ethane-1,2-diamine；1,2-Ethanediamine | 107-15-3 | C2H8N2 | 详情 | 详情 |
| （IX） | 66753 | (E)-N-(2-(diethylamino)ethyl)-5-(((2-(diethylamino)ethyl)imino)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide | C20H37N5O | 详情 | 详情 | |
| (X） | 60384 | 5-fluoro-1,3-dihydro-2H-indol-2-one | 56341-41-4 | C8H6FNO | 详情 | 详情 |
| (XI） | 66752 | (Z)-N-[2-(Diethylamino)ethyl]-5-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide | 326914-13-0 | C22H27FN4O2 | 详情 | 详情 |
| (I) | 27907 | Acetoacetic acid tert-butyl ester;3-Oxo-butanoic acid 1,1-dimethylethyl estertert-butyl 3-oxobutanoate | 1694-31-1 | C8H14O3 | 详情 | 详情 |
| (III) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (IV) | 63354 | 2-(1,1-dimethylethyl) 4-ethyl 3,5-dimethyl-1H-pyrrole-2,4-dicarboxylate | 86770-31-2 | C14H21NO4 | 详情 | 详情 |
| (V) | 60380 | ethyl 2,4-dimethyl-1H-pyrrole-3-carboxylate | 2199-51-1 | C9H13NO2 | 详情 | 详情 |
| (VI) | 60381 | ethyl 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylate | 2199-59-9 | C10H13NO3 | 详情 | 详情 |
| (VII) | 60382 | 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid | 253870-02-9 | C8H9NO3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)
| 【1】 Harada K, Nishino S, Hirotsu K, et aL. 2002. Process for producing 5-fluorooxyindole and for producing intermediate therefor. W0 2002006228 |
Extended Information