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【结 构 式】 
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【分子编号】44291 【品名】3-Indolylacetonitrile;3-Cyanomethyl-1H-indole;3-(Cyanomethyl)indole;Indole-3-acetonitrile;3-Indoleacetonitrile;2-(3-indolyl)acetonitrile;2-(1H-indol-3-yl)acetonitrile;2-(1H-Indol-3-yl)acetonitrile; 3-Indolylacetonitrile 【CA登记号】771-51-7 |
【 分 子 式 】C10H8N2 【 分 子 量 】156.187 【元素组成】C 76.9% H 5.16% N 17.94% |
合成路线1
该中间体在本合成路线中的序号：(VI)Alkylation of 3-indolylacetonitrile (VI) with ethyl bromoacetate provided indoleacetate ester (VII). Condensation of the cyano group of (VII) with amino thiophenol (V) in hot EtOH furnished benzothiophene (VI). The ethyl ester group of (VI) was finally hydrolyzed with NaOH to the title carboxylic acid.
| 【2】 Jones, J.H.; Jones, M.L.; Gunn, D.; Van Zandt, M.C. (The Institutes for Pharmaceutical Discovery, Inc.); Substd. indolealkanoic acids. WO 9950268 . |
| 【3】 Jacot, J.; Sredy, J. (The Institutes for Pharmaceutical Discovery, Inc.); Methods of reducing serum glucose and triglyceride levels and for inhibiting angiogenesis using substd. indolealkanoic acids. WO 0032180 . |
| 【4】 Van Zandt, M.; Sredy, J. (The Institutes for Pharmaceutical Discovery, Inc.); Compsns. containing a substd. indolealkanoic acid and an angiotensin converting enzyme inhibitor. WO 0164205 . |
| 【5】 Boyd, M.; Robinson, D. (The Institutes for Pharmaceutical Discovery, Inc.); Methods for lowering uric acid levels. WO 0151489 . |
| 【1】 Jones, J.H.; Gunn, D.; Jones, M.L.; Van Zandt, M.C.; Lavoie, D.J.; Sawicki, D.; Sredy, J.; Howard, E.; Podjarny, A.D.; Substituted indolealkanoic acids as novel aldose reductase inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 307. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 44290 | 2-amino-3,4,6-trifluorobenzenethiol; 2-amino-3,4,6-trifluorophenylhydrosulfide | C6H4F3NS | 详情 | 详情 | |
| (VI) | 44291 | 3-Indolylacetonitrile;3-Cyanomethyl-1H-indole;3-(Cyanomethyl)indole;Indole-3-acetonitrile;3-Indoleacetonitrile;2-(3-indolyl)acetonitrile;2-(1H-indol-3-yl)acetonitrile;2-(1H-Indol-3-yl)acetonitrile; 3-Indolylacetonitrile | 771-51-7 | C10H8N2 | 详情 | 详情 |
| (VII) | 44292 | ethyl 2-[3-(2-nitriloethyl)-1H-indol-1-yl]acetate | C14H14N2O2 | 详情 | 详情 | |
| (VIII) | 44293 | ethyl 2-[3-[(4,5,7-trifluoro-1,3-benzothiazol-2-yl)methyl]-1H-indol-1-yl]acetate | C20H15F3N2O2S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Methylation of 6-nitroindole (I) using either iodomethane and NaH or dimethyl carbonate and Na2CO3 provides 1-methyl-6-nitroindole (II), which is subsequently acylated with oxalyl chloride in CH2Cl2 to furnish the glyoxylyl chloride (III). Condensation of chloride (III) with 1-methylindole-3-acetic acid (IV) in the presence of Et3N gives the bis(indolyl)maleic anhydride (V), which is then converted to the target maleimide derivative by heating with ammonia in aqueous DMF in a sealed vessel at 140 °C .
In a related procedure, quaternization of 3-(dimethylaminomethyl)-indole (VI) with butyl bromide, followed by amine displacement with NaCN yields 2-(3-indolyl)acetonitrile (VII), which is alkylated using dimethyl carbonate and K2CO3 in hot DMF to give the 1-methylindole derivative (VIII). Treatment of compound (VIII) with isopropanol and HCl (generated from acetyl chloride and i-PrOH) affords imidate (IX), which is finally condensed with the indoleglyoxylyl chloride (III) in the presence of DIEA, followed by treatment with H2SO4 .
| 【1】 Davis, P.D., Hill, C.H., Lawton, G. (F. Hoffmann-La Roche AG). Substituted pyrroles. AU 8929658, EP 0328026, JP 1989233281, US 5057614. |
| 【2】 Davis, P.D., Hill, C.H., Lawton, G. et al. Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem 1992, 35(1): 177-84. |
| 【3】 Jiang, X. (F. Hoffmann La Roche AG). Methylation of indole compounds using dimethyl carbonate. CA 2405937, EP 1276721, JP 2003531192, JP 2007254487, US 6326501, WO 2001081305. |
| 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) | 39294 | 6-Nitroindole; 6-Nnitro-1H-indole | 4769-96-4 | C8H6N2O2 | 详情 | 详情 |
| (II) | 39295 | 1-methyl-6-nitro-1H-indole | C9H8N2O2 | 详情 | 详情 | |
| (III) | 39296 | 2-(1-methyl-6-nitro-1H-indol-3-yl)-2-oxoacetyl chloride | C11H7ClN2O4 | 详情 | 详情 | |
| (IV) | 39297 | 1-Methylindole-3-acetic acid; 2-(1-Methyl-1H-indol-3-yl)acetic acid | 1912-48-7 | C11H11NO2 | 详情 | 详情 |
| (V) | 39298 | 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-furandione | C22H15N3O5 | 详情 | 详情 | |
| (VI) | 37568 | N,N-Dimethyl-1H-indole-3-methanamine;Gramine;N-(1H-indol-3-ylmethyl)-N,N-dimethylamine; 3-(dimethylaminomethyl)-indole[;]1H-indol-3-yl-N,N-dimethylmethanamine | 87-52-5 | C11H14N2 | 详情 | 详情 |
| (VII) | 44291 | 3-Indolylacetonitrile;3-Cyanomethyl-1H-indole;3-(Cyanomethyl)indole;Indole-3-acetonitrile;3-Indoleacetonitrile;2-(3-indolyl)acetonitrile;2-(1H-indol-3-yl)acetonitrile;2-(1H-Indol-3-yl)acetonitrile; 3-Indolylacetonitrile | 771-51-7 | C10H8N2 | 详情 | 详情 |
| (VIII) | 69305 | 1-Methylindole-3-acetonitrile;1-Methylindole-3-acetonitrile;N-Methylindole-3-acetonitrile;3-(Cyanomethyl)-1-methylindole;2-(1-methyl-1H-indol-3-yl)acetonitrile | 51584-17-9 | C11H10N2 | 详情 | 详情 |
| (IX) | 69306 | isopropyl 2-(1-methyl-1H-indol-3-yl)acetimidate hydrochloride | C14H18N2O.HCl | 详情 | 详情 |