|
【结 构 式】 
|
【分子编号】39297 【品名】1-Methylindole-3-acetic acid; 2-(1-Methyl-1H-indol-3-yl)acetic acid 【CA登记号】1912-48-7 |
【 分 子 式 】C11H11NO2 【 分 子 量 】189.21388 【元素组成】C 69.83% H 5.86% N 7.4% O 16.91% |
合成路线1
该中间体在本合成路线中的序号：(IV)6-Nitroindole (I) was methylated using iodomethane and NaH and the resulting 1-methyl-6-nitroindole (II) was acylated with oxalyl chloride in dichloromethane to furnish the glyoxylyl chloride (III). Subsequent condensation of (III) with 1-methylindole-3-acetic acid (IV) in the presence of Et3N gave the bisindolylmaleic anhydride (V). This was finally converted into the target maleimide by heating with ammonia in aqueous DMF in a sealed vessel at 140 C.
| 【1】 Hill, C.H.; Wilkinson, S.E.; Hurst, S.A.; Lawton, G.; Keech, E.; Davis, P.D.; Nixon, J.S.; Turner, S.E.; Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. J Med Chem 1992, 35, 1, 177. |
| 【2】 Davis, P.D.; Hill, C.H.; Lawton, G. (F. Hoffmann-La Roche AG); Substd. pyrroles. AU 8929658; EP 0328026; JP 1989233281; US 5057614 . |
| 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) | 29841 | Oxalyl chloride; 2-Chloro-2-oxoacetyl chloride | 79-37-8 | C2Cl2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |