|
【结 构 式】 
|
【分子编号】47562 【品名】tert-butyl (1R)-2-(7-cyano-2,3-dihydro-1H-indol-5-yl)-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate 【CA登记号】 |
【 分 子 式 】C27H32F3N3O4 【 分 子 量 】519.5641096 【元素组成】C 62.42% H 6.21% F 10.97% N 8.09% O 12.32% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The optical resolution of amine (X), performed by treatment with (+)-mandelic acid in ethanol, followed by crystallization of the resulting salt and then treatment with Na2CO3 affords the desired (R)-enantiomer (XI). Compound (XI) is protected with Boc2O to give the corresponding carbamate (XII), which is deacetylated with NaOH in ethanol to yield the intermediate (XIII). Hydrolysis of the cyano group of (XIII) with NaOH and H2O2 in DMSO furnishes the corresponding carboxamide (XIV), which is condensed with 3-(tert-butyldimethylsilyloxy)propyl 4-nitrobenzenesulfonate (XV) by means of K2CO3 and a crown ether in dioxane to provide the indoline adduct (XVI). Finally, desilylation of (XVI) with TBAF in THF yields the 3-hydroxypropyl derivative (XVII), which by removal of the Boc-protecting group by means of TFA in dichloromethane gives KMD-3213.
| 【1】 Sorbera, L.A.; Castaner, J.; Silvestre, J.S.; KMD-3213. Drugs Fut 2001, 26, 6, 553. |
| 【2】 Kitazawa, M.; Ban, M.; Okazaki, K.; Ozawa, M.; Yazaki, T.; Yamagishi, R. (Kissei Pharmaceutical Co., Ltd.); Indoline cpds. for the treatment of dysuria. EP 0600675; JP 1994220015; US 5387603 . |
| 【3】 Kitazawa, M.; Ozawa, M.; Okazaki, K.; Yamagishi, R.; Yazaki, T.; Saka, M. (Kissei Pharmaceutical Co., Ltd.); Indole derivs.. JP 1995330726 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 47557 | 1-acetyl-5-[2-([2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino)propyl]-7-indolinecarbonitrile | C24H26F3N3O3 | 详情 | 详情 | |
| (XI) | 47560 | 1-acetyl-5-[(2R)-2-([2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino)propyl]-7-indolinecarbonitrile | C24H26F3N3O3 | 详情 | 详情 | |
| (XII) | 47561 | tert-butyl (1R)-2-(1-acetyl-7-cyano-2,3-dihydro-1H-indol-5-yl)-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C29H34F3N3O5 | 详情 | 详情 | |
| (XIII) | 47562 | tert-butyl (1R)-2-(7-cyano-2,3-dihydro-1H-indol-5-yl)-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C27H32F3N3O4 | 详情 | 详情 | |
| (XIV) | 47563 | tert-butyl (1R)-2-[7-(aminocarbonyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C27H34F3N3O5 | 详情 | 详情 | |
| (XV) | 47564 | 3-[[tert-butyl(dimethyl)silyl]oxy]propyl 4-nitrobenzenesulfonate | C15H25NO6SSi | 详情 | 详情 | |
| (XVI) | 47565 | tert-butyl (1R)-2-[7-(aminocarbonyl)-1-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C36H54F3N3O6Si | 详情 | 详情 | |
| (XVII) | 47566 | tert-butyl (1R)-2-[7-(aminocarbonyl)-1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C30H40F3N3O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)
| 【1】 LIU JF.2008.Alpha 1A-adrenoceptor antagonists. WO 2008/106125 A2. |
| 【2】 Kitazawa M, Ban M. Okazaki K, et al.1995.1,5,7-Trisubstituted indoline compounds and salts thereof. US 5387603. |
| 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) | 47548 | 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-1-propanone | C13H15NO2 | 详情 | 详情 | |
| (II) | 47549 | 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-bromo-1-propanone | C13H14BrNO2 | 详情 | 详情 | |
| (III) | 47550 | 1-[5-(2-bromopropyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C13H16BrNO | 详情 | 详情 | |
| (IV) | 47551 | 1-[5-(2-bromopropyl)-7-nitro-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C13H15BrN2O3 | 详情 | 详情 | |
| (V) | 47552 | 1-[7-amino-5-(2-bromopropyl)-2,3-dihydro-1H-indol-1-yl]-1-ethanone | C13H17BrN2O | 详情 | 详情 | |
| (VI) | 47553 | 1-acetyl-5-(2-bromopropyl)-7-indolinecarbonitrile | C14H15BrN2O | 详情 | 详情 | |
| (VII) | 47554 | 1-acetyl-5-(2-azidopropyl)-7-indolinecarbonitrile | C14H15N5O | 详情 | 详情 | |
| (VIII) | 47555 | 1-acetyl-5-(2-aminopropyl)-7-indolinecarbonitrile | C14H17N3O | 详情 | 详情 | |
| (IX) | 47557 | 1-acetyl-5-[2-([2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino)propyl]-7-indolinecarbonitrile | C24H26F3N3O3 | 详情 | 详情 | |
| (X) | 47560 | 1-acetyl-5-[(2R)-2-([2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino)propyl]-7-indolinecarbonitrile | C24H26F3N3O3 | 详情 | 详情 | |
| (XI) | 47561 | tert-butyl (1R)-2-(1-acetyl-7-cyano-2,3-dihydro-1H-indol-5-yl)-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C29H34F3N3O5 | 详情 | 详情 | |
| (XII) | 47562 | tert-butyl (1R)-2-(7-cyano-2,3-dihydro-1H-indol-5-yl)-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C27H32F3N3O4 | 详情 | 详情 | |
| (XIII) | 47563 | tert-butyl (1R)-2-[7-(aminocarbonyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C27H34F3N3O5 | 详情 | 详情 | |
| (XIV) | 47565 | tert-butyl (1R)-2-[7-(aminocarbonyl)-1-(3-[[tert-butyl(dimethyl)silyl]oxy]propyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C36H54F3N3O6Si | 详情 | 详情 | |
| (XV) | 47566 | tert-butyl (1R)-2-[7-(aminocarbonyl)-1-(3-hydroxypropyl)-2,3-dihydro-1H-indol-5-yl]-1-methylethyl[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]carbamate | C30H40F3N3O6 | 详情 | 详情 |