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【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information