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【结 构 式】

【分子编号】67779

【品名】isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate

【CA登记号】 

【 分 子 式 】C18H22BrNO2

【 分 子 量 】364.282

【元素组成】C 59.35% H 6.09% Br 21.93% N 3.84% O 8.78%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XV)

Condensation of indole-6-carboxylic acid (VI) with cyclopentanone (VII) in the presence of aqueous NaOH and glycerol at 100 °C or KOH in aqueous MeOH at 75 °C yields the cyclopentene derivative (VIII), which is reduced to the corresponding cyclopentane (IX) by catalytic hydrogenation over Pd/C in THF or Pd(OH)2 in MeOH . Simultaneous esterification and N-methylation of the indole-carboxylic acid (IX) with CO(OMe)2 by means of K2CO3 in NMP at 130 °C , or sequential esterification with MeI and K2CO3 in DMF, followed by Nmethylation of the resultant indolyl-carboxylate with MeI using NaH in DMF , affords methyl 3-cyclopentyl-1-methylindole-6-carboxylate (X) . Bromination of intermediate (X) with Br2, optionally in the presence of NaOAc in acetonitrile or i-PrOAc, gives the 2-bromoindole derivative (XI) , which is then condensed with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XII) in the presence of Pd(OAc)2, TFP and Et3N in DME at 68 °C to provide boronate (XIIIa) . In an alternative procedure, transesterification of the methyl ester (X) with i-PrOLi in i-PrOH at 65 °C produces the more stable isopropyl ester (XIV), which is then brominated with Br2 in acetonitrile or i-PrOAc to afford the bromoindole derivative (XV). Condensation of bromide (XV) with 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (XII) using Pd(TFP)2Cl2 or Pd(OAc)2, TFP and Et3N in acetonitrile at 82 °C yields boronate (XIIIb) . Finally, Suzuki coupling of pinacol boronates (XIIIa) or (XIIIb) with 5-bromo-2-iodopyrimidine (XVI) in the presence of K3PO4 at 76 °C, followed by ester hydrolysis of the resulting adducts (XVIIa) or (XVIIb) with NaOH in NMP, DMSO or i-PrOH , affords carboxylic acid (I) .

1 Boecher, W., Haefner, C., Kukolj, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Combination therapy for treating HCV infection. CN 103228278, EP 2621495, JP 2013540112, KR 2013116245, US 2012135949, WO 2012041771.
2 Brickl, R.-S., Chen, S., Chung, J. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Solid state forms of a potent HCV inhibitor. CN 103153987, EP 2621921, JP 2013543495, KR 2013108326, US 2012122887, US 8598183, US 2014057928, WO 2012044520.
3 Mensa, F., Nehmiz, G. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient subgenotype populations. WO 2013147749.
4 Mensa, F. (Boehringer Ingelheim Pharma GmbH & Co. KG). Oral combination therapy for treating HCV infection in specific patient sub-population. WO 2013147750.
5 LaPlante, S.R., Boes, M., Brochu, C. et al. Conformation-based restrictions and scaffold replacements in the design of hepatitis C virus polymerase inhibitors. Discovery of deleobuvir (BI 207127). J Med Chem 2014, 57(5): 1845-54.
6 Tsantrizos, Y.S., Chabot, C., Beaulieu, P. et al. (Boehringer Ingelheim Pharma GmbH & Co. KG). Viral polymerase inhibitors. CN 102911161, CN 103304541, CN 103319464, CN 103333162, EP 1718608, EP 2626354, JP 2007523094, JP 2010195818, JP 2010280740, KR 2012091276, US 2005222236, US 8030309, WO 2005080388.
7 Khodabocus, A., Lu, Z.-H., Senanayake, C.H., Wei, H., Zhang, Y. (Boehringer Ingelheim Pharma GmbH & Co. KG). Process for preparing 2,3-disubstituted indoles. CN 103524495, EP 1853589, EP 2530082, JP 2008530117, KR 2014022796, US 2006183752, US 7642352, WO 2006086657.
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中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XIIIa) 67776 methyl 3-cyclopentyl-1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate   C22H30BNO4 详情 详情
(XIIIb) 67777 isopropyl 3-cyclopentyl-1-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate   C24H34BNO4 详情 详情
(XVIIa) 67781 methyl 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate C20H20BrN3O2 详情 详情
(XVIIb) 67780 isopropyl 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate   C22H24BrN3O2 详情 详情
(I) 67763 2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxylic acid   C19H18BrN3O2 详情 详情
(VI) 67771 indole-6-carboxylic acid 1670-82-2 C9H7NO2 详情 详情
(VII) 15113 cyclopentanone 120-92-3 C5H8O 详情 详情
(VIII) 67772 3-(cyclopent-1-en-1-yl)-1H-indole-6-carboxylic acid   C14H13NO2 详情 详情
(IX) 67773 3-cyclopentyl-1H-indole-6-carboxylic acid   C14H15NO2 详情 详情
(X) 67774 methyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate   C16H19NO2 详情 详情
(XI) 67775 methyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate   C16H18BrNO2 详情 详情
(XII) 55457 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane; Pinacolborane 25015-63-8 C6H13BO2 详情 详情
(XIV) 67778 isopropyl 3-cyclopentyl-1-methyl-1H-indole-6-carboxylate   C18H23NO2 详情 详情
(XV) 67779 isopropyl 2-bromo-3-cyclopentyl-1-methyl-1H-indole-6-carboxylate   C18H22BrNO2 详情 详情
(XVI) 67782 5-bromo-2-iodopyrimidine 183438-24-6 C4H2BrIN2 详情 详情
Extended Information