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【结 构 式】

【分子编号】67556

【品名】(R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoate

【CA登记号】 

【 分 子 式 】C17H20ClFN2O4

【 分 子 量 】370.808

【元素组成】C 55.06% H 5.44% Cl 9.56% F 5.12% N 7.55% O 17.26%

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:(VII)

Condensation of 6-chloro-5-fluoroindole (I) with L-serine and Ac2O in AcOH at 80 °C yields 2-acetamido-3-(6-chloro-5-fluoroindol-3-yl)propanoic acid (III), which by kinetic resolution using L-aminoacylase provides the desired (R)-enantiomer (IV). Hydrolysis of N-acetylated compound (IV) by means of HCl yields the free amino acid (V), which is then esterified with MeOH in the presence of SOCl2 at 0 °C to afford the corresponding methyl ester (VI). N-Protection of the amine group of compound (VI) with Boc2O by means of NaHCO3 in THF/H2O generates carbamate (VII), which by ester reduction with LiAlH4 in refluxing Et2O at 0 °C produces the primary alcohol (VIII). Activation of alcohol (VIII) as its mesylate (IX) using MsCl in the presence of Et3N in CH2Cl2 at 0 °C, followed by reduction with LiAlH4 in Et2O gives tert-butyl 2-(6-chloro-5-fluoroindol-3-yl)-1(S)-methylethylcarbamate (X). Hydrolysis of carbamate (X) with HCl in MeOH yields the corresponding amine (XI), which is finally submitted to Pictet-Spengler cyclization with 5-chloroisatin (XII) in the presence of p-TsOH in EtOH at 110 °C .

1 Ang, S.H., Krastel, P., Leong, S.Y., Tan, L.J., Wong, W.L.J., Yeung, B.K.S., Zou, B. (Novartis AG). Spiro-indole derivatives for the treatment of parasitic diseases. CN 102015711; EP 2722333; KR 2010135320; EP 2285808;JP 2011518852; US 8399453; US 2011275613; WO 2009132921; US 2009275560; US 8053442.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 67560 (R)-1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine   C11H12ClFN2 详情 详情
(I) 30025 6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole 122509-72-2 C8H5ClFN 详情 详情
(II) 67551 (R)-2-amino-3-hydroxypropanoic acid C3H7NO3 详情 详情
(III) 67552 2-acetamido-3-(6-chloro-5-fluoroindol-3-yl)propanoic acid   C13H12ClFN2O3 详情 详情
(IV) 67553 (R)-2-acetamido-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoic acid   C13H12ClFN2O3 详情 详情
(V) 67554 (R)-2-amino-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoic acid   C11H10ClFN2O2 详情 详情
(VI) 67555 (R)-methyl 2-amino-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoate   C12H12ClFN2O2 详情 详情
(VII) 67556 (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(6-chloro-5-fluoro-1H-indol-3-yl)propanoate   C17H20ClFN2O4 详情 详情
(VIII) 67557 (R)-tert-butyl (1-(6-chloro-5-fluoro-1H-indol-3-yl)-3-hydroxypropan-2-yl)carbamate   C16H20ClFN2O3 详情 详情
(IX) 67558 (R)-2-((tert-butoxycarbonyl)amino)-3-(6-chloro-5-fluoro-1H-indol-3-yl)propyl methanesulfonate   C17H22ClFN2O5S 详情 详情
(X) 67559 (R)-tert-butyl (1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-yl)carbamate   C16H20ClFN2O2 详情 详情
(XII) 14099 5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin 17630-76-1 C8H4ClNO2 详情 详情
Extended Information