【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% |
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 |