5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one -Drug Synthesis Database

【结构式】

【分子编号】67564

【品名】5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one

【CA登记号】　

【分子式】C₁₉H₁₄Cl₂FN₃O

【分子量】390.244

【元素组成】C 58.48% H 3.62% Cl 18.17% F 4.87% N 10.77% O 4.10%

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：(XVIII)

Vilsmeier-Haack formylation of 6-chloro-5-fluoroindole (I) with dimethylformamide (XIII) by means of POCl3 gives 6-chloro-5-fluoroindole-3-carbaldehyde (XIV), which by Henry reaction with nitroethane (XV) in the presence of NH4OAc yields 6-chloro-5-fluoro-3-(2-nitroprop-1-enyl)indole (XVI). Reduction of the unsaturated nitro compound (XVI) by means of LiAlH4 in refluxing THF provides the trypt amine derivative (XVII), which is then subjected to Pictet-Spengler cyclization with 5-chloroisatin (XII) by means of p-TsOH in EtOH at 110 °C to afford spiro racemate (XVIII). Finally, chiral chromatography of racemate (XVIII) affords the desired (1R,3S)-enantiomer .

参考文献中间体

合成目标

【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.
【2】 Yeung, B.K., Zou, B., Rottmann, M. et al. Spirotetrahydro beta-carbolines (spiroindolones): a new class of potent and orally efficacious compounds for the treatment of malaria. J Med Chem 2010, 53(14): 5155-64.

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)	30025	6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole	122509-72-2	C₈H₅ClFN	详情	详情
(XII)	14099	5-Chloro-1H-indole-2,3-dione; 5-Chloroisatin	17630-76-1	C₈H₄ClNO₂	详情	详情
(XIII)	33491	Dimethylformamide	68-12-2	C₃H₇NO	详情	详情
(XIV)	67561	6-chloro-5-fluoroindole-3-carbaldehyde		C₉H₅ClFNO	详情	详情
(XV)	12117	Nitroethane; 1-Nitroethane	79-24-3	C₂H₅NO₂	详情	详情
(XVI)	67562	(Z)-6-chloro-5-fluoro-3-(2-nitroprop-1-en-1-yl)-1H-indole		C₁₁H₈ClFN₂O₂	详情	详情
(XVII)	67563	1-(6-chloro-5-fluoro-1H-indol-3-yl)propan-2-amine		C₁₁H₁₂ClFN₂	详情	详情
(XVIII)	67564	5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyrido[3,4-b]indol]-2-one		C₁₉H₁₄Cl₂FN₃O	详情	详情

Extended Information