6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole -Drug Synthesis Database

【结构式】

【分子编号】30025

【品名】6-Chloro-5-fluoroindole; 6-Chloro-5-fluoro-1H-indole

【CA登记号】122509-72-2

【分子式】C₈H₅ClFN

【分子量】169.5855432

【元素组成】C 56.66% H 2.97% Cl 20.91% F 11.2% N 8.26%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

Condensation of 6-chloro-5-fluoroindole (I) with (R)-2-methyloxyran (II) in the presence of NaH produced the chiral indolylpropanol (III). After conversion of (III) to the corresponding mesylate (IV) with methanesulfonyl chloride and triethylamine, displacement by NaN3 with inversion of the configuration afforded the (S)-azide (V). Subsequent hydrogenation of (V) using PtO2 yielded the title amine, which was isolated as the fumarate salt.

参考文献中间体

合成目标

【1】 Bos, M. (F. Hoffmann-La Roche AG); 1-Aminoethylindoles. CA 2132883; EP 0655440; US 5494928 .

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
(II)	16662	(2R)-2-Methyloxirane; (R)-(+)-Propylene oxide	15448-47-2	C₃H₆O	详情	详情
(III)	30026	(2R)-1-(6-chloro-5-fluoro-1H-indol-1-yl)-2-propanol		C₁₁H₁₁ClFNO	详情	详情
(IV)	30027	(1R)-2-(6-chloro-5-fluoro-1H-indol-1-yl)-1-methylethyl methanesulfonate		C₁₂H₁₃ClFNO₃S	详情	详情
(V)	30028	1-[(2S)-2-azidopropyl]-6-chloro-5-fluoro-1H-indole; (1S)-2-(6-chloro-5-fluoro-1H-indol-1-yl)-1-methylethyl azide		C₁₁H₁₀ClFN₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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 .

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.

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

合成路线3

该中间体在本合成路线中的序号：(I)

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