6-(trifluoromethyl)-1H-indole-2,3-dione -Drug Synthesis Database

【结构式】

【分子编号】39337

【品名】6-(trifluoromethyl)-1H-indole-2,3-dione

【CA登记号】

【分子式】C₉H₄F₃NO₂

【分子量】215.1315096

【元素组成】C 50.25% H 1.87% F 26.49% N 6.51% O 14.87%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

3-(Trifluoromethyl)aniline (I) was protected as the tert-butyl carbamate (II) by treatment with Boc2O at 80 C. Lithiation of (II) with sec-butyllithium at -78 C, followed by condensation with diethyl oxalate afforded keto ester (III). Subsequent acid hydrolysis of the Boc group of (III) with concomitant cyclization gave rise to 6-(trifluoromethyl)isatin (IV). Addition of Grignard reagent (V) to (IV) produced the 3-hydroxy-3-aryloxindole (VI). Conversion of (VI) to the corresponding 3-fluoro oxindole was then effected by treatment with diethylaminosulfur trifluoride at low temperature. Finally, optical resolution by means of chiral HPLC furnished the title (S)-enantiomer.

参考文献中间体

合成目标

【1】 Hewawasam, P.; et al.; The synthesis and characterization of BMS-204352 (MaxiPost) and related 3-fluorooxindoles as openers of maxi-K potassium channels. Bioorg Med Chem Lett 2002, 12, 7, 1023.
【2】 Starrett, J.E. Jr.; Hewawasam, P.; Ortiz, A.A.; et al.; Synthesis, pharmacokinetic analysis and MCAO stroke activity of the maxi-K opener BMS-204352. Pottasium Channels: Struct Funct Ther Util (March 11 2000, Tahoe City) 2000, Abst 315.
【3】 Martín, L.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; BMS-204352. Drugs Fut 2001, 26, 1, 9.
【4】 Hewawasam, P.; Meanwell, N.A.; Gribkoff, V.K. (Bristol-Myers Squibb Co.); 3-Substd. oxindole derivs. as potassium channel modulators. CA 2176183; EP 0747354; JP 1996333336; US 5565483; US 5602169 .

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)	26347	3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride	98-16-8	C₇H₆F₃N	详情	详情
(II)	39335	tert-butyl 3-(trifluoromethyl)phenylcarbamate		C₁₂H₁₄F₃NO₂	详情	详情
(III)	39336	ethyl 2-[2-[(tert-butoxycarbonyl)amino]-4-(trifluoromethyl)phenyl]-2-oxoacetate		C₁₆H₁₈F₃NO₅	详情	详情
(IV)	39337	6-(trifluoromethyl)-1H-indole-2,3-dione		C₉H₄F₃NO₂	详情	详情
(V)	39338	bromo(5-chloro-2-methoxyphenyl)magnesium		C₇H₆BrClMgO	详情	详情
(VI)	39339	3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one		C₁₆H₁₁ClF₃NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The reaction of 3-(trifluoromethyl)aniline (I) with Boc2O gives the carbamate (II), which is condensed with 14C labeled diethyl oxalate (III) by means of BuLi to yield the ketoester (IV). The cyclization of (IV) by means of refluxing aq. HCl affords the labeled 6-(trifluoromethyl)isatin (V), which is condensed with 5-chloro-2-methoxyphenylmagnesium bromide (VI) to provide the hydroxyketone (VII). The fluorination of (VII) with DAST gives the target compound as a racemic mixture (VIII), which is finally submitted to optical resolution by chiral HPLC.

参考文献中间体

合成目标

【1】 Dischino, D.D.; Gribkoff, V.K.; Hewawasam, P.; Luke, G.M.; Rinehart, J.K.; Spears, T.L.; Starrett, J.E. Jr.; Synthesis of 3H and 14C labeled (S)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one, MaxiPost(TM). An agent for post-stroke neuroprotection. J Label Compd Radiopharm 2003, 46, 2, 139.

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)	26347	3-(trifluoromethyl)phenylamine; 3-(trifluoromethyl)aniline; 3-aminobenzotrifluoride	98-16-8	C₇H₆F₃N	详情	详情
(II)	39335	tert-butyl 3-(trifluoromethyl)phenylcarbamate		C₁₂H₁₄F₃NO₂	详情	详情
(III)	17571	Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate	95-92-1	C₆H₁₀O₄	详情	详情
(III)	64193	allyl (2R,3S,4R,5R)-2-[({(2R,3R,4R,5S,6R)-5-{[bis(allyloxy)phosphoryl]oxy}-4-{[(3R)-3-methoxydecyl]oxy}-6-(methoxymethyl)-3-[(Z)-11-octadecenoylamino]tetrahydro-2H-pyran-2-yl}oxy)methyl]-6-{[tert-butyl(dimethyl)silyl]oxy}-4-(decyloxy)-5-[(3-oxotetradecanoyl)amino]tetrahydro-2H-pyran-3-yl carbonate		C₈₂H₁₅₁N₂O₁₈PSi	详情	详情
(IV)	39336	ethyl 2-[2-[(tert-butoxycarbonyl)amino]-4-(trifluoromethyl)phenyl]-2-oxoacetate		C₁₆H₁₈F₃NO₅	详情	详情
(IV)	64197	ethyl 2-[2-[(tert-butoxycarbonyl)amino]-4-(trifluoromethyl)phenyl]-2-oxoacetate		C₁₆H₁₈F₃NO₅	详情	详情
(V)	39337	6-(trifluoromethyl)-1H-indole-2,3-dione		C₉H₄F₃NO₂	详情	详情
(V)	64198	6-(trifluoromethyl)-1H-indole-2,3-dione		C₉H₄F₃NO₂	详情	详情
(VI)	39338	bromo(5-chloro-2-methoxyphenyl)magnesium		C₇H₆BrClMgO	详情	详情
(VII)	39339	3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one		C₁₆H₁₁ClF₃NO₃	详情	详情
(VII)	64199	3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one		C₁₆H₁₁ClF₃NO₃	详情	详情
(VIII)	43889	3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one		C₁₆H₁₀ClF₄NO₂	详情	详情
(VIII)	64200	3-(5-Chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-2,3-dihydro-1H-indol-2-one		C₁₆H₁₀ClF₄NO₂	详情	详情

Extended Information