Flindokalner, BMS-204352, MaxiPost

合成路线:A chiral process for the synthesis of the title compound was later reported.Chlorination of 2-methoxyphenylacetic acid (VII) with sulfuryl chloride gave (VIII),which was further converted to the corresponding methyl ester (IX) by treatment with dimethyl sulfate and K2CO3.Conversion of (IX) to the lithium enolate with lithium hexamethyldisilazide,followed by condensation with aryl fluoride (X) yielded the diarylacetic ester (XI).This was reacted with N-fluoro-bis(phenylsulfonyl)amine to provide fluoro ester (XII).Basic hydrolysis afforded the racemic carboxylic acid (XIII),which was resolved via conversion to the diastereoisomeric salts with (S)-alpha-methylbenzylamine.Reduction of the nitro group from the desired (S)-enantiomer (XIV),and subsequent acidic treatment then produced the title oxindole derivative.

参考文献标题:Preparation of 3-fluoro oxindole derivs.
文献作者:Thottathil,J.K.; Pendri,Y.R.; Martinez,E.J.; Hewawasam,P.(Bristol-Myers Squibb Co.)
参考来源:WO 9816222


合成路线: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.

参考文献标题:Synthesis,pharmacokinetic analysis and MCAO stroke activity of the maxi-K opener BMS-204352
文献作者:Starrett,J.E.Jr.; Hewawasam,P.; Ortiz,A.A.; et al.
参考来源:Pottasium Channels: Struct Funct Ther Util (March 11 2000,Tahoe City) 2000,Abst 315


合成路线: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.

合成路线:A chiral process for the synthesis of the title compound was later reported.Chlorination of 2-methoxyphenylacetic acid (VII) with sulfuryl chloride gave (VIII),which was further converted to the corresponding methyl ester (IX) by treatment with dimethyl sulfate and K2CO3.Conversion of (IX) to the lithium enolate with lithium hexamethyldisilazide,followed by condensation with aryl fluoride (X) yielded the diarylacetic ester (XI).This was reacted with N-fluoro-bis(phenylsulfonyl)amine to provide fluoro ester (XII).Basic hydrolysis afforded the racemic carboxylic acid (XIII),which was resolved via conversion to the diastereoisomeric salts with (S)-alpha-methylbenzylamine.Reduction of the nitro group from the desired (S)-enantiomer (XIV),and subsequent acidic treatment then produced the title oxindole derivative.

参考文献标题:BMS-204352
文献作者:Mart韓,L.; Castar,R.M.; Sorbera,L.A.; Castar,J.
参考来源:Drugs Fut 2001,26(1),9


合成路线: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.

合成路线:A chiral process for the synthesis of the title compound was later reported.Chlorination of 2-methoxyphenylacetic acid (VII) with sulfuryl chloride gave (VIII),which was further converted to the corresponding methyl ester (IX) by treatment with dimethyl sulfate and K2CO3.Conversion of (IX) to the lithium enolate with lithium hexamethyldisilazide,followed by condensation with aryl fluoride (X) yielded the diarylacetic ester (XI).This was reacted with N-fluoro-bis(phenylsulfonyl)amine to provide fluoro ester (XII).Basic hydrolysis afforded the racemic carboxylic acid (XIII),which was resolved via conversion to the diastereoisomeric salts with (S)-alpha-methylbenzylamine.Reduction of the nitro group from the desired (S)-enantiomer (XIV),and subsequent acidic treatment then produced the title oxindole derivative.

参考文献标题:The synthesis and characterization of BMS-204352 (MaxiPost) and related 3-fluorooxindoles as openers of maxi-K potassium channels
文献作者:Hewawasam,P.; Gribkoff,V.K.; Pendri,Y.; Dworetzky,S.I.; Meanwell,N.A.; Martinez,E.J.; Boissard,C.G.; Post-Munson,D.J.; Trojnacki,J.T.; Yeleswaram,K.; Pajor,L.M.; Knipe,J.O.; Gao,Q.; Perrone,R.; Starrett,J.E.Jr.
参考来源:Bioorg Med Chem Lett 2002,12(7),1023


合成路线: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.

合成路线:The methylation of the phenolic OH of indanone (I) with tritium labeled methyl iodide and Cs2CO3 gives the methyl ether (II).The fluorination of the remaining OH of (II) with DAST yields the target compound as a racemic mixture,that is optically resolved by chiral HPLC.
参考文献标题: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
文献作者:Dischino,D.D.; Gribkoff,V.K.; Hewawasam,P.; Luke,G.M.; Rinehart,J.K.; Spears,T.L.; Starrett,J.E.Jr.
参考来源:J Label Compd Radiopharm 2003,46(2),139