Flindokalner, BMS-204352, MaxiPost, -Drug Synthesis Database

【结构式】

【药物名称】Flindokalner, BMS-204352, MaxiPost

【化学名称】(+)-3(S)-(5-Chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-2,3-dihydro-1H-indol-2-one

【CA登记号】187523-35-9, 187523-36-0 ((R)-isomer), 183720-28-7 (racemate)

【分子式】C₁₆H₁₀ClF₄NO₂

【分子量】359.7102

【开发单位】Bristol-Myers Squibb (Originator)

【药理作用】Cerebrovascular Diseases, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Large Conductance BK(Ca) Channel Activators, Voltage-Gated KCNQ Channel Activators

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

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

【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

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.

参考文献中间体

【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】 Martín, L.; Castañer, R.M.; Sorbera, L.A.; Castañer, J.; BMS-204352. Drugs Fut 2001, 26, 1, 9.
【3】 Thottathil, J.K.; Pendri, Y.R.; Martinez, E.J.; Hewawasam, P. (Bristol-Myers Squibb Co.); Preparation of 3-fluoro oxindole derivs.. WO 9816222 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	19706	2-(2-methoxyphenyl)acetic acid	93-25-4	C₉H₁₀O₃	详情	详情
(VIII)	39340	2-(5-chloro-2-methoxyphenyl)acetic acid		C₉H₉ClO₃	详情	详情
(IX)	39341	methyl 2-(5-chloro-2-methoxyphenyl)acetate		C₁₀H₁₁ClO₃	详情	详情
(X)	39342	1-fluoro-2-nitro-4-(trifluoromethyl)benzene	367-86-2	C₇H₃F₄NO₂	详情	详情
(XI)	39343	methyl 2-(5-chloro-2-methoxyphenyl)-2-[2-nitro-4-(trifluoromethyl)phenyl]acetate		C₁₇H₁₃ClF₃NO₅	详情	详情
(XII)	39344	methyl 2-(5-chloro-2-methoxyphenyl)-2-fluoro-2-[2-nitro-4-(trifluoromethyl)phenyl]acetate		C₁₇H₁₂ClF₄NO₅	详情	详情
(XIII)	39345	2-(5-chloro-2-methoxyphenyl)-2-fluoro-2-[2-nitro-4-(trifluoromethyl)phenyl]acetic acid		C₁₆H₁₀ClF₄NO₅	详情	详情
(XIV)	39346	(2S)-2-(5-chloro-2-methoxyphenyl)-2-fluoro-2-[2-nitro-4-(trifluoromethyl)phenyl]ethanoic acid		C₁₆H₁₀ClF₄NO₅	详情	详情

合成路线3

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

【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

合成路线4

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.

参考文献中间体

【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	分子式	供应商	用于合成
(I)	64259	3-(5-chloro-2-hydroxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one	C₁₅H₉ClF₃NO₃	详情	详情
(II)	39339	3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one	C₁₆H₁₁ClF₃NO₃	详情	详情
(II)	64260	3-(5-chloro-2-methoxyphenyl)-3-hydroxy-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one	C₁₆H₁₁ClF₃NO₃	详情	详情
(III)	43889	3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one	C₁₆H₁₀ClF₄NO₂	详情	详情
(III)	64261	3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one	C₁₆H₁₀ClF₄NO₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)