Ranirestat, SX-3202((+)-(S)-isomer), SX-3030(racemate), AS-3201, SX-3201
雷尼司他Chemical Name: (-)-(R)-2-(4-Bromo-2-fluorobenzyl)spiro[1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4,3'-pyrrolidine]-1,2',3,5'-tetraone
CAS No. 147254-64-6, 147254-65-7 ((+)-enantiomer), 147193-59-7 (racemate)
项目整合开发状态: Phase II
项目研究机构: Dainippon Pharmaceutical (Originator)
合成路线:The alkylation of ethyl 2-(benzyloxycarbonylamino)cyanoacetate (I) with ethyl bromoacetate and anhydrous potassium carbonate in acetone gives diethyl 2-(benzyloxycarbonylamino)-2-cyanosuccinate (II),which is hydrolyzed by means of hydrogen peroxide and sodium carbonate in acetone/water,yielding 3-(benzyloxycarbonylamino)-3-(ethoxycarbonyl)pyrrolidine-2,5-dione (III).Racemic (III) is then resolved by means of crystallization with cinchonidine in ethanol to give the (-)-enantiomer (IV) (>99.5% e.e.).Hydrogenolysis of (IV) over Pd/C in ethanol,followed by treatment with 2,5-dimethoxytetrahydrofuran in acetic acid,affords (-)-3-(ethoxycarbonyl)-3-(pyrrol-1-yl)pyrrolidine-2,5-dione (VI).Treatment of (VI) with trichloroacetyl chloride in ethyl acetate,followed by condensation with 4-bromo-2-fluorobenzylamine in the presence of triethylamine,gives AS-3201 (>99.4% e.e.).
📌 参考资料/链接：
参考文献标题:Novel,highly potent aldose reductase inhibitors: (R)-(-)-2-(4-Bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone (AS-3201) and its congeners
文献作者:Negoro,T.; Murata,M.; Ueda,S.; Fujitani,B.; Ono,Y.; Kuromiya,A.; Komiya,M.; Suzuki,M.; Matsumoto,J.
参考来源:J Med Chem 1998,41(21),4118-29
📄 详细内容
合成路线:The alkylation of ethyl 2-(benzyloxycarbonylamino)cyanoacetate (I) with ethyl bromoacetate and anhydrous potassium carbonate in acetone gives diethyl 2-(benzyloxycarbonylamino)-2-cyanosuccinate (II),which is hydrolyzed by means of hydrogen peroxide and sodium carbonate in acetone/water,yielding 3-(benzyloxycarbonylamino)-3-(ethoxycarbonyl)pyrrolidine-2,5-dione (III).Racemic (III) is then resolved by means of crystallization with cinchonidine in ethanol to give the (-)-enantiomer (IV) (>99.5% e.e.).Hydrogenolysis of (IV) over Pd/C in ethanol,followed by treatment with 2,5-dimethoxytetrahydrofuran in acetic acid,affords (-)-3-(ethoxycarbonyl)-3-(pyrrol-1-yl)pyrrolidine-2,5-dione (VI).Treatment of (VI) with trichloroacetyl chloride in ethyl acetate,followed by condensation with 4-bromo-2-fluorobenzylamine in the presence of triethylamine,gives AS-3201 (>99.4% e.e.).
参考文献标题:AS-3201
文献作者:Negoro,T.; Komiya,M.; Ono,Y.
参考来源:Drugs Fut 2000,25(2),131