Lefradafiban, BIBU-104XX, BIBU-104

来达非班Chemical Name: 2-[5(S)-[4'-[N1-(Methoxycarbonyl)amidino]biphenyl-4-yloxymethyl]-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester
CAS No. 149503-79-7
项目整合开发状态: Phase III
项目研究机构: Boehringer Ingelheim (Originator)
合成路线:The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III),which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V).The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI),which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII).The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX),which by treatment with HCl in methanol and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X).Finally,this compound is hydrolyzed with NaOH in methanol to afford the target acetic acid derivative.

合成路线:The condensation of 5(S)-(trityloxymethyl)-2-pyrrolidinone (I) with benzyl chloroformate (II) and BuLi in THF gives the carbamate (III),which is alkylated with tert-butyl 2-chloroacetate (IV) and LHMDS in THF to yield 2-[1-(benzyloxycarbonyl)-2-oxo-5(S)-(trityloxymethyl)pyrrolidin-2(S)-yl]acetic acid tert-butyl ester (V).The hydrogenation of (V) with H2 over Pd/C in hot tert-butanol affords 2-[5(S)-(hydroxymethyl)-2-oxopyrrolidin-2(S)-yl]acetic acid tert-butyl ester (VI),which is treated with MsCl and TEA in dichloromethane to provide the methanesulfonate (VII).The condensation of (VII) with 4'-hydroxybiphenyl-4-carbonitrile (VIII) by means of potassium tert-butoxide in DMF gives the adduct (IX),which by treatment with HCl in methanol,and with ammonia in the same solvent yields 2-[5(S)-(4'-amidinobiphenyl-4-yloxymethyl)-2-oxopyrrolidin-3(S)-yl]acetic acid methyl ester (X).Finally,this compound is condensed with methyl chloroformate (XI) by means of NaOH in dichloromethane to afford the target compound.