Argipidine, Argatroban monohydrate, GN1600, DK-7419, MDI-805, OM-805, MCI-9038, MD-805, Argatroban Injection, Acova, Slonnon, Novastan

合成路线:The condensation of N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine (I) with ethyl 4-methylpiperidine-2-carboxylate (II) by means of isobutyl chloroformate (A) and triethylamine in THF gives ethyl 1-[N(G)-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methylpiperidine-2-carboxylate (III),which is protected with HCl in ethyl acetate yielding ethyl 1-(N(G)-nitro-L-arginyl)-4-methylpiperidine-2-carboxylate (IV).The condensation of (IV) with 3-methylquinoline-8-sulfonyl chloride (V) by means of triethylamine in chloroform affords ethyl 1-(N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate (VI),which is hydrolyzed with NaOH in ethanol-water giving 1-[N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid (VII).Finally,this compound is deprotected and reduced by hydrogenation with H2 over Pd/C in ethanol.

参考文献标题:N2-Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
文献作者:Kikumoto,R.; Tamao,Y.; Onkubo,K.; Tezuka,T.; Tonomura,S.; Hihikata,A.; Okamoto,S.(Mitsubishi Chemical Corp.)
参考来源:US 4201863


合成路线:The condensation of N(G)-nitro-N2-(tert-butoxy-carbonyl)-L-arginine (I) with ethyl 4-methylpiperidine-2-carboxylate (II) by means of isobutyl chloroformate (A) and triethylamine in THF gives ethyl 1-[N(G)-nitro-N2-(tert-butoxycarbonyl)-L-arginyl]-4-methylpiperidine-2-carboxylate (III),which is protected with HCl in ethyl acetate yielding ethyl 1-(N(G)-nitro-L-arginyl)-4-methylpiperidine-2-carboxylate (IV).The condensation of (IV) with 3-methylquinoline-8-sulfonyl chloride (V) by means of triethylamine in chloroform affords ethyl 1-(N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylate (VI),which is hydrolyzed with NaOH in ethanol-water giving 1-[N(G)-nitro-N2-(3-methyl-8-quinolinylsulfonyl)-L-arginyl]-4-methyl-2-piperidinecarboxylic acid (VII).Finally,this compound is deprotected and reduced by hydrogenation with H2 over Pd/C in ethanol.

参考文献标题:MD-805
文献作者:Castar,J.; Grau,M.; Blancafort,P.; Serradell,M.N.
参考来源:Drugs Fut 1982,7(11),810


合成路线:A new short synthesis of argatroban has been reported: The protection of 4-methylpiperidine (I) with (Boc)2O gives the carbamate (II),which is condensed with benzyl chloroformate by means of sec-butyl lithium and TMEDA in ethyl ether to yield (?-trans-1-(tert-butoxycarbonyl)-4-methylpiperidine-2-carboxylic acid benzyl ester (III).Deprotection of the NH group of (III) with HCl in ethyl acetate affords (?-trans-4-methylpiperidine-2-carboxylic acid benzyl ester (IV),which is condensed with the protected arginine derivative (V) by means of isobutyl chloroformate and TEA to provide the corresponding amide as a diastereomeric mixture.Resolution of this mixture by flash chromatography furnishes the desired diastereomer (VI),which is treated with HCl in ethyl acetate in order to remove the Boc-protecting group to yield compound (VII).Condensation of compound (VII) with 3-methylquinoline-8-sulfonyl chloride (VIII) by means of TEA in dichloromethane affords the expected sulfonamide (IX).Finally,this compound is submitted to hydrogenation with H2 over Pd/C in AcOH/ethanol in order to produce debenzylation,cleavage of the NO2 group and hydrogenation of the pyridine ring to yield argatroban.
参考文献标题:A short synthesis of argatroban: A potent selective thrombin inhibitor
文献作者:Cossy,J.; Belotti,D.
参考来源:Bioorg Med Chem Lett 2001,11(15),1989


产品链接: CAS No. 141396-28-3››

产品链接: CAS No.74863-84-6››