Efegatran sulfate hydrate, LY-294468, GYKI-14766
N-甲基-D-苯丙氨酸-L-脯氨基-L-精氨酸硫酸盐水合物依非加群Chemical Name: N-Methyl-D-phenylalanyl-L-prolyl-L-arginal sulfate hydrate; N-Methyl-D-phenylalanyl-N-[4-guanidino-1(S)-formylbutyl]-L-prolinamide sulfate hydrate
CAS No. 126721-07-1, 105806-66-4 (anhydrous), 105806-65-3 (anhydrous free base)
项目整合开发状态: Phase II
项目研究机构: Gedeon Richter (Originator), Institute for Drug Research (Originator), Lilly (Licensee)
合成路线:The synthesis of GYKI-14766 is as follows:N2-tert-Butoxycarbonyl-L-arginine (I) was converted to the N6-benzyloxycarbonyl derivative (II).Treatment of (II) with isobutoxycarbonyl chloride and N-methylmorpholine gave the aminolactam (III).Dicyclohexylcarbodiimide-mediated esterification of N-benzyloxycarbonyl-D-phenylalanine (IV) with 2,4,5-trichlorophenol gave the active ester (V),which was coupled with L-proline to the dipeptide (VI).Methylation with iodomethane afforded the N-methyl derivative isolated as the cyclohexylamine salt (VII).The fragments (III) and (VII) were coupled via the mixed anhydride of (VII),generated as in the case of (II),giving the tripeptide lactam (VIII).Reduction with lithium aluminum hydride at low temperature converted (VIII) to the aldehyde (IX),which was finally deprotected to the end product.
📌 参考资料/链接：
参考文献标题:Highly active and selective anticoagulants: D-Phe-Pro-Arg-H,a free tripeptide aldehyde prone to spontaneous inactivation and its stable N-methyl derivative,D-MePhe-Pro-Arg-H
文献作者:Szl,E.; Bagdy,D.; Bajusz,S.; et al.
参考来源:J Med Chem 1990,33(6),1729-35
📄 详细内容
合成路线:The synthesis of GYKI-14766 is as follows:N2-tert-Butoxycarbonyl-L-arginine (I) was converted to the N6-benzyloxycarbonyl derivative (II).Treatment of (II) with isobutoxycarbonyl chloride and N-methylmorpholine gave the aminolactam (III).Dicyclohexylcarbodiimide-mediated esterification of N-benzyloxycarbonyl-D-phenylalanine (IV) with 2,4,5-trichlorophenol gave the active ester (V),which was coupled with L-proline to the dipeptide (VI).Methylation with iodomethane afforded the N-methyl derivative isolated as the cyclohexylamine salt (VII).The fragments (III) and (VII) were coupled via the mixed anhydride of (VII),generated as in the case of (II),giving the tripeptide lactam (VIII).Reduction with lithium aluminum hydride at low temperature converted (VIII) to the aldehyde (IX),which was finally deprotected to the end product.
参考文献标题:GYKI-14766
文献作者:N骻radi,M.
参考来源:Drugs Fut 1992,17(12),1087
产品链接: CAS No. 126721-07-1›› 产品链接: CAS No.105806-65-3››