Napsagatran, Ro-46-6240/010(monoH2O), Ro-46-6240
奈沙加群 奈沙加群 Chemical Name: 2-[3-[N-[1-Amidinopiperidin-3(S)-ylmethyl]carbamoyl]-N-cyclopropyl-2(S)-(2-naphthylsulfonamido)propionamido]acetic acid; N-[N4-[1-Amidinopiperidin-3(S)-ylmethyl]-N2-(2-naphthylsulfonyl)-L-asparaginyl]-(N-cyclopropyl)-glycine
CAS No. 154397-77-0, 159668-20-9 (monoH2O)
项目整合开发状态: Phase II
项目研究机构: Roche (Originator)
合成路线:A general synthesis of this entire class of thrombin inhibitors has been published recently.An alternative synthesis for the preparation of napsagatran is outlined in Scheme 21319301a:L-Aspartic acid is sulfonated with naphthalenesulfochloride to give the sulfonamide (I).Reaction of (I) with formaldehyde leads to the oxazolinone (II),which is reacted with N-cyclopropylglycine ethyl ester (III) to afford the aspartate (IV).Condensation of (IV) with the guanidine (IX) and saponification of the ethyl ester group provides napsagatran.For the preparation of the guanidine (IX),picolylamine is hydrogenated to give the racemic 3-aminomethyl-piperidine,from which the desired enantiomer (V) is isolated as dibenzoyltartrate by crystallization.Reaction of piperidine (V) with acetoacetate affords the protected piperidine (VI),which is amidinated with amidinotriazole (VII) to give the protected guanidine (VIII).Deprotection of (VIII) with hydrochloric acid provides the enantiomerically pure guanidine (IX) as dihydrochloride.
📌 参考资料/链接：
参考文献标题:Design and synthesis of potent and highly selective thrombin inhibitors
文献作者:Hilpert,K.; Ackermann,J.; Banner,D.W.; Gast,A.; Gubernator,K.; Hadvary,P.; Labler,L.; Muller,K.; Schmid,G.; Tschopp,T.B.; et al.
参考来源:J Med Chem 1994,37(23),3889-901
📄 详细内容
合成路线:A general synthesis of this entire class of thrombin inhibitors has been published recently.An alternative synthesis for the preparation of napsagatran is outlined in Scheme 21319301a:L-Aspartic acid is sulfonated with naphthalenesulfochloride to give the sulfonamide (I).Reaction of (I) with formaldehyde leads to the oxazolinone (II),which is reacted with N-cyclopropylglycine ethyl ester (III) to afford the aspartate (IV).Condensation of (IV) with the guanidine (IX) and saponification of the ethyl ester group provides napsagatran.For the preparation of the guanidine (IX),picolylamine is hydrogenated to give the racemic 3-aminomethyl-piperidine,from which the desired enantiomer (V) is isolated as dibenzoyltartrate by crystallization.Reaction of piperidine (V) with acetoacetate affords the protected piperidine (VI),which is amidinated with amidinotriazole (VII) to give the protected guanidine (VIII).Deprotection of (VIII) with hydrochloric acid provides the enantiomerically pure guanidine (IX) as dihydrochloride.
参考文献标题:Napsagatran
文献作者:Gast,A.; Kirchhofer,D.; Soukup,M.; Roux,S.; Ackermann,J.; Hilpert,K.; Tschopp,T.B.; Schmid,G.
参考来源:Drugs Fut 1995,20(5),476
产品链接: CAS No. 154397-77-0›› 产品链接: CAS No.159668-20-9››