YM-75466, YM-466(free base), YM-60828(free base)
Chemical Name: 2-[N-(7-Amidinonaphthalen-2-ylmethyl)-N-[4-[1-(1-iminoethyl)piperidin-4-yloxy]phenyl]sulfamoyl]acetic acid methanesulfonate
CAS No. 201933-41-7 (free base)
项目整合开发状态: Phase I
项目研究机构: Yamanouchi (Originator)
合成路线:The intermediate aniline (IV) was synthesized by Mitsunobu coupling between N-Boc-4-piperidinol (I) and p-nitrophenol (II),followed by catalytic hydrogenation of the resultant nitrophenyl ether (III).7-Formyl-2-naphthalenecarbonitrile (VI) was prepared by oxidation of the bromomethyl(naphthalene) (V) employing either trimethylamine N-oxide or dimethylsulfoxide in the presence of silver tetrafluoroborate.Reductive alkylation of aniline (IV) with aldehyde (VI) by means of sodium triacetoxyborohydride produced the secondary amine (VII),which was subsequently acylated with ethyl 2-(Chlorosulfonyl)acetate (VIII) to furnish sulfonamide (IX).The required amidine (X) was then obtained by Pinner reaction of nitrile (IX) with ethanolic HCl,followed by treatment with ammonium acetate.The deprotected piperidine moiety of (X) was further subjected to condensation with ethyl acetimidate to give the bis-amidine compound (XI).The ethyl ester group of (XI) was finally hydrolyzed under acidic conditions,yielding the target carboxylic acid.
📌 参考资料/链接：
参考文献标题:Novel amidinonaphthyl derivs.or salt thereof
文献作者:Hirayama,F.; Koshio,H.; Matsumoto,Y.; Kawasaki,T.; Kaku,S.; Yanagisawa,I.(Yamanouchi Pharmaceutical Co.,Ltd.)
参考来源:EP 0798295; US 5869501; WO 9616940
📄 详细内容
合成路线:The intermediate aniline (IV) was synthesized by Mitsunobu coupling between N-Boc-4-piperidinol (I) and p-nitrophenol (II),followed by catalytic hydrogenation of the resultant nitrophenyl ether (III).7-Formyl-2-naphthalenecarbonitrile (VI) was prepared by oxidation of the bromomethyl(naphthalene) (V) employing either trimethylamine N-oxide or dimethylsulfoxide in the presence of silver tetrafluoroborate.Reductive alkylation of aniline (IV) with aldehyde (VI) by means of sodium triacetoxyborohydride produced the secondary amine (VII),which was subsequently acylated with ethyl 2-(Chlorosulfonyl)acetate (VIII) to furnish sulfonamide (IX).The required amidine (X) was then obtained by Pinner reaction of nitrile (IX) with ethanolic HCl,followed by treatment with ammonium acetate.The deprotected piperidine moiety of (X) was further subjected to condensation with ethyl acetimidate to give the bis-amidine compound (XI).The ethyl ester group of (XI) was finally hydrolyzed under acidic conditions,yielding the target carboxylic acid.
参考文献标题:The discovery of YM-60828: A potent,selective and orally-bioavailable factor Xa inhibitor
文献作者:Hirayama,F.; Koshio,H.; Katayama,N.; Kurihara,H.; Taniuchi,Y.; Sato,K.; Hisamichi,N.; Sakai-Moritani,Y.; Kawasaki,T.; Matsumoto,Y.; Yanagisawa,I.
参考来源:Bioorg Med Chem 2002,10(5),1509