YM-128, YM-68128
Chemical Name: 2-[4-[4-[4-(N-Hydroxyamidino)phenyl]-3-oxopiperazin-1-yl]piperidin-1-yl]acetic acid ethyl ester
CAS No. 199801-52-0
项目整合开发状态: Preclinical
项目研究机构: Merck KGaA (Originator), Yamanouchi (Originator)
合成路线:Alkylation of methyl 4-oxo-3-piperidinecarboxylate (I) with ethyl bromoacetate provided piperidineacetate (II).Subsequent decarbomethoxylation of (II) using LiCl in boiling DMF produced piperidone (III).On the other hand,coupling between 4-aminobenzonitrile (IV) and N-Boc-glycine (V) via activation with carbonyldiimidazole gave amide (V).The Boc group of (V) was then deprotected with HCl in EtOAc to yield 2-amino-N-(4-cyanophenyl)acetamide (VI).Reductive condensation of amine (VI) with piperidone (III) employing NaBH(OAc)3 furnished adduct (VII),which was further reductocondensed with chloroacetaldehyde to give chloroethyl amine (VIII).Cyclization of (VIII) in the presence of NaH generated piperazinone (IX).Finally,addition of hydroxylamine to the cyano group of (IX) provided the corresponding hydroxyamidine.
📌 参考资料/链接：
参考文献标题:Substd.amidinobenzene derivs.and medicinal compsns.thereof
文献作者:Matsumoto,Y.; Akamatsu,S.; Ichihara,M.; Kawasaki,T.; Kaku,S.; Yanagisawa,I.(Merck Patent GmbH; Yamanouchi Pharmaceutical Co.,Ltd.)
参考来源:EP 0905129; US 6057324; WO 9745413
📄 详细内容
合成路线:Alkylation of methyl 4-oxo-3-piperidinecarboxylate (I) with ethyl bromoacetate provided piperidineacetate (II).Subsequent decarbomethoxylation of (II) using LiCl in boiling DMF produced piperidone (III).On the other hand,coupling between 4-aminobenzonitrile (IV) and N-Boc-glycine (V) via activation with carbonyldiimidazole gave amide (V).The Boc group of (V) was then deprotected with HCl in EtOAc to yield 2-amino-N-(4-cyanophenyl)acetamide (VI).Reductive condensation of amine (VI) with piperidone (III) employing NaBH(OAc)3 furnished adduct (VII),which was further reductocondensed with chloroacetaldehyde to give chloroethyl amine (VIII).Cyclization of (VIII) in the presence of NaH generated piperazinone (IX).Finally,addition of hydroxylamine to the cyano group of (IX) provided the corresponding hydroxyamidine.
参考文献标题:Novel orally active GPIIb/IIIa antagonists: Synthesis and structure-activity relationship studies of oxopiperazine derivatives
文献作者:Suzuki,K.; Tsukamoto,S.; Yanagisawa,I.; Matsumoto,Y.; Ichihara,M.; Akamatsu,S.; Kaku,S.; Kawasaki,T.
参考来源:Symp Med Chem 1999,Abst 1P-02