FR-227369
Chemical Name: N-(9-Methylsulfonyl-2,3-dihydro-1-benzoxepin-4-ylcarbonyl)guanidine methanesulfonate
CAS No. 248958-47-6, 248958-46-5 (free base), 248958-45-4 (hydrochloride)
项目整合开发状态: Preclinical
项目研究机构: Fujisawa (Originator)
合成路线:Diazotization of ethyl 3-amino-2-(3-ethoxycarbonylpropoxy)benzoate (I),followed by treatment of the resultant diazonium salt with potassium xanthogenate,afforded the aryl xanthate (II).Basic hydrolysis of (II) furnished the mercapto diacid (III).The methylthio analogue (IV) was prepared by alkylation of the thiol group with iodomethane and K2CO3.Subsequent Fischer esterification of the carboxyl groups produced diester (V),which was subjected to a Dieckmann cyclization to furnish the benzoxepin derivative (VI).Ketone (VI) reduction with NaBH4 gave hydroxyester (VII).This was dehydrated to the unsaturated ester (VIII) upon heating with p-toluenesulfonic acid in toluene.Oxidation of sulfide (VIII) with m-chloroperbenzoic acid yielded sulfone (IX).Then,displacement of the ester group of (IX) with guanidine (X) provided the title acyl guanidine,which was isolated as the mesylate salt.Alternatively,ester (VIII) was first treated with guanidine (X),producing the acyl guanidine (XI),and the sulfide group of (XI) was further oxidized to sulfone with m-chloroperbenzoic acid .
📌 参考资料/链接：
参考文献标题:Guanidine derivs.
文献作者:Inoue,Y.; Akahane,A.; Takenaka,K.; Minagawa,M.(Fujisawa Pharmaceutical Co.,Ltd.)
参考来源:EP 1073650; US 6346527; WO 9955690
📄 详细内容
合成路线:Diazotization of ethyl 3-amino-2-(3-ethoxycarbonylpropoxy)benzoate (I),followed by treatment of the resultant diazonium salt with potassium xanthogenate,afforded the aryl xanthate (II).Basic hydrolysis of (II) furnished the mercapto diacid (III).The methylthio analogue (IV) was prepared by alkylation of the thiol group with iodomethane and K2CO3.Subsequent Fischer esterification of the carboxyl groups produced diester (V),which was subjected to a Dieckmann cyclization to furnish the benzoxepin derivative (VI).Ketone (VI) reduction with NaBH4 gave hydroxyester (VII).This was dehydrated to the unsaturated ester (VIII) upon heating with p-toluenesulfonic acid in toluene.Oxidation of sulfide (VIII) with m-chloroperbenzoic acid yielded sulfone (IX).Then,displacement of the ester group of (IX) with guanidine (X) provided the title acyl guanidine,which was isolated as the mesylate salt.Alternatively,ester (VIII) was first treated with guanidine (X),producing the acyl guanidine (XI),and the sulfide group of (XI) was further oxidized to sulfone with m-chloroperbenzoic acid .
参考文献标题:Synthesis and structure activity relationships on benzoxepine derivatives as novel Na+/H+ exchange inhibitors
文献作者:Takenaka,K.; et al.
参考来源:21st Symp Med Chem (Nov 28 2001,Kyoto) 2001,Abst 1P-14