AR-C85095MX
Chemical Name: 5-(5H-Dibenzo[a,d]cyclohepten-5-yl)-5'-O-[[(1,1-dichloro-1-phosphonomethyl)(hydroxy)phosphoryloxy](hydroxy)phosphoryl]-4-thiouridine tetrasodium salt
CAS No. 214480-01-0, 214480-70-3 (free acid)
项目整合开发状态: Biological Testing
项目研究机构: AstraZeneca (Originator)
合成路线:Regioselective lithiation of the tris-O-silylated uridine (I) with sec-butyllithium in the presence of TMEDA,followed by addition to dibenzosuberenone (II) afforded the 5-(dibenzocycloheptenyl)uridine derivative (III).Subsequent reduction of the tertiary alcohol of (III) with triethylsilane in the presence of boron trifluoride,followed by re silylation with tert-butyldimethylsilyl chloride furnished (IV).The 4-thiouridine derivative (V) was then obtained by thionation of (IV) with phosphorus pentasulfide in refluxing pyridine.Removal of the O-silyl protecting groups of (V) was effected by treatment with HF-pyridine,yielding (VI).Phosphorylation of the primary hydroxyl of (VI) with phosphoryl chloride in the presence of 1,8-bis-(dimethylamino)naphthalene in trimethyl phosphate,followed by condensation with dichloromethylenebisphosphonic acid gave rise to the target triphosphate analogue,which was finally converted to the corresponding tetrasodium salt by passage through a cation-exchange resin.
📌 参考资料/链接：
参考文献标题:Novel phosphate cpds.and their use as medicaments
文献作者:Meghani,P.; Kindon,N.; Thom,S.(AstraZeneca AB; AstraZeneca plc)
参考来源:WO 9845309
📄 详细内容
合成路线:Regioselective lithiation of the tris-O-silylated uridine (I) with sec-butyllithium in the presence of TMEDA,followed by addition to dibenzosuberenone (II) afforded the 5-(dibenzocycloheptenyl)uridine derivative (III).Subsequent reduction of the tertiary alcohol of (III) with triethylsilane in the presence of boron trifluoride,followed by re silylation with tert-butyldimethylsilyl chloride furnished (IV).The 4-thiouridine derivative (V) was then obtained by thionation of (IV) with phosphorus pentasulfide in refluxing pyridine.Removal of the O-silyl protecting groups of (V) was effected by treatment with HF-pyridine,yielding (VI).Phosphorylation of the primary hydroxyl of (VI) with phosphoryl chloride in the presence of 1,8-bis-(dimethylamino)naphthalene in trimethyl phosphate,followed by condensation with dichloromethylenebisphosphonic acid gave rise to the target triphosphate analogue,which was finally converted to the corresponding tetrasodium salt by passage through a cation-exchange resin.
参考文献标题:SAR leading to the discovery of AR-C 85095MX,a potent and selective P2Y2 antagonist
文献作者:Kindon,N.; Jewel,R.; Johnson,T.; McInally,J.; Meghani,P.; Thom,S.
参考来源:11th RSC-SCI Med Chem Symp (Sept 9 2001,Cambridge) 2001,Abst P8