Cangrelor sodium, AR-C69931MX
坎格雷洛Chemical Name: 5'-O-[[[Dichloro(phosphono)methyl](hydroxy)phosphoryloxy](hydroxy)phosphoryl]-N-[2-(methylsulfanyl)ethyl]-2-(3,3,3-trifluoropropylsulfanyl)adenosine tetrasodium salt
CAS No. 163706-06-7 (free acid)
项目整合开发状态: Phase II
项目研究机构: The Medicines Co. (Proprietary), AstraZeneca Charnwood (Originator)
合成路线:2-Mercaptoadenosine (I) was S-alkylated with 1-chloro-3,3,3-trifluoropropane (II) in the presence of NaH to give trifluoropropyl sulfide (III).Subsequent acetylation of (III) with Ac2O at 80 C provided (IV),which was N-alkylated with methylthioethyl iodide (V) and NaH yielding (VI).Further hydrolysis of the resulting (VI) with 0.1 M NaOH in refluxing MeOH furnished adenosine derivative (VII).The 5'-hydroxyl group of (VII) was then phosphorylated by reaction with phosphoryl chloride in cold triethyl phosphate followed by aqueous work-up.The resulting 5'-monophosphate (VIII) was treated with carbonyl diimidazole and tri-n-butylamine to produce the phosphoryl imidazole intermediate (IX),which was finally condensed with dichloromethylenebis(phosphonic acid) (X).The target compound was isolated as the tetrasodium salt upon treatment with NaI in methanol-acetone.
合成路线:Alkylation of mercaptopurine (I) with 3-chloro-1,1,1-trifluoropropane (II) in the presence of NaH gave thioether (III).After protection of the amino group of (III) as the acetamide (IV) by means of Ac2O and NaOAc,N-alkylation with 2-(methylthio)ethyl iodide (V) yielded (VI),which was deacetylated by hydrolysis with NaOH in refluxing MeOH.Subsequent treatment with POCl3 produced the intermediate phosphoryl chloride (VIII).Then,condensation of this acid chloride with dichloromethylene bisphosphonic acid (IX) in the presence of tributylamine in triethyl phosphate yielded the title compound,which was isolated as the tetrasodium salt.Alternatively,hydrolysis of acid chloride (VIII) in the presence of ammonium bicarbonate gave phosphate salt (X),which was treated with carbonyldiimidazole,and the activated intermediate (XI) was then condensed with bisphosphonate (IX) to furnish the target compound.
📌 参考资料/链接：
参考文献标题:N-Alkyl-2-substd.ATP analogues
文献作者:Ingall,A.H.; Cage,P.A.; Kindon,N.D.(Celltech Medeva plc)
参考来源:EP 0683789; JP 1996506335; US 5721219; WO 9418216
📄 详细内容
合成路线:2-Mercaptoadenosine (I) was S-alkylated with 1-chloro-3,3,3-trifluoropropane (II) in the presence of NaH to give trifluoropropyl sulfide (III).Subsequent acetylation of (III) with Ac2O at 80 C provided (IV),which was N-alkylated with methylthioethyl iodide (V) and NaH yielding (VI).Further hydrolysis of the resulting (VI) with 0.1 M NaOH in refluxing MeOH furnished adenosine derivative (VII).The 5'-hydroxyl group of (VII) was then phosphorylated by reaction with phosphoryl chloride in cold triethyl phosphate followed by aqueous work-up.The resulting 5'-monophosphate (VIII) was treated with carbonyl diimidazole and tri-n-butylamine to produce the phosphoryl imidazole intermediate (IX),which was finally condensed with dichloromethylenebis(phosphonic acid) (X).The target compound was isolated as the tetrasodium salt upon treatment with NaI in methanol-acetone.
合成路线:Alkylation of mercaptopurine (I) with 3-chloro-1,1,1-trifluoropropane (II) in the presence of NaH gave thioether (III).After protection of the amino group of (III) as the acetamide (IV) by means of Ac2O and NaOAc,N-alkylation with 2-(methylthio)ethyl iodide (V) yielded (VI),which was deacetylated by hydrolysis with NaOH in refluxing MeOH.Subsequent treatment with POCl3 produced the intermediate phosphoryl chloride (VIII).Then,condensation of this acid chloride with dichloromethylene bisphosphonic acid (IX) in the presence of tributylamine in triethyl phosphate yielded the title compound,which was isolated as the tetrasodium salt.Alternatively,hydrolysis of acid chloride (VIII) in the presence of ammonium bicarbonate gave phosphate salt (X),which was treated with carbonyldiimidazole,and the activated intermediate (XI) was then condensed with bisphosphonate (IX) to furnish the target compound.
参考文献标题:SAR studies on AR-C 69931MX,a potent and selective intravenous anti-aggregatory/anti-thrombotic agent with a novel mechanism of action
文献作者:Cage,P.A.; Bailey,A.; Kindon,N.D.; et al.
参考来源:15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998,Edinburgh) 1998,Abst P.281
产品链接: CAS No. 163706-06-7››