Donetidine, SK&F-93574
多奈替丁Chemical Name: 5-[(1,2-Dihydro-2-oxo-4-pyridinyl)methyl]-2-[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]amino]-4(1H)-pyrimidone
CAS No. 99248-32-5, 72716-91-7 (triHCl)
项目整合开发状态: Phase I
项目研究机构: GlaxoSmithKline (Originator)
合成路线:The condensation of 6-methylpyridine-3-carboxaldehyde (I) with malonic acid (II) by means of piperidine in refluxing pyridine gives 3-(6-methyl-3-pyridyl)acrylic acid (III),which is esterified with ethanol and H2SO4 as usual to afford ethyl 3-(6-methyl-3-pyridyl)acrylate (IV).The reduction of (IV) with H2 over Pd/C in ethanol affords ethyl 3-(6-methyl-3-pyridyl)propionate (V),which is cyclized with ethyl formate (VI) and thiourea (VII) by means of Na in ether-ethanol yielding 5-(6-methyl-3-pyridylmethyl)-2-thiouracil (VIII).The methylation of (VIII) with methyl iodide and NaOH in hot water gives 5-(6-methyl-3-pyridyl-methyl)-2-methylthio-4-pyrimidone (IX),which is finally condensed with 2-[(5-dimethylaminomethylfuran-2-yl)methylthio]ethylamine (X) in refluxing pyridine.
合成路线:The reaction of 2-chloro-4-cyanopyridine (I) with sodium methoxide in refluxing methanol gives 2-methoxy-4-cyanopyridine (II),which by reduction with H2 over Raney-Ni and semicarbazide HCl in water-ethanol is converted to 2-methoxypyridine-4-carboxyaldehyde (III).The condensation of (III) with malonic acid (IV) by means of piperidine in hot pyridine yields 3-(2-methoxy-4-pyridyl)acrylic acid (V),which is esterified with ethanol and H2SO4 to the ethyl ester (VI).The reduction of (VII) with H2 over Pd/C in ethanol affords the corresponding propionate (VII).Formylation of (VII) with ethyl formate and NaH gives ethyl 2-formyl-3-(2-methoxy-4-pyridyl)propionate (VIII),which is cyclized with nitroguanidine (IX) by means of sodium methoxide in refluxing methanol yielding 2-nitroamino-5-12-methoxy-4-pyridylmethylpyrimidin-4(1H)-one (X).The reaction of (X) with 2-[5-(dimethylaminomethyl)-2 furylmethylthio]ethylamine in refluxing ethanol gives the O-methyl derivative of SK&F 93574 (XII),whicn is finally deprotected with HCl in refluxing ethanol.
📌 参考资料/链接：
参考文献标题:Pyrimidine compounds
文献作者:Brown,T.H.; Ife,R.J.(SmithKline Beecham plc)
参考来源:DD 140252; EP 0003677; ES 477667; US 4234588; US 4649141
📄 详细内容
合成路线:The reaction of 2-chloro-4-cyanopyridine (I) with sodium methoxide in refluxing methanol gives 2-methoxy-4-cyanopyridine (II),which by reduction with H2 over Raney-Ni and semicarbazide HCl in water-ethanol is converted to 2-methoxypyridine-4-carboxyaldehyde (III).The condensation of (III) with malonic acid (IV) by means of piperidine in hot pyridine yields 3-(2-methoxy-4-pyridyl)acrylic acid (V),which is esterified with ethanol and H2SO4 to the ethyl ester (VI).The reduction of (VII) with H2 over Pd/C in ethanol affords the corresponding propionate (VII).Formylation of (VII) with ethyl formate and NaH gives ethyl 2-formyl-3-(2-methoxy-4-pyridyl)propionate (VIII),which is cyclized with nitroguanidine (IX) by means of sodium methoxide in refluxing methanol yielding 2-nitroamino-5-12-methoxy-4-pyridylmethylpyrimidin-4(1H)-one (X).The reaction of (X) with 2-[5-(dimethylaminomethyl)-2 furylmethylthio]ethylamine in refluxing ethanol gives the O-methyl derivative of SK&F 93574 (XII),whicn is finally deprotected with HCl in refluxing ethanol.
参考文献标题:Chemical process
文献作者:Adger,B.M.; Lewis,N.J.(SmithKline Beecham plc)
参考来源:EP 0141560
合成路线:The reaction of 2-chloro-4-cyanopyridine (I) with sodium methoxide in refluxing methanol gives 2-methoxy-4-cyanopyridine (II),which by reduction with H2 over Raney-Ni and semicarbazide HCl in water-ethanol is converted to 2-methoxypyridine-4-carboxyaldehyde (III).The condensation of (III) with malonic acid (IV) by means of piperidine in hot pyridine yields 3-(2-methoxy-4-pyridyl)acrylic acid (V),which is esterified with ethanol and H2SO4 to the ethyl ester (VI).The reduction of (VII) with H2 over Pd/C in ethanol affords the corresponding propionate (VII).Formylation of (VII) with ethyl formate and NaH gives ethyl 2-formyl-3-(2-methoxy-4-pyridyl)propionate (VIII),which is cyclized with nitroguanidine (IX) by means of sodium methoxide in refluxing methanol yielding 2-nitroamino-5-12-methoxy-4-pyridylmethylpyrimidin-4(1H)-one (X).The reaction of (X) with 2-[5-(dimethylaminomethyl)-2 furylmethylthio]ethylamine in refluxing ethanol gives the O-methyl derivative of SK&F 93574 (XII),whicn is finally deprotected with HCl in refluxing ethanol.
参考文献标题:SK&F-93574
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1986,11(8),671
产品链接: CAS No. 99248-32-5››