Lupitidine hydrochloride, SK&F-93479

鲁匹替丁 Chemical Name: 2-[2-[(5-Dimethylaminomethylfuran-2-yl)methylthio]ethylamino]-5-(6-methylpyridyl-3-ylmethyl)pyrimid-4-one trihydrochloride
CAS No. 72716-75-7, 83903-06-4 (free base)
项目整合开发状态: Preclinical
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.