• English
  • 简体中文
Login Register
Current Location: Home > Feedback Help Print

【结 构 式】

【药物名称】Icotidine trihydrochloride, SK&F-93319(free base), SK&F-93319-A3

【化学名称】2-[4-(3-Methoxypyridin-2-yl)butylamino]-5-(6-methylpyridin-3-ylmethyl)pyrimidin-4(1H)-one trihydrochloride

【CA登记号】71351-65-0, 71351-79-6 (free base)

【 分 子 式 】C21H28Cl3N5O2

【 分 子 量 】488.84861

【开发单位】GlaxoSmithKline (Originator)

【药理作用】 

合成路线1

2-Chloro-3-nitropyridine (I) is condensed with diethyl 2-(2-cyanoethyl)malonate (II) by means of NaH in refluxing THF fo give 1-cyano-3,3-bis(ethoxycarbonyl)-3-(3-nitro-2-pyridinyl)propane (III), which is hydrolyzed with NaOH io aqueous ethanol and decarboxylated in aqueous HCl to afford 2-(3-cyanopropyl)-3-nitropyridine (IV). Hydrogenation of (IV) over Pd/C in ethanol gives 3 amino-2-(3-cyanopropyl)pyridine (V), which is diazotized with NaNO2 in dilute H2SO4 and hydrolyzed to 2-(3-cyanopropyl)-3-hydroxypyridine (VI). Methylation of (VI) with MeI by means of NaH in Me2SO yields 2-(3-cyanopropyl)-3-methoxypyridine (VII), which is then reduced with LiAlH4 to provide 2-(4-amino-butyl)-3-methoxypyridine (VIII). The final stage is to condense (VIII) with 2-nitroamino-5-(6-methyl)-3-pyridinylmethyl)-4-pyrimidinone (XIII) in refluxing pyridine. Synthesis of the pyrimidinone (XIII) reagent commences with 2-methylpyridine-4-aldehyde (IX), which is condensed with malonic acid and decarboxylated in pyridine containing piperidine to afford 3-(6-methyl-3pyridinyl)acrylic acid (X). Esterification of (X) with ethanol-H2SO4, followed by reduction with H2 over Pd/C in ethanol gives ethyl (2-mcthyl-5-pyridinyl)ethanoate (XI), which with ethyl formate in the presence of NaH in glyme furnishes 1-(ethoxycarbonyl)-1-formyl-2-(2 methyl-5-pyridinyl)ethane (XII). Condensation of (XII) with nitroguanidine in ethanol in the presence of NaOEt provides the 4-pyrimidinone (XIII).

1 Durant, G.J.; Ganellin, C.R.; Sach, G.S. (SmithKline Beecham plc); Guanidines, thioureas and 1,1-diamino-2-nitroethyl. GB 1564502; US 4426526 .
2 Durant, G.J.; Brown, T.H.; Ganellin, C.R. (SmithKline Beecham plc); Pyridylalkylpyrimidone cpds., process for preparin. EP 0017679 .
3 Prous, J.; Castaner, J.; Icotidine trihydrochloride. Drugs Fut 1987, 12, 1, 24.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(I) 10321 2-Chloro-3-nitropyridine 5470-18-8 C5H3ClN2O2 详情 详情
(II) 22941 diethyl 2-(2-cyanoethyl)malonate 17216-62-5 C10H15NO4 详情 详情
(III) 22942 diethyl 2-(2-cyanoethyl)-2-(3-nitro-2-pyridinyl)malonate C15H17N3O6 详情 详情
(IV) 22943 4-(3-nitro-2-pyridinyl)butanenitrile C9H9N3O2 详情 详情
(V) 22944 4-(3-amino-2-pyridinyl)butanenitrile C9H11N3 详情 详情
(VI) 22945 4-(3-hydroxy-2-pyridinyl)butanenitrile C9H10N2O 详情 详情
(VII) 22946 4-(3-methoxy-2-pyridinyl)butanenitrile C10H12N2O 详情 详情
(VIII) 22947 4-(3-methoxy-2-pyridinyl)-1-butanamine; 4-(3-methoxy-2-pyridinyl)butylamine C10H16N2O 详情 详情
(IX) 22949 6-methylnicotinaldehyde C7H7NO 详情 详情
(X) 22950 (E)-3-(6-methyl-3-pyridinyl)-2-propenoic acid C9H9NO2 详情 详情
(XI) 22951 ethyl 3-(6-methyl-3-pyridinyl)propanoate C11H15NO2 详情 详情
(XII) 22952 ethyl 2-formyl-3-(6-methyl-3-pyridinyl)propanoate C12H15NO3 详情 详情
(XIII) 22953 5-(6-Methylpyridin-3-ylmethyl)-2-(nitroamino)pyrimidin-4(1H)-one C11H11N5O3 详情 详情
Extended Information