【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 |