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【结 构 式】 
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【药物名称】Lupitidine hydrochloride, SK&F-93479 【化学名称】2-[2-[(5-Dimethylaminomethylfuran-2-yl)methylthio]ethylamino]-5-(6-methylpyridyl-3-ylmethyl)pyrimid-4-one trihydrochloride 【CA登记号】72716-75-7, 83903-06-4 (free base) 【 分 子 式 】C21H30Cl3N5O2S 【 分 子 量 】522.92855 |
【开发单位】GlaxoSmithKline (Originator) 【药理作用】Histamine H2 Receptor Antagonists |
合成路线1
A new synthesis of lupitidine has been described: The condensation of 5-(2-methylpyridin-5-yl)-2-(nitroamino)pyrimidin-4(3H)-one (I) with 2-(2-furylmethylthio)ethylamine (II) in refluxing pyridine gives 2-[2-(2-furylmethylthio)ethylamino]-5-(2-methylpyridin-5-ylmethyl)pyrimidin-4(3H)-one (III), which is then submitted to a conventional Mannich condensation with formaldehyde and dimethylamine in acetic acid.
| 【1】 Parsons, M.E.; Rawlings, D.A.; Ife, R.J.; Brown, T.H.; Blakemore, R.C.; Blurton, P.; Armitage, M.A.; Durant, G.J.; Slingsby, B.P.; Ganellin, C.R.; Isocytosine H2-receptor histamine antagonists. III. The synthesis and biological activity of lupitidine (SK&F 93479) and related compounds. Eur J Med Chem 1990, 25, 217-26. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10001 | 5-(2-Methylpyridin-5-yl)-2-(nitroamino)pyrimidin-4(3H)-one | 72716-93-9 | C11H11N5O3 | 详情 | 详情 |
| (II) | 10002 | 2-[(2-Furylmethyl)sulfanyl]-1-ethanamine; 2-[(2-Furylmethyl)sulfanyl]ethylamine; 2-(2-Aminoethyl) furfuryl thiol ether | 36415-21-1 | C7H11NOS | 详情 | 详情 |
| (III) | 10003 | 2-([2-[(2-Furylmethyl)sulfanyl]ethyl]amino)-5-[(6-methyl-3-pyridinyl)methyl]-4(3H)-pyrimidinone | 72717-05-6 | C18H20N4O2S | 详情 | 详情 |
合成路线2
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.
| 【1】 Brown, T.H.; Ife, R.J. (SmithKline Beecham plc); Pyrimidine compounds. DD 140252; EP 0003677; ES 477667; US 4234588; US 4649141 . |
| 【2】 de Angelis, L.; Serradell, M.N.; Castaner, J.; Blancafort, P.; SKF-93,479. Drugs Fut 1982, 7, 3, 175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 22949 | 6-methylnicotinaldehyde | C7H7NO | 详情 | 详情 | |
| (II) | 12963 | Malonic acid | 141-82-2 | C3H4O4 | 详情 | 详情 |
| (III) | 22950 | (E)-3-(6-methyl-3-pyridinyl)-2-propenoic acid | C9H9NO2 | 详情 | 详情 | |
| (IV) | 36446 | ethyl (E)-3-(6-methyl-3-pyridinyl)-2-propenoate | C11H13NO2 | 详情 | 详情 | |
| (V) | 22951 | ethyl 3-(6-methyl-3-pyridinyl)propanoate | C11H15NO2 | 详情 | 详情 | |
| (VI) | 16602 | ethyl formate | 109-94-4 | C3H6O2 | 详情 | 详情 |
| (VII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VIII) | 36447 | 5-[(6-methyl-3-pyridinyl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone | C11H11N3OS | 详情 | 详情 | |
| (IX) | 36448 | 5-[(6-methyl-3-pyridinyl)methyl]-2-(methylsulfanyl)-4(3H)-pyrimidinone | C12H13N3OS | 详情 | 详情 | |
| (X) | 13851 | 2-[([5-[(Dimethylamino)methyl]-2-furyl]methyl)sulfanyl]-1-ethanamine; N-[(5-[[(2-Aminoethyl)sulfanyl]methyl]-2-furyl)methyl]-N,N-dimethylamine | C10H18N2OS | 详情 | 详情 |