【结 构 式】 |
【药物名称】Bimakalim, SR-44866, EMD-52692 【化学名称】2,2-Dimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran-6-carbonitrile 【CA登记号】117545-11-6 【 分 子 式 】C17H14N2O2 【 分 子 量 】278.31333 |
【开发单位】Merck KGaA (Originator) 【药理作用】Angina pectoris, Treatment of, CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, K(ATP) Channel Activators |
合成路线1
The cyclization of 3-acetyl-4-hydroxybenzonitrile (I) with acetone by means of pyrrolidine in toluene gives 2,2-dimethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carbonitrile (II), which is reduced with NaBH4 yielding the corresponding alcohol (III). The dehydration of (III) with p-toluenesulfonic acid in refluxing toluene affords 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (IV), which is treated with m-chloroperbenzoic acid (MCPBA) to give the corresponding epoxide (V) . The condensation of (V) with pyridin-2(1H)-one (VI) by means of pyridine or benzyl trimethylammonium hydroxide (2) in refluxing ethanol yields trans-3-hydroxy-2,2-dimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-3,4-dihydro-2H-1-benzopyran-6-carbonitrile (VII), which is finally dehydrated with NaOH in refluxing dioxane , or with NaH in refluxing THF. When the condensation of epoxide (V) with pyridone (VI) is carried out with NaH in DMSO mixtures of the intermediate (VII) and the final compound bimakalim are obtained; these compounds are easily separated.
【1】 Robinson, C.; Robinson, K.A.; Castaner, J.; Bimakalim. Drugs Fut 1996, 21, 4, 351. |
【2】 Hausler, G.; Gericke, R.; Wurziger, H.; Baumgarth, M.; Lues, I.; De Peyer, J.; Bergmann, R. (Merck Patent GmbH); Chroman derivs. AU 8782689; DE 3726261; EP 0273262; JP 1988170376 . |
【3】 Garcia, G.; Di Malta, a.; Gautier, P. (Sanofi-Synthelabo ); 2,2-Dimethylchromene derivs., preparation process and pharmaceutical compsns. containing them. AU 8823660; EP 0312432; EP 0556872; FR 2621587; JP 1990000180 . |
【4】 Hausler, G.; Gericke, R.; Wurziger, H.; Baumgarth, M.; Lues, I.; Bergmann, R.; De Peyer, J. (Merck Patent GmbH); Chroman derivs. AU 8936440; DE 3820506; EP 0346724; JP 1990040375; US 5387587 . |
【5】 Bergmann, R.; Gericke, R.; Synthesis and antihypertensive activity of 4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyrans and related compounds, new channel activators. J Med Chem 1990, 33, 2, 492-504. |
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) | 12857 | 3-Acetyl-4-hydroxybenzonitrile | C9H7NO2 | 详情 | 详情 | |
(II) | 12858 | 2,2-Dimethyl-4-oxo-6-chromanecarbonitrile | C12H11NO2 | 详情 | 详情 | |
(III) | 12859 | 4-Hydroxy-2,2-dimethyl-6-chromanecarbonitrile | C12H13NO2 | 详情 | 详情 | |
(IV) | 12860 | 2,2-Dimethyl-2H-chromene-6-carbonitrile | C12H11NO | 详情 | 详情 | |
(V) | 12861 | 2,2-Dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile | C12H11NO2 | 详情 | 详情 | |
(VI) | 12862 | 2(1H)-Pyridinone | 142-08-5 | C5H5NO | 详情 | 详情 |
(VII) | 12863 | (3S,4R)-3-Hydroxy-2,2-dimethyl-4-[2-oxo-1(2H)-pyridinyl]-3,4-dihydro-2H-chromene-6-carbonitrile | C17H16N2O3 | 详情 | 详情 |