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【结 构 式】 
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【药物名称】CL-218872 【化学名称】3-Methyl-6-[3-(trifluoromethyl)phenyl]-1,2,4-triazolo[4,3-b]pyridazine 【CA登记号】66548-69-4 【 分 子 式 】C13H9F3N4 【 分 子 量 】278.23868 |
【开发单位】Wyeth Pharmaceuticals (Originator) 【药理作用】Anxiolytics, PSYCHOPHARMACOLOGIC DRUGS |
合成路线1
The reaction of 3-trifluoromethylbenzaldehyde (I) with morpholine (II) and potassium cyanide by means of p-toluenesulfonic acid in refluxing THF gives alpha-(3-trifluoromethylphenyl)-4-morpholineacetonitrile (III), which is condensed with ethyl acrylate (IV) by means of KOH in THF yielding gamma-cyano-gamma-(3-trifluoromethylphenyl)-4-morpholinebutyric acid ethyl ester (V). The cyclization of (V) with hydrazine in refluxing ethanol affords 4,5-dihydro-6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VI), which is dehydrogenated by treatment with Br2 in hot acetic acid to give 6-(3-trifluoromethylphenyl)-3(2H)-pyridazinone (VII). The reaction of (VII) with POCl3 at 100 C affords 3-chloro-6-(3-trifluoromethylphenyl)pyridazine (VIII), which is finally cyclized with acetylhydrazine (IX) in refluxing n-butanol.
| 【1】 Allen, G.R. Jr.; Hanifin, J.W. Jr.; Moran, D.B.; Albright, J.D.; 6-Phenyl-1,2,4-triazolo{8 4,3-b{9 pyridazine hypotensive agents. US 4112095 . |
| 【2】 Albright, J.D.; et al.; Synthesis and anxiolytic activity of 6-(substituted-phenyl)-1,2,4-triazolo[4,3-b]pyridazines. J Med Chem 1981, 24, 5, 592-600. |
| 【3】 Owen, R.T.; Serradell, M.N.; Blancafort, P.; Castaner, J.; CL-218,872. Drugs Fut 1983, 8, 3, 191. |
| 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) | 35964 | 3-(trifluoromethyl)benzaldehyde | 454-89-7 | C8H5F3O | 详情 | 详情 |
| (II) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (III) | 35965 | 2-(4-morpholinyl)-2-[3-(trifluoromethyl)phenyl]acetonitrile | C13H13F3N2O | 详情 | 详情 | |
| (IV) | 10164 | ethyl acrylate | 140-88-5 | C5H8O2 | 详情 | 详情 |
| (V) | 35966 | ethyl 4-cyano-4-(4-morpholinyl)-4-[3-(trifluoromethyl)phenyl]butanoate | C18H21F3N2O3 | 详情 | 详情 | |
| (VI) | 35937 | 3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol | C14H12ClN3O | 详情 | 详情 | |
| (VII) | 35968 | 6-[3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone | C11H7F3N2O | 详情 | 详情 | |
| (VIII) | 35969 | 3-chloro-6-[3-(trifluoromethyl)phenyl]pyridazine | C11H6ClF3N2 | 详情 | 详情 | |
| (IX) | 29262 | acetohydrazide | 1068-57-1 | C2H6N2O | 详情 | 详情 |