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【结 构 式】 
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【药物名称】FR-167653 【化学名称】7-(4-Fluorophenyl)-2-(phenylglyoxyloyl)-8-(4-pyridyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine sulfate 【CA登记号】 【 分 子 式 】C24H20FN5O6S 【 分 子 量 】525.5193 |
【开发单位】Fujisawa (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, IL-1 Inhibitors, p38 Protein Kinase Inhibitors, TNF-alpha Antagonists |
合成路线1
The lithium derivative of 4-picoline (I) was acylated with ethyl 4-fluorobenzoate (II) to afford ketone (III). Condensation of (III) with dimethylformamide dimethylacetal provided enaminone (IV) which was subsequently cyclized with hydroxylamine to give the diaryl isoxazole (V). Isoxazole ring opening in (V) under basic conditions led to keto nitrile (VI). Chlorination of (VI) by means of POCl3, followed by reaction with hydrazine, furnished the amino pyrazole (VII). The diazonium salt (VIII) prepared from amino pyrazole (VII) was then added to the phosphorane aldehyde (IX) to generate the pyrazolotriazine (X). Hydrogenation of the triazine ring of (X) employing NaBH3CN produced the tetrahydro pyrazolotriazine (XI). This was finally acylated by phenylglyoxylic acid (XII) to yield the target alpha-oxo amide.
| 【1】 Kawai, Y.; Yamazaki, H.; Tanaka, H.; Oku, T. (Fujisawa Pharmaceutical Co., Ltd.); Pyrazolitriazines with interleukin-1 and tumour necrosis factor inhibitory activity. EP 0686156; JP 1996507056; WO 9419350 . |
| 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) | 31150 | 4-methylpyridine | 108-89-4 | C6H7N | 详情 | 详情 |
| (II) | 22830 | ethyl 4-fluorobenzoate | 451-46-7 | C9H9FO2 | 详情 | 详情 |
| (III) | 45005 | 1-(4-fluorophenyl)-2-(4-pyridinyl)-1-ethanone | C13H10FNO | 详情 | 详情 | |
| (IV) | 55996 | (Z)-3-(dimethylamino)-1-(4-fluorophenyl)-2-(4-pyridinyl)-2-propen-1-one | C16H15FN2O | 详情 | 详情 | |
| (V) | 55997 | 4-[5-(4-fluorophenyl)-4-isoxazolyl]pyridine | C14H9FN2O | 详情 | 详情 | |
| (VI) | 55998 | 3-(4-fluorophenyl)-3-oxo-2-(4-pyridinyl)propanenitrile | C14H9FN2O | 详情 | 详情 | |
| (VII) | 55999 | 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-ylamine; 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-amine | C14H11FN4 | 详情 | 详情 | |
| (VIII) | 56000 | 5-(4-fluorophenyl)-4-(4-pyridinyl)-1H-pyrazole-3-diazonium | C14H9FN5 | 详情 | 详情 | |
| (IX) | 55468 | 2-(triphenylphosphoranylidene)acetaldehyde | C20H17OP | 详情 | 详情 | |
| (X) | 56001 | 7-(4-fluorophenyl)-8-(4-pyridinyl)pyrazolo[5,1-c][1,2,4]triazine | C16H10FN5 | 详情 | 详情 | |
| (XI) | 56002 | 7-(4-fluorophenyl)-8-(4-pyridinyl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine | C16H14FN5 | 详情 | 详情 | |
| (XII) | 55589 | Benzoylformic acid; Phenylglyoxylic acid | 611-73-4 | C8H6O3 | 详情 | 详情 |