【结 构 式】 |
【药物名称】 【化学名称】N-Hydroxy-N-[3-[1-(4-methoxyphenyl)-5-(4-methylphenyl)-1H-pyrazol-3-yl]-2-propynyl]urea 【CA登记号】 【 分 子 式 】C21H20N4O3 【 分 子 量 】376.41855 |
【开发单位】R.W. Johnson (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Cyclooxygenase Inhibitors, Lipoxygenase Inhibitors |
合成路线1
Condensation of 4-methylacetophenone (I) with ethyl diethoxyacetate (II) in the presence of lithium hexamethyldisilazide afforded diketoacetal (III). Formation of pyrazole (V) was accomplished by treatment of (III) with 4-methoxy-phenylhydrazine (IV). Subsequent acid hydrolysis of the diethyl acetal gave aldehyde (VI), which was condensed with carbon tetrabromide using triphenyl phosphine to furnish dibromoethylene compound (VII). Elimination of HBr in (VII) by treatment with tetrabutylammonium fluoride produced bromo-acetylene (VIII). After lithium-bromine exchange, addition of paraformaldehyde yielded the propargyl alcohol (IX). Further Mitsunobu coupling of (IX) with N,O-bis(phenoxycarbonyl)hydroxylamine (X) gave the N,O-bis-protected N-alkyl hydroxylamine (XI). This was finally converted to the title N-hydroxyurea by treatment with methanolic ammonia.
【1】 Wetter, S.K.; Connolly, P.J.; Beers, K.N.; et al.; N-Hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase. Bioorg Med Chem Lett 1999, 9, 7, 979. |
【2】 Chen, R.; Wachter, M.; Connolly, P. (Ortho-McNeil Pharmaceutical, Inc.); Acetylenic 1,5-diarylpyrazoles as antiinflammatory agents. US 5925769 . |
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) | 12685 | 4-Chloroacetophenone; 1-(4-Chlorophenyl)-1-ethanone; p-Chloroacetophenone | 99-91-2 | C8H7ClO | 详情 | 详情 |
(II) | 25674 | ethyl 2,2-diethoxyacetate | 6065-82-3 | C8H16O4 | 详情 | 详情 |
(III) | 34716 | 1-(4-chlorophenyl)-4,4-diethoxy-1,3-butanedione | C14H17ClO4 | 详情 | 详情 | |
(IV) | 12688 | 4-Hydrazinophenyl methyl ether; 1-(4-Methoxyphenyl)hydrazine | 3471-32-7 | C7H10N2O | 详情 | 详情 |
(V) | 34717 | 4-[5-(4-chlorophenyl)-3-(diethoxymethyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(diethoxymethyl)-1-(4-methoxyphenyl)-1H-pyrazole | C21H23ClN2O3 | 详情 | 详情 | |
(VI) | 34718 | 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carbaldehyde | C17H13ClN2O2 | 详情 | 详情 | |
(VII) | 34719 | 4-[5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1H-pyrazol-1-yl]phenyl methyl ether; 5-(4-chlorophenyl)-3-(2,2-dibromovinyl)-1-(4-methoxyphenyl)-1H-pyrazole | C18H13Br2ClN2O | 详情 | 详情 | |
(VIII) | 34720 | 3-(2-bromoethynyl)-5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole; 4-[3-(2-bromoethynyl)-5-(4-chlorophenyl)-1H-pyrazol-1-yl]phenyl methyl ether | C18H12BrClN2O | 详情 | 详情 | |
(IX) | 34725 | 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-propyn-1-ol | C19H15ClN2O2 | 详情 | 详情 | |
(X) | 19646 | 1-[([[(phenoxycarbonyl)oxy]amino]carbonyl)oxy]benzene | C14H11NO5 | 详情 | 详情 | |
(XI) | 34726 | 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(3-[(phenoxycarbonyl)[(phenoxycarbonyl)oxy]amino]-1-propynyl)-1H-pyrazole | C33H24ClN3O6 | 详情 | 详情 |