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【结 构 式】 
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【药物名称】SC-964, SC-77964 【化学名称】1-Cyclopropyl-5-[4-[4-(trifluoromethoxy)phenoxy]phenylsulfonyl]piperidine-3-carbohydroxamic acid hydrochloride 【CA登记号】226396-02-7, 308824-37-5 (free base) 【 分 子 式 】C22H24ClF3N2O6S 【 分 子 量 】536.95858 |
【开发单位】Pfizer (Originator) 【药理作用】Oncolytic Drugs, Angiogenesis Inhibitors, Matrix Metalloproteinase Inhibitors, MMP-13 (Collagenase 3) Inhibitors, MMP-2 (Gelatinase A) Inhibitors, MMP-3 (Stromelysin 1) Inhibitors |
合成路线1
Ethyl nipecotate (I) was protected as the tert-butyl carbamate (II) upon treatment with Boc2O in THF. The lithium enolate of ester (II) was then sulfenylated with the disulfide (IV), prepared by oxidation of 4-fluorothiophenol (III), yielding thioether (V). This was further oxidized to the corresponding sulfone (VI) using meta-chloroperbenzoic acid. Acid cleavage of the Boc protecting group of (VI) gave piperidine (VII), which was converted to the N-cyclopropyl amine (IX) by reductive alkylation with [(1-ethoxycyclopropyl)oxy]trimethylsilane (VIII) in the presence of NaBH3CN. Displacement of the aryl fluoride of (IX) with 4-(trifluoromethoxy)phenol (X) under basic conditions afforded the diaryl ether (XI). After saponification of the ester group of (XI), the resultant carboxylic acid (XII) was coupled to O-(tetrahydropyranyl)hydroxylamine by means of EDC to produce the protected hydroxamate (XIII). Finally, removal of the tetrahydropyranyl protecting group of (XIII) with HCl in dioxan afforded the title compound.
| 【1】 Villamil, C.I.; et al.; Design and synthesis of 4,4-disubstituted piperidine alpha-sulphone hydroxamates as potent and selective MMP inhibitors: The discovery of SC-77964. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 258. |
| 【2】 Aromatic sulfone hydroxamic acid metalloprotease inhibitor. WO 0050396 . |
| 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) | 17410 | Ethyl isonipecotate; ethyl 4-piperidinecarboxylate | 1126-09-6 | C8H15NO2 | 详情 | 详情 |
| (II) | 49847 | 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine | 142851-03-4 | C13H23NO4 | 详情 | 详情 |
| (III) | 22971 | 4-fluorobenzenethiol; 4-fluorophenylhydrosulfide; 4-Fluorothiophenol | 371-42-6 | C6H5FS | 详情 | 详情 |
| (IV) | 52287 | bis(4-fluorophenyl) disulfide; 1-fluoro-4-[(4-fluorophenyl)disulfanyl]benzene | C12H8F2S2 | 详情 | 详情 | |
| (V) | 52288 | 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfanyl]-1,4-piperidinedicarboxylate | C19H26FNO4S | 详情 | 详情 | |
| (VI) | 52289 | 1-(1,1-dimethylethyl) 4-ethyl 4-[(4-fluorophenyl)sulfonyl]-1,4-piperidinedicarboxylate | C19H26FNO6S | 详情 | 详情 | |
| (VII) | 52290 | ethyl 4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate | C14H18FNO4S | 详情 | 详情 | |
| (VIII) | 52291 | Cyclopropanone ethyl trimethylsilyl acetal; (1-Ethoxycyclopropoxy)trimethylsilane | C8H18O2Si | 详情 | 详情 | |
| (IX) | 52292 | ethyl 1-cyclopropyl-4-[(4-fluorophenyl)sulfonyl]-4-piperidinecarboxylate | C17H22FNO4S | 详情 | 详情 | |
| (X) | 18780 | 4-(trifluoromethoxy)phenol | 828-27-3 | C7H5F3O2 | 详情 | 详情 |
| (XI) | 52293 | ethyl 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylate | C24H26F3NO6S | 详情 | 详情 | |
| (XII) | 52294 | 1-cyclopropyl-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxylic acid | C22H22F3NO6S | 详情 | 详情 | |
| (XIII) | 52295 | 1-cyclopropyl-N-(tetrahydro-2H-pyran-2-yloxy)-4-{[4-({4-[(trifluoromethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-4-piperidinecarboxamide | C27H31F3N2O7S | 详情 | 详情 |