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【结 构 式】 
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【药物名称】 【化学名称】2,3-Dimethoxy-6-[4-[4-(trifluoromethyl)phenoxy]piperidin-1-ylsulfonyl]benzohydroxamic acid 【CA登记号】279221-23-7 【 分 子 式 】C21H23F3N2O7S 【 分 子 量 】504.48586 |
【开发单位】Pfizer (Originator) 【药理作用】Antiarthritic Drugs, Oncolytic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Angiogenesis Inhibitors, MMP-13 (Collagenase 3) Inhibitors, MMP-2 (Gelatinase A) Inhibitors |
合成路线1
Coupling between N-Boc-4-piperidinol (I) and 4-fluorobenzotrifluoride (II) in the presence of cesium carbonate afforded ether (III). Subsequent acidic cleavage of the Boc protecting group of (III) furnished piperidine (IV) (1). Acylation of piperidine (IV) with 3,4-dimethoxybenzenesulfonyl chloride (V) yielded the corresponding sulfonamide (VI). Regioselective metalation of (VI) by means of tert-butyllithium, followed by quenching with dry carbon dioxide gave rise to the carboxylic acid (VII). This was converted to the corresponding acid chloride (VIII) employing oxalyl chloride, and then condensed with O-tetrahydropyranylhydroxylamine (IX). The resultant tetrahydropyranyl-protected hydroxamate (X) was finally deprotected by treatment with an in situ generated solution of methanolic HCl.
| 【1】 Barta, T.E.; et al.; Selective, orally active MMP inhibitor with an aryl backbone. Bioorg Med Chem Lett 2001, 11, 18, 2481. |
| 【2】 Villamil, C.I.; Becker, D.P.; Bedell, L.J.; Freskos, J.N.; Rao, S.N.; Getman, D.P.; Decrescenzo, G.A.; Mischke, B.V.; Barta, T.E.; McDonald, J.J. (Pharmacia Corp.); Hydroxamic acid derivs. as matrix metalloprotease inhibitors. EP 1177173; WO 0069819 . |
| 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) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (II) | 52131 | 4-Fluorobenzotrifluoride; alpha,alpha-4-Tetrafluorotoluene | 402-44-8 | C7H4F4 | 详情 | 详情 |
| (III) | 52132 | tert-butyl 4-[4-(trifluoromethyl)phenoxy]-1-piperidinecarboxylate | C17H22F3NO3 | 详情 | 详情 | |
| (IV) | 52133 | 4-[4-(trifluoromethyl)phenoxy]piperidine; 4-piperidinyl 4-(trifluoromethyl)phenyl ether | C12H14F3NO | 详情 | 详情 | |
| (V) | 47469 | 3,4-dimethoxybenzenesulfonyl chloride | 23095-31-0 | C8H9ClO4S | 详情 | 详情 |
| (VI) | 52134 | 1-[(3,4-dimethoxyphenyl)sulfonyl]-4-piperidinyl 4-(trifluoromethyl)phenyl ether; 1-[(3,4-dimethoxyphenyl)sulfonyl]-4-[4-(trifluoromethyl)phenoxy]piperidine | C20H22F3NO5S | 详情 | 详情 | |
| (VII) | 52135 | 2,3-dimethoxy-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzoic acid | C21H22F3NO7S | 详情 | 详情 | |
| (VIII) | 52136 | 2,3-dimethoxy-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzoyl chloride | C21H21ClF3NO6S | 详情 | 详情 | |
| (IX) | 52106 | 2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine | C5H11NO2 | 详情 | 详情 | |
| (X) | 52137 | 2,3-dimethoxy-N-(tetrahydro-2H-pyran-2-yloxy)-6-([4-[4-(trifluoromethyl)phenoxy]-1-piperidinyl]sulfonyl)benzamide | C26H31F3N2O8S | 详情 | 详情 |