【结 构 式】 |
【药物名称】 【化学名称】5-Phenyl-2-[4-(pyridin-4-ylcarbonyl)phenylsulfonylmethyl]pentanohydroxamic acid hydrochloride 【CA登记号】203248-89-9 【 分 子 式 】C24H25ClN2O5S 【 分 子 量 】488.99425 |
【开发单位】Celltech (Originator) 【药理作用】Antiarthritic Drugs, Oncolytic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, MMP-2 (Gelatinase A) Inhibitors, MMP-8 (Neutrophil Collagenase) Inhibitors, MMP-9 (Gelatinase B) Inhibitors |
合成路线1
Alkylation of the sodium salt of dibenzyl malonate (I) with 1-bromo-3-phenylpropane (II) afforded the (phenylpropyl)malonate (III). The benzyl ester groups of (III) were removed by hydrogenolysis in the presence of Pd/C to produce the intermediate malonic acid (IV). Subsequent condensation of diacid (IV) with formaldehyde in the presence of piperidine proceeded with concomitant decarboxylation, yielding 2-methylene-5-phenylpentanoic acid (V). Addition of HBr to the unsaturated acid (V) gave bromide (VI). Condensation of (VI) with thiophenol (VIII), prepared by nucleophilic displacement of 4-(4-chlorobenzoyl)pyridine (VI) with sodium hydrogen sulfide, furnished the sulfide adduct (IX). This was oxidized to the corresponding sulfone (X) by treatment with Oxone(R). Conversion of (X) to the desired hydroxamic acid was carried out by coupling with O-tert-butyldimethylsilyl hydroxylamine, followed by deprotection of the resulting O-silyl hydroxamate (XI) with tetrabutylammonium fluoride.
【1】 Baxter, A.D.; et al.; Arylsulphonyl hydroxamic acids: Potent and selective matrix metalloproteinase inhibitors. Bioorg Med Chem Lett 2001, 11, 11, 1465. |
【2】 Owen, D.A.; Montana, J.G.; Keily, J.F.; Watson, R.J.; Baxter, A.D. (Celltech Group plc); Hydroxamic and carboxylic acid derivs. having MMP and TNF inhibitory activity. EP 0968182; JP 2000517297; WO 9805635 . |
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) | 16013 | dibenzyl malonate | 15014-25-2 | C17H16O4 | 详情 | 详情 |
(II) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
(III) | 52539 | bis(phenylmethyl) 2-(3-phenylpropyl)propanedioate | C26H26O4 | 详情 | 详情 | |
(IV) | 52540 | 2-(3-phenylpropyl)propanedioic acid | C12H14O4 | 详情 | 详情 | |
(V) | 52541 | 2-(3-phenylpropyl)-2-propenoic acid | C12H14O2 | 详情 | 详情 | |
(VI) | 52542 | 2-(bromomethyl)-5-phenylpentanoic acid | C12H15BrO2 | 详情 | 详情 | |
(VII) | 52543 | (4-chlorophenyl)(4-pyridinyl)methanone | C12H8ClNO | 详情 | 详情 | |
(VIII) | 52544 | 4-pyridinyl(4-sulfanylphenyl)methanone | C12H9NOS | 详情 | 详情 | |
(IX) | 52545 | 5-phenyl-2-({[4-(4-pyridinylcarbonyl)phenyl]sulfanyl}methyl)pentanoic acid | C24H23NO3S | 详情 | 详情 | |
(X) | 52546 | 5-phenyl-2-({[4-(4-pyridinylcarbonyl)phenyl]sulfonyl}methyl)pentanoic acid | C24H23NO5S | 详情 | 详情 | |
(XI) | 52547 | N-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-phenyl-2-({[4-(4-pyridinylcarbonyl)phenyl]sulfonyl}methyl)pentanamide | C30H38N2O5SSi | 详情 | 详情 |