【结 构 式】 |
【药物名称】 【化学名称】3(R)-(Cyclopentylmethyl)-2(R)-[N-methyl-N-(methylsulfonyl)aminomethyl]-4-oxo-4-(1-piperidinyl)butyrohydroxamic acid 【CA登记号】 【 分 子 式 】C18H33N3O5S 【 分 子 量 】403.54481 |
【开发单位】British Biotech (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, MMP-1 (Interstitial Collagenase) Inhibitors |
合成路线1
The intermediate amide (IV) can be obtained by two related methods. The homochiral methylenesuccinate (I) was coupled with piperidine (II) in the presence of EDC and HOBt to afford amide (III). Subsequent stereoselective conjugate addition of methylamine produced the (R,R)-amine (IV). In a related procedure, conjugate addition of methylamine to unsaturated ester (V) gave adduct (VI). Acid cleavage of the tert-butyl ester of (VI) generated carboxylic acid (VII), which was then coupled with piperidine (II) to provide (IV). Sulfonamide (VIII) was prepared by condensation of amine (IV) with methanesulfonyl chloride. Hydrogenolysis of the benzyl ester of (VIII) yielded acid (IX), which was finally coupled with hydroxylamine producing the title hydroxamic acid.
【1】 Bellamy, C.L.; Beckett, R.P.; Martin, F.M.; et al.; The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors. Bioorg Med Chem Lett 1999, 9, 19, 2887. |
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) | 40352 | (2R)-3-[(benzyloxy)carbonyl]-2-(cyclopentylmethyl)-3-butenoic acid | C18H22O4 | 详情 | 详情 | |
(II) | 10158 | Piperidine | 110-89-4 | C5H11N | 详情 | 详情 |
(III) | 40353 | benzyl 2-[(1R)-1-(cyclopentylmethyl)-2-oxo-2-(1-piperidinyl)ethyl]acrylate | C23H31NO3 | 详情 | 详情 | |
(IV) | 40354 | benzyl (2R,3R)-3-(cyclopentylmethyl)-2-[(methylamino)methyl]-4-oxo-4-(1-piperidinyl)butanoate | C24H36N2O3 | 详情 | 详情 | |
(V) | 40355 | 4-benzyl 1-(tert-butyl) (2R)-2-(cyclopentylmethyl)-3-methylenebutanedioate | C22H30O4 | 详情 | 详情 | |
(VI) | 40356 | 4-benzyl 1-(tert-butyl) (2R,3R)-2-(cyclopentylmethyl)-3-[(methylamino)methyl]butanedioate | C23H35NO4 | 详情 | 详情 | |
(VII) | 40357 | (2R,3R)-4-(benzyloxy)-2-(cyclopentylmethyl)-3-[(methylamino)methyl]-4-oxobutyric acid | C19H27NO4 | 详情 | 详情 | |
(VIII) | 40358 | benzyl (2R,3R)-3-(cyclopentylmethyl)-2-[[methyl(methylsulfonyl)amino]methyl]-4-oxo-4-(1-piperidinyl)butanoate | C25H38N2O5S | 详情 | 详情 | |
(IX) | 40359 | (2R,3R)-3-(cyclopentylmethyl)-2-[[methyl(methylsulfonyl)amino]methyl]-4-oxo-4-(1-piperidinyl)butyric acid | C18H32N2O5S | 详情 | 详情 |