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【结 构 式】 
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【药物名称】KB-R7785 【化学名称】N-[4-(Hydroxyamino)-2(R)-isobutyl-3(S)-methylsuccinyl]-L-2-phenylglycine methylamide 【CA登记号】168158-16-5, 168393-60-0 (stereoisomer), 168393-52-0 (undefined isomer), 168393-53-1 (undefined isomer, monosodium salt) 【 分 子 式 】C18H27N3O4 【 分 子 量 】349.43359 |
【开发单位】Kanebo (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Heart Failure Therapy, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, ONCOLYTIC DRUGS, Stroke, Treatment of, Heparin-Binding Epidermal Growth Factor (HB-EGF) Shedding Inhibitors, MMP-9 (Gelatinase B) Inhibitors, TNF-alpha Antagonists |
合成路线1
Esterification of (S)-2-bromo-4-methylpentanoic acid (I) with isobutylene in the presence of H2SO4 affords the corresponding tert-butyl ester (II). Subsequent alkylation of dibenzyl malonate with bromoester (II) gives triester (III). After acidic tert-butyl group cleavage in (III), the resultant acid (IV) is coupled with L-phenylglycine-N-methylamide (V), yielding diamide (VI). Transfer hydrogenolysis of the dibenzyl ester (VI) with ammonium formate and Pd/C produces diacid (VII). Mannich reaction of malonic acid (VII) with formaldehyde and piperidine, with concomitant decarboxylation, leads to the alpha-methylene carboxylic acid (VIII), which is further coupled to O-benzyl hydroxylamine giving hydroxamate (IX). Simultaneous double bond hydrogenation and O-debenzylation of (IX) then produces a diastereomeric mixture of alpha-methyl hydroxamic acids, from which the desired diastereoisomer is isolated by preparative HPLC.
| 【2】 Hirayama, R.; Tsukida, T.; Yamamoto, M.; Ikeda, S.; Sakamoto, F.; Obata, Y.; Matsuo, K. (Kanebo Pharmaceuticals, Ltd.); Acylphenylglycine deriv. and preventive and remedy for diseases caused by increased collagenase activity containing said cpd. as active ingredient. EP 0712838; JP 1995101925; US 5795891; WO 9504715 . |
| 【1】 Hirayama, R.; et al.; Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors. Bioorg Med Chem 1997, 5, 4, 765. |
| 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) | 26058 | (2S)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
| (II) | 26059 | tert-butyl (2S)-2-bromo-4-methylpentanoate | C10H19BrO2 | 详情 | 详情 | |
| (III) | 16014 | 1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate | C27H34O6 | 详情 | 详情 | |
| (IV) | 56999 | (2R)-2-{2-(benzyloxy)-1-[(benzyloxy)carbonyl]-2-oxoethyl}-4-methylpentanoic acid | C23H26O6 | 详情 | 详情 | |
| (V) | 57000 | (2S)-2-amino-N-methyl-2-phenylethanamide | C9H12N2O | 详情 | 详情 | |
| (VI) | 57001 | dibenzyl 2-[(1R)-3-methyl-1-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)butyl]malonate | C32H36N2O6 | 详情 | 详情 | |
| (VII) | 57002 | 2-[(1R)-3-methyl-1-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)butyl]malonic acid | C18H24N2O6 | 详情 | 详情 | |
| (VIII) | 57003 | 2-[(1R)-3-methyl-1-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)butyl]acrylic acid | C18H24N2O4 | 详情 | 详情 | |
| (IX) | 57004 | (2R)-N~4~-(benzyloxy)-2-isobutyl-N~1~-[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]-3-methylenebutanediamide | C25H31N3O4 | 详情 | 详情 |
合成路线2
An alternative, stereoselective synthesis has been reported. The alkylation of the chiral N-acyl oxazolidinone (I) with benzyl L-2-[(trifluoromethylsulfonyl)oxy]propionate (II) leads to the succinic acid derivative (III). After hydrogenolysis of the benzyl ester group of (III), the resultant carboxylic acid (IV) is esterified with isobutylene and H2SO4 to afford the tert-butyl ester (V). Removal of the chiral auxiliary group of (V) is then effected by hydrolysis with lithium peroxide, yielding acid (VI). Subsequent coupling of (VI) with L-phenylglycine-N-methylamide (VII) provides diamide (VIII). Acidic tert-butyl ester cleavage in (VIII) gives acid (IX), which is condensed with O-benzyl hydroxylamine to furnish hydroxamate (X). The O-benzyl group of (X) is finally removed by catalytic hydrogenolysis over Pd/C.
| 【1】 Hirayama, R.; et al.; Synthesis and biological evaluation of orally active matrix metalloproteinase inhibitors. Bioorg Med Chem 1997, 5, 4, 765. |
| 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) | 25391 | (4S)-4-benzyl-3-(4-methylpentanoyl)-1,3-oxazolidin-2-one | C16H21NO3 | 详情 | 详情 | |
| (II) | 43504 | benzyl (2S)-2-[[(trifluoromethyl)sulfonyl]oxy]propanoate | C11H11F3O5S | 详情 | 详情 | |
| (III) | 57005 | benzyl (2S,3R)-3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2,5-dimethylhexanoate | C26H31NO5 | 详情 | 详情 | |
| (IV) | 57006 | (2S,3R)-3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2,5-dimethylhexanoic acid | C19H25NO5 | 详情 | 详情 | |
| (V) | 57007 | tert-butyl (2S,3R)-3-{[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-2,5-dimethylhexanoate | C23H33NO5 | 详情 | 详情 | |
| (VI) | 57008 | (2R)-2-[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]-4-methylpentanoic acid | C13H24O4 | 详情 | 详情 | |
| (VII) | 57000 | (2S)-2-amino-N-methyl-2-phenylethanamide | C9H12N2O | 详情 | 详情 | |
| (VIII) | 57009 | tert-butyl (2S,3R)-2,5-dimethyl-3-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)hexanoate | C22H34N2O4 | 详情 | 详情 | |
| (IX) | 57010 | (2S,3R)-2,5-dimethyl-3-({[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]amino}carbonyl)hexanoic acid | C18H26N2O4 | 详情 | 详情 | |
| (X) | 57004 | (2R)-N~4~-(benzyloxy)-2-isobutyl-N~1~-[(1S)-2-(methylamino)-2-oxo-1-phenylethyl]-3-methylenebutanediamide | C25H31N3O4 | 详情 | 详情 |