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【结 构 式】 
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【分子编号】16014 【品名】1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate 【CA登记号】 |
【 分 子 式 】C27H34O6 【 分 子 量 】454.56336 【元素组成】C 71.34% H 7.54% O 21.12% |
合成路线1
该中间体在本合成路线中的序号：(V)The treatment of D-leucine (I) with NaNO2, H2SO4 and NaBr gives 2(R)-bromo-5-methylpentanoic acid (II), which is esterified with isobutene and H2SO4 to the corresponding tert-butyl ester (III). The condensation of (III) with dibenzyl malonate (IV) by means of potassium tert-butoxide in DMF yields the malonyl derivative (V), which is treated with trifluoroacetic acid to hydrolyze the tert-butyl ester, and without isolation is condensed with L-phenylalanine methyl amide (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC), affording 4-benzyloxy-3-(benzyloxycarbonyl)-2(R)-isobutylsuccinyl-L-phenylalanine methylamide (VII). The elimination of the benzyl groups of (VII) by hydrogenolysis over Pd/C in ethanol gives the dicarboxylic acid (VIII), which by partial decarboxylation and reaction with aqueous formaldehyde and piperidine yields 4-hydroxy-2(R)-isobutyl-3-methylenesuccinyl-L-phenylalanine methylamide (IX). The addition of thiophene-2-thiol (X) to the double bond of (IX) affords 4-hydroxy-2(R)-isobutyl-3(S)-(2-thienylsulfanylmethyl)succinyl-L-phenylalanine methylamide (XI), which is finally treated with hydroxylamine and hydroxybenzotriazole in dichloromethane/DMF.
| 【1】 Ngo, J.; Graul, A.; Castaner, J.; Batimastat. Drugs Fut 1996, 21, 12, 1215. |
| 【2】 Campion, C.; Davidson, A.H.; Dickens, J.P.; Crimmin, M.J. (British Biotech plc); Hydroxamic acid based collagenase inhibitors. US 5240958; US 5310763; WO 9005719 . |
| 【3】 Beckett, R.P.; Crimmin, M.J.; Galloway, W.A.; Matrix metalloproteinase inhibitors in the treatment of rheumatoid arthritis and cancer. 205th ACS Natl Meet (March 28-April 2, Denver) 1993, Abst MEDI 147. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 15926 | 2-methyl-1-propene; isobutylene | 115-11-7 | C4H8 | 详情 | 详情 | |
| (I) | 16010 | D-leucine | 328-38-1 | C6H13NO2 | 详情 | 详情 |
| (II) | 16011 | (2R)-2-bromo-4-methylpentanoic acid | C6H11BrO2 | 详情 | 详情 | |
| (III) | 16012 | tert-butyl (2R)-2-bromo-4-methylpentanoate | C10H19BrO2 | 详情 | 详情 | |
| (IV) | 16013 | dibenzyl malonate | 15014-25-2 | C17H16O4 | 详情 | 详情 |
| (V) | 16014 | 1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate | C27H34O6 | 详情 | 详情 | |
| (VI) | 16015 | (2S)-2-amino-N-methyl-3-phenylpropanamide | C10H14N2O | 详情 | 详情 | |
| (VII) | 16016 | dibenzyl 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonate | C33H38N2O6 | 详情 | 详情 | |
| (VIII) | 16017 | 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonic acid | C19H26N2O6 | 详情 | 详情 | |
| (IX) | 16018 | 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]acrylic acid | C19H26N2O4 | 详情 | 详情 | |
| (X) | 16019 | 2-Thienylhydrosulfide; 2-Thiophenethiol | 7774-74-5 | C4H4S2 | 详情 | 详情 |
| (XI) | 16020 | (2S,3R)-3-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-5-methyl-2-[(2-thienylsulfanyl)methyl]hexanoic acid | C23H30N2O4S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)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 |