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【结 构 式】 
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【分子编号】16013 【品名】dibenzyl malonate 【CA登记号】15014-25-2 |
【 分 子 式 】C17H16O4 【 分 子 量 】284.31164 【元素组成】C 71.82% H 5.67% O 22.51% |
合成路线1
该中间体在本合成路线中的序号：(IV)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：(VI)In a different procedure, dibenzyl malonate (VI) was alkylated with tetradecyl bromide (B) to afford (VII). This was then condensed with N-phthaloyl-L-alanyl chloride (VIII) in the presence of NaH, and the resulting keto diester (IX) was subjected to hydrogenolysis of the benzyl esters and further thermal decarboxylation to furnish ketone (X). Ketone reduction with simultaneous partial reduction of the phthaloyl group yielded (XI) and (XII) as a diastereomeric mixture. After chromatographic separation, the desired isomers were deprotected by reductive cleavage with NaBH4 to provide the corresponding amino alcohol.
| 【1】 Cuadros, R.; et al.; The marine compound spisulosine, an inhibitor of cell proliferation, promotes the disassembly of actin stress fibers. Cancer Letters 2000, 152, 1, 23. |
| 【2】 Garcia Gravalos, D.; Warwick, R.A.; Avila, J.; Rinehart, K.L.; Fregeau, N.L.; Faircloth, G.T. (University of Illinois); Spisulosine cpds. having antitumour activity. WO 9952521 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 47267 | 1-bromotetradecane | 112-71-0 | C14H29Br | 详情 | 详情 |
| (XIa) | 47272 | 3-hydroxy-2-[(1S,2R)-2-hydroxy-1-methylheptadecyl]-1-isoindolinone | C26H43NO3 | 详情 | 详情 | |
| (XIb) | 47273 | 3-hydroxy-2-[(1S,2S)-2-hydroxy-1-methylheptadecyl]-1-isoindolinone | C26H43NO3 | 详情 | 详情 | |
| (XIIa) | 47274 | 2-(hydroxymethyl)-N-[(1S,2R)-2-hydroxy-1-methylheptadecyl]benzamide | C26H45NO3 | 详情 | 详情 | |
| (XIIb) | 47275 | 2-(hydroxymethyl)-N-[(1S,2S)-2-hydroxy-1-methylheptadecyl]benzamide | C26H45NO3 | 详情 | 详情 | |
| (VI) | 16013 | dibenzyl malonate | 15014-25-2 | C17H16O4 | 详情 | 详情 |
| (VII) | 47268 | dibenzyl 2-tetradecylmalonate | C31H44O4 | 详情 | 详情 | |
| (VIII) | 47269 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl chloride | C11H8ClNO3 | 详情 | 详情 | |
| (IX) | 47270 | dibenzyl 2-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoyl]-2-tetradecylmalonate | C42H51NO7 | 详情 | 详情 | |
| (X) | 47271 | 2-[(1S)-1-methyl-2-oxoheptadecyl]-1H-isoindole-1,3(2H)-dione | C26H39NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Dibenzyl malonate (I) was alkylated with 3-(trifluoromethyl)benzyl bromide (II) in the presence of Na in DMF to yield the 3-(trifluoromethyl)benzylmalonate (III). Further alkylation of (III) with 1,4-dibromobutane (IV) provided the bromobutyl derivative (V). Condensation of the known 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8-one (VI) with bromide (V) in the presence of NaH and NaI furnished adduct (VII). The keto group of (VII) was then reduced to alcohol (VIII) employing NaBH4 in MeOH-CH2Cl2. Finally, hydrogenolysis of the benzyl ester groups of (VIII) in the presence of Pd/C and Et3N afforded the title dicarboxylate triethylammonium salt.
| 【1】 Bookser, B.C.; Kasibhatla, S.R.; Erion, M.D.; AMP deaminase inhibitors. 4. Further N3-substituted coformycin aglycon analogues: N3-alkylmalonates as ribose 5'-monophosphate mimetics. J Med Chem 2000, 43, 8, 1519. |
| 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) | 40803 | 1-(bromomethyl)-3-(trifluoromethyl)benzene | 402-23-3 | C8H6BrF3 | 详情 | 详情 |
| (III) | 40804 | dibenzyl 2-[3-(trifluoromethyl)benzyl]malonate | C25H21F3O4 | 详情 | 详情 | |
| (IV) | 11883 | 1,4-Dibromobutane; 1,4-Butylene bromide | 110-52-1 | C4H8Br2 | 详情 | 详情 |
| (V) | 40805 | dibenzyl 2-(4-bromobutyl)-2-[3-(trifluoromethyl)benzyl]malonate | C29H28BrF3O4 | 详情 | 详情 | |
| (VI) | 40806 | 6,7-dihydroimidazo[4,5-d][1,3]diazepin-8(3H)-one | C6H6N4O | 详情 | 详情 | |
| (VII) | 40807 | dibenzyl 2-[4-[8-oxo-7,8-dihydroimidazo[4,5-d][1,3]diazepin-3(6H)-yl]butyl]-2-[3-(trifluoromethyl)benzyl]malonate | C35H33F3N4O5 | 详情 | 详情 | |
| (VIII) | 40808 | dibenzyl 2-[4-[8-hydroxy-7,8-dihydroimidazo[4,5-d][1,3]diazepin-3(6H)-yl]butyl]-2-[3-(trifluoromethyl)benzyl]malonate | C35H35F3N4O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)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 |