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【结 构 式】 
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【分子编号】26664 【品名】2,5-dimethoxytetrahydro-3-furancarbaldehyde 【CA登记号】 |
【 分 子 式 】C7H12O4 【 分 子 量 】160.16988 【元素组成】C 52.49% H 7.55% O 39.96% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (I) with 2-(trimethylsilyl)-1,3-dithiane (II) by means of BuLi in THF gives the expected condensation product (III), which is treated with HgCl2 and methanol in THF/water yielding 2-(2,5-dimethoxytetrahydrofuran-3-yl)acetic acid methyl ester (IV). The cyclization of (IV) with 4'-aminobiphenyl-4-carbonitrile (V) by means of CDE in hot trifluorocetic acid affords the biphenylylpyrrole (VI), which is hydrolyzed with LiOH and condensed with the chiral auxiliary 4(S)- benzyloxazolidin-2-one (VII) by means of pivaloyl chloride, BuLi and TEA in THF giving the acylated thiazolidine (VIII). The stereocontrolled reaction of (VIII) with benzyl bromoacetate (IX) by means of sodium hexamethyldisylazane (NaHMDS) in THF yields the succinamic ester (X), which is hydrolyzed with LiOH in THF/water to afford the succinic acid monoester (XI). The amidation of (XI) with 3(S)-amino-4,4-dimethyltetrahydrofuran-2-one (XII) by means of TBTU and NMM in DMF provides the succinamic ester derivative (XIII), which is debenzylated by hydrogenation with H2 over Pd/C in methanol.
| 【1】 Deal, J.G.; Bender, S.L.; Chong, W.K.M.; et al.; Preparation of various P1'-heterocyclic succinamide inhibitors of matrix metalloproteases (MMP's). 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 197. |
| 【2】 Bender, S.L.; Castelhano, A.L.; Chong, W.K.M.; Abreo, M.A.; Billedeau, R.J.; Chen, J.J.; Deal, J.G. (Agouron Pharmaceuticals, Inc.; Syntex (USA), Inc.); Heteroaryl succinamides and their use as metalloproteinase inhibitors. EP 0937042; JP 2000511201; US 6008243; WO 9817643 . |
| 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) | 26664 | 2,5-dimethoxytetrahydro-3-furancarbaldehyde | C7H12O4 | 详情 | 详情 | |
| (II) | 16517 | 1,3-dithian-2-yl(trimethyl)silane; 2-Trimethylsilyl-1,3-dithiane | 13411-42-2 | C7H16S2Si | 详情 | 详情 |
| (III) | 26665 | 3-(1,3-dithian-2-ylidenemethyl)-2,5-dimethoxytetrahydrofuran | C11H18O3S2 | 详情 | 详情 | |
| (IV) | 26666 | methyl 2-(2,5-dimethoxytetrahydro-3-furanyl)acetate | C9H16O5 | 详情 | 详情 | |
| (V) | 26667 | 4'-amino[1,1'-biphenyl]-4-carbonitrile | 4854-84-6 | C13H10N2 | 详情 | 详情 |
| (VI) | 26668 | methyl 2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]acetate | C20H16N2O2 | 详情 | 详情 | |
| (VII) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (VIII) | 26669 | 4'-(3-[2-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-2-oxoethyl]-1H-pyrrol-1-yl)[1,1'-biphenyl]-4-carbonitrile | C29H23N3O3 | 详情 | 详情 | |
| (IX) | 26670 | benzyl (3S)-4-[(4S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutanoate | C38H31N3O5 | 详情 | 详情 | |
| (X) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (XI) | 26671 | (2S)-4-(benzyloxy)-2-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-oxobutyric acid | C28H22N2O4 | 详情 | 详情 | |
| (XII) | 26672 | (3S)-3-amino-4,4-dimethyldihydro-2(3H)-furanone | C6H11NO2 | 详情 | 详情 | |
| (XIII) | 26673 | benzyl (3S)-3-[1-(4'-cyano[1,1'-biphenyl]-4-yl)-1H-pyrrol-3-yl]-4-[[(3S)-4,4-dimethyl-2-oxotetrahydro-3-furanyl]amino]-4-oxobutanoate | C34H31N3O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Treatment of 3,4-difluoronitrobenzene (I) with benzylamine yielded nitroaniline (II), which was reduced to diamine (III) by hydrogenation over Pt/C. Protection of (III) with benzyl chloroformate produced the bis(carbamate) (IV). Conversion of (IV) to the chiral oxazolidinone (VI) was accomplished by treatment with (R)-glycidyl butyrate (V) and n-butyllithium. The alcohol group of (VI) was converted to mesylate (VII) and then displaced with potassium phthalimide to give (VIII). Further hydrazinolysis of (VIII), followed by acetylation of the resulting amine gave acetamide (IX). Hydrogenation of (IX) in the presence of Pd/C removed both N-benzyl and carbamate groups to give the primary amine (X). Condensation of (X) with 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (XI) in refluxing AcOH furnished the required 3-formylpyrrole (XII). The resulting aldehyde (XII) was then condensed with hydroxylamine and the intermediate oxime was finally converted to the target nitrile employing PPh3 as the dehydrating agent.
| 【1】 Genin, M.J.; et al.; Substituent effects on the antibacterial activity of novel highly potent nitrogen-bound azolylphenyl oxazolidinones. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-138. |
| 【2】 Genin, M.J.; Hutchinson, D.K.; Allwine, D.A.; Hester, J.B.; Emmert, D.E.; Garmon, S.A.; Ford, C.W.; Zurenko, G.E.; Hamel, J.C.; Schaadt, R.D.; Stapert, D.; Yagi, B.H.; Friis, J.M.; Shobe, E.M.; Adams, W.J.; Nitrogen-carbon-linked (azolylphenyl)oxazolidinones with potent antibacterial activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. J Med Chem 1998, 41, 26, 5144. |
| 【3】 Anderson, D.J.; Allwine, D.A.; Genin, M.J.; et al.; Substituted effects of the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. J Med Chem 2000, 43, 5, 953. |
| 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) | 17013 | 1,2-difluoro-4-nitrobenzene; 3,4-Difluoronitrobenzene | 369-34-6 | C6H3F2NO2 | 详情 | 详情 |
| (II) | 28497 | N-benzyl-2-fluoro-4-nitroaniline | C13H11FN2O2 | 详情 | 详情 | |
| (III) | 28498 | N-(4-amino-2-fluorophenyl)-N-benzylamine | C13H13FN2 | 详情 | 详情 | |
| (IV) | 28499 | benzyl benzyl(4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl)carbamate | C29H25FN2O4 | 详情 | 详情 | |
| (V) | 18385 | (2R)oxiranylmethyl butyrate;(R)-glycidyl butyrate | 60456-26-0 | C7H12O3 | 详情 | 详情 |
| (VI) | 28500 | benzyl benzyl[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]carbamate | C25H23FN2O5 | 详情 | 详情 | |
| (VII) | 28501 | [(5R)-3-(4-[benzyl[(benzyloxy)carbonyl]amino]-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate | C26H25FN2O7S | 详情 | 详情 | |
| (VIII) | 28502 | benzyl benzyl(4-[(5S)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl)carbamate | C33H26FN3O6 | 详情 | 详情 | |
| (IX) | 28503 | benzyl 4-[(5S)-5-[(acetamido)methyl]-2-oxo-1,3-oxazolidin-3-yl]-2-fluorophenyl(benzyl)carbamate | C27H26FN3O5 | 详情 | 详情 | |
| (X) | 28504 | N-[[(5S)-3-(4-amino-3-fluorophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl]acetamide | C12H14FN3O3 | 详情 | 详情 | |
| (XI) | 26664 | 2,5-dimethoxytetrahydro-3-furancarbaldehyde | C7H12O4 | 详情 | 详情 | |
| (XII) | 28505 | N-([(5S)-3-[3-fluoro-4-(3-formyl-1H-pyrrol-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl)acetamide | C17H16FN3O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 4-amino-1-benzylpiperidine (I) with 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (II) under modified Paal-Knorr conditions produced the pyrrole derivative (III). Construction of the target oxazole ring was then achieved by cyclocondensation reaction of aldehyde (III) with tosylmethyl isocyanide in the presence of NaOMe.
| 【1】 Hubner, H.; Gmeiner, P.; Haubmann, C.; Piperidinylpyrroles: Design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands. Bioorg Med Chem Lett 1999, 9, 21, 3143. |
| 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) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (II) | 26664 | 2,5-dimethoxytetrahydro-3-furancarbaldehyde | C7H12O4 | 详情 | 详情 | |
| (III) | 41973 | 1-(1-benzyl-4-piperidinyl)-1H-pyrrole-3-carbaldehyde | C17H20N2O | 详情 | 详情 |