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【结 构 式】 
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【分子编号】56634 【品名】1,2,3,4-butanetetracarboxylic acid;1,2,3,4-Tetracarboxybutane 【CA登记号】1703-58-8 |
【 分 子 式 】C8H10O8 【 分 子 量 】234.1626 【元素组成】C 41.03% H 4.3% O 54.66% |
合成路线1
该中间体在本合成路线中的序号：(XV)Cyclization of the tetracarboxylic acid (XV) gives 4-oxocyclopentane-1,2-dicarboxylic acid (XVI), which is esterified with ethanol and sulfuric acid to yield the diester (XVII). Reaction of diester (XVII) with methyl-(triphenyl)phosphonium bromide and t-BuOK in THF affords 4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (XVIII), which is hydrolyzed with KOH in THF/water to provide the corresponding free acid (XIX). The anhydrization of (XIX) by means of propionic anhydride at 135 C gives anhydride (III), which is submitted to an enantioselective quinine-mediated alcoholysis with 3-phenyl-2-propen-1-ol (XX) to yield (1R,2S)-2-amino-4-methylenecyclopentane-1-carboxylic acid 3-phenyl-2-propenyl monoester (XXI). Degradation of the free carboxylic acid group of (XXI) by means of DPPA, TEA and alcohol (XX) in hot toluene affords carbamate (XXII), which is finally fully deprotected with Pd(OAc)2 and PPh3 in ethanol.
| 【1】 Mittendorf, J.; Kunisch, F.; Matzke, M.; Militzer, H.-C.; Schmidt, A.; Schonfeld, W.; Novel antifungal beta-amino acids: Synthesis and activity against Candida albicans. Bioorg Med Chem Lett 2003, 13, 3, 433. |
| 【2】 Sorbera, L.A.; Castañer, J.; Bozzo, J.; PLD-118. Drugs Fut 2002, 27, 11, 1049. |
| 【3】 Schoenfeld, W.; Discovery, synthesis and SAR of beta-amino acid BAY 10-888/PLD-118, a novel antifungal for treatment of yeast infections. 42nd Intersci Conf Antimicrob Agents Chemother (Sept 27 2002, San Diego) 2002, Abst F-811. |
| 【4】 Mittendorf, J. (Bayer AG); Efficient and highly enantioselective process for the preparation of enantiomerically pure cyclopentane-beta-amino acids . EP 0805145 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 56629 | (3aR,6aS)-5-methylenetetrahydro-1H-cyclopenta[c]furan-1,3(3aH)-dione | C8H8O3 | 详情 | 详情 | |
| (XV) | 56634 | 1,2,3,4-butanetetracarboxylic acid;1,2,3,4-Tetracarboxybutane | 1703-58-8 | C8H10O8 | 详情 | 详情 |
| (XVI) | 56635 | 4-oxo-1,2-cyclopentanedicarboxylic acid | C7H8O5 | 详情 | 详情 | |
| (XVII) | 56636 | diethyl 4-oxo-1,2-cyclopentanedicarboxylate | C11H16O5 | 详情 | 详情 | |
| (XVIII) | 56638 | diethyl 4-methylene-1,2-cyclopentanedicarboxylate | C12H18O4 | 详情 | 详情 | |
| (XIX) | 56639 | 4-methylene-1,2-cyclopentanedicarboxylic acid | C8H10O4 | 详情 | 详情 | |
| (XX) | 13951 | (E)-3-Phenyl-2-propen-1-ol | 104-54-1 | C9H10O | 详情 | 详情 |
| (XXI) | 27283 | (1S,2R)-4-methylene-2-([[(E)-3-phenyl-2-propenyl]oxy]carbonyl)cyclopentanecarboxylic acid | C17H18O4 | 详情 | 详情 | |
| (XXII) | 56637 | (E)-3-phenyl-2-propenyl (1R,2S)-4-methylene-2-{[({[(E)-3-phenyl-2-propenyl]oxy}carbonyl)amino]carbonyl}cyclopentanecarboxylate | C27H27NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVI)Esterification of 1,2,3,4-butanetetracarboxylic acid (XXXVI) with EtOH in the presence of H2SO4 in refluxing toluene yields the corresponding tetraethyl ester (XXXVII), which upon treatment with NaOMe in MeOH followed by HCl in refluxing H2O yields trans-4-oxocyclopentane-1,2-dicarboxylic acid (rac-[XXXVIII]). Reduction of intermediate (XXXVIII) with H2 over Rh/C in the presence of NaOH in H2O followed by treatment with H2SO4 in acetone furnishes meso-4-hydroxycyclopentane-1,2-dicarboxylic acid (rac-[XXXIX]), which upon treatment with ethyl chloroformate in the presence of Et3N in THF affords lactone acid (rac-[VI]). Acid rac-(VI) is esterified with benzyl alcohol in the presence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and DMAP in EtOAc. Benzyl ester (rac-[XL]) is treated with Amberlyst-15 or MsOH in MeOH, affording racemic cyclopentanol (rac-[XVIII]). Finally, racemate rac-(XVIII) is resolved by chiral HPLC, yielding the desired (R,R,R)-isomer intermediate (XVIII) .
Intermediate (XV) is prepared from intermediate (XVIII) by hydrogenolysis with H2 over Pd/C in THF or DMF and subsequent amidation of the resulting carboxylic acid (XLI) with N-methylhex-5-enamine (VII) in the presence of DIEA, HATU or O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU) in DMF or acetonitrile, or EDC in the presence or absence of DMAP in THF or CH2Cl2, or EEDQ in refluxing THF .
| 【1】 Llinas-Brunet, M., Bailey, M.D., Cameron, D. et al. (Boehringer Ingelheim [Canada] Ltd.). Hepatitis C inhibitor tri-peptides. CA 2338946, EP 1105413, EP 2028186, JP 2002522554, US 6323180, WO 2000009543. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(VI) | 69297 | racemic 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylic acid | C7H8O4 | 详情 | 详情 | |
| rac-(XL) | 69300 | racemic benzyl 3-oxo-2-oxabicyclo[2.2.1]heptane-5-carboxylate | C14H14O4 | 详情 | 详情 | |
| rac-(XVIII) | 69298 | racemic 1-benzyl 2-methyl 4-hydroxycyclopentane-1,2-dicarboxylate | C15H18O5 | 详情 | 详情 | |
| (VII) | 69268 | N-methylhex-5-enamine;N-methylhex-5-en-1-amine | C7H15N | 详情 | 详情 | |
| (XV) | 69276 | (1S,2S,4S)-methyl 2-(hex-5-en-1-yl(methyl)carbamoyl)-4-hydroxycyclopentanecarboxylate | C15H25NO4 | 详情 | 详情 | |
| (XVIII) | 69299 | (1S,2S,4S)-1-benzyl 2-methyl 4-hydroxycyclopentane-1,2-dicarboxylate | C15H18O5 | 详情 | 详情 | |
| (XXXVI) | 56634 | 1,2,3,4-butanetetracarboxylic acid;1,2,3,4-Tetracarboxybutane | 1703-58-8 | C8H10O8 | 详情 | 详情 |
| (XXXVII) | 69294 | tetraethyl butane-1,2,3,4-tetracarboxylate | C16H26O8 | 详情 | 详情 | |
| (XXXVIII) | 69295 | racemic 4-oxocyclopentane-1,2-dicarboxylic acid | C7H8O5 | 详情 | 详情 | |
| (XXXIX) | 69296 | racemic 4-hydroxycyclopentane-1,2-dicarboxylic acid | C7H10O5 | 详情 | 详情 | |
| (XLI) | 69301 | (1S,2S,4S)-4-hydroxy-2-(methoxycarbonyl)cyclopentanecarboxylic acid | C8H12O5 | 详情 | 详情 |