|
【结 构 式】 
|
【分子编号】44022 【品名】(3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether 【CA登记号】 |
【 分 子 式 】C26H26FNO3 【 分 子 量 】419.4957832 【元素组成】C 74.44% H 6.25% F 4.53% N 3.34% O 11.44% |
合成路线1
该中间体在本合成路线中的序号：(XV)The condensation of 4-fluorobenzaldehyde (I) with ethyl acetoacetate (II) by means of piperidine, followed by a treatment with hot NaOH and esterification with methanol in acid medium, gives 3-(4-fluorophenyl)glutaric acid dimethyl ester (III), which is stereoselectively hydrolyzed with liver esterase in aqueous acetone, yielding the monoester (IV) with a 95% ee. The selective reduction of the ester group of (IV) with LiH and LiBH4 in THF affords the chiral 5-hydroxypentanoic acid (V), which is esterified with dimethyl sulfate in methanol to the corresponding methyl ester (VI). The reaction of (VI) with MsCl and TEA in toluene gives the mesylate (VII), which is cyclized with benzylamine (VIII) and TEA in toluene, affording the chiral piperidone (IX).The reaction of (IX) with dimethyl carbonate (X) and NaH in hot toluene yields the chiral carboxylate (XI), which is reduced at the carboxylate and ketonic groups with LiAlH4 or BH3 in DMSO, providing the chiral piperidine methanol derivative (XII). The reaction of (XII) with MsCl and TEA in toluene yields the mesylate (XIII), which is condensed with the phenol derivative (XIV) by means of NaH in hot DMF, affording the adduct (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.
| 【1】 Yu, M.S.; Lantos, I.; Cacchio, T.; Peng, Z.-Q.; Yu, J.; Asymmetric synthesis of (-)-paroxetine using PLE hydrolysis. Tetrahedron Lett 2000, 41, 30, 5647. |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (III) | 44013 | dimethyl 3-(4-fluorophenyl)pentanedioate | C13H15FO4 | 详情 | 详情 | |
| (IV) | 44014 | (3S)-3-(4-fluorophenyl)-5-methoxy-5-oxopentanoic acid | C12H13FO4 | 详情 | 详情 | |
| (V) | 44015 | lithium (3R)-3-(4-fluorophenyl)-5-hydroxypentanoate | C11H12FLiO3 | 详情 | 详情 | |
| (VI) | 44016 | methyl (3R)-3-(4-fluorophenyl)-5-hydroxypentanoate | C12H15FO3 | 详情 | 详情 | |
| (VII) | 44017 | methyl (3R)-3-(4-fluorophenyl)-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]pentanoate | C15H21FO3S | 详情 | 详情 | |
| (VIII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IX) | 44018 | (4R)-1-benzyl-4-(4-fluorophenyl)-2-piperidinone | C18H18FNO | 详情 | 详情 | |
| (X) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (XI) | 44019 | methyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-2-oxo-3-piperidinecarboxylate | C20H20FNO3 | 详情 | 详情 | |
| (XII) | 44020 | [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol | C19H22FNO | 详情 | 详情 | |
| (XIII) | 44021 | (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)piperidine | C22H28FNOS | 详情 | 详情 | |
| (XIV) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XV) | 44022 | (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether | C26H26FNO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)The reduction of L-pyroglutamic acid (I) with NaBH4 gives the chiral pyrrolidinone (II), which is cyclized with benzaldehyde (III) by means of Ts-OH in refluxing toluene to yield the N,O-acetal (IV). The reaction of (IV) with isobutyl chloroformate (V) and phenylselanyl chloride by means of LiHMDS in THF affords the selenoester (VI), which is treated directly with H2O2 in dichloromethane to provide the unsaturated bicyclic lactam (VII). The diastereoselective reaction of (VII) with lithium di(4-fuorophenyl)cuprate (VIII) gives the all-trans trisubstituted pyrrolidone (IX). The reduction of the carbonyl group (IX) with BH3 in THF that also causes the cleavage of the C-O bond of the oxazolidinone yields the pyrrolidine methanol derivative (X), which is submitted to ring expansion by treatment with MsCl, DCE and TEA to afford the expected trisubstituted 3-chloropiperidine (XI). The dechlorination of (XI) by means of Bu3SnH and AIBN in refluxing toluene provides the trans-1-benzyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid isobutyl ester (XII), which is reduced with LiAlH4 in THF to furnish the carbinol (XIII). The reaction of (XIII) with Ms-Cl and TEA in dichloromethane gives the corresponding mesylate (XIV), which is condensed with 1,3-benzodioxol-5-ol (XV) by means of sodium isopropoxide in refluxing isopropanol to yield the aryl ether (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol to afford the target trans-piperidine derivative.
| 【1】 Liu, L.T.; Hong, P.-C.; Huang, H.-L.; Chen, S.-F.; Wang, C.-L. J.; Wen, Y.-S.; ASsymetric syntheses of trans-3,4-disubstituted 2-piperidinones and piperidines. Tetrahedron Asymmetry 2001, 12, Suppl. 3, 419-26. |
| 【2】 Cossy, J.; et al.; Ring expansion: Formal total synthesis of (-)-paroxetine. Tetrahedron Lett 2001, 42, 33, 5705. |
| 【3】 Thottathil, J.K.; et al.; Conversion of L-pyroglutamic acid to 4-alkyl substituted L-prolines. The synthesis of trans-4-cyclohexyl L-proline. J Org Chem 1986, 51, 16, 3140. |
| 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) | 12085 | (2R)-5-Oxotetrahydro-1H-pyrrole-2-carboxylic acid; 5-Oxo-D-proline; D-Pyroglutamic acid; (R)-(+)-2-Pyrrolidone-5-carboxylic acid | 4042-36-8 | C5H7NO3 | 详情 | 详情 |
| (II) | 56485 | (5S)-5-(hydroxymethyl)-2-pyrrolidinone | C5H9NO2 | 详情 | 详情 | |
| (III) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (IV) | 38561 | (3R,7aS)-3-phenyltetrahydro-5H-pyrrolo[1,2-c][1,3]oxazol-5-one | 103201-79-2 | C12H13NO2 | 详情 | 详情 |
| (V) | 13423 | 1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate | 543-27-1 | C5H9ClO2 | 详情 | 详情 |
| (VI) | 56478 | isobutyl (3R,7aS)-5-oxo-3-phenyl-6-(phenylselanyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate | C23H25NO4Se | 详情 | 详情 | |
| (VII) | 56479 | isobutyl (3R,7aS)-5-oxo-3-phenyl-5,7a-dihydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate | C17H19NO4 | 详情 | 详情 | |
| (VIII) | 56475 | C27H25CuF4Li | 详情 | 详情 | ||
| (IX) | 56480 | isobutyl (3R,6S,7R,7aS)-7-(4-fluorophenyl)-5-oxo-3-phenyltetrahydro-1H-pyrrolo[1,2-c][1,3]oxazole-6-carboxylate | C23H24FNO4 | 详情 | 详情 | |
| (X) | 56481 | isobutyl (3S,4R,5S)-1-benzyl-4-(4-fluorophenyl)-5-(hydroxymethyl)-3-pyrrolidinecarboxylate | C23H28FNO3 | 详情 | 详情 | |
| (XI) | 56482 | isobutyl (3S,4R,5R)-1-benzyl-5-chloro-4-(4-fluorophenyl)-3-piperidinecarboxylate | C23H27ClFNO2 | 详情 | 详情 | |
| (XII) | 56483 | isobutyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-piperidinecarboxylate | C23H28FNO2 | 详情 | 详情 | |
| (XIII) | 44020 | [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol | C19H22FNO | 详情 | 详情 | |
| (XIV) | 56484 | [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl methanesulfonate | C20H24FNO3S | 详情 | 详情 | |
| (XV) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XVI) | 44022 | (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether | C26H26FNO3 | 详情 | 详情 |