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【结 构 式】 
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【分子编号】44012 【品名】tert-butyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C24H28FNO5 【 分 子 量 】429.4884632 【元素组成】C 67.12% H 6.57% F 4.42% N 3.26% O 18.63% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The diastereo- and enantioselective condensation of the protected secondary amine (I) with the nitroalkene (II) by means of BuLi in toluene and in the presence of (-)-sparteine gives the (S,S)-carbamate (III) as a single diastereomer. The hydrolysis of the carbamate (III) with HCl in chloroform yields the aldehyde (IV), which is reduced with NaBH4, affording the alcohol (V). The reduction of the nitro group of (V) with Pd/C and ammonium formate gives the amine (VI), which is protected with Boc2O to provide the carbamate (VII). The reaction of (VII) with MsCl and TEA affords the corresponding mesylate (VIII), which is cyclized by means of potassium tert-butoxide in THF, yielding the protected piperidine (IX). Elimination of the Tips group of (IX) with TBAF affords the carbinol (X), which is treated with MsCl and TEA to give the mesylate (XI). The condensation of (XI) with 1,3-benzodioxol-5-ol (XII) by means of NaH in DMF yields the expected adduct (XIII), which is finally deprotected with TFA to furnish the target chiral compound.
| 【1】 Johnson, T.A.; et al.; Highly diastereoselective and enantioselective carbon- -carbon bond formations in conjugate additions of lithiated N-boc allylamines to nitroalkenes: Enantioselective synthesis of 3,4- and 3,4,5-substituted piperidines including (-)-paroxetine. J Am Chem Soc 2001, 123, 5, 1004. |
| 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) | 44001 | tert-butyl (Z)-3-(4-fluorophenyl)-2-propenyl(phenyl)carbamate | C20H22FNO2 | 详情 | 详情 | |
| (II) | 44002 | triisopropyl[[(E)-3-nitro-2-propenyl]oxy]silane; (E)-3-nitro-2-propenyl triisopropylsilyl ether | C12H25NO3Si | 详情 | 详情 | |
| (III) | 44003 | tert-butyl (Z,3R,4S)-3-(4-fluorophenyl)-5-nitro-4-[[(triisopropylsilyl)oxy]methyl]-1-pentenyl(phenyl)carbamate | C32H47FN2O5Si | 详情 | 详情 | |
| (IV) | 44004 | (3R,4S)-3-(4-fluorophenyl)-5-nitro-4-[[(triisopropylsilyl)oxy]methyl]pentanal | C21H34FNO4Si | 详情 | 详情 | |
| (V) | 44005 | (3R,4S)-3-(4-fluorophenyl)-5-nitro-4-[[(triisopropylsilyl)oxy]methyl]-1-pentanol | C21H36FNO4Si | 详情 | 详情 | |
| (VI) | 44006 | (3R,4S)-5-amino-3-(4-fluorophenyl)-4-[[(triisopropylsilyl)oxy]methyl]-1-pentanol | C21H38FNO2Si | 详情 | 详情 | |
| (VII) | 44007 | tert-butyl (2S,3R)-3-(4-fluorophenyl)-5-hydroxy-2-[[(triisopropylsilyl)oxy]methyl]pentylcarbamate | C26H46FNO4Si | 详情 | 详情 | |
| (VIII) | 44008 | tert-butyl (2S,3R)-3-(4-fluorophenyl)-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-2-[[(triisopropylsilyl)oxy]methyl]pentylcarbamate | C29H52FNO4SSi | 详情 | 详情 | |
| (IX) | 44009 | tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-{[(triisopropylsilyl)oxy]methyl}-1-piperidinecarboxylate | C26H44FNO3Si | 详情 | 详情 | |
| (X) | 44010 | tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate | C17H24FNO3 | 详情 | 详情 | |
| (XI) | 44011 | tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-({[methyl(dimethylene)-lambda~6~-sulfanyl]oxy}methyl)-1-piperidinecarboxylate | C20H30FNO3S | 详情 | 详情 | |
| (XII) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XIII) | 44012 | tert-butyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate | C24H28FNO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The reaction of the chiral oxazolopyridinone (I) with benzyl chloroformate and phenylselenium bromide by means of LHMDS in THF gives the intermediate (II), which is treated with O3 and oxygen to yield the unsaturated ester (III). The condensation of (III) with the arylcopper derivative (IV) in THF affords a mixture of cis- and trans-isomers that are separated by chromatography. The desired trans-isomer (V) is reduced with AlCl3 and LiAlH4 in THF, giving the carbinol (VI), which by elimination of the chiral auxiliary with H2 over Pd(OH)2 in ethyl acetate, followed by protection of the piperidine nitrogen with Boc2O, provides the carbamate (VII). The reaction of (VII) with MsCl in pyridine yields the corresponding mesylate (VIII), which is condensed with 1,3-benzodioxol-5-ol (IX) by means of NaH in refluxing THF to furnish the protected intermediate (X). Finally, this compound is deprotected with TFA in dichloromethane.
| 【1】 Llor, N.; Cantó, M.; Hidalgo, J.; Amat, M.; Luque, J.; Miravitlles, C.; Molins, E.; Orozco, M.; Bosch, J.; Pérez, M.; Synthesis of enatiopure trans-3,4-disubstituted piperidines. An enantiodivergent synthesis of (+)- and (-)-paroxetine. J Org Chem 2000, 65, 10, 3074. |
| 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) | 44023 | (3R,8aR)-3-phenylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridin-5-one | C13H15NO2 | 详情 | 详情 | |
| (II) | 44024 | benzyl (3R,8aR)-5-oxo-3-phenyl-6-(phenylselanyl)hexahydro-5H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate | C27H25NO4Se | 详情 | 详情 | |
| (III) | 44025 | benzyl (3R,8aR)-5-oxo-3-phenyl-2,3,8,8a-tetrahydro-5H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate | C21H19NO4 | 详情 | 详情 | |
| (IV) | 44026 | C7H4CuFLiN | 详情 | 详情 | ||
| (V) | 44027 | benzyl (3R,6S,7R,8aR)-7-(4-fluorophenyl)-5-oxo-3-phenylhexahydro-5H-[1,3]oxazolo[3,2-a]pyridine-6-carboxylate | C27H24FNO4 | 详情 | 详情 | |
| (VI) | 44028 | ethyl 4-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]-3-oxobutanoate | C20H24FNO2 | 详情 | 详情 | |
| (VII) | 44010 | tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-piperidinecarboxylate | C17H24FNO3 | 详情 | 详情 | |
| (VIII) | 44011 | tert-butyl (3S,4R)-4-(4-fluorophenyl)-3-({[methyl(dimethylene)-lambda~6~-sulfanyl]oxy}methyl)-1-piperidinecarboxylate | C20H30FNO3S | 详情 | 详情 | |
| (IX) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (X) | 44012 | tert-butyl (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)-1-piperidinecarboxylate | C24H28FNO5 | 详情 | 详情 |