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经典合成反应标准操作—氨基的保护及脱保护 药明康德新药开发有限公司
2.3.2.1 三乙胺用于脱除笏甲氧羰基示例
STrFmocHNO1OAllylDEACH3CNH2NO2STrOAllyl
Shu-Li You and Jeffery W. Kelly., J. Org. Chem. 2003, 68, 9506
Diethylamine (30 mL) was added to a solution of 5 (5.63 g, 9 mmol) in CH3CN (30 mL), and the resulting mixture was stirred at 25 °C for 30 min to ensure complete removal of the Fmoc protecting group. After concentration in vacuo, the reaction mixture was azeotroped to dryness with CH3CN (2 x 30 mL) to give compound 2 (3.4 g, 89%).
20%的哌啶用于脱除笏甲氧羰基示例1
NNNONHFmocPiperidineNHNONH2MeOHNH12
US6329389
Piperidine (0.66 ml) was addede to a solution of compound 1 (0.797 g) in MeOH (10 ml) at room temperature. The reaction mixture was stirred at room temperature for 18 h, then concentrated and the residue was purified by alumina column chromatography (rthyl acetate/methanol = 10/1) to obtain compound 2 (0.382 g, 76%).
HNClOHNOHNOOHNHFmocHNOClHNOHNOOHNH2PiperidineDMF12
US6331640
Piperidine (0.88 ml, 0.89 mmol) was addede to a solution of compound 1 (116 mg, 0.18 mmol) in DMF (5 ml) at room temperature. The solution was stirred at room temperature for 30 min, and then solvent was evaporated. The resulting white solid was triturated with ether five times and dried in vacuo to give compound 2 (59 mg, 81%) as an off-white solid.
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经典合成反应标准操作—氨基的保护及脱保护 药明康德新药开发有限公司
2.4. 烯丙氧羰基（Alloc）
烯丙氧羰基（Alloc）同前面提到的Cbz、Boc和Fmoc不同，它对酸、碱等都很稳定，在它的存在下，Cbz、Boc和Fmoc等可选择性去保护，而它的脱去则通常在Pd(0)的存在下进行。
2.4.1 烯丙氧羰基（Alloc）的引入
Alloc-Cl在有机溶剂/Na2CO3、NaHCO3溶液或吡啶中同氨基化合物反应则可得到Aloc保护的氨基衍生物[1]。
1. E. J. Corey, J. W. Suggs., J. Org. Chem., 1973, 38, 3223
2.4.1.1氨基酸的烯丙氧羰基（Alloc）的引入示例
OHONH2OOOAlloc-Claq. NaHCO3, THFOOOHNHAlloc
Micale, Nicola; Vairagounder, Rajendran et al J. Med. Chem., 2004, 47(26), 6455-6458
12To a stirred solution of compound 1 (3.0 g, 15.86 mmol) in a mixture of aq. NaHCO3 and THF (8/2, 20 mL) was added allylchloro formate (2.54 mL, 23.81 mmol), dropwise and at 0 °C. The mixture was stirred at room temperature for 12 h and then diluted with ethyl acetate and washed 3 N HCl, dried and the solvent removed in vacuo to give compound 2 as a pale yellow oil, which was used without further purification (3.55 g, 82%).
2.4.1.2一般氨基的烯丙氧羰基（Alloc）的引入示例
1. HCl/EtOAcNBocCONH2HNBoc2. Alloc-Cl, Et3NNAllocCONH2HNAlloc
H. Imamura; A. Shimizu et al., Tetrahedron, 2000, 56(39), 7705
To a solution of 17 (1.0 g, 1.97 mmol) in EtOAc (10 ml) was added 4 M HCl/EtOAc (20 mL), and the mixture was stirred for 6 h at room temperature. After evaporation, to the suspension of the residue in CH2Cl2 (40 mL) were added triethylamine (2.75 mL, 19.7 mmol) and allyl chloroformate (0.627 mL, 5.91 mmol) at -10°C. The reaction mixture was poured into H2O
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经典合成反应标准操作—氨基的保护及脱保护 药明康德新药开发有限公司
and the whole was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/acetone = 8:1) to give 18 (863 mg, 92.1%) as a foam. [ a]D25=19.6 (c =1.0, CHCl3).
2.4.2 烯丙氧羰基（Alloc）的脱去
Alloc保护基对酸、碱等较强的稳定性，它们通常只用Pd(0)，如Pd(PPh3)4或Pd(PPh3)2Cl2存在的条件去保护。例如，Alloc衍生物用Pd(PPh3)4/Me2NTMS处理，可以得到易水解的氨基甲酸TMS酯 [1]。脱去含硫衍生物中的Alloc 时，如蛋氨酸，Pd(PPh3)4/二甲基环己二酮/TH则不会被毒化[2]。如果在酸性条件下脱除Alloc，则最好采用Pd(PPh3)2Cl2/Bu3SnH/p-NO2C6H4OH/CH2Cl2[3]。在异戊烯酯或肉桂酸酯存在下，可用Pd(OAc)2/TPPT/CH3CN/Et3N/H2O去保护，但随时间的增加，这些酯也会反应，并且氨基甲酸异戊烯酯和烯丙基碳酸酯同样被断裂[4]。当加入Boc2O、AcCl、TsCl、或丁二酸酐时，Pd(PPh3)2Cl2/Bu3SnH可将Alloc基转变为其它的胺衍生物。另外，Alloc也可在Pd(PPh3)4/HCOOH/TEA[5]或AcOH/NMO催化脱去[6]。
1. A. Merzouk, F. Guibe., Tetrahedron Lett., 1992, 33, 477
2. H. Kunz, C. Unverzagt., Angew. Chem. Int. Ed. Engl., 1984, 23, 436
3. O. Dangles, F. Guibe et al., J. Org. Chem., 1987, 52, 4984; P. Four, F. Guibe., Tetrahedron Lett., 1982, 23, 1825
4. S. Lemaire-Audoire, M. Savignac et al., Tetrahedron Lett., 1994, 35, 8783; E. Blart, J. M. Bernard et al., Tetrahedron Lett., 1997, 38, 2955; J. P. Genet, E. Blart et al., Tetrahedron Lett., 1993, 34, 4189
5. Y. Kanda, H. Arai et al., J. Med. Chem., 1992, 35, 2781 6. J. Lee, J. H. Griffin, T. I. Nicas., J. Org. Chem., 1996, 61, 3983
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经典合成反应标准操作—氨基的保护及脱保护 药明康德新药开发有限公司
2.4.2.1 Pd(PPh3)4-THF体系脱除烯丙氧羰基（Alloc）示例
EEOOOTMSNHAllocEEOPd(PPh3)4THFOOTMSNH2
Y. Matsushima; H. Itoh etal., J. Chem. Soc. Perkin Trans. 1., 2004, 7, 949
To a solution of the Alloc protected ester (140.7 mg, 0.2.23 mmol) and 1,3-dimethylbarbituric acid (228 mg, 1.46 mmol) in THF (15 mL) was added tetrakis(triphenylphosphine)palladium (43.9 mg, 0.0379 mmol, 17 mol%), and the resulting mixture was stirred at rt for 27 h. The mixture was then poured into saturated aq. NaHCO3 and extracted four times with Et2O. The combined extract was dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (CHCl3/MeOH, 20 : 1 to 2 : 1) to give the corresponding free amino ester as a colorless oil (79.5 mg, 65%).
2.4.2.2 Pd(PPh3)4/Me2NTMS体系脱除烯丙氧羰基（Alloc）示例
ONSiOSHNMeOOONSPd(PPh3)4, TMS-DMATMS-TFA, CH2Cl2MeOONHAllocONSiOSHNONSNH2
P. Angehrm; S. Buchmann et al., J. Med. Chem., 1992, 47(6), 1487
To a solution of 112 (0.97 g, 1.4 mmol) in CH2Cl2 (19 mL) were added dimethylamino- trimethylsilane (1.32 mL, 8.4 mol) and trimethylsilyl trifluoroacetate (1.45 mL, 8.4 mmol). The solution was stirred at 20 °C for 10 min, and then Pd(PPh3)4 (97 mg, 0.084 mmol) was added and stirring was continued for 2.5 h. The mixture was evaporated and the residual oil was dissolved in EtOAc (50 mL). The solution was washed with 10% aq NaHCO3 and brine, dried, and evaporated. The residue was chromatographed (SiO2; EtOAc/hexane 1:2) to give 113 (0.67 g, 78%): foam; TLC Rf ) 0.27 (EtOAc).
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