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
3.1.1.1 邻苯二甲酸酐引入邻苯二甲酰基示例
OOSCOOMeNH2.HClOSCOOMeNPhtEt3N, Toluene
P. Meffre, P. Durand., Org. Syn., 76, 123
Into a 2-L, round-bottomed flask fitted with a Dean-Stark apparatus, reflux condenser, and drying tube containing calcium chloride are placed L-methionine methyl ester hydrochloride (50.0 g, 0.25 mol), phthalic anhydride (37.1 g, 0.25 mol), triethylamine (100 mL, 0.72 mol), and toluene (1 L). The mixture is magnetically stirred and heated under reflux for 4.5 hr at which point approximately 4.5 mL of water has separated. The reaction mixture is allowed to cool to room temperature and the precipitated triethylamine hydrochloride (34 g) is collected by suction filtration. The filtrate is washed with four 300-mL portions of 1 N aqueous hydrochloric acid followed by three 300-mL portions of water. The organic layer is dried over magnesium sulfate , filtered, and the filtrate is concentrated under reduced pressure using a rotary evaporator. The residual oil is placed under reduced pressure for 12 hr at 0.1-0.5 mm, followed by trituration with 200 mL of pentane to give 59 g (80%) of product as a white solid after collection and drying at room temperature under reduced pressure (mp 37-40°C). mp 37-40°C,; [α]20 D ?41.6° (CHCl3, c 1.49).
3.1.1.2 邻苯二甲酸单乙酯引入邻苯二甲酰基示例
COOHNH2OHOH7COOEtNPhtOHOH8PyBOP, i-Pr2NEt
N. Aguilar; A. Moyano et al., J. Org. Chem., 1998, 11, 3560
To a suspension of PyBOP (2.84 g, 5.46 mmol, 1.1 equiv) in dry THF (10 mL) was added a solution of 2-ethoxycarbonylbenzoic acid (1.08 g, 5.46 mmol, 1.1 equiv) in THF (10 mL) and i-Pr2NEt (1.27 mL, 7.44 mmol, 1.5 equiv), and the resulting mixture was stirred for 30-40 min at rt. Afterwards, this solution was added to a suspension of 7 (0.898 g) in THF (10 mL) at 0 °C, and the mixture was stirred at rt for 3 h. The solvent was eliminated in vacuo, and the residue was heated at 85 °C overnight. The reaction mixture was then dissolved in 250 mL of
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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
dichloromethane and washed with saturated NaHCO3 solution (2 x 100 mL) and with brine (100 mL). The organic layer was dried (Na2SO4) and evaporated to give a crude product which
was
purified
by
column
chromatography
to
yield
1.28
g
of
(2S,3S)-4-phenyl-3-phthalimidobutane-1,2- diol (8) (83%) as a white solid: mp 91-93 °C.
3.1.1.3 N-乙氧羰基邻苯二甲酰胺引入邻苯二甲酰基示例:
ONHOEtOCOClEt3N, DMFNCOOEtOO
Worster, Paul M; Leznoff, Clifford C et al., J. Org. Chem., 1980, 45(1), 174-175 Ethyl chloroformate (115 mL, 1.29 mol) was added dropwise over a period of 90 min to a stirred solution of phthalimide (149.9 g, 1.02 mol) and triethylamine (160 mL, 1.15 mol) in dimethylformamide (500 mL) at 0-5°C under argon. The reaction mixture was allowed to warm to room temperature and stand for 4 h. It then was slowly added to an agitated mixture of ice and water (3 L). The solid product was collected and extracted with two portions of chloroform (450 mL and then 50 mL). The extract was dried (Na2SO4), cooled overnight in the refrigerator, and filtered to remove phthalimide (mp 238°C). The chloroform solution was concentrated to about 350 mL, diluted with petroleum ether (bp 60-80 °C; 350 mL) and allowed to stand at room temperature to give N-(ethoxycarbony1)phthalimide (179 g, followed by two additional crops for a total of 212 g, 95% yield): mp 83°C.
ONCOOEtOONH21OOONPht2NaHCO3
W. Shijun; Y. Zhujun et al., Org. Lett., 2004, 16, 2721
The solution of compound 1 (150.2 mg, 1.05 mmol) in THF (4 mL) was treated with N-(ethoxycarbonyl)-phthalimide (230 mg, 1.05 mmol), and NaHCO3 (88 mg, 1.05 mmol) at 0°C. The reaction was stirred for 7 h at rt, and separated. The aqueous layer was extracted with EtOAc (4 x 5 mL). The combined organic extracts were washed with saturated aqueous NH4Cl (3 x 3 mL) and brine (3 mL), dried (Na2SO4), and concentrated in vacuo. Chromatography (hexane/EtOAc = 5/1) provided 9 as an oil (215 mg, 75%).
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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
3.1.2 邻苯二甲酰基的脱去
Pht-氨基衍生物很容易用肼处理脱去。一般用水合肼的醇溶液回流2 小时[1, 4]或用肼的水或醇溶液室温放置1-2 天都可完全脱去Pht保护基[2]。在此条件下Cbz、Boc、甲酰基、Trt、Tos等均可不受影响。在肼效果差的情况下，NaBH4/i-PrOH-H2O(6:1)和AcOH在80℃反应5-8小时，这个方法是很有效的(见下式)[3]。另外，浓HCl回流也容易脱去Pht保护基[4]。
ONaBH4NRONROHNROO+RNH2OHOHO
1. J. C. Sheehan, D. W. Chapman et al., J. Am. Chem. Soc., 1952, 74, 3822; F. E. King et al., J. Chem. Soc., 1951, 243, 2976
2. F. Dasgupta, P. J. Garegg., J. Carbohydr. Chem., 1988, 7, 701 3. J. O. Osby; M. G. Martin et al., Tetrahedron Lett., 1984, 25, 2093-2096 4. Lee, Chang-Hee; Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074
3.1.2.1 NH2NH2/MeOH脱除邻苯二甲酰胺示例
OONPht12NH2
N2H4/MeOHOOW. Shijun; Y. Zhujun et al., Org. Lett., 2004, 16, 2721
To a solution of compound 1 (313 mg, 1.04 mmol) in MeOH (6 mL) was added hydrazine monohydrate (0.1 mL, 1.67 mmol) at 0 °C. After being stirred at same temperature for 3h, the solvents were removed in vacuo and the residue was re-dissolved into water (10 mL). The pH of solution was then adjusted to 1-2 by adding 1N HCl at 0 °C. The whole mixture was stirred for 1 h at rt, and then filtered. The filtrate was treated with solid Na2CO3 until the pH reached 9-10. The mixture was extracted with CH2Cl2 (10 mL x 4). The combined extracts were dried (Na2SO4), concentrated and dried in vacuo to provide compound 2 (209 mg, quantitatively) as a yellowish oil.
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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
3.1.2.2 NH2NH2/EtOH脱除邻苯二甲酰胺示例
HNHNNPhtNH2NH2EtOH1HNHNNH22
Lee, Chang-Hee; Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074
Compound 1 (1.66 g, 4.77 mmol) was dissolved in ethanol (50 mL), and then hydrazine monohydrate (0.93 mL, 19 mmol) was added. The resulting mixture was heated at reflux for 24 h and then cooled to room temperature. The mixture then was combined with aqueous NaOH (50 mL) and extracted with CH2Cl2. The solvent was removed in vacuo to afford compound 2 (0.79 g, 76%), which was used directly in the next step without further purification.
3.1.2.3 HCl脱除邻苯二甲酰胺示例
ONPht1conc. HClONH2.HCl2
Lee, Chang-Hee; Lee, Jin-Suk et al., J. Org. Chem., 2005, 6, 2067-2074
Compound 1 (1.0 g, 3.86 mmol) and concentrated HCl (3 mL) was heated for 60 h at 100 °C. After the mixture was allowed to cool to room temperature, water (20 mL) was added. The solid precipitate that formed was removed by filtration and discarded, and the aqueous layer was washed with diethyl ether twice, with these washings also being discarded. The water was removed in vacuo, and the remaining solid was dried to give compound 2 (0.61 g, 95%), which was then used to the next step without further purification due to its instability.
3.1.2.4 NaBH4/i-PrOH-H2O(6:1)和AcOH脱除示例
OHNPhtNH1OHNaBH4, AcOHi-PrOH, H2ONH2HNH2OOH
J. O. Osby; M. G. Martin et al., Tetrahedron Lett., 1984, 25, 2093-2096
To a stirred solution of compound 1 (0.36 g, 1 mmol) in 2-propanol (7.7 ml) and H2O (1.3 ml) was added NaBH4 (0.19 g, 5 mmol). After stirring 24 h, TLC indicated complete consumption
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