经典化学合成反应标准操作
1．Curtius 重排合成胺及相应的衍生物
Curtius重排是一种常用的将羧酸转化为少一个碳的胺及相应衍生物的方法。 其机理如下
ROClRON3RONNNRONNNR-N=C=O+N2H2OR-NH2BnOHR-NHCbzR-NHBocR'NH2ONHR'RHNtBuOHROOH首先酰氯被转化为酰基叠氮，其加热重排脱去一分子氮气后得到相应的异氰酸酯，异氰酸酯水解或和其他亲核试剂反应得到胺及相应的衍生物。 早期的合成方法都是将酸转变为相应的酰氯，再生成酰基叠氮。 后来Shiori（JACS，1972，94，6203）等人报道了DPPA和羧酸在室温下很温和的生成酰基叠氮，可一锅法合成胺。若直接用过量的醇或直接用醇做溶剂可得到相应的胺的衍生物。如用苄醇可一步得到Cbz保护的胺; 用叔丁醇可一步得到Boc保护的胺。
ROOHR-N=C=OR-NH2PON3PhOPhODPPARON3H2OROOHR-N=C=OPON3PhOPhODPPARON3R'OHR'OHRNHOOR'
一般情况下，用此方法直接做胺并不是一个好的方法，特别是制备烷基胺，其主要经典合成反应标准操作— 其它方法制备胺
Page 1 of 14 有两个原因：一是得到的胺特别是烷基胺不易纯化；二是加水分解异氰酸酯时得到的胺会和未反应完全的异氰酸酯反应成脲，因此分解时要剧烈搅拌， 另外也有人使用稀酸水解异氰酸酯得到相应的胺的盐酸盐。
1.1 酰基叠氮重排合成胺示例
FFOCO2H1. SOCl22. NaN3, H2O, acetoneFFONH2
2,6-difluoro-4-methoxyphenyl carboxylic acid (2.00 g, 10.6 mmol) was dissolved in thionyl
chloride (16 mL). One drop of DMF was added and the mixture was heated to reflux for 2 h.
The crude mixture was evaporated to dryness and the residue was dissolved in 5mL acetone.
A solution of sodium azide (970 mg, 14.9 mmol) in water (2 mL ) was added dropwise at
room temperature. After 30 min, water (10 mL) was added and the solution was extracted
with toluene (50 mL). The organic layers were dried over sodium sulfate and heated to reflux
for 30 min. Then 10 mL of a 45% sodium hydroxide solution was added and the mixture was
heated for a further 30 min. The organic layer was separated, dried over sodium sulfate and
evaporated. The residue was purified by column chromatography (dichloromethane) to yield
660 mg (39%) of the title compound.
Reference: Tetrahedron Lett., 2004, 45, 95 - 98.
1.2 使用DPPA合成胺示例
CO2HOONO21. DPPA/THF2. HeatNH2OONO278%
2-benzyloxy-3-methoxy-4-nitroanilin acid (27.9 g, 91.8 mmol) was dissolved in THF (400
mL) and treated with Et3N (30 mL). Diphenylphosphoryl azide (26.5 g, 96.4 mmol) was
added dropwise and the reaction mixture was stirred for 3 h at 25 oC. H2O (150 mL) was
added and the reaction mixture was refluxed for 2 h. The solvent was removed in vacuo and 经典合成反应标准操作— 其它方法制备胺
Page 2 of 14 the residue was treated with saturated aqueous K2CO3 (100 mL), diluted with H2O (500 mL),
and extracted with EtOAc (2 × 500 mL). The combined organic extracts were washed with
saturated aqueous NaCl (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude
residue was purified by flash chromatography (SiO2, 25% EtOAc−hexanes) to afford the title
compound (19.5 g, 78%) as a yellow solid.
Reference: J. Am. Chem. Soc., 2004, 126, 8396 - 8398.
叠氮酰胺在H2O里加热重排成胺还是有一些报道的。如下：
经典合成反应标准操作— 其它方法制备胺
Page 3 of 14
经典合成反应标准操作— 其它方法制备胺
Page 4 of 14 1.3 使用DPPA和苄醇合成Cbz保护的胺示例
OHOHOO+OHCbzHNNHCbzDPPA, DIEAToluene
Under an argon atmosphere, a mixture of acid (200 mg, 0.59 mmol), diisopropyl ethylamine
(0.36 mL, 2.0 mmol), diphenylphosphoryl azide (0.32 mL, 1.5 mmol) in toluene (25 mL) was
heated at reflux for 3 h. After being cooled to room temperature, benzyl alcohol (0.2 mL, 2
mmol) was added, and the mixture was stirred for another 1h. After removing the solvent in
vacuo, silica gel column chromatography gave the title compound (230 mg, 0.50 mmol, 85%).
Reference: J. Org. Chem., 2001, 6, 557 - 563.
1.4 使用DPPA和叔丁醇合成Boc保护的胺示例
由于叔丁醇的活性不高，一般都使用叔丁醇作溶剂，在研究过程中我们发现若在反应液中加入3-5当量的Boc2O可抑制副反应，提高反应产率。
OOFOOHDPPAt-BuOHOOFNHBoc
Dry tert-butyl alcohol (123 mL), triethylamine (16.7 g, 0.65 mol), and DPPA (45.5 g, 0.165
mol) were added to a solution of 5-fluoro-1,3-benzodioxole-4-carboxylic acid (29 g, 0.157mol)
in dioxane (430 mL) under nitrogen. The mixture was heated at 100 °C for 4.5 h. Upon
cooling, the cloudy mixture was filtered. The filtrate was evaporated under vacuum, diluted in
ethyl acetate, washed with a 5% aqueous citric acid, a 5% aqueous sodium bicarbonate, water,
and brine, dried over magnesium sulfate, and concentrated under vacuum to provide desired
compound (37.6 g, 93%).
Reference: J. Med. Chem. 2004, 47, 871-887 经典合成反应标准操作— 其它方法制备胺
Page 5 of 14 2. Hofmann 降解
Hofmann降解是将伯酰胺通过氧化降解成少一个碳原子的伯胺, 其机理如下：
ONRHH-OHON-RHBrBrONRBrH-OHON-RBr-Br-ONRH2OOHNRHOONHRHORNH2+ CO2
最早期的Hofmann降解是使用NaOH水溶液和Br2来实施的。这个条件比较剧烈，后续有许多改进的方法陆续被报道，主要是通过改进氧化剂和碱。如Keillor等人1997年报道了用NBS做氧化剂，DBU做碱，甲醇中回流25分钟就得到了甲氧羰基保护的胺（JOC, 1997, 62, 7495-7496）.
2.1 经典的Br2-NaOH体系Hofmann 降解示例
OOHNHTsNH2OBr2NaOHOOHNHTsNH2
Sodium hydroxide (3.48 kg, 87.0 mol) was dissolved in water (22 L), and the solution was
cooled to 0°C. Bromine (0.63 L, 11.8 mol) was added over 30 min while the temperature was
maintained at 0-10°C. In a second vessel, (R)-tosylasparagine (2.86 kg, 9.48 mol) was added
in portions to a solution of NaOH (0.8 kg, 20.0 mol) in water (7.2 L) kept cold at 0-10°C. The
solution was cooled to 0°C, and the sodium hypobromite solution was added over 10 min
while maintaining a temperature <10°C. After the addition, the resulting yellow solution was
aged for 15 min at 10-15°C, and then heated to 40°C within 30 min. Heating was suspended
and the reaction temperature was allowed to increase to 50°C over 20 min due to the
exothermic reaction. When the internal temperature dropped to 45°C, the reaction solution
was heated to 70°C over 20 min and kept at 70°C for 10 min. HPLC analysis measured a 90%
solution yield of compound 2. The reaction was cooled to 10-15°C, and with vigorous stirring
the pH of the mixture was adjusted to 7 by the addition of concentrated hydrochloric acid (4