其他方法合成胺-060123

其他方法合成胺-060123

经典化学合成反应标准操作其他方法合成胺

编者：刘国超

药明康德新药开发有限公司化学合成部

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

R O

Cl R

O

N3R

O

N N N R

O

N N

R-N=C=O

+

N2

2

O

R-NH2

BnOH

R-NHCbz

R-NHBoc

R'NH2

O

NHR'

RHN

t BuOH

R O

OH

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。

R O

OH R-N=C=O

R-NH2 P

O

N3

PhO

PhO

DPPA

R

O

N3

H2O

R O

OH R-N=C=O

P

O

N3

PhO

PhO

DPPA

R

O

N3

R'OH

R'OH

R

N

H

O

O

R'

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

F F

O

CO2H

1. SOCl

2. NaN3, H2O, acetone

F F

O

NH2

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

CO2H

O

O NO2

NH2

O

O

NO2 78%

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 o C. H2O (150 mL) was added and the reaction mixture was refluxed for 2 h. The solvent was removed in vacuo and 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