氯甲酸酯与胺反应制备脲

胺先与氯甲酸酯反应得到相应的R氧基碳酰胺，然后再与另一分子胺反应生成脲。本方法适用范围也很广，对那些底物很昂贵、或较难得到的，本方法尤为适用。一般来说比较常用的为氯甲酸对硝基苯酯和氯甲酸苯酯, 另外还有氯甲酸2－异丙烯酯，氯甲酸2-三氟乙基酯或氯甲酸2-三氯乙基酯等等。

下面以氯甲酸对硝基苯酯为例作为介绍：

氯甲酸对硝基苯酯主要用于伯胺的反应，其反应机理是中间体对硝基苯氧基碳酰胺在碱性条件下，脱去对硝基苯酚得到相应的异氰酸酯，然后再与另一分子胺反应得到脲。使用本方法一个主要的注意点是第一步对硝基苯氧基碳酰胺的制备，一定要选择好相应的碱，用好当量。另外也有文献在第一步用过量的碱生成异氰酸酯的溶液，马上再与另一分子胺反应。该法的一个缺点就是有时产生的黄色的副产物对硝基苯酚，不易除干净（一般用强碱洗）。

氯甲酸对硝基苯酯也可以与仲胺反应生成脲，一般在DMAP-CH3CN，加热体系进行胺交换。

1、 芳香伯胺的对硝基苯氧基碳酰胺和脲的合成示例 【WO2004/9558 A2 (2004/01/29)】

To a solution of methyl 3-aminobenzoate (1.0g, 6.5 mmol) and pyridine (1.0 mL) in 100 mL of dichloromethane was added asolution of 4- nitrophenylchloroformate (1.4 g, 6.7 mmol) in 10 mL of dichloromethanedropwise at 0oC under N2 atmosphere. The resultingmixture was stirred at r.t. for 20 h，then partitioned between before poured into ice-water. The mixture was extracted withDCM (3 x 100 mL). The combined organic phases were washed with 0.5 N aq. HCL and brine, dried over anhydrous Na2SO4 and filtered. Thefiltrate was concentrated to give the crude product, which was purified bycolumn to afford 2.1 g of 3-[3-(4-tert-Butyl-phenyl)-ureido]-benzoic acidmethyl ester (94 %)

2、 脂肪伯胺的对硝基苯氧基碳酰胺和脲的合成示例 （J. Org. Chem. 2004, 46-53）

To a solution of 4-nitrophenyl chloroformate(2.3 g, 11 mmol) in 20 mL of CH2Cl2 was added a solution of benzyl glycinate (0.62 g, 3.8mmol) in 4 mL of 1:1 CH2Cl2/ pyridine at 0 °C dropwise. The solution was stirred for30 min and then diluted with 100 mL of CH2Cl2. The reaction mixture was washedwith 1 M NaHSO4 (3 x 50 mL) and brine (3 x 50 mL). The organicphase was concentrated to the crude product, which was purified by columnchromatography to afford 0.81 g of N-(4-nitrophenyloxycarbonyl)benzyl glycinate(65%) as white solid. To thesolution of N-(4-nitrophenyloxycarbonyl)benzyl glycinate (0.79 g,2.4 mmol) in 10 mL of benzene were added 1,6-aminohexanol (0.34 g, 2.9 mmol),DMAP (88 mg, 0.72 mmol) and diisopropylethylamine (0.46 g, 3.6 mmol) at roomtemperature. The reaction mixture was stirred at for 30 min before diluted with50 mL of CH2Cl2. The mixture was washed with 1 M NaHSO4 (3 x 50 mL), 2% Na2CO3 (3 x 50 mL) and brine (3 x50 mL). The organic phase was dried and concentrated to the crude product,which was purified by column chromatography to afford 0.61 g of [3-(6-hydroxyhexyl)ureido]aceticacid benzyl Ester (86%) as white solid..

3、 利用氯甲酸对硝基苯酯一锅法合成脲示例 （J. Med. Chem. 2001, 1021-1024）

To a solution of 1-(2,6-dichloro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indazol-6-ylamine(374 mg, 1.0 mmol) and diisopropylethylamine (640 mg, 5.0 mmol) in 100 mL ofDCM was added a solution of 4-nitrophenyl chloroformate (220 mg, 1.1 mmol) in10 mL of DCM at –20 oC under N2 atmosphere. The resultingmixture was stirred for 30 min and then added 3-amino-4-(3,4-difluoro-phenyl)-1-phenyl-butan-2-one(275 mg, 1.0 mmol). After stirred at – 20 oC for 30 min, the mixturewas warmed to room temperature and then stirred for another 6 h before pouredinto water. The reaction mixture was extractedwith DCM (3 x 100 mL). The combined organic phases were washed with brine (3 x50 mL), dried over anhydrous Na2SO4 and filtered. Thefiltrate was concentrated to the crude product, which was purified by columnchromatography to afford 175 mg of 1-[1-(2,6-dichloro-benzyl)-3-pyrrolidin-1-ylmethyl-1H-indazol-6-yl]-3-[1-(3,4-difluoro-benzyl)-2-oxo-3-phenyl-propyl]-urea (26 %)

4、 氯甲酸对硝基苯酯用于仲胺的脲合成示例 （J. Med. Chem. 1999, 5254-5265）

To a solution of 5-oxo-5-piperidin-3-yl-3-pyridin-3-yl-pentanoicacid methyl ester (2.9 g, 10 mmol) in DCM (200 mL) wasadded 4-nitrophenylchloroformate (2.0 g, 10 mmol) and NMM (6.0 mL, 30 mmol) at0 oC. The resulting mixture was stirred for 2 h before poured intowater (15 mL). After separated, the organic layer was dried over anhydrous Na2SO4 and evaporatedto oil, which was dissolved in 100 mL of MeCN. The solution was then treated by[4,4']bipiperidinyl-1-carboxylic acid tert-butyl ester (4.3 g, 15 mmol) and DMAP(1.2 g, 10 mmol), and heated to reflux for 24 h. After removal of the solvent,the residue was dissolved in EtOAc (200 mL). The organic phase was washed with 1N NaOH (3 x 100 mL), brine (3 x 100 mL) and dried over anhydrous Na2SO4. Afterfiltered, the filtrate was concentrated to the crude product, which was purifiedby silica gel chromatography to afford 4.1g of 1'-[3-(4-methoxycarbonyl-3-pyridin-3-yl-butyryl)-piperidine-1-carbonyl]-[4,4']bipiperidinyl-1-carboxylicacid tert-butyl ester (69 %)

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