脲的合成汇总

1，三光气和胺反应制备脲

三光气和胺反应制备脲，主要分为两种方法，一种是和伯胺先生成异氰酸酯中间体，另外一种是和仲胺先生成氯甲酰胺中间体。

一、三光气先和伯胺生成异氰酸酯制备脲

除了一些常用的伯胺的异氰酸酯可以购买到以外，在药物化学中决大多数异氰酸酯是无法购得的，因此需要自己合成异氰酸酯。常用异氰酸酯的合成方法是伯胺与三光气反在碱性条件下生成异氰酸酯，而后异氰酸酯与另一分子胺反应生成脲，第二步反应其实同前。对于低沸点的异氰酸酯，第一步反应完后最好将其蒸馏出来，再投第二步反应，这样下一步产物相对干净。如果异氰酸酯沸点很高，一般生成异氰酸酯后，直接一锅用到下一部，但必须严格控制三光气的用量（注意三光气用底物胺的1/3的量）。光气与双光气也适用本方法，但考虑到使用的方便性和安全问题，一般使用三光气。

异氰酸酯与胺反应成脲是最为方便的一种方法，特别对于那些可以直接在市场上买到的异氰酸酯，一般这类反应收率也很高。但本方法最重要的一点是：反应物的用量是取决于底物的活性。通常是等量的底物在非质子性溶剂反应，加入适量的碱有利于反应的进行。如果其中一个底物的活性较差的话，可以适当增加用量。常用的溶剂有：二氯甲烷、四氢呋喃等。

三光气与伯胺反应生成脲示例（Tetrahedron, 2002, 639-652）

 To a stirred solution of 3-chloro-4-nitro-phenylamine (1.72 g,10 mmoL)and diisopropyl ethylamine (2.1 g, 20 mmol) in 100 mL of dry DCM was addeda solution of triphosgene (0.99 g, 3.3 mmol) in 10 mL of DCM. The resulting mixturewas stirred at 0 ^oC for 3 hours and then treated with aniline (930mg, 10 mmol). The reaction mixture was allowed to warm to room temperatureovernight. After removal of the solvent, the residue partitioned between ethylacetate and saturated bicarbonate solution. The organic layer was separated, washedwith brine, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated to the residue, which was purified by columnchromatography on silica to afford 1.9 g of the 1-(3-chloro-4-nitro-phenyl)-3- phenyl-urea(65 %).

异氰酸酯与胺反应生成脲示例（J. Med. Chem. 2005, 1697-1700）

To a solution of 3-chloro-4-nitro-phenylamine(1.72 g, 10 mmoL) and triethylamine (3 mL, 20 mmol) in 100 mL of THF was addedisocyanato-benzene (1.19 g, 10 mmol) in 10 mL of THF at 0 oCdropwise. After the addition was completed, the resulting mixture was allowedto raise room temperature and stirred overnight before being poured into water(150 mL). The mixture was extracted with DCM (3 x 100 mL). The combined organicphases were washed with brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated to give the crude product, whichwas purified by column to afford 2.4 g of 1-(3-chloro-4-nitro-phenyl)-3- phenyl-urea(80 %)

二、 三光气先和仲胺生成氯甲酰胺制备脲

对于仲胺由于无法形成异氰酸酯，我们可以通过其与三光气反应得到氯甲酰胺然后再与另一个胺反应。一般仲胺的氯甲酰胺中间体对水是稳定的，可以分离纯化出来。

三光气与仲胺反应氯甲酰胺 （ J. Org. Chem. 2004, 3787-3793）

 
To a solution of 2-allyl-piperidine (0.63 g, 5 mmol) and pyridine (0.52g, 6.6 mmol) in 50 mL of dichloromethane was added a solution of triphosgene(0.66 g, 2.2 mmol) in 10 mL of dichloromethane at 0 ^oC dropwise over40 min. The resulting mixture was then warmed to room temperature and stirredovernight. The reaction mixture was added 50 mL of 1 N of aqueous HCl solutiondropwise. After separation, the aqueous phase was extracted with DCM (3 x 50mL). The combined organic phases were washed with a saturatedNaHCO₃solution and brine ( 3 x 50 mL ), then dried over MgSO₄. After removal of the solvent, thecrude product was taken into Et₂O andthe solids were filtered. The filtrate was concentrated to 860 mg of carbamoylchloride as yellow oil (92 %).

氯甲酰胺与胺反应脲

 A solution of 2-allyl-piperidine-1-carbonylchloride (1.87 g, 10 mmol), triethylamine (5 mL), and 4-chloro-3-fluoro-phenylamine(1.7 g, 12 mmol) in 100 mL of anhydrous dioxane was stirred at room temperatureunder nitrogen for 26 h and then concentrated to dry under vacuum. The residuewas dissolved in 100 mL of dichloromethane, and washed with 0.5 N of aqueousHCl solution and brine, After dried over anhydrous Na₂SO₄and filtered, the filtrate was concentrated to the crude product, which was purifiedby flash column chromatography to afford 2-Allyl-piperidine-1-carboxylic acid(4-chloro-3-fluoro-phenyl)-amide (2.3g, 77 %)

2,羰基二咪唑 (CDI) 与胺反应生成脲

胺也可以先与羰基二咪唑 (CDI)反应，形成一个中间体，然后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，本方法也很适用。但由于CDI 不稳定，放置时间长，遇水会分解，造成加料不准确，容易生成较难分离的二聚体。因此反应前确定CDI 的质量尤为关键。

一、羰基二咪唑与芳香伯胺反应生成脲（Tetrahedron, 2003; 5603 – 5608）

To a solution of 3-chloro-4-nitro-phenylamine (1.72 g, 10 mmoL) and triethylamine (1.0 g, 10mmol) in 50 mL of DMF was added CDI (1.61 g, 10 mmol) at room temperature under N2 atmosphere. The mixture was stirred at that temperature for 1 h and then added a solution of aniline (1.0 g, 11 mmol) in 5 mL of DMF. After stirred for another 10 h, the reaction mixture was poured into water (100 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (5 x 100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford 2.0 g of 1-(3-chloro-4-nitro-phenyl)-3- phenyl-urea (68 % yield)

二、羰基二咪唑与脂肪胺反应生成脲（J. Med. Chem. 1992; 2446-2451）

To a solution of 3-(3-piperidin-1-ylmethyl-phenoxy)-propylamine (2.48 g, 10 mmoL) and diisopropylethylamine (1. 4 mL, 10 mmol) in DMF (50 mL) was added CDI (1.61 g, 10 mmol) at room temperature under N2 atmosphere. The mixture was stirred at that temperature for 1h and then a solution of i-BuNH2 (146 mg, 20 mmol) in 5 mL of DMF was added to the mixture. The reaction mixture was stirred at room temperature overnight before poured into water (100 mL). The mixture was extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine (5 x 100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by column to afford 2.75 g of 1-isobutyl-3-[3-(3-piperidin-1-ylmethyl-phenoxy)-propyl]-urea (80 %).

3,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 0^oC under N₂ atmosphere. The resultingmixture was stirred at r.t. for 20 h before poured into ice-water. The mixture was extracted withDCM (3 x 100 mL). The combined organic phases were washed with 0.5 Naq. HC1 andbrine, 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 N₂atmosphere. 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 %)

4,氰酸钾与胺反应制备脲

氰酸钾与胺反应生成脲

对于没有任何取代基的脲，一般主要通过氰酸钾与胺反应得到，一般这类反应在水和醋酸的混合溶剂中进行。

氰酸钾与胺反应生成脲示例 （J. Am. Chem. Soc.,1992 10715-10721）

 To asolution of o-aminophenol (1.1 g, 10 mmol) in 20 mL of glacial acetic acid andwater (1:1) was added a solution of potassium cyanate (1.6g, 20 mmol) in waterdropwise. The resulting solution was stirred at r.t. for 3 h. After removal ofthe solvent, the residue was dissolved in EtOAc (100 mL). The organic phase waswashed with sodium bicarbonate solution and brine, dried over anhydrous Na2SO4and filtered. The filtrate was concentrated to the crude product, which was recrystallizedonce from methanol and then several times from acetone-hexane to afford 1.2 gof white needles (2-Hydroxy-phenyl)-urea (80 %).