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 %)

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