三光氣和胺反應制備脲，主要分為兩種方法，一種是和伯胺先生成異氰酸酯中間體，另外一種是和仲胺先生成氯甲酰胺中間體。

一、三光氣先和伯胺生成異氰酸酯制備脲

除了一些常用的伯胺的異氰酸酯可以購買到以外，在藥物化學中決大多數異氰酸酯是無法購得的，因此需要自己合成異氰酸酯。常用異氰酸酯的合成方法是伯胺與三光氣反在堿性條件下生成異氰酸酯，而后異氰酸酯與另一分子胺反應生成脲，第二步反應其實同前。對于低沸點的異氰酸酯，第一步反應完后最好將其蒸餾出來，再投第二步反應，這樣下一步產物相對干凈。如果異氰酸酯沸點很高，一般生成異氰酸酯后，直接一鍋用到下一部，但必須嚴格控制三光氣的用量（注意三光氣用底物胺的1/3的量）。光氣與雙光氣也適用本方法，但考慮到使用的方便性和安全問題，一般使用三光氣。

異氰酸酯與胺反應成脲是最為方便的一種方法，特別對于那些可以直接在市場上買到的異氰酸酯，一般這類反應收率也很高。但本方法最重要的一點是：反應物的用量是取決于底物的活性。通常是等量的底物在非質子性溶劑反應，加入適量的堿有利于反應的進行。如果其中一個底物的活性較差的話，可以適當增加用量。常用的溶劑有：二氯甲烷、四氫呋喃等。

三光氣與伯胺反應生成脲示例（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 %).

異氰酸酯與胺反應生成脲示例（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、 三光氣先和仲胺生成氯甲酰胺制備脲

對于仲胺由于無法形成異氰酸酯，我們可以通過其與三光氣反應得到氯甲酰胺然后再與另一個胺反應。一般仲胺的氯甲酰胺中間體對水是穩定的，可以分離純化出來。

三光氣與仲胺反應氯甲酰胺 （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 %).

氯甲酰胺與胺反應脲

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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