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1、脲的合成方法随着药物化学的发展，脲结构越来越多的在药物中出现，以建立独特的药 物-靶点相互作用模式和调节类药性质。本文主要总结含脲化合物的合成方法。通常含脲的分子可以分为对称性脲和非对称性脲两大类，对称性脲的合成 相对简单，而非对称性脲的合成相对难一些。由于非对称性脲的合成大多适用 于对称性脲的合成，所以我们着重介绍非对称脲合成的一些常用方法。1、使用光气或光气等价物合成脲衍生物经典的脲衍生物制备方法涉及到光气或光气衍生物(如三光气)等试剂。这 类方法通常是伯胺与三光气在碱性条件下生成异氰酸酯中间体，异氰酸酯再与不 同胺类亲核试剂反应生成N、N-二取代或N、N、N-三取代的脲衍生物。对于低 沸
2、点的异氰酸酯，第一步反最好将其蒸馏出来，这样下一步反应相对干净。如果 异氰酸酯沸点很高，采用“一锅法”也可以，但必须严格控制三光气的用量 (三 光气的用量为底物胺的 1/3)。triphosgene尺BaseA rCoIr2r.3nhBaseScheme 1.通过三光气合成脲1.1 三光气与胺生成脲实例将三光气0.011 g (0.037 mmol)溶解在3 mL二氯甲烷中，N2保护，冰盐浴 条件降温至0口，滴加含有(S) -1-(吡啶-3-基)乙-1-胺盐酸盐0.030 g(0.107 mmol)及三乙胺0.086 g (0.852 mmol)的二氯甲烷溶液(2 mL)。反应液在0温 搅拌反
3、应5 min后。加入6-甲基-N-(5-甲基-1H-吡唑-3-基)-2-(哌啶-4-基)嘧啶-4-胺三氟乙酸盐0.05 g(0.107 mmol)和三乙胺0.086 g(0.852 mmol)，室温搅拌20 min。反应完毕后，向反应液中加入50mL的二氯甲烷稀释，用10 mL饱 和食盐水洗涤。收集有机相，无水硫酸钠干燥，过滤。浓缩滤液所得粗品，经柱 层析纯化得到白色粉末状固体目标物 32 mg。1.2使用氯甲酰胺与胺反应生成脲对于仲胺由于无法形成异氰酸酯，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。triphosger
4、cR3R4NHR1 R3Scheme 2.通过氯甲酰胺合成脲1.3仲胺通过氯甲酰胺反应生成脲实例1, 2bar was evacuated andA 100 mL two-necked flask with a magnetic stirringbackfilled with nitrogen three times. Triphosgene (5.0 mmol) and CH,Cl2 (30 mL) were added to the flask. The mixture was cooled at 0 C and dehydrated pyridine (3.0 mL) was slowl
5、y added to the flask. After stirring for 15 min at 0 C, secondary amine (10 mmol) was slowly added to the mixture. The mixture was warmed to room temperature and stirred for 6 h at room temperature. The reaction mixture was carefully quenched by 1 M HCl (10 mL) and was extracted with CH2Cl2 (10 mL x
6、 3). The organic layer was washed with water and brine, then dried over MgSO4. After the filtration, the solution was concentrated under reduced pressure. This material was used in the subsequent step without further purification.H4-Isopropylaniline (18.7 mM) and triethylamine (20 mM) were dissolved
7、 in tetrahydrofuran (50ml) and piperidine-1-carbonyl chloride (18.7 mM) were added to the solution. The solution was maintained at 20-25 C for 10 h, and the reaction mixture was filtered to separate triethylamine hydrochloride. Filtrate was distilled under vacuo,residue was dissolved in ethylacetate
8、 and washed with water. Organic portion was collected, dried over sodium sulfate and concentrated under vacuo. Crude product was further purified by column chromatography. The crude product was recrystallised with ethanol followed by filtration and drying to obtain product. N-(4-isopropylphenyl) pip
9、eridine-1-carboxamide: The silica gel eluent was DCM/ethylacetate 70:30, yield: 65%.2、通过更安全的光气替代物合成脲衍生物2.1 N, N-羰基二咪唑(CDI)CDI 是一种广泛使用的光气替代物。胺先与 CDI 反应，形成一个中间体，然 后与另一分子胺反应生成脲。该类反应的优点是 CDI 不产生氯或氯化副产物， 但由于 CDI 不稳定，放置时间久，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。Scheme 3. 通过 CDI 合成脲2.1.1 CDI 与胺生成脲
10、实例=A4在一 50 ml 的三口瓶中依次加入 CDI 0.104 g (0.643 mmol) 、DCM 5 ml 。氮气保护下冰盐浴降温至0。在一 10 ml试管加入(S) -1-(吡啶-3-基)乙-1-胺盐酸盐 0.146 g (0.707 mmol)，三乙胺 0.390 g(3.86 mmol), DCM 5ml，混合均匀 后缓慢将该溶液加入反应体系中。低温反应约 30 min 后，向反应体系中加入含 有6-甲基-N-(5-甲基-1H-吡唑-3-基)-2-(哌啶-4-基)嘧啶-4-胺三氟乙酸盐0.35 g(0.643 mmol)，三乙胺0.390 g(3.86 mmol)的DCM溶液5
11、 ml。加毕后室温下反 应。待反应完毕后，将反应液倒入100 ml纯化水中，DCM萃取。合并有机相加 入无水硫酸钠干燥。随后过滤、浓缩并经柱层析纯化得到白色固体167 mg。2.2 1,1-羰基双苯并三唑（CBT）CBT 是一种安全，温和的光气替代品，适用于制备不对称脲衍生物。例如， CBT 与仲胺（7）反应得到相应的氨基甲酰基苯并三唑衍生物（8）。（8）随后 与另一种仲胺（9）反应，温和的生成了四取代的不对称脲衍生物（10）。对于 环状和脂肪族胺衍生物，反应只需在室温下进行，并且产率较高，而对于芳香族 胺可能需要更高的温度或者回流条件。RflRjNH(CBTScheme 4. 通过 CBT
12、合成脲2.2.1 CBT与胺生成脲实例CBT(1.06 g, 4 mmol) was dissolved in dry THF (40 mL) under a dry atmosphere of nitrogen, and aniline (0.37 mL, 4 mmol) was added. The reaction mixture was stirred at room temperature for 27 h, octylamine (0.65 mL, 4 mmol) was then added, and the resulting reaction mixture was stir
13、red at room temperature for 27 h before being extracted with diethyl ether (3x40 mL). The ethereal extracts were successively washed with 2 N HC1 (2x20 mL), 2 N NaOH (2x20 mL), and saturated NaCl (30 mL), dried with MgSO4, and filtered. Removal of the solvent under reduced pressure gave 4a as a whit
14、e powder (840 mg, 85%).2.3 荒酸二甲酯( DMDTC)DMDTC可以作为光气的有效替代品，该反应可以在水中进行，方便高效的 生成单取代，二取代和三取代的脲衍生物。RflIRzNHHZO. 25X?HZO. 5070 CR3R4NHScheme 6. 通过 DMDTC 合成脲2.23.1 DMDTC与胺生成脲实例H尹，前-罚CStep 1. hexylamine (2.02g, 20 mmol) was added dropwise over a period of 10 min to a suspension of S,S-dimethyl dithiocarbona
15、te (1.22 g, 10 mmol) in H 2O (5 mL), under vigorous stirring. The reaction was mildly exothermic, and during the addition the temperature of the mixture was maintained at 2025 C with an ice-water bath. The progress of the reaction was monitored by GC and GC-MS analyses. During the reaction an emulsi
16、on was formed. Stirring at r.t. (2025 C) was maintained until disappearance of S,S-dimethyl dithiocarbonate(2 h). The mixture was then treated with cold CH2Cl2/aq 5% HCl (2:1, 100 mL). The aqueous soln was separated and extracted with CH2Cl2 (30 mL). The combined organic extracts were washed with H2O (30 mL), dried (Na2SO4), and eva
