脲的介绍
合成脲及半脲常用的一些试剂
前面分享的内容中有提到过一些合成脲的试剂,大致可分为以下几种类型,使用方法也都有文献报道,至于可靠不可靠,只有自己试了才知道,我也不清楚。
合成脲,不论是用哪种试剂,一般都需要分两步、一锅来进行;即:第一步一分子氨(胺)在碱的作用下先和试剂生成活性中间态(或异氰酸酯),有些活性中间态是可以进行分离纯化的,切记该活性中间态不可接触醇或胺类物质,否则变质。第二步该活性中间态(或异氰酸酯)在碱的作用下与另一分子氨(胺或醇)反应,生成目标产物脲或半脲。以苯胺与吗啡啉(甲醇)为例,大致过程可表示为:
Add TEA (0.64 mL, 4.6 mmol) to a solution of substituted aniline (0.46 mmol) and BTC (136 mg) in dry DCM. Stirred the mixture for 10 minutes at room temperature. Add biphenyl amine (100 mg) to the mixture. Stirred the reaction solution at 40°C for 2h. Concentrate the reaction solution. Purify the product by a flash column. 98% yield. |
WO2010032856 A1: (Step 1) The compound (0.20 g) was dissolved in THF (5 mL), and 4-nitrophenyl chlorocarbonate (0.099g) and DIPEA (0.086 mL) were added dropwise at 5oC. The reaction mixture was stirred at 5°C for 1h, poured into saturated aqueous NH4Cl solution, and the mixture was extracted with EA. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a white powder (0.23 g). (Step 2) A solution of the compound (0.23 g) obtained in step 1 and 1-(methylsulfonyl)piperazine (0.22 g) in NMP (5 mL) was stirred at 135°C for 11h. The reaction mixture was poured into water, and extracted twice with EA. The extract was washed with saturated aqueous NH4Cl solution and saturated brine, dried and concentrated. The residue was purified by silica gel column chromatography. 93% yield. |
活性酯类试剂有时也会用到,因其结构中不含氯,所以不会有难闻的气味。这类试剂不如上述两种试剂的活性那么高,相对比较温和。其实CDI也可以归属于该类试剂,因此就放在一起介绍了。
WO2010148197 A1: In a flask containing (1S,3R)-N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)-N3-(2-(methylamino)ethyl)cyclohexane-1,3-diamine, 47c, (0.020 g, 0.048 mmol) in DMF was added DIEA(0.025 mL, 0.144 mmol) and bis(4-nitrophenyl) carbonate (0.016 g, 0.053 mmol). The reaction mixture was stirred at rt for 3h. |
环状脲(内脲)的合成
半脲的合成方法参考与脲的合成方法,讲的直白一点就是在第二步把胺(氨)换成醇。这里不再过多重复介绍。
合成脲的一些注意事项
硝基苯酯类试剂
反应第一步中间态的监测
氨(胺)或醇的活性不够
第二步所用的氨(胺)或醇的亲核性很差,我比较建议大家用活性酯类试剂;直白一点就是先做成活性酯,纯化出来,然后再与活性差的氨(胺)或醇的钠(锂或钾)盐反应;或用高沸点溶剂,高温下反应。
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