硫脲的合成

硫脲Thiourea在石油化工、医药化工同样具有泛的应用前景，很多医药分子中都还有硫脲的结构片断。例如目前市场上很多口服降糖药、抗甲状腺药都属于硫脲类分子。手性硫脲类催化剂用于不对称合成也成为最近研究的热点。硫脲的化学合成通常有下列一些方法。

一、异硫氰酸酯与胺反应生成硫脲

To a solution of tert-butylisothiocyanate (5.0 mL, 39 mmol) in dichloromethane (200 mL) were added isopropylamine (4.0 mL, 47 mmol) and diisopropylethylamine (DIEA) (6.8 mL, 39 mmol), and the mixture was stirred at rt for 2h. The reaction mixture was diluted with EtOAc, washed with 10 percent citric acid (2x), saturated NaHCO3 (2x), H20 (2x), and brine (1x). The organic layer was dried (MgS04) and evaporated to the crude product, which was purified by column to afford 1-tert-butyl-3-isopropyl-thiourea (3.3 g, 52 %).

二、硫光气与胺反应生成硫脲

To a solution of 8.5 g of 3-chloro-5-fluoroaniline in 150 ml of benzene was added a solution of 2.2 g of thiophosgene in 10 ml of benzene dropwise at room temperature under nitrogen. The resulting mixture was stirred at 60 oC for 3 hours and then cooled to room temperature. After filtered, the filtrate was concentrated to the oil, which was followed by a solution of t-pentylamine (3.4 g ) in 30 ml of benzene. The mixture was stirred at room temperature for another 30 minutes. The reaction mixture was evaporated in vacuo and the resulting solid recrystallized from cyclohexane to give 2.2 g of the title compound as colorless needles 1-(3-chloro-5-fluoro-phenyl)-3-(2,2-dimethyl-propyl)-thiourea.

三、硫代羰基二咪唑与胺反应生成硫脲

To a mixture of 1,1'-thiocarbonyldiimidazole (535 mg) and acetonitrile (7 ml) was added a solution of 3-(N,N-Dimethyl) aniline (272 mg) in acetonitrile (7 ml) dropwise over period of 15 minutes at 0℃ under nitrogen. After stirring for 2 hours at ambient temperature, 2-(aminomethyl) pyridine (433 mg) was added to the mixture. The reaction mixture was then heated to 60 oC for 4 hours. After cooling to room remperature, the reaction mixture was evaporated to the residue, which was purified by column (DCM / MeOH) to give 1-(3-Dimethylamino-phenyl)-3-pyridin-2- ylmethyl-thiourea (423 mg).

四、利用硫代氯甲基苯酯合成硫脲

A mixture of n- Bu2NH and [4-(4-ethyl-phenylamino)-phenyl]-thiocarbamic acid O-phenyl ester (348) in ethanol was heated to reflux under N2 atmosphere for 16 h. After removal of the solvent, the residue was dissolved in DCM. The organic phase was washed with 1 N of sodium hydroxide (3 x 50 mL), 1 N of HCl aqueous solution and brine (5 X 50 mL). After dried over anhydrous Na2SO4 and filtered, the filtrate was concentrated to give the crude product, which was purified by column to afford 1,1-dibutyl-3-[4-(4-ethyl-phenylamino)-phenyl]-thiourea

五、通过硫代甲巯基碳酰合成硫脲

A mixture of 4-methyl-pyrimidin-2-ylamine (2.2 g, 20 mmol) and pyridin-2-yl-dithiocarbamic acid methyl ester (3.6 g, 20 mmol) in 100 mL of toluene was heated to reflux for 10 h. After removal of the solvent, the residue was recrystallized from methanol to afford 3.4 g of 1-(4-methyl-pyrimidin-2-yl)-3-pyridin-2-yl-thiourea.

六、硫代试剂（如Lawesson试剂）与脲反应得到硫脲

To 4.0 g of 1-(2,4-di-tert-butyl-3-hydroxy-phenyl)-3-(4-nitro-benzyl)-urea was added 6.0 g of a lawson reagent dissolved in 50 mL of 1,4-dioxane at room temperature under N2 atmosphere. The resulting mixture was heated to reflux for 15 h before poured into 150 mL of water. The mixture was extracted with ethyl acetate (3 x 100 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to the crude product, which was purified by a silica gel column to give 2.5 g of 1-(2,4-Di-tert-butyl-3-hydroxy-phenyl)-3-(4-nitro-benzyl)-thiourea (60 %).

本文内容来自传说中的药明康德宝典。。。。，版权归原作者所有。