A phosgene- and metal-free synthesis of unsymmetrical arylurea derivatives utilizing 3-substituted dioxazolones and commercially available amines has been developed. The 3-substituted dioxazolones serve as the precursors of the in situ generated isocyanate intermediates in the presence of non-toxic sodium acetate as a base and methanol as a solvent under mild heating conditions. A series of unsymmetrical phenylureas including N, N’- mono-, di-, and trisubstituted derivatives are chemoselectively obtained in moderate to excellent yields from a broad scope of both 3-substituted dioxazolones and amines without a significant amount of the symmetrical byproducts. In many cases, the resulting unsymmetrical phenylureas are easily separated by filtration allowing no chromatographic purification. These investigations provide an opportunity for facile, practical, and eco-friendly synthesis of unsymmetrical diarylureas. Application of this method is demonstrated toward the gram-scale preparation of anti-cancer drugs, sorafenib and the 3-cycle continuous synthesis in conjugation with the recycle of sodium acetate and methanol process of known herbicide, daimuron.

已经开发出利用3-取代的二恶唑酮和可商购的胺的无光气和无金属的不对称芳基脲衍生物的合成方法。在无毒的乙酸钠作为碱和甲醇作为溶剂的情况下，在温和的加热条件下，3-取代的二恶唑啉酮用作原位生成的异氰酸酯中间体的前体。一系列不对称的苯基脲，包括N，N'-从广泛范围的3-取代的二恶唑酮和胺中以化学产率至中等的产率化学选择性地获得单，二和三取代的衍生物，而没有大量的对称副产物。在许多情况下，很容易通过过滤分离得到的不对称苯基脲，无法进行色谱纯化。这些研究为不对称二芳基脲的简便，实用和环保合成提供了机会。证明了该方法在克级抗癌药物索拉非尼的制备中的应用以及与已知除草剂daimuron的乙酸钠和甲醇工艺循环结合的3周期连续合成。