Synthesis Of Aromatic Urea Compounds) And Its Stability Study In Alcohol

In this thesis, phenyl chloroformate was chosen as the carbonyl source. Several series of aromatic urea compounds were synthesized under mild conditions using this reagent. The stability of these series of aromatic urea compounds in alcohol solvents was studied. All the stability results are summarized and elaborated. Data obtained from this thesis work will be useful for people to use in the development of urea-containing drugs in the synthesis and purification.The synthesis and identification work of these aromatic urea compounds were completed in this thesis. A good route was developed and the process parameters were as fellows:aromatic amine as the substrate in THF and DMF, and phenyl chloroformate was added at0-5℃to form activated intermediate, the intermediate was reacted then with the other amine component in the presence of diisopropyl ethyl amine to obtain the desired aromatic urea. High conversion was obtained under mild conditions. Two parts of the ureas designed are aromatic amine with electron-withdrawing groups or electron-donating groups, and aliphatic amine of ethyl piperazine, diethylamine, ammonia, piperidine, and morpholine. Thirty two symmetrical or unsymmetrical aromatic ureas can be obtained in two simple steps, and their structures were characterized.The stability of these aromatic urea compounds in alcohol solvents was studied. Research results indicated that aromatic urea compounds were not stable in high temperature. Nucleophilic substitution of the ureas by the alcohol forms carbamates. In a special case, isoamyl alcohol was used as the solvent and an acceleration experiment was carried out to study the stability of the final products. The ratio R of the reaction products and raw materials in different time systems was used to reflect its rate of alcoholysis, the results show that its substitution rate is related with temperature and the reaction time, the higher the temperature, the faster the replace rate; with the longer reaction time, substitutes will also increase. Aromatic urea compounds with electron-donating group substituted aromatic amines have high stability in the alcohol; on the contrary, those with electron-withdrawing substituents have low stability.Stability studies of unsymmetrical urea compounds indicated that when one side of the urea bridge connects with an aromatic amine and the other side connects with an aliphatic amine, the urea part of the aromatic side was more stable because the tautomerism of benzene ring and the carbonyl (-CON-) formed a conjugated system, which stabilized the urea bond between aromatic amines and the carbonyl group. The stability is in the order of diethylamine, piperidine, morpholine aromatic urea> ethylpiperazine aromatic urea> aromatic amine urea. When both ends are connected to different aromatic amines, each of which was likely to leave, symmetrical aromatic urea will be formatted at the same time.From the research results obtained during this thesis, we conclude that aromatic ureas are not stable in alcohol solvents. Its degradation to the corresponding amine component and the carbamate molecule increase with the temperature increase and time elongation. Therefore, when alcohol solvent was used in the purification of urea-containing compounds (especially for molecules drug used for human being), great attention should be paid with impurity detection, and the reaction temperature as well as the reaction time.