Study On Synthesis Technology Of Lomustine

Lomustine is a broad spectrum of anti-tumor drugs, which is carmustine’s analog, it has a good effect of cancer treatment. Since the current synthesis method of lomustine exist some weak points, like higher costs, toxicity, low yield and so on, so it is necessary to carry out further research on the synthesis of lomustine.The paper choosed urea and ethanolamine as raw materials, after cyclization reaction, ring-opening reaction, chlorination and nitrosation, lomustine could be synthesized. This method had easily obtained raw materials, low cost, mild reaction conditions, high yield advantages. Through the study of various intermediates and target compound synthesis parameters, and ultimately got the optimal conditions.2-Oxazolidinone was synthesized by using urea and ethanolamine as raw material, DMF as solvent, the optimal conditions were as follows:ethanolamine 6.0mL (0.10mol), n(ethanolamine):n(urea) is 1:1.15, the reaction temperature was 170 ℃, the reaction time was 7h, DMF 25mL, the average yield of product 2-oxazolidinone could reach to 87.2%.N-(2-Hydroxyethyl)-N’-cyclohexylurea was synthesized by homemade 2-oxazolidinone and cyclohexane, the optimal conditions were as follows: 2-oxazolidone 8.7g (0.10mol), n(2-oxazolidinone): n(cyclohexylamine) was 1:1.20, the reaction temperature was 120℃, the reaction time was 20min, the accelerated rate of cyclohexylamine was 1.0mL/min, the average yield of product N-(2-hydroxyethyl)-N’-cyclohexylurea could reach to 68.3%.N-(2-Chloroethyl)-N’-cyclohexylurea was synthesized by homemade N-(2-hydroxyethyl)-N’-cyclohexylurea and thionylchloride, the optimal conditions were as follows:N-(2-hydroxyethyl)-N’-cyclohexylurea 9.3g (0.05mol), n(N-(2-hydroxyethyl)-N’-cyclohexyl urea):n(thionyl chloride) 1:1.50, the reaction temperature is 60℃, the reaction time was 5h, chloroform 25mL, the average yield of product N-(2-Chloroethyl)-N’-cyclohexylurea could reach to 89.2%.Lomustine was synthesized by homemade N-(2-chloroethyl)-N’-cyclohexylurea and sodium nitrite under nitrosation, the optimal conditions were as follows:N-(2-chloroethyl)-N’-cyclohexyl urea 4.1g (0.02mol), n(N-(2-chloroethyl)-N’-cyclohexyl urea): n(sodium nitrite) was 1:1.20, anhydrous formic acid 60mL, the reaction temperature was 10 ℃, the reaction time was 2.5h, the average yield of product lomustine could reach to 88.4%.The paper explored a new method for the synthesis of cyclohexylurea: cyclohexylurea was synthesized by using urea and cyclohexylamine as raw material, hydrochloric acid was used as catalyst, water was used as reaction solvent, the optimal conditions were as follows:cyclohexylamine 11.5mL (0.10mol), n(cyclohexylamine): n(urea) was 1:1.20, hydrochloric acid 0.05mol, water lOmL, the reaction temperature was 90 ℃, the reaction time was 20h, the average yield of product cyclohexylurea could reach to 82.1%.Each reaction have done laboratory scale-up experiments, which showed the optimum conditions were reliable. The process reduced the reaction time, simplified procedure and improved production efficiency effectively, it has further reduced production costs.