Study On Synthesis Of Lenalidomide And Its Intermediates

Methyl2-bromomethyl-3-nitrobenzoate and3-Amino-2,6-piperidinedione are important intermediates of lenalidomide, based on literature, a commercial and pratical synthesis route with methyl2-methyl-3-nitrobenzoate and N-carbobenzyloxy-L-glutamine as start materials was chosen. Lenalidomide was successfully prepared by bromination, cyclizing reaction, amino deprotection, aminolysis, reduction. The route has advantage of cheapness, shortness, condition wildness and easiness in controlling.In first bromination reaction, a relatively low toxicity of1,2-dichloroethane was adopted as solvent, which has not been reported. The amount of free radical initiator azobisisobuty-ronitrile and bromo reagent N-bromosuccinimide were determined, and the recrystallized condition was affirmed. After optimized, the yield was69.0%, the purity was98.0%.In second cyclizing reaction, the relatively low price of N-benzyloxy carbonyl-L-gluta-mine as material, N,N’-carbonyl diimidazole as condensing agent,1,4-dioxane as solvent, the mole ratio and reaction temprature were optimized, the yield was73.6%.In third amino deprotection, two different deprotecting reagent were adopted:Pd/C H2hydrochloric acid and40%hydrobromide, and the optimal reaction conditions was respectively affirmed.In fourth aminolysis reaction, optimal reaction conditions were obtained by single factor experiment, the mole ratio of triethylamine and material was2.2:1, the temperature was8℃, under this condition, the yield was55.7%.In fifth nitro reduction reaction, Pd/C H2and Fe powder were chosed as two different reducting reagents, ultimately the catalytic hydrogenation of Pd/C was determined as the best reduction method, under this condition, the yield was98.9%.