Study On The New Synthesis Process Of Anti-tumor Drug Lenalidomide

Lenalidomide is currently one of the best selling anticancer drugs.In 2016,the global sales reached 6 billion 974 million US dollars.It has unique curative effect on treating myeloma,myelodysplastic syndrome,leukemia and other diseases.In order to produce lenalidomide with low cost,high yield and environmentally friendly condition,this paper,4-aminoisoindoline-1-one was obtained from 3-nitrophthalimide after three steps of carbonyl reduction,dehydroxylation and nitroreduction,which was not reported in literature.The 2-bromo dimethyl glutarate was obtained by acylation,bromine substitution and esterification with glutaric acid as raw material.After getting the two intermediate followed by substitution,hydrolysis and cyclization,we successfully synthesized the anticancer drug lenalidomide.The intermediates obtained in the test were characterized by chromatographic detection,melting point measurement,nuclear magnetic resonance,mass spectrometry detection and other techniques.The main contents of this paper are as follows:Studies on the synthesis of intermediate 4-aminoisoindoline-1-one: Using 3-nitrophthalimide as raw materials in methanol and dichloromethane as solvent under the condition of adding potassium borohydride to obtain the intermediate I;intermediate I in the condition of dichloromethane as solvent,three fluorine acetic acid,three ethyl silane as reduction system can get intermediate II;intermediate II in the condition of ethanol as solvent,zinc powder and concentrated hydrochloric acid as reductant system can get 4-aminoisoindoline-1-one.The optimum adding ratio,reaction time and reaction temperature of the synthetic intermediate 4-aminoisoindoline-1-one are discussed in this paper.The total yield of the final three-step reaction is 81.4%,the purity of the crude product is about 97.5%,and the purity after refining is above 99%.Studies on the synthesis of intermediate 2-bromo dimethyl glutarate: Glutaric acid as the raw material,Sulfoxide chloride was added with trichloromethane as the solvent,DMF as the catalyst,and the solvent reflux.Add bromine to reflux for 20 hours,and then add methanol at the temperature of 0?,the initial 2-bromo dimethyl glutarate will be produced from esterification.After washing,the distillates of 100?~110? were collected at 7.5mmHg and heating at 170?.The purity of the distillates was more than 96%,and the yield was 50.3%.Studies on the synthesis of lenalidomide: Using 4-aminoisoindoline-1-one and 2-bromo dimethyl glutarate as the raw material,after substitution,hydrolysis and cyclization three steps,we can get lenalidomide.We determined the optimal reaction system in each step and reaction time,reaction temperature,adding ratio and other factors.The purity of the crude product is about 96%,the purity of the refined product is above 99%,which is meet the requirement of the drug.The synthetic process doesn't use the methyl 2-bromomethyl-3-nitrobenzoate which is the mainly raw material using in synthesized lenalidomide.This new process gives a new way to synthesized lenalidomide.At the same time,the cost of the new process is about 15% of the currently process.All raw materials used in the new synthesis process are in low prices,less toxic,friendlier to the environment,simple in operation and suitable for industrial production.