Study On The Synthesis Of The Key Intermediate Of Lenalidomide

Lenalidomide is a safe and effective antitumor drug approved by the FDA on27th,Dec.,2005.In 2018,it has sales of 9.685 billion U.S.dollars,ranking the third in the world.It is widely used in the treatment of a variety of diseases,such as multiple myeloma and myelodysplastic syndrome.At present,the synthesis of lenalidomide mainly include two routes,both routes using 2-methyl-3-nitrobenzoate as the starting material.The first route prepares lenalidomide through bromination,cyclization,reduction and other steps.The process was simple and suitable for industrial production.However,the use of carbon tetrachloride as solvent in the reaction generated environmentally unfriendly problems.The second route prepares lenalidomide through bromination,amination,substitution,cyclization,reduction and other steps.The raw materials were easily available,and the separation and purification of product were simple.However,the use of sodium amide in the cyclization reaction generated potential risks,and the reaction conditions were more severe.In order to avoid the use of highly toxic solvents and solve problems such as harsh reaction conditions,it is of valuable to develop new methods that are environmentally friendly,simple and efficient.Based on these issues,the main research content of this article include the following:1.According to the literature research,the existing synthetic routes were summarized.Four new synthetic strategies were designed,and the synthesis experiments were carried out separately.The results showed that the design routes A,B,and C suffered great difficulties due to the chlorination ring opening of nitro-phthalide,C-N coupling,and the amination of aryl halides,making these three design strategies less practical;The synthesis experiments of design route D went well and the lenalidomide precursor was successfully synthesized.2.On the basis of route D,the reaction conditions of each step were optimized.In the first step,3-nitrophthalic acid was used as the starting material,which reacted with urea forming 3-nitrophthalimide through cyclization reaction,and the yield was98%;In the second step,4-nitroisoindoline was synthesized with a yield of 75%under the catalysis of Na BH₄ and BF₃·Et₂O.In the third step,4-nitroisoindoline was reacted with 3-bromo-2,6-piperidinedione to form 3-?4-nitro-1,3-dihydroisoindol-2-yl?piperidine-2,6-dione,and the yield was 72%.Finally,a oxidant reaction taken place synthesizing 3-?4-nitro-1-oxo-1,3-dihydroisoindol-2-yl?piperidine-2,6-dione with a yield of 78%,which is a key intermediate of lenalidomide.The total yield of this route was 41.3%.The final product was confirmed by NMR and MS.The purity of the final product was 99.3%by HPLC.In this paper,a new route for the synthesis of lenalidomide precursor has been developed,which has the advantages of mild reaction conditions,simple operation,higher reaction yield,etc.,and makes the raw materials for the synthesis of lenalidomide easier to obtain.In general,this route has the value of implement ability and subsequent optimization,and it has a good reference significance for the research and development of pharmaceutical intermediates.