An improved procedure for synthesis of lenalidomide as an active pharmaceutical ingredient

Lenalidomide is a second-generation immunomodulatory drug widely used in the treatment of multiple myeloma and myelodysplastic syndromes. Market studies indicate that the demand for lenalidomide rising steadily due to the increasing prevalence of multiple myeloma. As a result of its high effectiveness in the treatment and improved survival rates, lenalidomide has become the second best-selling drug in the field of oncology. So far, many methods have been developed for synthesis of lenalidomide, but they are plagued by issues. Finding a method that ensures the highest efficiency, minimal impurity, and cost-effectiveness remains a challenge for researchers. In this study, we chose a three steps method for synthesis of lenalidomide: 1) bromination of 2-methyl-3-nitrobenzoate, 2) coupling reaction with 3-aminopiperidine-6,2-dione hydrochloride and 3) reduction of nitro group to an amine group. All three steps were optimized regarding to different key parameters such as: initiator, solvent, temperature, time, molar ratio of the reactants, reducing agents and also purification process. Then lenalidomide was synthesized in the optimized condition and characterized by different spectroscopic methods. The results showed desirable purity and yield which are comparable with the other methods published in literature. Using of solvent free condition for the first step, safe solvents for the other steps, economical and safe reducing agent for the last step, minimizing by-products, simplify purification process and good yield are advantages of our method. These consequences make this procedure cost-effective and compatible with the environment. • According to the latest Global Cancer Observatory statistics in 2018, approximately 0.9 % of all cancer diagnoses are related to multiple myeloma (MM). • Lenalidomide (LNA) is effective in patients with MM, alone and in combination with other drugs such as dexamethasone and bortezomib. • A three-step method for synthesis of LNA was conducted including 1) bromination of 2-methyl-3-nitrobenzoate, 2) coupling with 3-aminopiperidine-6,2-dione hydrochloride and 3) reduction of nitro group to an amine. • All steps were optimized and characterized by different spectroscopic methods. • Using solvent-free conditions for the first step, safe solvents for the other steps, an economical and safe reducing agent, minimizing by-products, simplifying the purification process, and achieving a good yield are advantages of this method. • These consequences make this procedure cost-effective and compatible with the environment.