Synthesis Of Antineoplastic Agent Lenalidomide And Environmentally Friendly Synthesis Of Its Key Intermediate

Lenalidomide,chemically named 3-(4-amino-1,3-dihydro-1-oxo-2H-is-oindol-2-yl)-2,6-piperidinedione,is a novel immunomodulator developed by Celgene corporation.Lenalidomide is a derivative of thalidomide,but show improved antiangiogenesis properties and immunomodulator activity while demonstrate almost no neurotoxicity and teratogenicity.Nowadays,lenalidomide is wildly used in clinical for the treatment of multiple myeloma and myelodysplastic syndromes,and shows great therapeutic effects.In recent years,clinical trials aimed at assessing other indications of lenalidomide are performed,and results have shown that lenalidomide has significant therapeutic effects on other solid tumors such as endometrial cancer,cervical cancer,ovarian cancer,lung cancer,pancreatic cancer,colorectal cancer,melanoma and so on.The reported synthetic route towards lenalidomide is relatively simp le,but there are some problems such as the high price of raw materials,the relatively complicated operation and the impurity content.Part ? Synthesis of Antineoplastic Agent lenalidomideObjective: To simplify the synthesis of lenalidomide and optimize the synthesis and purification of key intermediates.Methods: 3-nitro-o-xylene was chosen as the starting material,after selective oxidation,to get 2-methyl-3-nitrobenzoic acid,and then after esterification and bromination to prepare key intermediates 2-bromomethyl-3-nitrobenzoicacid methyl ester.Subsequently,cyclized with 3-amino-2,6-piperidinedione hydrochloride,and then reduced nitro to afford target drug lenalidomide.Synthesis and purification of the key intermediates 2-bromomethyl-3-nitrobenzoate and lenalidomide were established.The intermediates and products were identified by mass spectrometry,NMR and other means.Content determination were performed by means of HPLC.Results: A more simplify,accessible,environment friendly synthetic routine of lenalidomide was discovered.The purification of lenalidomide was optimized and a more practical method was established.Conclusions: The synthesis process of lenalidomide is simplified and optimized,the synthesis cost is reduced and the pollution is reduced.The green synthesis of the key intermediate 2-methyl-3-nitrobenzoic acid was discussed.The product and intermediate structures were confirmed by mass spectrometry and nuclear magnetic resonance.A suitable purification method was established.The content was determined by HPLC.Part ? Environmentally Friendly Synthesis of Its Key intermediate 2-methyl-3-nitrobenzoic acidObjective: To explore the green synthesis of the key intermediate 2-methyl-3-nitrobenzoic acid.Methods: N-butyl nitrite was chosen as the cyanide reagent,and through experiments to determine the best catalyst and dosage of it.Results: The determined reaction conditions were: n-butyl nitrite(5 equiv),Pd(OAc)2(10 mol%),NHPI(20 mol%).Conclusions: We have developed a novel method for the direct synthesis of aromatic nitriles from the corresponding methyl arenes under palladium-catalyzed conditions using TBN as the nitrogen source.This direct conversion of a methyl group into a cyano group proceeds under mild conditions,with high efficiency.