Scalable and green process for the synthesis of anticancer drug lenalidomide

Computer-Assisted Retrosynthesis Based on Molecular Similarity

“…Following closely at rank 3 is a nitro reduction, consistent with published literature pathways. 60 , 61 The subsequent retro alkylation to open the five-membered ring is the next step in both literature pathways, although one begins from the nitrophthalic anhydride, 60 and the other uses the methyl ester, rather than the acid chloride. 61 The latter reference begins with the bromination by N -bromosuccinimide (NBS), precisely as suggested.…”

E3 Ligase Ligands in Successful PROTACs: An Overview of Syntheses and Linker Attachment Points

“…Two examples of active PHOTACs (Reynders et al, 2020) are presented in Scheme 19, each SCHEME 14 | Syntheses of lenalidomide ( 68), N-alkylated lenalidomide derivatives 69, and N-acylated derivatives 70. Reagents and conditions: a) NBS, AIBN, CCl 4 , reflux, 8 h, 88% yield (Balaev et al, 2013); a) NBS, AIBN, MeOAc, reflux, 18 h, 98% yield (Ponomaryov et al, 2015); a) NBS, AIBN, CCl 4 , reflux, 24h, 49% yield (Chaulet et al, 2011); b) 3-aminopiperidine-2,6-dione, Et 3 N, DMF, 50°C, 15 h, 86% yield (Balaev et al, 2013); b) 3-aminopiperidine-2,6-dione hydrochloride, K 2 CO 3 , NMP, 35°C for 1 h, then 55°C for 18 h, 89% yield (Ponomaryov et al, 2015); 3-aminopiperidine-2,6-dione, Et 3 N, MeCN, 55°C, 18 h, 57% yield (Chaulet et al, 2011); c) Pd(OH) 2 , H 2 , dioxane, 50-60°C, 78% yield (Balaev et al, 2013); c) Fe, NH 4 Cl, H 2 O, EtOH, 80°C, 4 h, 75% yield (Ponomaryov et al, 2015); c) Pd/C, H 2 , MeOH, DMF, quant. (Chaulet et al, 2011); d) linker-I or linker-Br, DIPEA, NMP, 110°C, 12 h, 48-84% yield for linkers used (Note: yield includes a following Boc deprotection on the linker) (Qiu et al, 2019); e) linker-CO 2 H, pyridine, POCl 3 , MeCN, rt, 3 h, about 40% yield for linkers used (Zhang et al, 2020a).…”

“…Compound 66 was obtained by bromination of the starting nitrobenzene derivative 65 with N -bromosuccinimide (NBS) in CCl 4 using azobisisobutyronitrile (AIBN) as an initiator of radical bromination, with reported yields of 88% ( Balaev et al, 2013 ) and 49% ( Chaulet et al, 2011 ). An alternative, high-yielding (98%) and green approach for this bromination was presented, where the reaction was carried out in a non-halogenated solvent, i.e., methyl acetate ( Ponomaryov et al, 2015 ). The following condensation with the glutarimide ring was achieved by the addition of a base and heating the solution at 50–55°C, yielding 57% (Et 3 N in MeCN; Chaulet et al, 2011 ), 86% (Et 3 N in DMF; Balaev et al, 2013 ), and 89% (K 2 CO 3 in NMP, Ponomaryov et al, 2015 ) of the desired nitro product 67 .…”

“…An alternative, high-yielding (98%) and green approach for this bromination was presented, where the reaction was carried out in a non-halogenated solvent, i.e., methyl acetate ( Ponomaryov et al, 2015 ). The following condensation with the glutarimide ring was achieved by the addition of a base and heating the solution at 50–55°C, yielding 57% (Et 3 N in MeCN; Chaulet et al, 2011 ), 86% (Et 3 N in DMF; Balaev et al, 2013 ), and 89% (K 2 CO 3 in NMP, Ponomaryov et al, 2015 ) of the desired nitro product 67 . Optimal conditions for the subsequent reduction to lenalidomide ( 68 ), i.e., a Pd/C-catalyzed hydrogenation, were described ( Chaulet et al, 2011 ).…”

Comparison of Two Reagents for Thionations

“…However, its toxicity, leading to teratogenesis and thrombosis, remains an issue for users. [54][55][56] Seeking for improved pharmacological properties 38 has been thionated which finally led to 40 as illustrated in Scheme 13.…”