Alternative synthesis of lenalidomide

Балаев, А. Н.; Okhmanovich, K. A.; Fedorov, V. E.

doi:10.1007/s11094-013-0868-7

Cited by 6 publications

(8 citation statements)

References 1 publication

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“…This is in accordance with other literature data regarding the racemization of thalidomide [20,21]. A possible explanation of the nonracemic nature of the sample is that it might have been synthesized from L-glutamine and during the synthetic process, complete racemization did not occur [20,22].…”

Section: Hplc Methods Developmentsupporting

confidence: 92%

Chiral separation of lenalidomide by liquid chromatography on polysaccharide‐type stationary phases and by capillary electrophoresis using cyclodextrin selectors

Szabó

Foroughbakhshfasaei

Gál

et al. 2018

J of Separation Science

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Complementary techniques were applied for the investigation of the chiral recognition and enantiomeric resolution of lenalidomide using various cyclodextrins and polysaccharides as chiral selectors. The high-performance liquid chromatography enantioseparation of the anticancer drug was achieved using polysaccharide-type chiral stationary phases in polar organic mode. Elution order and absolute configuration were elucidated by combined circular dichroism spectroscopy and time-dependent density functional theory calculations after the isolation of pure enantiomers. Chiral selector dependent and mobile-phase dependent reversal of the enantiomer elution order was observed, and the nonracemic nature of the lenalidomide sample was also demonstrated. Eight anionic cyclodextrins were screened for their ability to discriminate between the uncharged enantiomers by using capillary electrophoresis. Only two derivatives presented chiral interactions, these cases being interpreted in terms of apparent stability constants and complex mobilities. The best results were delivered by sulfobutylether-β-cyclodextrin, where quasi-equal stability constants were recorded and the enantiodiscrimination process was mainly driven by different mobilities of the transient diastereomeric complexes. The optimized high-performance liquid chromatography (Chiralcel OJ column, pure ethanol with 0.6 mL/min flow rate, 40°C) and capillary electrophoresis methods (30 mM sulfobutylether-β-cyclodextrin, 30 mM phosphate pH 6.5, 12 kV applied voltage, 10°C) were validated for the determination of 0.1% (R)-lenalidomide as a chiral impurity, which could be important if a racemic switch is achieved.

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Section: Hplc Methods Developmentsupporting

confidence: 92%

Chiral separation of lenalidomide by liquid chromatography on polysaccharide‐type stationary phases and by capillary electrophoresis using cyclodextrin selectors

Szabó

Foroughbakhshfasaei

Gál

et al. 2018

J of Separation Science

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“…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).…”

Section: Cereblon Photochemically Targeting Chimerasmentioning

confidence: 99%

“…Additionally, some lenalidomide-based PROTACs displayed a higher level of induced target degradation than their pomalidomide-based counterparts ( Qiu et al, 2019 ). 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 ).…”

Section: E3 Ligasesmentioning

confidence: 99%

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

et al. 2021

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Proteolysis-targeting chimeras (PROTACs) have received tremendous attention as a new and exciting class of therapeutic agents that promise to significantly impact drug discovery. These bifunctional molecules consist of a target binding unit, a linker, and an E3 ligase binding moiety. The chemically-induced formation of ternary complexes leads to ubiquitination and proteasomal degradation of target proteins. Among the plethora of E3 ligases, only a few have been utilized for the novel PROTAC technology. However, extensive knowledge on the preparation of E3 ligands and their utilization for PROTACs has already been acquired. This review provides an in-depth analysis of synthetic entries to functionalized ligands for the most relevant E3 ligase ligands, i.e. CRBN, VHL, IAP, and MDM2. Less commonly used E3 ligase and their ligands are also presented. We compare different preparative routes to E3 ligands with respect to feasibility and productivity. A particular focus was set on the chemistry of the linker attachment by discussing the synthetic opportunities to connect the E3 ligand at an appropriate exit vector with a linker to assemble the final PROTAC. This comprehensive review includes many facets involved in the synthesis of such complex molecules and is expected to serve as a compendium to support future synthetic attempts towards PROTACs.

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“…CV value should not exceed 15% for the QC samples, except for the LOQ, which should not exceed 20%. 8 There are three different methods for the determination of LOD and LOQ as indicated in ICH guidelines. However in this study, to determine the LOD and LOQ, the signal-tonoise ratio was calculated by comparing results for samples with known concentrations to blank samples.…”

Section: Methods Validationmentioning

confidence: 99%

“…The temperature used for the evaporation did not compromise the stability of the drug, according to several studies. [8][9][10] The solid obtained was further diluted in 110 µL of mobile phase and centrifuged for 2 min at 10,200 rpm. The supernatant was transferred into an HPLC vial, and a volume of 80 µL of this solution was injected into the HPLC system.…”

Section: General Proceduresmentioning

confidence: 99%

A Wide Linearity Range Method for the Determination of Lenalidomide in Plasma by High-Performance Liquid Chromatography: Application to Pharmacokinetic Studies

et al. 2016

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A wide linearity range analytical method for the determination of lenalidomide in patients with multiple myeloma for pharmacokinetic studies is required. Plasma samples were ultrasonicated for protein precipitation. A solid-phase extraction was performed. The eluted samples were evaporated to dryness under vacuum, and the solid obtained was diluted and injected into the high-performance liquid chromatography (HPLC) system. Separation of lenalidomide was performed on an Xterra RP C18 (250 mm length × 4.6 mm i.d., 5 µm) using a mobile phase consisting of phosphate buffer/acetonitrile (85:15, v/v, pH 3.2) at a flow rate of 0.5 mL · min The samples were monitored at a wavelength of 311 nm. A linear relationship with good correlation coefficient (r = 0.997, n = 9) was found between the peak area and lenalidomide concentrations in the range of 100 to 950 ng · mL The limits of detection and quantitation were 28 and 100 ng · mL, respectively. The intra- and interassay precisions were satisfactory, and the accuracy of the method was proved. In conclusion, the proposed method is suitable for the accurate quantification of lenalidomide in human plasma with a wide linear range, from 100 to 950 ng · mL This is a valuable method for pharmacokinetic studies of lenalidomide in human subjects.

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Alternative synthesis of lenalidomide

Cited by 6 publications

References 1 publication

Chiral separation of lenalidomide by liquid chromatography on polysaccharide‐type stationary phases and by capillary electrophoresis using cyclodextrin selectors

Chiral separation of lenalidomide by liquid chromatography on polysaccharide‐type stationary phases and by capillary electrophoresis using cyclodextrin selectors

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

A Wide Linearity Range Method for the Determination of Lenalidomide in Plasma by High-Performance Liquid Chromatography: Application to Pharmacokinetic Studies

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