Attrition‐Enhanced Deracemization of the Antimalaria Drug Mefloquine

Engwerda, Anthonius H. J.; Maassen, Rick; Tinnemans, Paul; Meekes, Hugo; Rutjes, Floris P. J. T.; Vlieg, Elias

doi:10.1002/ange.201811289

Cited by 6 publications

(1 citation statement)

References 43 publications

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“…Mefloquine is sold as a racemate of erythro ( anti ) isomer; however, there exist a number of reported asymmetric syntheses 3 and procedures for the separation 4 or conversion of enantiomers. 5 The dextrorotary compound was proven to be more effective against Plasmodium than its levorotary antipode. The latter is also much more toxic and prone to induce psychotic behavior.…”

Section: Introductionmentioning

confidence: 99%

Chiral Vicinal Diamines Derived from Mefloquine

2021

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Novel 1,2-diamines based on the mefloquine scaffold prepared in enantiomerically pure forms resemble 9-amino- Cinchona alkaloids. Most effectively, 11-aminomefloquine with an erythro configuration was obtained by conversion of 11-alcohol into azide and hydrogenation. Alkylation of a secondary amine unit was needed to arrive at diastereomeric threo -11-aminomefloquine and to introduce diversity. Most of the substitution reactions of the hydroxyl group to azido group proceeded with net retention of the configuration and involved actual aziridine or plausible aziridinium ion intermediates. Enantiomerically pure products were obtained by the resolution of either the initial mefloquine or one of the final products. The evaluation of the efficacy of the obtained vicinal diamines in enantioselective transformations proved that erythro -11-aminomefloquine is an effective catalyst in the asymmetric Michael addition of nitromethane to cyclohexanone (up to 96.5:3.5 er) surpassing epi -aminoquinine in terms of selectivity.

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Section: Introductionmentioning

confidence: 99%

Chiral Vicinal Diamines Derived from Mefloquine

2021

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Spontaneous Resolution by Crystallization of an Octanuclear Iron(III) Complex Using Only Racemic Reagents

et al. 2019

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The P and M enantiomers of the octanuclear [Fe8(μ4‐O)4(μ‐4‐Cl‐pz)12Cl4] complex, having T symmetry, were resolved by temporary substitution of chloride ligands by racemic 4‐sBu‐phenolates and subsequent crystallization, where the (S)‐ and (R)‐phenolates coordinate selectively to the M and P complexes, respectively. The complexes were characterized by circular dichroism analysis and X‐ray structure determination. This work constitutes a rare example of enantiomeric recognition resulting in spontaneous resolution upon crystallization.

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Combining Incompatible Processes for Deracemization of a Praziquantel Derivative under Flow Conditions

Valenti

Tinnemans²,

Baglai

et al. 2021

Angewandte Chemie

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An efficient deracemization method for conversion of the racemate to the desirable (R)-enantiomer of Praziquantel has been developed by coupling incompatible racemization and crystallization processes. By a library approach, a derivative that crystallizes as a conglomerate has been identified. Racemization occurs via reversible hydrogenation over a palladium on carbon (Pd/C) packed column at 130 8C, whereas deracemization is achieved by alternating crystal growth/ dissolution steps with temperature cycling between 5-15 8C. These incompatible processes are combined by means of a flow system resulting in complete deracemization of the solid phase to the desired (R)-enantiomer (98 % ee). Such an unprecedented deracemization by a decoupled crystallization/racemization approach can readily be turned into a practical process and opens new opportunities for the development of essential enantiomerically pure building blocks that require harsh methods for racemization.

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Attrition‐Enhanced Deracemization of the Antimalaria Drug Mefloquine

Cited by 6 publications

References 43 publications

Chiral Vicinal Diamines Derived from Mefloquine

Chiral Vicinal Diamines Derived from Mefloquine

Spontaneous Resolution by Crystallization of an Octanuclear Iron(III) Complex Using Only Racemic Reagents

Combining Incompatible Processes for Deracemization of a Praziquantel Derivative under Flow Conditions

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