49752-90-1Relevant academic research and scientific papers
Chiral Vicinal Diamines Derived from Mefloquine
Boratyński, Przemys?aw J.,Kowalczyk, Rafa?,Kucharski, Dawid J.
, p. 10654 - 10664 (2021/08/20)
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.
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
supporting information, p. 1670 - 1673 (2019/01/04)
Mefloquine is an important drug for prevention and treatment of malaria. It is commercially available as a racemic mixture, wherein only one enantiomer is active against malaria, while the other one causes severe psychotropic effects. By converting the drug into a compound that crystallizes as a racemizable racemic conglomerate, the deracemization of mefloquine into the desired enantiomer was achieved.
Base metal-catalyzed benzylic oxidation of (aryl)(heteroaryl)methanes with molecular oxygen
Sterckx, Hans,De Houwer, Johan,Mensch, Carl,Herrebout, Wouter,Tehrani, Kourosch Abbaspour,Maes, Bert U.W.
, p. 144 - 153 (2016/04/05)
The methylene group of various substituted 2- and 4-benzylpyridines, benzyldiazines and benzyl(iso)quinolines was successfully oxidized to the corresponding benzylic ketones using a copper or iron catalyst and molecular oxygen as the stoichiometric oxidant. Application of the protocol in API synthesis is exemplified by the alternative synthesis of a precursor to the antimalarial drug Mefloquine. The oxidation method can also be used to prepare metabolites of APIs which is illustrated for the natural product papaverine. ICP-MS analysis of the purified reaction products revealed that the base metal impurity was well below the regulatory limit.
A Robust, Recyclable Resin for Decagram Scale Resolution of (±)-Mefloquine and Other Chiral N-Heterocycles
Kreituss, Imants,Chen, Kuang-Yen,Eitel, Simon H.,Adam, Jean-Michel,Wuitschik, Georg,Fettes, Alec,Bode, Jeffrey W.
, p. 1553 - 1556 (2016/02/12)
Decagram quantities of enantiopure (+)-mefloquine have been produced via kinetic resolution of racemic mefloquine using a ROMP-gel supported chiral acyl hydroxamic acid resolving agent. The requisite monomer was prepared in a few synthetic steps without chromatography and polymerization was safely performed on a >30 gram scale under ambient conditions. The reagent was readily regenerated and reused multiple times for the resolution of 150 grams of (±)-mefloquine and other chiral N-heterocylces.
A Concise and Highly Enantioselective Total Synthesis of (+)-anti- and (-)-syn-Mefloquine Hydrochloride: Definitive Absolute Stereochemical Assignment of the Mefloquines
Rastelli, Ettore J.,Coltart, Don M.
supporting information, p. 14070 - 14074 (2016/01/25)
A concise asymmetric (>99:1 e.r.) total synthesis of (+)-anti- and (-)-syn-mefloquine hydrochloride from a common intermediate is described. The key asymmetric transformation is a Sharpless dihydroxylation of an olefin that is accessed in three steps from commercially available materials. The Sharpless-derived diol is converted into either a trans or cis epoxide, and these are subsequently converted into (+)-anti- and (-)-syn-mefloquine, respectively. The synthetic (+)-anti- and (-)-syn-mefloquine samples were derivatized with (S)-(+)-mandelic acid tert-butyldimethylsilyl ether, and a crystal structure of each derivative was obtained. These are the first X-ray structures for mefloquine derivatives that were obtained by coupling to a known chiral, nonracemic compound, and provide definitive confirmation of the absolute stereochemistry of (+)-anti- as well as (-)-syn-mefloquine.
Absolute configuration and antimalarial activity of erythro-mefloquine enantiomers
Dassonville-Klimpt, Alexandra,Cezard, Christine,Mullie, Catherine,Agnamey, Patrice,Jonet, Alexia,Da Nascimento, Sophie,Marchivie, Mathieu,Guillon, Jean,Sonnet, Pascal
, p. 642 - 646 (2013/07/26)
Mefloquine (MQ), an antimalarial drug, is used as a racemate of (-)- and (+)-enantiomers, which display biological differences. The question concerning their exact configuration remains a matter of debate. The absolute configuration of the two MQ enantiomers as well as their biological activity has been established, thus confirming the importance of the stereochemistry in the design of MQ analogues that have fewer adverse side effects (see figure). Copyright
Trapped in misbelief for almost 40 years: Selective synthesis of the four stereoisomers of mefloquine
Schuetzenmeister, Nina,Mueller, Michael,Reinscheid, Uwe M.,Griesinger, Christian,Leonov, Andrei
supporting information, p. 17584 - 17588 (2014/01/06)
Here we report the synthesis of all four stereoisomers of mefloquine. Mefloquine (Lariam) is an important anti-malaria drug that is applied as a racemate of the erythro form. However, the (-)-isomer induces psychosis, while the (+)-enantiomer does not have this undesired side effect. There are six syntheses of which five lead to the wrong enantiomer without the authors of these syntheses noting that they had synthesized the wrong compound. At the same time physical chemistry investigations had assigned the absolute configuration correctly and the last enantioselective synthesis that took these results into account delivered the correct absolute configuration. Since various synthetic approaches failed to provide the correct stereoisomers in previous syntheses, we submit here a synthetic approach with a domino Sonogashira-6π- electrocyclisation as key step that confirmed synthetically the correct absolute configuration of all four isomers. Five to four: A total synthesis that yields all four stereoisomers of the important antimalarial drug mefloquine (Lariam) has been developed. This five-step approach with a domino Sonogashira-6π- electrocyclisation as key step has confirmed synthetically the correct absolute configuration of all four isomers (see scheme).
Asymmetric total synthesis of the antimalarial drug (+)-mefloquine hydrochloride via chiral N-amino cyclic carbamate hydrazones
Knight, John D.,Sauer, Scott J.,Coltart, Don M.
supporting information; experimental part, p. 3118 - 3121 (2011/08/03)
Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction of a chiral α-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary.
RESOLUTION OF MEFLOQUINE WITH O,O-DI-P-AROYLTARTARIC ACID
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Page 5, (2008/06/13)
A process for increasing the optical purity of a mixture of enantiomers of mefloquine, used a substantially single enantiomer of a O, O-di-p-aroyltartaric acid as a resolving agent.
