Narcotic drug methohexital: synthesis by enantioselective catalysis.
The narcotic drug methohexital 1 contains two asymmetric carbon atoms and, thus, consists of four isomers, two diastereomeric pairs of enantiomers. The commercial drug is the so-called alpha-racemate, one pair of diastereomers only. A method was developed to prepare differently enriched mixtures of methohexital isomers without resorting to lengthy and expensive optical resolutions. A model reaction for the synthesis of methohexital is the palladium-catalyzed allylation of 1,5-dimethyl-barbituric acid 3, which is optimized and checked by molecular modeling. Catalysts with the best ligands are used in the allylation of the methohexital precursor 7, which contains the C(6) sidechain at the tetrahedral center of the barbiturate skeleton. The product stereochemistry was determined by the contribution of the enantioselective Pd catalysts and by the fact that the allylation is a kinetic resolution. The methohexital isomer mixtures obtained were evaluated with the corneal stimulus test of rats. Methohexital compositions were found, which are superior to the commercially used alpha-racemate (Brevimytal).
Brunner
H
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Institut für Anorganische Chemie, Universität Regensburg, 93040 Regensburg, Germany. henri.brunner@chemie.uni-regensburg.de
D018686:Anesthetics, Intravenous / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002384:Catalysis; D008723:Methohexital / Q000138:chemical synthesis* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009294:Narcotics / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism
D018686:Anesthetics, Intravenous; D009294:Narcotics; D008723:Methohexital