Synthesis of deuterated dextromethorphan derivatives

Abstract

Dextromethorphan is a widely used NMDA receptor antagonist and sodium channel blocker. Deuterated dextromethorphan and dextrorphan were synthesized via the N-desmethyldextromethorphan intermediate for pharmacokinetic study.

Easy-to-Implement Hydrogen Isotope Exchange for the Labeling of N-Heterocycles, Alkylkamines, Benzylic Scaffolds, and Pharmaceuticals

“…Direct exchange on the N -methyl groups of 23 and 29 is of huge interest, since they represent major metabolism sites. Multistep methods for the synthesis of labeled 23 and 28 using demethylation/methylation strategies exist, but lead to low overall yields (32% and 41%, respectively). , Once again, performing the labeling experiment on 28 with [Ir­(OMe)­(1,5-COD)] 2 precatalyst has only led to a low deuterium incorporation ([10] on the N -methyl group and [8] on the carbon center in meta position of the methoxy group). In order to confirm the nature of observed catalytically active species found with model substrates, TEM analyses of the reaction mixtures were also performed for pharmaceuticals 26 and 28 (see Figure and the SI).…”

New Spiro[cycloalkane-pyridazinone] Derivatives with Favorable Fsp3 Character

“…Changing the solvent to toluene improved the yields and N-phenyl derivatives (14-18) were isolated (Scheme 7). N-methyl derivatives were also prepared by N-alkylation reactions [52]. By starting from the previously isolated pyridazinone derivatives (8b, 8c, 9, 10) and alkylating them with methyl iodide in tetrahydrofuran in the presence of sodium hydride, the N-methylated compounds (19)(20)(21)(22) were isolated in medium yields.…”

“…By starting from the previously isolated pyridazinone derivatives (8b, 8c, 9, 10) and alkylating them with methyl iodide in tetrahydrofuran in the presence of sodium hydride, the N-methylated compounds (19)(20)(21)(22) were isolated in medium yields. In the preparation of N-benzylated derivatives we first chose the classical potassium carbonate method, but it did not produce the desired product, so we changed to cesium carbonate, which enabled us to isolate our desired N-benzylated pyridazinone derivatives in medium N-methyl derivatives were also prepared by N-alkylation reactions [52]. By starting from the previously isolated pyridazinone derivatives (8b, 8c, 9, 10) and alkylating them with methyl iodide in tetrahydrofuran in the presence of sodium hydride, the N-methylated compounds (19)(20)(21)(22) were isolated in medium yields.…”