Issue in Honor of Prof Csaba Szantay ARKIVOC 2008 (iii) 182-193
easily transformed into a rearranged product.18 In the presence of sodium hydride19 in tetrahydrofuran the conversion of the methylation was more than 95%.
The most common reagents for O-demethylation are boron tribromide or hydrogen bromide. Both methods were studied. The latter transformed easily the N-CD3-derivative of dextromethorphan into the corresponding N-CD3-dextrorphan.
Scheme 2 summarizes our synthetic pathway.
The quality of our N-CD3-derivative of dextromethorphan 5 and N-CD3-dextrorphan 6 was checked by GC-MS, HPLC, NMR and MS measurements. The purity of the obtained N-CD3dextromethorphan was >99% by HPLC, and 97-98% by GC-MS. The GC-MS technique allowed to detect the N-CH, N-CH2, and N-CH3 contamination too.
The NMR spectrum of dextromethorphan hydrobromide showed a complex diastereomeric mixture because of a,ß-protonation, which makes it difficult to determine possible N-CH3, N- CH2D and N-CHD2 contamination. Figure 2 shows the 1H NMR spectrum of the commercially available (Sigma-Aldrich) dextromethorphan hydrobromide.
Figure 2. Partial 1NMR spectrum of dextromethorphan hydrobromide monohydrate (Sigma D2531) in DMSO-d6 showing the aliphatic chemical shift region.
It is more advantageous to study the spectrum of the corresponding base, which is less ambiguous. Figure 3 shows the 1H NMR spectrum of dextrorphan base 2 prepared from dextromethorphan 1 hydrobromide monohydrate (Sigma) by treatment with hydrogen bromide followed with aqueous ammonia. The N-methyl peak can be seen at ~ 2.3 ppm in DMSO-d6.
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