Interestingly, the deuterated form of the drug Tetrabenazine, in which the 6 deuterium atoms are on the 2 methyl ether groups, has seven advantages over the non-deuterated drug. The reaction shown in the diagram produced the key intermediate.
Potassium carbonate is a strong enough base to deprotonate the diphenol and form the potassium salt without generating water. This increases reactivity since hydration of the phenoxide anion would otherwise reduce its nucleophilicity. In addition, the use of 18-crown-6 as the phase-transfer catalyst complexes well to the potassium ion introduced by the potassium carbonate and the activated non-hydrated crown-K-phenoxide complex is soluble in acetone and can react at mild temperature. When using 18-crown-6 and 3 equiv deuterated methyl iodide, the yield was quantitative in 12 hours on a 100 gram scale.
When using TBAB and 2.2 equiv CD3I, the yield was 87% after 36 hours of reaction. It is possible that the yield using TBAB would have been higher if 3 equiv of CD3I were used though the attempt to minimize the excess of the expensive CD3I was commendable. Given the limited excess of CD3I and the possibility that the bromide of TBAB may have formed the volatile CD3Br in situ, it is possible that the reaction stalled when the small excess of CD3I was consumed. We can assume that the PTC reaction conditions could be optimized to achieve high yield with the less expensive quaternary ammonium phase-transfer catalyst instead of the expensive crown ether.
The inventors also demonstrated that PTC played a key role in the reaction since when they performed the reaction under the same conditions but without TBAB, the yield after 36 hours was only 72%.
When using the soft iodide anion as a leaving group in PTC systems, it is sometimes possible that the iodide may poison the tetrabutylammonium phase-transfer catalyst, however, the fact that the competition for association with the quat cation was between iodide and an organophilic phenoxide, probably means that quat catalyst poisoning by iodide was not likely.
Avoiding the use of hydroxide as well as working at mild temperature were probably beneficial to minimize side reactions of the aldehyde and N-alkylation.
In general, PTC is the best method for performing etherification and it is not surprising that the inventors chose PTC for this application.
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