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A DMAP-Catalyzed Approach to the Industrial-Scale Preparation of N‑6-Demethylated 9,10-Dihydrolysergic Acid Methyl Ester: A Key Cabergoline and Pergolide Precursor
journal contribution
posted on 2015-02-20, 00:00 authored by Zdenko Časar, Tomaž MesarA scalable new approach
for the preparation of N-6-demethylated 9,10-dihydrolysergic
acid methyl ester using 2,2,2-trichloroethyl
chloroformate was developed. A key discovery that enabled the efficient
and industrial-scalable process is linked to the rigorous extrusion
of water in the reaction system and application of an organic catalyst
such as 4-(N,N-dimethylamino)pyridine
(DMAP) instead of the alkali metal bicarbonate additives. Namely,
in the previously known process, the concomitant presence of bicarbonates
and traces of water triggers side reaction cycles that produce and
accumulate hydrochloric acid and water. The former slows down the
reaction. Moreover, these cycles cause the formation of multiple carbonate
and alcohol-type side products to a significant extent that provide
a low-quality N-6-demethylated product. All of these
shortcomings are circumvented by the application of DMAP as a catalyst
and the use of a reaction medium free of water. This approach allows
operation on an industrial scale (51 kg batch) with higher yields,
shorter reaction times, and improved product quality.