Practical Synthesis of 8α-Amino-2,6-dimethylergoline: An Industrial Perspective

8 α-Amino-2,6-dimethylergoline is the key intermediate for the synthesis of a number of ergot derivatives under clinical development. They are structurally related to the better known lysergic acid and its derivative, the diethylamide (LSD). The use of lysergic acid or its isomer, paspalic acid, both of which are readily available by fermentation on an industrial scale, as a starting material for the synthesis of 8α-amino-2,6-dimethylergoline appears to be the obvious choice as the basic structural elements already exist. Whereas the transformation of the acid function to the amino moiety proceeded under well-established conditions, the introduction of the single methyl group posed a major challenge to the industrial chemist. Various methodologies are available to solve this problem, and the approach that involves direct metalation and methylation is found to be most suitable for up-scaling to multiton quantities. The importance of using on-line monitoring techniques (FT-IR) in process research and development will be exemplified by this report.