The development of a kilogram scale protocol for a Suzuki−Miyaura cross-coupling step toward the synthesis of the drug candidate LSZ102 is described. Particularly, the use of the surfactant TPGS-750-M in water as a medium for the transformation and its impact on the selectivity and quality are reported. Minimization of typical impurities generated during the cross-coupling (e.g., dehalogenation) has been in focus during our study. The environmental and cost impacts using such a process are also discussed.

The development of the synthetic process to the selective estrogen receptor degrader (SERD) drug candidate LSZ102 from the medicinal chemistry synthesis to the streamlined large-scale manufacturing route is described. The synthesis of LSZ102 could be significantly improved in regard to overall yield, removal of all chromatographic purifications, and reduction in the number of steps by revisiting the original disconnection strategy. Key features of the final process include construction of the benzothiophene core via Higa cyclization, late-stage phenolation using a Pd-catalyzed hydroxylation of an aryl bromide, and end-game assembly through a Pd-catalyzed C–H activation step. The overall yield could be significantly improved, and the costs could be reduced.

8α-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.

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