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.
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