Synthesis Development of the Selective Estrogen Receptor
Degrader (SERD) LSZ102 from a Suzuki Coupling to a C–H Activation
Strategy
Posted on 2020-07-17 - 15:36
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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Baenziger, Markus; Baierl, Marcel; Devanathan, Krishnaswamy; Eswaran, Sumesh; Fu, Peng; Gschwend, Bjoern; et al. (2020). Synthesis Development of the Selective Estrogen Receptor
Degrader (SERD) LSZ102 from a Suzuki Coupling to a C–H Activation
Strategy. ACS Publications. Collection. https://doi.org/10.1021/acs.oprd.0c00076