Synthesis Development of the Selective Estrogen Receptor Degrader (SERD) LSZ102 from a Suzuki Coupling to a C–H Activation Strategy

Abstract

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.

A General Kilogram Scale Protocol for Suzuki–Miyaura Cross-Coupling in Water with TPGS-750-M Surfactant

“…The research and early development synthesis to LSZ102 ( 1 ) features a Suzuki–Miyaura cross-coupling as the ultimate transformation starting from the brominated intermediate 5 and the pinacolborane derivative 6 (Scheme ). , …”

“…Initially, the Suzuki coupling of 5 (1 equiv) and 6 (1.7 equiv) used tetrakis­triphenyl­phosphine palladium Pd­(PPh 3 ) 4 (7.5 mol %) in a mixture of 1,4-dioxane and water . The main impurity of the cross-coupling was the debromination product 2 (Figure ), while protodeboronation was more readily controlled.…”

“…After extensive studies, the reversed-phase (RP) chromatographic purification of the API was replaced by a sequence of recrystallizations in methanol/H 2 O to produce the compound pure 7 in a good 85% yield with an improved impurity profile. The liberation of the free acid 1 was then performed after three extractions of dicyclohexylamine by n -heptane from an aqueous basic solution of the compound pure 7 …”

“…The synthesis of such a molecule can be challenging and needs to respond to supply need, quality requirement, and efficiency constraints. Efforts toward the identification and development of a revised and streamlined synthetic route to the clinical candidate LSZ102 ( 1 ) have been described in a preceding paper …”

Recent Applications of Pd-Catalyzed Suzuki-Miyaura and Buchwald-Hartwig Couplings in Pharmaceutical Process Chemistry.

“…Baenziger and coworkers 26 from Novartis developed synthetic methods for streamlined large-scaled manufacturing of LSZ102, 27 a selective estrogen receptor degrader drug candidate for treating breast cancer. The new methods significantly improved the overall yield and reduced the cost.…”