RESUMO
We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.
Assuntos
Alcenos/química , Carbono/química , Cinamatos/química , Cinamatos/síntese química , Indazóis/química , Indazóis/síntese química , Receptores de Estrogênio/metabolismo , Técnicas de Química Sintética , Cinamatos/farmacologia , Indazóis/farmacologia , Cetonas/química , EstereoisomerismoRESUMO
An efficient synthesis of a selective estrogen receptor degrader, GDC-0810, bearing a challenging stereodefined (E)-tetrasubstituted all-carbon olefin core, is reported. The described synthetic route involves a highly diastereoselective addition of an arylmagnesium reagent 3a to ketone 4, yielding the key tertiary alcohol 2a in >99:1 dr. The corresponding tert-butyl carbonate derivative was identified among other leaving groups to provide the desired olefin geometry in a 98:2 E/Z ratio via a concerted elimination. A four-step telescoped process was then developed starting from the tertiary alcohol 2a to produce GDC-0810 API as a pyrrolidine salt in 70% yield.
Assuntos
Receptores de Estrogênio/antagonistas & inibidores , Álcoois , Alcenos , Cetonas , Estrutura Molecular , EstereoisomerismoRESUMO
Enolizations of highly substituted acyclic ketones used in the syntheses of tetrasubstituted olefin-based anticancer agents are described. Lithium hexamethyldisilazide (LiHMDS)-mediated enolizations are moderately Z-selective in neat tetrahydrofuran (THF) and E-selective in 2.0 M THF/hexane. The results of NMR spectroscopy show the resulting enolates to be statistically distributed ensembles of E,E-, E,Z-, and Z,Z-enolate dimers with subunits that reflect the selectivities. The results of rate studies trace the preference for E and Z isomers to tetrasolvated- and pentasolvated-monomer-based transition structures, respectively. Enolization using LiHMDS in N,N-dimethylethylamine or triethylamine in toluene affords a 65:1 mixture of LiHMDS-lithium enolate mixed dimers containing E and Z isomers, respectively. Spectroscopic studies show that condition-dependent complexation of ketone to LiHMDS occurs in trialkylamine/toluene. Rate data attribute the high selectivity exclusively to monosolvated-dimer-based transition structures.