Automated synthesis of prexasertib and derivatives enabled by continuous-flow solid-phase synthesis.
Nat Chem
; 13(5): 451-457, 2021 05.
Article
em En
| MEDLINE
| ID: mdl-33875818
ABSTRACT
Recent advances in end-to-end continuous-flow synthesis are rapidly expanding the capabilities of automated customized syntheses of small-molecule pharmacophores, resulting in considerable industrial and societal impacts; however, many hurdles persist that limit the number of sequential steps that can be achieved in such systems, including solvent and reagent incompatibility between individual steps, cumulated by-product formation, risk of clogging and mismatch of timescales between steps in a processing chain. To address these limitations, herein we report a strategy that merges solid-phase synthesis and continuous-flow operation, enabling push-button automated multistep syntheses of active pharmaceutical ingredients. We demonstrate our platform with a six-step synthesis of prexasertib in 65% isolated yield after 32 h of continuous execution. As there are no interactions between individual synthetic steps in the sequence, the established chemical recipe file was directly adopted or slightly modified for the synthesis of twenty-three prexasertib derivatives, enabling both automated early and late-stage diversification.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirazinas
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Pirazóis
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Técnicas de Química Sintética
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Técnicas de Síntese em Fase Sólida
Limite:
Humans
Idioma:
En
Revista:
Nat Chem
Assunto da revista:
QUIMICA
Ano de publicação:
2021
Tipo de documento:
Article