RESUMO
A flexible and integrated flow-chemistry-synthesis-purification compound-generation and sample-management platform has been developed to accelerate the production of small-molecule organic-compound drug candidates in pharmaceutical research. Central to the integrated system is a Mitsubishi robot, which hands off samples throughout the process to the next station, including synthesis and purification, sample dispensing for purity and quantification analysis, dry-down, and aliquot generation.
Assuntos
Técnicas de Química Combinatória/métodos , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Compostos Orgânicos/isolamento & purificação , Compostos Orgânicos/farmacologia , Manejo de Espécimes/métodos , Compostos Orgânicos/síntese químicaRESUMO
We present a study on ultrasound-promoted click chemistry reactions in a meso-flow reactor synthesis system with a copper reactor and a custom sonication piezoelectric transducer. Copper catalyzed Huisgen 1,3-dipolar cycloadditions were studied in flow with this system. Our results demonstrate that 1,4-disubstituted 1,2,3-triazole products can be generated at low temperatures and with short reaction time in good yield, due to the rate enhancement effect of sonication.
Assuntos
Química Click/métodos , Reologia , Ultrassom/métodos , Área Sob a Curva , Temperatura , Transdutores , Triazóis/síntese química , Triazóis/químicaRESUMO
Experiments were performed to demonstrate the potential of counter-current chromatography (CCC) for the isolation of drugs and their metabolites from biological matrices relevant to the metabolism studies of pharmaceutical research. Examples of typical drugs are spiked into biological media ex vivo to provide test samples for analysis. A mass spectrometer hyphenated to a CCC allows for the detection of small molecule drugs within the matrix through selected ion monitoring, and fraction collection can provide material for further structural elucidation by NMR.
Assuntos
Líquidos Corporais/química , Distribuição Contracorrente/métodos , Preparações Farmacêuticas/isolamento & purificação , Métodos Analíticos de Preparação de Amostras , Animais , Bile/química , Análise Química do Sangue , Distribuição Contracorrente/instrumentação , Cães , Humanos , Espectrometria de Massas , Preparações Farmacêuticas/sangue , SolventesRESUMO
Experiments were performed to evaluate whether counter-current chromatography (CCC) could function as an alternative purification method to reversed-phase high-performance liquid chromatography (RP-HPLC) and normal-phase supercritical fluid chromatography (SFC). RP-HPLC and SFC are the routine methods currently used in our high-throughput purification (HTP) facility for the purification of high-throughput organic synthesis (HTOS) libraries and medicinal chemistry reaction mixtures. Pre-equilibration of the solvent mixture layers was not mandatory for effective chromatography when hexanes-ethyl acetate-methanol-water (HEMW) solvent mixtures were used. Key to the use of CCC for high-throughput applications is the ability to effectively select a solvent system appropriate to each library member. Pilot-scale CCC elution time was used to estimate a starting solvent ratio and RP-HPLC retention time was then used to adjust solvent ratios within a particular library. It was also found that dimethyl sulfoxide (DMSO) and DMSO-methanol were suitable as sample injection solvents when using the HEMW solvent systems.
Assuntos
Distribuição Contracorrente/métodos , Compostos Orgânicos/química , Bibliotecas de Moléculas Pequenas , Acilação , Cromatografia Líquida de Alta Pressão , Dimetil Sulfóxido/química , Desenho de Equipamento , Ibuprofeno/isolamento & purificação , Cetoprofeno/isolamento & purificação , Metanol/química , Solubilidade , Solventes/químicaRESUMO
A diverse set of 16 high-throughput organic synthesis libraries, consisting of 48 samples per library, has been purified by both preparative supercritical fluid chromatography (SFC) and preparative high-performance liquid chromatography (HPLC). This paper details the relative effectiveness of these two purification techniques in terms of success, yield, and purity of final product.