RESUMEN
Chromatographic resolution of enantiomers has become the accepted method for generation of active pharmaceutical intermediates (APIs) in early phase development. Continuous processes such as simulated moving bed (SMB) are recognized as alternative approaches for manufacturing of larger quantities of enantiomerically pure compounds. Steady state recycle (SSR) technology was initially described in 1998 [C.M. Grill, L. Miller, J. Chromatogr. A 827 (1998) 359] and has recently become a common technique in some laboratories. Batch chromatography, SSR, and SMB processes should be considered "phase appropriate" technologies. Phase appropriate technology refers to the scale of separation required in a step of the drug development process. SSR is phase appropriate technology for producing 100 g to several kilogram quantities of material. In this report, we will describe development and scale up of chiral separations utilizing the SSR technique for six different APIs utilizing several different chiral stationary phases and compare the efficiencies of both SSR and batch chromatographic techniques.
Asunto(s)
Cromatografía Liquida/métodos , Preparaciones Farmacéuticas/aislamiento & purificación , Preparaciones Farmacéuticas/química , Espectrofotometría UltravioletaRESUMEN
The gamma hydroxyl present in the aliphatic side chain of the natural products pseudomycin A and C' provided a unique handle for the pH dependent side-chain deacylation. Low pH reaction conditions were used to cleave the side chain with minimal degradation of the peptide core. The pseudomycin nucleus intermediate obtained from the deacylation of pseudomycin A was pivotal in the synthesis of novel side-chain analogues. A practical synthesis of a minor fermentation factor pseudomycin C' and related analogues is reported.
Asunto(s)
Péptidos Cíclicos/química , Acilación , Animales , Antifúngicos/síntesis química , Antifúngicos/farmacología , Aspergillus fumigatus/efectos de los fármacos , Candida/efectos de los fármacos , Cryptococcus neoformans/efectos de los fármacos , Histoplasma/efectos de los fármacos , Ratones , Pruebas de Sensibilidad Microbiana , Modelos Animales , Micosis/tratamiento farmacológico , Pruebas de Sensibilidad Parasitaria , Péptidos Cíclicos/farmacología , Relación Estructura-Actividad , Tasa de SupervivenciaRESUMEN
Cdc25A assay-guided fractionation of a fermentation broth derived from a Streptomyces sp. resulted in the isolation of four novel naphthoquinones 1-4. Structures of these compounds were deduced by NMR and mass spectrometry. Two of them, 3 and 4, incorporate a modified cysteine residue which is observed for the first time in this class of natural products. Naphthoquinones 1-4 showed weak activity against cdc25A phosphatase.