RESUMO
The implementation of self-optimizing flow reactors has been mostly limited to model reactions or known synthesis routes. In this work, a self-optimizing flow photochemistry platform is used to develop an original synthesis of the bioactive fragment of Salbutamol and derivatives. The key photochemical steps for the construction of the aryl vicinyl amino alcohol moiety consist of a C-C bond forming reaction followed by an unprecedented, high yielding (>80 %), benzylic oxidative cyclization.
Assuntos
Albuterol , Ciclização , Oxirredução , FotoquímicaRESUMO
Electroorganic synthesis is a promising tool to design sustainable transformations and discover new reactivities. However, the added setup complexity caused by electrodes in the system impedes efficient screening of reaction conditions. Herein, we present a microfluidic platform that enables automated high-throughput experimentation (HTE) for electroorganic synthesis at a 15-microliter scale. Two HTE modules are demonstrated: 1)â the rapid electrochemical reaction condition screening for a radical-radical cross-coupling reaction on micro-fabricated interdigitated electrodes, and 2)â measurements of kinetics for mediated anodic oxidations using the microliter-scale cyclic voltammetry. The presented modular approach could be deployed for a range of other electroorganic chemistry applications beyond the demonstrated functionalities.
RESUMO
A number of groups have studied the application of continuous bioreactors and continuous chromatographic systems as part of efforts to develop an integrated continuous biomanufacturing process. The objective of this study was to examine the feasibility of using a countercurrent staged diafiltration process for continuous protein formulation with reduced buffer requirements. Experiments were performed using a polyclonal immunoglobulin (IgG) with Cadence™ Inline Concentrators. Model equations were developed for the product yield, impurity removal, and buffer requirements as a function of the number of stages and the stage conversion (ratio of permeate to feed flow rate). Data from a countercurrent two-stage system were in excellent agreement with model calculations, demonstrating the potential of using countercurrent staged diafiltration for protein formulation. Model simulations demonstrated the importance of the countercurrent staging on both the extent of buffer exchange and the amount of buffer required per kg of formulated product. The staged diafiltration process not only provides for continuous buffer exchange, it could also provide significant reductions in the number of pump passes while providing opportunities for reduced buffer requirements.
Assuntos
Biotecnologia/métodos , Filtração/métodos , Imunoglobulina G/isolamento & purificação , Soro/químicaRESUMO
Computer-aided synthesis planning (CASP) tools can propose retrosynthetic pathways and forward reaction conditions for the synthesis of organic compounds, but the limited availability of context-specific data currently necessitates experimental development to fully specify process details. We plan and optimize a CASP-proposed and human-refined multistep synthesis route toward an exemplary small molecule, sonidegib, on a modular, robotic flow synthesis platform with integrated process analytical technology (PAT) for data-rich experimentation. Human insights address catalyst deactivation and improve yield by strategic choices of order of addition. Multi-objective Bayesian optimization identifies optimal values for categorical and continuous process variables in the multistep route involving 3 reactions (including heterogeneous hydrogenation) and 1 separation. The platform's modularity, robotic reconfigurability, and flexibility for convergent synthesis are shown to be essential for allowing variation of downstream residence time in multistep flow processes and controlling the order of addition to minimize undesired reactivity. Overall, the work demonstrates how automation, machine learning, and robotics enhance manual experimentation through assistance with idea generation, experimental design, execution, and optimization.