Dynamic response surface methodology using Lasso regression for organic pharmaceutical synthesis

To study the dynamic behavior of a process,time-resolved data are collected at different time instants during each of a series of experiments,which are usually designed with the design of experiments or the design of dynamic experiments methodologies.For utilizing such time-resolved data to model the dynamic behavior,dynamic response surface methodology(DRSM),a datadriven modeling method,has been proposed.Two approaches can be adopted in the estimation of the model parameters:stepwise regression,used in several of previous publications,and Lasso regression,which is newly incorporated in this paper for the estimation of DRSM models.Here,we show that both approaches yield similarly accurate models,while the computational time of Lasso is on average two magnitude smaller.Two case studies are performed to show the advantages of the proposed method.In the first case study,where the concentrations of different species are modeled directly,DRSM method provides more accurate models compared to the models in the literature.The second case study,where the reaction extents are modeled instead of the species concentrations,illustrates the versatility of the DRSM methodology.Therefore,DRSM with Lasso regression can provide faster and more accurate datadriven models for a variety of organic synthesis datasets.

Access to pyridines via cascade nucleophilic addition reaction of 1,2,3-triazines with activated ketones or acetonitriles

We studied the cascade nucleophilic addition reactions of 1,2,3-triazines with activated acetonitriles or ketones,which were used to construct highly substituted pyridines that are not easily accessed by conventional methods.The strategy addressed some structural diversity issues currently facing medicinal chemistry,and the resulting pyridines could be used as convenient precursors for the synthesis of related pharmaceuticals.In particular,our method was applied to the syntheses of the marketed drug etoricoxib and several biologically important molecules in a few steps.