Boguslaw Mudryk

Synthesis of the 6-Azaindole Containing HIV-1 Attachment Inhibitor Pro-Drug, BMS-663068

The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.

An Example of Utilizing Mechanistic and Empirical Modeling in Quality by Design

In this case study, we present an approach for employing modeling to help define the design space for a reaction with potential to generate an impurity that could impact the quality of an API. Our approach broadly consisted of (1) evaluating the reaction parameters that can affect the critical impurity level to develop appropriate assumptions for a mechanistic model, (2) developing and evaluating a mechanistic model to predict the formation of the critical impurity, (3) defining a design space based on the model output to reduce in practice the acceptable parameter space to a practical number of parameters, and (4) verifying the design space through experimental testing. This work resulted in a verified design space that can be practically employed and includes wide parameters ranges for manufacturing flexibility.

Model-Guided Design Space Development for a Drug Substance Manufacturing Process

This case study outlines an application of quality by design principles to a drug substance manufacturing process. A hybrid process chemistry model consisting of mechanistic and empirical components was developed to guide the selection and verification of a design space. A multistaged experimental plan was employed to address specific goals at each stage of model development and design space selection. In addition to the multivariate evaluation of process parameters, accounting for the quality attributes of input materials was shown to be an important consideration when choosing a design space. The merits of a model-guided approach to selecting an invariant, experimentally verified design space (as opposed to a fully model-defined dynamic design space) are discussed.

A practical synthesis of chloromethyl esters from acid chlorides and trioxane or paraformaldehyde promoted by zirconium tetrachloride

A practical synthesis of chloromethyl esters from acid chlorides and trioxane or paraformaldehyde using zirconium tetrachloride as the Lewis acid has been demonstrated. The new procedure is highly chemoselective and applies to a variety of acid chlorides.

A Mechanistic Study on the Amidation of Esters Mediated by Sodium Formamide

Kinetic and computational studies on the amidation of esters with mixtures of formamide and sodium methoxide are described. Rate studies are consistent with a fast deprotonation of formamide followed by two reversible acyl transfers affected by solvent participation. MP2 calculations suggest that the first acyl transfer between the ester and sodium formamide is rate-determining. The transition structures leading to the formation and collapse of the first tetrahedral intermediate are calculated to be isoenergetic.

Adventures in Atropisomerism: Total Synthesis of a Complex Active Pharmaceutical Ingredient with Two Chirality Axes

A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.