Design, synthesis and biological evaluation of novel cyclic malonamide derivatives as selective RIPK1 inhibitors.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign. Applying isosteric replacement, we successfully identified the malonamide scaffold, instead of the well-established serine template. Further structural optimization led to the design and synthesis of a series of analog inhibitors. The enantiomers of the most promising compound were tested on 97 different kinases. The active enantiomer proved to be kinase selective.

Continuous Stripping with Dense Carbon Dioxide.

The integration of flow chemistry into continuous manufacturing requires efficient, controllable, and continuous methods for the concentration of diluted solutions on relatively small scales. The design and application examples of a new continuous solvent removal process are presented. The continuous stripping method employing dense carbon dioxide is based on the formation of homogeneous mixtures of dilute organic solutions of the target molecules with a large excess of carbon dioxide at temperatures as low as 35 °C and pressures around 10 MPa. Subsequent pressure reduction results in the quick release of carbon dioxide and vaporization of a significant fraction of the organic solvent. The concentration of the solute in the separated liquid phase can be up to 40 times higher than in the feed. Among the many controllable process parameters, the most significant ones are the mass-flow rate ratio of carbon dioxide to the feed and the temperature of the phase separator. By careful setting of the operational parameters, the degree of concentration enhancement may be accurately controlled. The new apparatus-despite consisting of laboratory equipment and being built in a fume hood-could easily support pilot-scale synthetic flow chemistry, being a continuous, efficient alternative to thermal concentration methods.

C-N Bond Formation by Consecutive Continuous-Flow Reductions towards A Medicinally Relevant Piperazine Derivative.

A new, continuous-flow consecutive reduction method was developed for the C-N bond formation in the synthesis of the key intermediate of the antipsychotic drug cariprazine. The two-step procedure consists of a DIBAL-H mediated selective ester reduction conducted in a novel, miniature alternating diameter reactor, followed by reductive amination using catalytic hydrogenation on 5% Pt/C. The connection of the optimized modules was accomplished using an at-line extraction to prevent precipitation of the aluminum salt byproducts.

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds.

Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules.