Multistep Continuous‐Flow Synthesis in Medicinal Chemistry: Discovery and Preliminary Structure–Activity Relationships of CCR8 Ligands

Abstract

A three-step continuous-flow synthesis system and its application to the assembly of a new series of chemokine receptor ligands directly from commercial building blocks is reported. No scavenger columns or solvent switches are necessary to recover the desired test compounds, which were obtained in overall yields of 49-94%. The system is modular and flexible, and the individual steps of the sequence can be interchanged with similar outcome, extending the scope of the chemistry. Biological evaluation confirmed activity on the chemokine CCR8 receptor and provided initial structure-activity-relationship (SAR) information for this new ligand series, with the most potent member displaying full agonist activity with single-digit nanomolar potency. To the best of our knowledge, this represents the first published example of efficient use of multistep flow synthesis combined with biological testing and SAR studies in medicinal chemistry.

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

“…Furthermore, a continuous flow system showed particularly effective and versatile for the synthesis of a new series of chemokine receptor ligands from commercial raw materials [63]. Other examples of newly developed molecules through continuous flow reactors are reviewed by Rodrigues et al [64].…”

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

“…Hydrogen is commonly used in flow synthesis, 99,100 usually in excess amounts. When hydrogenation is followed by other steps, 9,26,29,33,101,102 a simple buffer flask allows the outgassing of hydrogen, after the pressure is reduced. However, in some cases the applied chemistry did not tolerate this method.…”

“…70,104 The combination of multiple, differently functionalized scavenger resins is a common practice for the removal of several different impurities. 44,66,33,102,[105][106][107] In an illustrative example, removal of homogeneous transition metal complexes was possible this way ( Fig. 17), which prevented harmful catalytic activity in downstream heterogeneous nitro group reductions in the flow synthesis of the fungicide Boscalid Ò .…”

A facile hybrid ‘flow and batch’ access to substituted 3,4-dihydro-2H-benzo[b][1,4]oxazinones

“…Recently there has been considerable progress in the use of flow chemistry approaches in multi-step synthesis, [8][9][10][11][12][13][14][15][16][17] the synthesis of drug like molecules, [18][19][20][21][22] selective hydrogenations 23 and in the use of unstable and /or dangerous reagents. [14][15][16]24,25 Herein, we envisaged a simple flow chemistry approach allowing a scalable access to two key intermediates for use in either flow chemistry library development or using robust batch approaches.…”