Chemical Assembly Systems: Layered Control for Divergent, Continuous, Multistep Syntheses of Active Pharmaceutical Ingredients

Abstract

While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels--choice of starting material, reagent, or order of reaction modules--enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, β-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49-75%).

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

“…15), when the product remains in the mother liquor, while the solid impurities are retained on the filter material (and then discarded by an appropriate mechanism). 27 There are several examples of extraction methods using liquidliquid phase separation 96,97 to eliminate the excess of the reagents, 21,65 co-products, 65 traces of solvents 39,80 or cosolvents, 29 which have been used in a previous step. Complete removal of water may require a column filled with solid MgSO 4 desiccant after the phase separation, as exemplified in the flow preparation of Milnacipran analogs.…”

“…80 The robust nature of liquid-liquid phase separation allows removal of multiple impurities at the same time. 25,28,29,39,98 Insoluble gases cause irreproducible residence time (due to the expansion of bubbles) and potential side reactions in downstream steps. Excess of gaseous reagents or co-products can be removed conveniently by using gas-liquid phase separation units.…”

“…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.…”

Efficient kinetic experiments in continuous flow microreactors

“…They provide the benefits of ease of process automation, higher heat and mass transfer rates and a more straightforward incorporation of inline analysis tools compared to traditional batch setups. [6][7][8][9][10][11] Continuous flow systems have been used for complex chemical synthesis, [12][13][14][15] gas-phase reactions, [16][17][18][19] photochemistry, [20][21][22][23] electrochemistry, 24,25 and reaction optimization [26][27][28] but their robustness for reaction kinetics is hindered by the need to take steady state measurements. [29][30][31][32] Recent studies have shown that transient flow data could be used to quickly generate kinetic data.…”

Enantioselective Organocatalysis in Microreactors: Continuous Flow Synthesis of a (S)-Pregabalin Precursor and (S)-Warfarin

“…The flow system used to produce all these APIs is based on different modular synthetic platforms, operating under a wide range of reaction conditions. By following different linking pathways of the modules, the synthetic platform gives access to several small molecule drugs in multigrams scale without requiring intermediate purification [14]. However, racemic mixtures of chiral APIs need to be resolved, since usually only one enantiomer is more active or effective.…”