Compact reaction-module on a pad for scalable flow-production of organophosphates as drug scaffolds.

Continuous pharmaceutical manufacturing receives intense attention as an alternative way to meet flexible market needs with the assurance of higher safety and quality control. Here, we report a compact reaction-module on a pad (CRP, 170 × 170 × 1.2 mm) for scale-up production of drug precursors in a continuous-flow. The CRP system was devised by stacking 9 films of the patterned polyimide to integrate micro-flow circuits, combining the functions of the even distribution of feeds, being completely mixed in less than a few milliseconds. A methodology of using a highly reactive species for the single-step synthesis of α-phosphonyloxy ketone, a drug scaffold, required the synthesis time of a few seconds in microfluidics. The fast reaction in the single CRP was capable of producing 19.2 g h-1 drug precursor, which indicates a solid step toward kilogram-scale pharmaceutical manufacturing in small footage.

Continuous-Flow Visible Light Organophotocatalysis for Direct Arylation of 2H-Indazoles: Fast Access to Drug Molecules.

A continuous-flow homogeneous photocatalytic method has been devised for the direct arylation of 2H-indazoles. This visible-light-promoted approach directly accesses a wide range of structurally diverse C3-arylated scaffolds of biological interest in a fast (1 min), single-step reaction by using eosin Y as an organophotocatalyst. Furthermore, a microreactor technology is also employed for the fast synthesis of liver X receptor inhibitor drugs with very good yields under metal-free conditions, whereas the reported methods required multiple steps and much longer reaction times (18-24 h).

Bis(amino)cyclopropenylidene-Catalyzed 1,6-Conjugate Addition of Aromatic Aldehydes to para-Quinone Methides: Expedient Access to α,α'-Diarylated Ketones.

A bis(amino)cyclopropenylidene-catalyzed direct method for the synthesis of α,α'-diarylated ketones from aromatic as well as heteroaromatic aldehydes has been developed. This unprecedented organocatalytic protocol offers access to a wide range of α,α'-diarylated ketones in moderate to excellent yields under mild conditions through umpolung of aldehydes followed by 1,6-conjugate addition with para-quinone methides.

N-heterocyclic carbene catalyzed highly chemoselective intermolecular crossed acyloin condensation of aromatic aldehydes with trifluoroacetaldehyde ethyl hemiacetal.

A highly chemoselective intermolecular crossed acyloin condensation between aromatic aldehydes and trifluoroacetaldehyde ethyl hemiacetal has been developed under mild reaction conditions using N-heterocyclic carbene as a catalyst. A wide range of aromatic aldehydes bearing electron-withdrawing and -donating substituents underwent a smooth transformation to their corresponding trifluoromethyl containing acyloin derivatives in moderate to good yields.