ratio of surface area to volume have unique features, such as efficient transfers of heat and mass, enabling diverse green and sustainable chemical processes. [3,4] The precise control of reaction time is one of the most outstanding advantage of the flow-synthetic methods. Highly reactive chemicals that are impossible to handle in conventional batch reactors can be controlled by the precise adjustment of retention time in a flow reactor. [5] In particular, it is highly striking to control the ultrafast chemistry associated with highly short-lived unstable intermediates at high flow rates that can maximize the mixing efficiency at short time in the confined microreaction space. [6] Moreover, the high flow rates may facilitate a high throughput production for industrial applications, which would overcome a longstanding limitation in low productivity of conventional microfluidics. [7] Recently, we reported the control of extremely ultrafast reactions, rapid intramolecular rearrangement via the newly devised microreactor with a small internal volume. [8] The polyimide (PI) film layered microfluidic device with high durability to chemicals and pressure demonstrated outpacing the intramolecular rearrangement reaction by controlling within submillisecond. [8a] However, the use of metal device is much more desirable rather than the polymer material for the temperature control of highly sensitive intermediates as well as the durability of device. Furthermore, the laser ablation technique to fabricate the channel structure in PI film is limited to constructing only rectangular cross-sectional channel that the edges of cross section cause a decrease of mixing efficiency. Thus, the complex mixing structure is required to increase the mixing efficiency in case of PI film-based devices. In order to carry out the ultrafast chemistry in a more effective manner, the new conceptual microreactor is still demanding to enhance the mixing efficiency in smaller reaction volume of the simpler design for facile manufacturing. Therefore, an advanced approach is very desirable to fabricate the well-designed microreactor with high-resolution geometry.3D printing techniques have widely been developed for applications in various academic and industrial fields. The additive manufacturing technology is also inevitably penetrating to the field of microfluidic device fabrication, because it enables a facile, one-step manufacture of monolithic flow reactors by High-resolution 3D-printed stainless steel metal microreactors (3D-PMRs) with different cross-sectional geometry are fabricated to control ultrafast intramolecular rearrangement reactions in a comparative manner. The 3D-PMR with circular channel demonstrates the improved controllability in rapid Fries-type rearrangement reactions, because of the superior mixing efficiency to rectangular cross-section channels (250 µm × 125 µm) which is confirmed based on the computational flow dynamics simulation. Even in case of very rapid intramolecular rearrangement of sterically small acetyl group ...

Continuous pharmaceutical manufacturing receives intense attention as an alternative way to meet flexible market needs with the assurance of higher safety and quality control.

A simple, room temperature approach for the fast single-step synthesis of α-phosphonyloxy ketone, a drug scaffold, has been developed which involves highly reactive species i.e., 1,2-dicarbonyls that readily react with trialkyl phosphites and formic acids in batch as well as in continuous-flow with the flow rate of 3 ml/min (t R = ∼4 s). The present approach reduced the synthesis time from hours to minutes in batch, which was further lowered to a few seconds precisely controlled by single capillary microfluidics. A wide range of 1,2-dicarbonyl deriva-Continuous-flow microreactors have recently attracted much attention as an important technique for synthesizing organic molecules including drug intermediates/molecules in a very short time under mild reaction conditions. [1][2][3][4] A high surface area to volume ratio in this microfluidic system promotes mass and heat transfer, leading to selectivity and conversion much superior to the levels obtainable by conventional batch processes. [2][3][4] Owing to their many complex issues such as inefficient mixing, non-uniformity in heat, and safety in the scale-up of batch process, in recently, flow approach is more attractive and reliable in both academia and industry. [1,2] Furthermore, high throughput production can be achieved by simply increasing reaction volume with larger dimension of channel, or/and by numbering up microreactor units in parallel. [5,6] In light of the push for continuous manufacturing of pharmaceutical products [7,8] microreactor can be an attractive alternative to the conventional batch process for many of the pharmaceutical products whose world-wide consumption is of the order of tons a year. Therefore, simple and fast continuous-flow methodologies are highly desirable to operate at high flow rate, enabling to satisfy the changing needs of pharmaceutical markets in a safe and environmentally benign, cost-effective manner.On the other hand, the organophosphate chemistry by itself is an interesting area of organic chemistry as well as life science in living organism such as DNA, RNA, ATP and cell membranes. [9] Moreover, various methodologies also reported for [a] Dr. 7730Scheme 4. Control experiments in batch to understand the reaction mechanism.Scheme 5. Plausible reaction mechanism for the synthesis of α-phosponyloxy ketone.

No abstract