Radial Synthesis Breaks New Internet Ground for Chemical Research and Production

Source: Sourav Chatterjee et al. Automated radial synthesis of organic molecules, Nature (2020). DOI: 10.1038/s41586-020-2083-5

The desire to quickly perform chemical synthesis without tedious manual operations has always driven the development of automated chemical synthesizers. Recently, the top international journal Nature reported the newest results from Chatterjee of the Max-Planck Institute of Colloids and Interfaces in Potsdam, Germany. An automated machine for radial synthesis. This fully automatic instrument enables linear and convergent synthesis and does not require manual reconfiguration between different processes. The same reactor can be used at different temperatures in a continuous process and can be flexibly used for the production of pharmaceuticals and other chemicals.

Automatic Machine for Radial synthesis

Conventional chemical synthesis is performed "batch" (in a flask) and requires multiple manual interventions by the chemist, including preparing, running, and stopping each reaction, and isolating the desired product. In contrast, mobile chemistry can increase the yield of synthetic routes and increase safety when hazardous components are involved. Generally, flow chemistry connects multiple reactor units in series for multi-step synthesis.
But this way, for each new target molecule, the reactor size, and temperature of the flow chemistry platform must be reconfigured.

Linear, Radial, Annular Flow Synthesis System

Working Principle of Radial Synthesizer

Chatterjee and colleagues' radial synthesizers are designed to overcome this problem. The radial synthesizer consists of four parts: Solvent and Reagent Delivery System (RDS)，Central Switching Station (CSS)，Spare Module (SM)，Collection vessel（CV）. The entire system is pressurized with nitrogen. Solution flow is controlled by two RDS flow controllers or by three mass flow controllers of the synthesizer (RDS and SM). 

                                                    a. Radial Synthesizer Consists of Four Parts

                                                    b. Equipment Photo

                                                    c. Six paths for the solution flow

                                                    For example, R-C refers to the solution starting from (R) DS and ending in the collection container (CV).

The main controller of the system's central exchange station uses a 16-port valve to direct reagents to different surrounding reactor modules. These modules are arranged radially around the central exchange station so that each reaction in the synthesis can be performed independently under optimal conditions. The central exchange station is equipped with online infrared (IR) monitoring and a 1H / 19F-NMR system. The effluent from each reactor is returned to the central hub for online analysis and then distributed to the next synthesis step. This step can be in the same reactor unit or in different reactors. This process is repeated for each reaction until the target molecule is synthesized.

The system can perform both linear synthesis and convergent aggregation and does not require reconfiguration between different synthesis processes. The same reactor can be used at different temperatures in a continuous process.
 The ability to store stable intermediates through the R–R or S–R paths enables convergence and linear synthesis, as well as the ability to optimize subsequent steps during route development.
Easily compare different synthesis methods on the same instrument and use solvent delivery systems to screen concentrations by diluting reagents online to speed optimization.

Radial synthesizer for drug and compound library synthesis

The authors synthesized the anticonvulsant rufinamide using linear and convergent synthesis methods, respectively. For convergent synthesis, two separate optimizations for the synthesis of azide 2 and amide 4 are required before the final copper-catalyzed cycloaddition reaction in the optimization. 
In the three-step reaction, the solvent, stoichiometry, concentration, temperature, catalyst and residence time were screened in the synthesizer. 
The R–C path was used to optimize the C1 and C2 steps, the conversion was monitored by flow online IR, and the yield was determined by analyzing samples offline.
Azide 2 and amide 4 were synthesized and stored in RDS and spare modules respectively before performing cycloaddition. After completing the cycloaddition optimization, a three-step synthesis was performed along the R-R, R-S, and S-C paths. Rufinamide crystallized within five minutes after the start of the reaction and was filtered and washed to provide pure Rutinamide in a yield of 70%.

Direct Synthesis of Rufinamide

When multiple synthetic routes can be used on one instrument, derivatives of the target compound can be easily obtained.

 
Library of Synthetic Rufinamide Derivatives

By adding a 420 nm photoreactor module, the researchers completed a nickel / photosynthetic C-N cross-coupling.

Open the age of chemistry based on Internet service models

The radial synthesis automation system ensures the repeatability of the reaction. As long as the same quality materials are input, the given synthesis instruction will be executed in the same way on another identical system.
Automated systems can also be used to generate reaction data such as reagents used, yields and conditions for machine learning in organic chemistry.
However, the system also has some flaws. For example, when processing solid reagents or solids formed during the reaction, the solids can be suspended in the slurry by stirring the reaction container, but the slurry will cause blockage through the tube or valve.
Another issue is how to achieve seamless integration of purification, separation and analysis procedures.
"With radial synthesis, we can largely eliminate manual work from chemistry," says Seeberger. If he has his way, chemistry will soon be operated like Internet services: "You may be sitting in front of your computer, but the server on which an application is running is somewhere else in the world," says Seeberger.
This, in turn, may help with big data analysis in chemistry. As the hardware matures, the focus will shift to developing the controls and artificial intelligence infrastructure required for chemical synthesis, freeing chemists from performing routine procedures, allowing them to focus on discovering new chemistry.
In the past two years, artificial intelligence has shown great advantages in the research of materials, chemistry, and physics.
From "Chemical AlphaGo" to "Chemputer", artificial intelligence is leading the "postmodernization" of basic scientific research.
In the era of AI2.0, grasping artificial intelligence technology not only means the improvement of scientific research efficiency, but also the arrival of scientific research "curve overtaking" opportunities. "