Automated Synthesis for the Safe Production of Organic Azides from Primary Amines.

Described herein is the development of an automated and reproducible process for the conversion of primary amines to organic azides utilizing prepacked capsules containing all the required reagents, including imidazole-1-sulfonyl azide tetrafluoroborate. Apart from manually loading the primary amine into the reaction vessel, the entire reaction and product isolation process can be achieved automatically, with no further user involvement, and delivers the desired organic azide in high purity. This practical and simple automated capsule-based method offers a convenient and safe way of generating organic azides without handling or exposure of potentially explosive reagents.

Cartridge-based Automated Synthesis - A New Tool for the Synthetic Chemist.

Despite recent advances in reaction methodologies, organic synthesis remains complex and challenging. Many of the fundamental processes in use have not changed in over 100 years, with a large proportion of the work being carried out manually, using lengthy procedures and difficult or hazardous reaction conditions. As such, organic synthesis still presents a bottle-neck in discovery research. Endeavours to automate synthesis in discovery, through robotic platforms, have so far not been widely successful because the highly complex nature of such machines, and the level of skill required for their operation, presents a barrier too great for most discov- ery chemists. Synple Chem has developed a safe, easy to use, efficiency-enhancing automated technology for the acceleration of discovery research. The automated flow-batch hybrid system utilises a range of innovative pre-packed reagent cartridges for different reaction classes, along with pre-programmed, highly optimised but editable reaction protocols. The combination of these three key elements, provides users with a convenient, easy to use, time-saving technology that makes the synthesis of molecules far simpler, faster and more efficient. The described technology offers all discovery chemists access to real synthesis automation without any of the barriers that have previously restricted its utility.

Automated, Capsule-Based Suzuki-Miyaura Cross Couplings.

The development of an automated process for Suzuki-Miyaura cross couplings is described, in which the complete reaction, workup, and product isolation are effected automatically with no user involvement, aside from loading of the starting materials and reaction capsule. This practical and simple method was successfully demonstrated to provide the desired biaryl products using a range of aryl bromides and boronic acids and is also effective for the late-stage functionalization of aryl halides in bioactive molecules.

A vending machine for drug-like molecules - automated synthesis of virtual screening hits.

As a result of high false positive rates in virtual screening campaigns, prospective hits must be synthesised for validation. When done manually, this is a time consuming and laborious process. Large "on-demand" virtual libraries (>7 × 1012 members), suitable for preparation using capsule-based automated synthesis and commercial building blocks, were evaluated to determine their structural novelty. One sub-library, constructed from iSnAP capsules, aldehydes and amines, contains unique scaffolds with drug-like physicochemical properties. Virtual screening hits from this iSnAP library were prepared in an automated fashion for evaluation against Aedes aegypti and Phytophthora infestans. In comparison to manual workflows, this approach provided a 10-fold improvement in user efficiency. A streamlined method of relative stereochemical assignment was also devised to augment the rapid synthesis. User efficiency was further improved to 100-fold by downscaling and parallelising capsule-based chemistry on 96-well plates equipped with filter bases. This work demonstrates that automated synthesis consoles can enable the rapid and reliable preparation of attractive virtual screening hits from large virtual libraries.

An integrated console for capsule-based, automated organic synthesis.

The current laboratory practices of organic synthesis are labor intensive, impose safety and environmental hazards, and hamper the implementation of artificial intelligence guided drug discovery. Using a combination of reagent design, hardware engineering, and a simple operating system we provide an instrument capable of executing complex organic reactions with prepacked capsules. The machine conducts coupling reactions and delivers the purified products with minimal user involvement. Two desirable reaction classes - the synthesis of saturated N-heterocycles and reductive amination - were implemented, along with multi-step sequences that provide drug-like organic molecules in a fully automated manner. We envision that this system will serve as a console for developers to provide synthetic methods as integrated, user-friendly packages for conducting organic synthesis in a safe and convenient fashion.