What Is an Automatic Chemical Synthesizer?
An automatic chemical synthesizer was developed to automate various organic synthesis processes that were previously performed manually. These devices contribute greatly to labor savings and efficiency in the field of research and development.
There are many types, including those still under development, but the main types already on the market include ordinary liquid-phase organic synthesizers, microwave peptide solid-phase synthesizers, and flow synthesizers.
Compared to analytical systems, these systems are still not as widely used at the laboratory level, but there is an active development of these systems.
Applications of Automatic Chemical Synthesizers
Applications range from organic compound and peptide synthesis at the laboratory level to parallel synthesis in drug screening and process development. The sizes range from small-scale products for small-scale studies to pilot plant-class large products for scale-up studies in process development.
In the laboratory, they are used in developing new reactions, optimize synthetic reaction pathways, etc. By automating these systems, reproducibility can be improved, reaction conditions can be controlled more precisely, and the amount of exposure of the experimenter to hazardous materials can be reduced. In addition, the system can automatically record experimental data on a computer, enabling more accurate and efficient recording of experiments, and accurate temperature monitoring can suppress thermal runaway when reagents are added.
In drug discovery screening, the system enables more efficient preparation of numerous lead compounds, leading to more efficient discovery of drug seeds through rapid and extensive screening.
In chemical process development, many issues must be solved in terms of synthesis efficiency, safety, and cost in order to scale up from laboratory scale synthesis to plant scale. Heat transfer and heat removal are particularly important, and can be monitored by using an automatic chemical synthesizer to measure reaction calorific values and other parameters to improve efficiency. Automation of concentration, addition rate, agitation, etc. by machine facilitates in situ monitoring, improves reproducibility, and enables efficient optimization of conditions.
Principle of Automatic Chemical Synthesizers
An automatic chemical synthesizer for liquid-phase synthesis is a mechanized version of the conventional test-tube type organic synthesis. The reaction vessel is installed in a thermostatic chamber with heating and cooling functions, and reagent addition and stirring (e.g., stirring blade or magnetic stirrer) are mechanically controlled at an appropriate speed. Experimental data is constantly monitored by various sensors and monitors, and is automatically recorded in the computer in a precise and detailed manner.
The peptide synthesizer mechanizes and automates peptide synthesis by the Merrifield solid phase synthesis method using a pump. In the Merrifield solid-phase synthesis method, the N-terminal protected amino acid is loaded onto a resin, and the cycle of de-protection, washing, condensation reaction with the N-terminal protected amino acid, and washing is repeated in the reaction vessel. The peptide solid-phase synthesis method is based on the N
Peptide solid-phase synthesis is mainly divided into two types depending on the protecting group used for N-terminal protection: tBoc and Fmoc. tBoc de-protection is mainly carried out under acidic conditions using trifluoroacetic acid (TFA), while Fmoc de-protection is carried out under basic conditions, mainly using piperidine. The Fmoc method uses basic conditions for deprotection, mainly with piperidine. The tBoc method is considered more prone to side reactions because of the acidic conditions under which the final product is extracted from the resin, and the byproducts of the Fmoc method can be easily removed with a solvent (DCM (dichloromethane) or DMF (dimethylformamide)). The Fmoc method is the most common method in recent years. An automatic chemical synthesizer has the advantage of shortening the reaction time and reducing costs by automating the process, as well as by irradiating the reaction vessel with microwave radiation, thereby shortening the reaction time compared with manual synthesis.
The flow synthesizer is a machine-controlled, automated system for flow chemistry (also called flow method or flow reaction), which has been the subject of active research in recent years. Conventional test-tube type reactions are called batch methods, but the batch method has been criticized for its problems of purification cost of synthetic intermediates, efficiency of heat transfer and stirring, and experimental waste. Flow synthesizers use columns or microfluidic channels instead of test tubes or flasks, and a pump is used to inject a solution of two or more reactants into the channel to carry out the reaction. While post-reaction purification is necessary for non-catalytic and homogeneous catalytic types, the use of columns with immobilized reactants or catalysts as reaction vessels can greatly reduce the cost of post-reaction purification operations.
In flow chemistry, the reaction vessel volume can be smaller than in the batch method, resulting in higher reaction efficiency, and the large surface area allows for faster heat exchange and more precise temperature control.