FemtoGram

ESA Biosciences has introduced new cells for use with the Coulochem® and CoulArray® systems that are designed for electrosynthesis in a flowing stream.

These electrodes use the signature coulometric flow-through design and maintenance-free reference electrode that are the hallmark of ESA cells, but with a size and geometry optimized for synthesis.

The synthesis of organic compounds or the modification of existing compounds is a necessary step in many chemical processes. For example, during drug development, determining structure and assessing the biological activity of drug metabolites is a crucial step in determining a compound's suitability for further development. Producing enough material for analysis with mass spec and NMR and to assess its biological activity requires the synthesis of microgram quantities. This process of synthesis can often take six months to a year using standard techniques.

To address this problem, ESA has developed an on-line, high-capacity electrosynthesis system, designed to simplify and speed up the process so you can generate microgram quantities by the oxidation of parent compounds in your laboratory. At the heart of the system are the synthesis cells (models 5125 and 5150), which can be controlled to enhance the generation of specific oxidation products. Typical products are a result of electrochemically mediated N-Oxidation, N-dealkylation of aliphatic amines, deamination and dehydrogenation, sulfoxide formation, sulfur dealkylation and oxidative dehalogenation.

While this approach has been used and published using standard ESA cells, yields were low. The design of the new synthesis cells greatly improves efficiency, and therefore, the yield obtained in a single pass.

The geometry and increased size of the 5125 and 5150 cells provide higher efficiency and allow complete oxidation to occur at a lower potential than other configurations.

The electrochemical synthesis approach using HPLC can be evaluated in a short period of time. Typically the 5125 cell (optimized for use with columns of analytical size) is placed before the column, on-line with Mass Spec. A potential is applied to the cell using the Coulochem III or CoulArray controller. The compound is injected. As it passes through the porous, high-capacity electrode, the compound is oxidized-producing products, many of which are identical to biologically derived metabolites. It is then a simple matter to connect the cell to an ESA HPLC system optimized for electrochemistry, to another HPLC system, or to flow split with the MS system to produce and collect the desired compounds. This can be done with the 5125 cell, or can be scaled up using the 5150 cell, (optimized for use with a semi-prep column). By controlling the potential, flow rate, concentration of starting compound, amount injected, and the mobile phase, it is possible to selectively enhance the production of specific products.

At a flow rate of 1.0 ml/min, the 5125 cell delivers near 100% conversion efficiency of up to at least 5 micrograms of starting material. With the 5150 cell, typical loads 5-10 times greater can be anticipated.

Using this approach, weeks to months may be eliminated from the synthesis steps. Even relatively labile species can be prepared freshly when needed, saving time and resources.

As potential is increased N-dealkylation (II, III) metabolites of the drug Amitryptilline(I) are selectively produced. With direct on-line synthesis and connection to MS the identity of the metabolites can be easily confirmed. I, II, III

ECD Innovations

Electrosynthesis