Owen W Gooding | PubMed Health

PubMed2004

Process optimization using combinatorial design principles: parallel synthesis and design of experiment methods.

The use of parallel synthesis techniques with statistical design of experiment (DoE) methods is a powerful combination for the optimization of chemical processes. Advances in parallel synthesis equipment and easy to use software for statistical DoE have fueled a growing acceptance of these techniques in the pharmaceutical industry. As drug candidate structures become more complex at the same time that development timelines are compressed, these enabling technologies promise to become more important in the future.

Combinatorial Chemistry Techniques↗

PubMedDate not supplied

Use of statistical design of experiments in the optimization of amide synthesis utilizing polystyrene-supported N-hydroxybenzotriazole resin.

Two fields that routinely perform reaction optimization studies are chemical development (prior to scale-up) and medicinal or combinatorial chemistry (prior to analogue synthesis or library production). To date, the use of statistical design of experiments (DoE) in conjunction with automated synthesizers has been applied in process research to a greater extent than in the medicinal or combinatorial laboratories. We have applied DoE in conjunction with an automated synthesizer to optimize the synthesis of amides employing resin-bound N-hydroxybenzotriazole (PS-HOBt) active esters as intermediates. This methodology allowed the rapid development of an improved protocol for the parallel synthesis of amides by conversion of carboxylic acids to PS-HOBt esters followed by treatment with appropriate amines. Product isolation involved only simple filtration and evaporation.

Amides↗