Process Chemistry

The role of the process chemists at the Merck Frosst Centre for Therapeutic Research is the design of elegant, practical, efficient, environmentally benign and economically viable chemical syntheses for new drugs.

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The route used by the Medicinal Chemistry group is first evaluated. Designed to produce a variety of target molecules, this synthesis may not be the best strategy for commercial production of the compound. With the advantage of knowing the final structure the process chemists can focus on creating the best synthesis. Often this involves a complete re-design.

There are a number of elements to consider, such as whether the synthesis should be linear or convergent. For HIV protease inhibitor CRIXIVAN^® (indinavir sulfate), for example, it is linear (chart 1), based on the discovery that the stereochemical center in intermediate 2 can be used to set three new centres in the final molecule.

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Reagent selection also involves many considerations, of which cost is only one. Higher yield, improved quality and improved productivity through faster reaction rate are also important. The final process is a balance between a myriad of factors, many of them specific to that process and not obvious at the onset.

Large-scale production is just a small part of the work of the process chemists, with most time spent evaluating potential routes and optimizing the chosen process. Definition of reaction parameters such as time, temperature or dilution, and an in-depth understanding of the chemistry involved, are crucial to ensure that the chemistry can be successfully scaled up.

Once the development phase of the project is complete, preparative chemistry takes over.

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