Challenges of Implementation
Chiral technology often originates in academic labs or small, resource-limited companies. We have observed many instances where an asymmetric reaction is strikingly effective in the laboratory, at small scale, but cannot easily be scaled to a manufacturing plant. The same shortcoming holds for chiral building blocks and intermediates, which often require a complete re-design of the process at significant cost in time and resources.
Chiral specialty companies must therefore recognize, before in-licensing chiral technology, the difference between a reaction and a process. Chiral Quest (www.chiralquest.com) kept this distinction in sight when, in 2000, it decided to commercialize several asymmetric hydrogenation catalysts from Xumu Zhang, Ph.D., a chiral chemistry specialist at The Pennsylvania State University.
By early 2005, Chiral Quest had developed synthesis routes for nine of Dr. Zhangs catalysts and scaled its production to multikilogram scale, sufficient for efficient, cost-effective manufacturing processes for metric tons of APIs and intermediates.
Quite often during pharmaceutical development projects, process chemists are called upon to develop several alternate, competitive routes to a given complex API. Development groups then assess each process according to material and energy costs, and settle on the best synthetic route. Critical factors in determining cost are: raw material and reagents, reactor productivity (combination of reaction time and concentration), yield, number of steps, and the need and availability of specialized equipment or technology (e.g., low temperature, high pressure, high-energy reagents). Although introducing the chiral center is a key aspect of costing out a synthesis, it must nevertheless be considered within the context of the total synthesis.
An easily forgotten aspect of chirality introduction is substrate manufacture. For APIs or advanced intermediates, the substrate must, of course, fit into the synthetic scheme, react favorably with the chiral reagent, and be physically available when the catalyst becomes available.
Simultaneous with its catalyst development efforts, Chiral Quest saw the need to devote resources to efficient routes for substrate manufacture as well. One way of addressing this critical need was through a partnership with Chemical Synthesis Services (CSS), a subsidiary of Almac Sciences. CSS provides process research and development for complex, multistep syntheses typically encountered in pharmaceutical process development.
Recognizing the complex set of choices faced by developers of chiral drugs, Chiral Quest and CSS collaborated on several target compounds to explore how asymmetric hydrogenation would fit within the synthesis of important chiral building blocks and APIs.