1999 Greener Synthetic Pathways Award
Lilly Research Laboratories
Practical Application of a Biocatalyst in Pharmaceutical Manufacturing
Innovation and Benefits: Lilly Research Laboratories developed a novel, low-waste process for drug synthesis. One key aspect uses yeast to replace a chemical reaction. Applying its process, Lilly eliminates approximately 41 gallons of solvent and 3 pounds of chromium waste for every pound of a drug candidate that it manufactures. Lilly's process also improves worker safety and increases product yield from 16 to 55 percent.
Summary of Technology: The synthesis of a pharmaceutical agent is frequently accompanied by the generation of a large amount of waste. This should not be surprising, as numerous steps are commonly necessary, each of which may require feedstocks, reagents, solvents, and separation agents. Lilly Research Laboratories has redesigned its synthesis of an anticonvulsant drug candidate, LY300164. This pharmaceutical agent is being developed for the treatment of epilepsy and neurodegenerative disorders.
The synthesis used to support clinical development of the drug candidate proved to be an economically viable process, although several steps proved problematic. A large amount of chromium waste was generated, an additional activation step was required, and the overall process required a large volume of solvent. Significant environmental improvements were realized upon implementing the new synthetic strategy. Roughly 9,000 gallons of solvent and 660 pounds of chromium waste were eliminated for every 220 pounds of LY300164 produced. Only three of the six intermediates generated were isolated, limiting worker exposure and decreasing processing costs. The synthetic scheme proved more efficient as well, with percent yield climbing from 16 to 55 percent.
The new synthesis begins with the biocatalytic reduction of a ketone to an optically pure alcohol. The yeast Zygosaccharomyces rouxii demonstrated good reductase activity but was sensitive to high product concentrations. To circumvent this problem, a novel three-phase reaction design was employed. The starting ketone was charged to an aqueous slurry containing a polymeric resin, buffer, and glucose, with most of the ketone adsorbed on the surface of the resin. The yeast reacted with the equilibrium concentration of ketone remaining in the aqueous phase. The resulting product was adsorbed onto the surface of the resin, simplifying product recovery. All of the organic reaction components were removed from the aqueous waste stream, permitting the use of conventional wastewater treatments.
A second key step in the synthesis was selective oxidation to eliminate the unproductive redox cycle present in the original route. The reaction was carried out using dimethylsulfoxide, sodium hydroxide, and compressed air, eliminating the use of chromium oxide, a possible carcinogen, and preventing the generation of chromium waste. The new protocol was developed by combining innovations from chemistry, microbiology, and engineering. Minimizing the number of changes to the oxidation state improved the efficiency of the process while reducing the amount of waste generated. The alternative synthesis presents a novel strategy for producing 5H-2,3-benzodiazepines. The approach is general and has been applied to the production of other anticonvulsant drug candidates. The technology is low-cost and easily implemented; it should have broad applications within the manufacturing sector.
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