Terrence Joseph Connolly

An eco-efficient pilot plant scale synthesis of two 5-substituted-6,7-dimethoxy-1-H-quinazoline-2,4-diones

Two 1-H-quinazoline-2,4-diones having substituents at the 5-position have been prepared on a pilot-plant scale using an eco-efficient process. The process started with the appropriately substituted ortho-nitrobenzoic acid and involved a catalytic hydrogenation, conversion of the generated aniline to a substituted urea, cyclization and precipitation of the desired 1-H-quinazoline-2,4-diones. The process is unique in that all stages of the process were conducted in water. The desired transformations were affected by manipulation of the pH of the reaction mixture, and addition of the necessary reagent. The products were isolated in near-quantitative yield and were analytically pure. The only waste streams were the aqueous filtrate and the noble metal catalyst. The process was demonstrated on scales up to 5 kg.

Early chemical development at Legacy Wyeth Research

This article describes an approach to early process development in the context of the productivity model in legacy Wyeth (i.e. to deliver two New Drug Applications per year for New Molecular Entities). As a result of the model, the cycle time from lead selection to phase I decreased and the number of compounds in early development increased. In response, Wyeth Chemical Development devised a resource-neutral approach to early process development, which is described here. This model harvested synergies from integrating advanced technologies and aggressive sourcing with a matrix research organization and efficient ways of working. It provided a model that met the business needs of our former organization while ensuring the timely delivery of high-quality active pharmaceutical ingredients and safe, scalable processes.