The chemical method for the preparation of the intermediate 14 was assessed in order to ensure safe scale up on pilot plants. Previous experience on the same kind of reactions

GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of central nervous system disorders and emesis. The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste. Through a targeted process of research and development, application of novel techniques and extensive route scouting, a new synthetic route for GW597599 was developed. This paper reports the optimisation work of the third and last stage in the chemical synthesis of GW597599 and the development of a pilot-plant-suitable process for the manufacturing of optically pure arylpiperazine derivative 1. In particular, the process eliminated the use of triphosgene in the synthesis of an intermediate carbamoyl chloride, substantially enhancing safety, overall yield, and throughput.

Process Safety Evaluation of bromo-(4-fluoro-2-methylphenyl)magnesium 19The proposed procedure for the bromo-(4-fluoro-2-methylphenyl)magnesium 19 formation was investigated from a process safety perspective to ensure that sound basis of safety existed prior to pilot plant scale up.

In the fine chemical industry new production processes are often implemented in multipurpose existing plants with minimum adaptation investments. When the new process involves a potential runaway reaction, a full thermodynamic and kinetic characterization of the system should be performed to evaluate whether the reaction can be safely scaled-up in the selected plant. However, a detailed kinetic characterization is often unsuited because of the huge development rate of new products. In this work a potential runaway reaction of the agrochemical industry, that is, the nitration of 2,4-dichloro benzotrifluoride through mixed acids, is investigated with the aim of implementing it with a minimum experimental effort in an existing plant already dedicated to a similar reaction, that is, the nitration of 4-chloro benzotrifluoride. It has been shown that, even performing very similar reactions, the Ψ number criterion cannot be implemented in a univocal way to monitor the multipurpose SBR operation. Such a goal can instead be reached through the general procedure based on the Ψ, X and MTSRad set of process indicators, which was previously applied to the monitoring of polymerization processes.