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The development and use of an in situ Raman spectroscopic method for the end-point detection of an etherification reaction, during a pilot plant scale manufacturing campaign, is described. Monitoring the reaction progress and minimising the level remaining of a chloropyrazine starting material at the reaction end-point were important, as the latter impacted a drug substance critical quality attribute (CQA). Furthermore, the etherification reaction required the use of a heterogeneous base (K 2 CO 3 ), and therefore the time to reach reaction completion could be scale dependent, owing to differences in reactor geometry and mixing characteristics. To provide valuable process understanding about the rate and extent of reaction during scale-up, a quantitative method utilising in situ Raman spectroscopy was developed. A series of laboratory scale reactions were performed to provide the spectroscopic and off-line reference measurements (HPLC) required for calibration model development. A quantitative multivariate calibration (PLS2) was developed to allow the concentration of starting material and reaction product to be predicted during the final 30% of the reaction using in situ generated Raman spectra. The root-mean square error of prediction (RMSEP) values for the 5-factor PLS2 model were 0.2% w/w and 0.1% w/w for ether 1 and phenol 2 respectively. This method was transferred and implemented in the pilot plant to detect the reaction end-point for a number of batches. During the initial batches, it was demonstrated that the results obtained from the Raman calibration model were equivalent to results obtained by off-line HPLC analysis. OPC was used to transfer the predicted results to the pilot plant control system, thus allowing scientists to remotely view the reaction progress in real-time.

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The optimisation and scale up of a manufacturing route to a key intermediate, acetic acid 4-acetylamino-3-(2-methyl-oxiranylmethoxy)phenyl ester (2), utilising a S N Ar coupling, the hydrogenation of a nitro moiety and the conversion of a chiral acetonide into a chiral epoxide is described along with other routes to access intermediate 2 including the chemoselective reduction of a nitro moiety in the presence of an epoxide.