Large scale synthesis of 5-ethoxycarbonyl-6-methyl-4-(2-nitro-phenyl)-3,4-dihydro-2(1H)pyridone

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Abstract

Chemical process scale-up, from laboratory to pilot or commercial scale, of a new chemical entity is commonly a complex process. It is influenced by several parameters, such as: temperature, agitation speed and its interactions. Temperature and agitation speed are closed related to the heat and movement transfers; two critical unit operations that affect the scale-up process. In addition, the sequential order of reagent addition could be one of the scale-up failures. Our project involves a multicomponent reaction with four members (4-MCR) for obtaining a 3,4-piridone derivative (Figure 1), a very important product for obtaining a novel neuroprotective compound which is in development. Thus, this study is focused to develop a practical way for scaling-up a multicomponent reaction with 4 components, from laboratory scale to pilot scale applying a combination of the brute force method and dimensionless numbers for scaling-up the process based on the significant physical forces governing it. Previous experimental results, Mondelo Rodríguez et al. (2017) demonstrated that the temperature and fluid agitation and its interaction are the most significant parameters affecting reaction yield. The Nusselt and Reynold numbers, in addition to other criteria applied, was used for calculating the agitation speed for the upper scale. Likewise, as the reaction product precipitated through the cooling process a critical agitation speed was determined applying Zwietering rule. The process showed high reproducibility at all scales, reaching good yields 70 – 75 % and high product purity upper than 99 % for all batches. The method applied allows the successful scalability of the process for increasing the scale to commercial.