Multivariate Analysis in the Selection of Greener Solvents for the Bromination of 2-Cyano-4’-methylbiphenyl

Abstract

4′-(Bromomethyl)-2-cyanobiphenyl (BCB) is a vital building block to various sartans, which are an important group of nonpeptide angiotensin II antagonists. The commercial manufacture of BCB from 2-cyano-4′-methylbiphenyl by Wohl−Ziegler bromination is, however, dependent on troublesome chlorinated solvents such as chlorobenzene or carbon tetrachloride. In this work, we use the response surface methodology (RSM) together with solvent principal components as an exploratory tool to identify greener solvent alternatives. We find that there is a significant interaction between solvent principal components, showing that the usual strategy of one-variable-at-a-time is not an applicable solvent selection method for this particular reaction. Based on the contour plot, we find that t 1 and t 2 of solvents should preferably be below −2 and −3, respectively, and within the outer limits of the model to find a solvent ideal for the conversion of 2-cyano-4′-methylbiphenyl into BCB, resulting in a yield of above 80%. We also find that especially carbonate esters such as propylene carbonate (experimental conversion and yield of 83.5 and 76.0%, respectively) or diethyl carbonate (experimental conversion and yield of 88.9 and 71.0%, respectively) are well predicted by the model and suitable replacements. The RSM approach together with solvent principal components is a powerful combination that may be useful for the "greening" of many other commercial important syntheses.

A Facile Method for Multigram Scale Light-Induced Synthesis of 4′-(Bromomethyl)-2-cyanobiphenyl

“…Delightfully, diethyl carbonate (DEC) gave a large improvement compared with EtOAc, whereas ethyl lactate did not work well. This observation for ethyl lactate was in accordance with results with alcohols in general in previous work, but remarkably, the yield in DEC was higher . Continuing with DEC, a trial at room temperature for 3 h (entry 23) confirmed that temperature does not seem important in the tested experimental space.…”

A tutorial review for research laboratories to support the vital path toward inherently sustainable and green synthetic chemistry

“…Acetone is an example that many guides classify as a recommended solvent, while AstraZeneca and GSK have labelled it as associated with issues due to impacted waste scores concerning VOC potential and biotreatment. 120,130,132 Common agreements within guides suggest that preferred solvents for pharmaceutical processes consist largely of alcohols and esters for example n-butanol and ethyl acetate, and water.…”

“…The utilisation of PCA solvent maps allows optimisation of a reaction to be carried out by a design of experiment (DoE) approach rather than a more laborious one variable at a time (OVAT) strategy. 132,135 The availability and application of such selection tools and guides is highly benecial (Fig. 11).…”