Multivariate analysis in the selection of greener solvents for the bromination of 2-cyano-4’-methylbiphenyl

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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 t1 and t2 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.

Original languageEnglish
JournalOrganic Process Research & Development
Volume25
Issue1
Pages (from-to)68-74
Number of pages7
ISSN1083-6160
DOIs
Publication statusPublished - Jan 2021

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