In linking to Neal Anderson yesterday, I see that he has a new post up and it's a bit of a doozy:
Arylboronic acids, but not the corresponding deboronated arenes, recently have been found to be weakly mutagenic in microbial assays [1]. Hence arylboronic acids may be considered potentially genotoxic impurities, and controlling the levels of residual arylboronic acids in APIs could become a regulatory requirement. The issues should be decided by toxicology studies for the specific arylboronic acids in question.Wait, what? Arylboronic acids might be genotoxic? Uh-oh. He then launches into a long discussion of how to cause protodeboronation of boronic acids to remove them from your API: (I think if you printed out his blogpost and sent it to Boron Molecular in North Carolina, either the envelope or the building would self-destruct.)
The Snieckus group found that deboronation occurred readily when pinacol was added to 4-pyridylboronic acid [12]. Percec and co-workers found that deboronation of neopentylglycol boronates, especially an ortho-substituted arylboronic acid ester, was catalyzed by nickel species [13]. Kuivila and co-workers found that CuCl2 catalyzed the deboronation of 2,6-dimethoxybenzeneboronic acid and other arylboronic acids, with formation of the corresponding aryl chlorides [14]. Unfortunately, adding reagents to a reaction mixture increases the burdens of analysis and impurity removal, but additives such as these may accelerate deboronation in difficult cases. Simply extending the reaction conditions, which are generally basic for efficient Suzuki coupling, or heating with some amount of aqueous hydroxide are probably the preferred treatments to decompose an arylboronic acid. By knowing the kinetics of the decomposition of the arylboronic acid it may be possible to show by QbD that analyses for the residual arylboronic acid in an API are not necessary.Read the whole thing.
CJ : At what dosage you see this weak mutagenic properties of boronic acid.
ReplyDeleteFrom the article: http://dx.doi.org/10.1016/j.mrgentox.2011.05.006
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Boronic acids and their esters are important building blocks in organic syntheses including those for drug substances and for which, as far as it can be determined, there are no published reports of testing for genotoxicity. A number of boronic acids have now been tested in this laboratory using Salmonella typhimurium strains TA1535, TA1537, TA98 and TA100 and Escherichia coli strain WP2uvrA(pKM101). Twelve of the 13 structures presented here were found to be mutagenic. All the compounds except one were active only in TA100 and/or WP2uvrA(pKM101), did not require S9 activation and produced relatively weak responses, i.e. no more than seven times the concurrent solvent-control values at >1000 μg/plate. The single exception was also weakly mutagenic for TA1537 in the presence of S9. Results with two compounds mutagenic for both TA100 and WP2uvrA(pKM101) showed no evidence of DNA-adduct formation detectable by 32P-postlabelling. It appears that boronic acids represent a novel class of bacterial mutagen that may not act by direct covalent binding to DNA. However, their mechanism of action remains to be elucidated and it cannot yet be determined whether or not they present a real genotoxic hazard.
Authors are at AZ, btw.
Yup. Its just one more genetox we Process chemists have to follow through many steps all the way through to the API - often controlling down to the ppm levels. Make friends with your Analytical chemist early in your project so you will know how just hard it is to get it under control. The earlier, the better. Genetox issues are not going away...
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