Control Strategy for Genotoxic Impurity BCME

Org. Process Res. Dev. 2020, 24, 1743. DOI: 10.1021/acs.oprd.0c00215

◆Bis(chloromethyl) ether (BCME; CAS #542-888-1) is a highly toxic compound and known mutagen, classified as an ICH M7 class 1 impurity.

◆In the synthesis of EMA401 (1), due to the simultaneous presence of hydrochloric acid and formaldehyde in the reaction mixture, the formation of BCME cannot be excluded a priori.

◆Both the calculated and measured purge factors were larger than the purge factor needed for an absolute worst-case scenario for the formation of BCME.

◆Thus, it can be concluded that, under the process conditions, any BCME potentially formed in the synthesis of tetrahydroisoquinoline 3 was purged below the TTC in the drug substance EMA401 (1).

Note

◆According to Alvarez and Rosen, BCME can be formed in achloromethylating medium (HCl-HCOH-ZnCl2) in concentrations of up to 300−500ppm.

◆Frankel and co-workers investigated the formation of BCME from formaldehyde and HCl in moist air with a yield of 0.01 mol %.