title: A one-pot synthesis of tetrazolones from acid chlorides: understanding functional group compatibility, and application to the late-stage functionalization of marketed drugs.
abstract: A one-pot and scalable synthesis of tetrazolones (tetrazol-5-ones) from acid chlorides using azidotrimethylsilane is presented. The reaction tolerates many functional groups and can furnish aryl-, heteroaryl-, alkenyl-, or alkyl-substituted tetrazolone products in moderate to excellent yield (14-94%). No reduction in yield was observed when the reaction was undertaken on a larger-scale (20-36 g). The method could be used for the late-stage functionalization of pharmaceuticals, to provide tetrazolone congeners of the marketed drugs aspirin, indomethacin, probenecid, telmisartan, bexarotene, niacin (vitamin B3), and the active metabolite of the recently-launched immuno-modulatory agent, BG-12 (Tecfidera®). The ability of a tetrazolone group to serve as a bioisostere of a carboxylic acid, and to improve drug pharmacokinetic profiles is also highlighted.
authors.affiliation: Rigel Pharmaceuticals, 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. mattduncton@yahoo.com mduncton@rigel.com.
authors.forename: Matthew A J
authors.initials: MA
authors.lastname: Duncton
authors.affiliation: Rigel Pharmaceuticals, 1180 Veterans Boulevard, South San Francisco, CA 94080, USA. mattduncton@yahoo.com mduncton@rigel.com.
authors.forename: Rajinder
authors.initials: R
authors.lastname: Singh
mesh_terms: D001241:Aspirin / Q000737:chemistry; D001386:Azides / Q000737:chemistry; D001562:Benzimidazoles / Q000737:chemistry; D001565:Benzoates / Q000737:chemistry; D000077610:Bexarotene; D002264:Carboxylic Acids / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D002712:Chlorides / Q000737:chemistry; D007213:Indomethacin / Q000737:chemistry; D009525:Niacin / Q000737:chemistry; D011339:Probenecid / Q000737:chemistry; D012821:Silanes / Q000737:chemistry; D000077333:Telmisartan; D013764:Tetrahydronaphthalenes / Q000737:chemistry; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D001386:Azides; D001562:Benzimidazoles; D001565:Benzoates; D002264:Carboxylic Acids; D002712:Chlorides; D012821:Silanes; D013764:Tetrahydronaphthalenes; D013777:Tetrazoles; C438544:azidotrimethylsilane; D009525:Niacin; D000077610:Bexarotene; D011339:Probenecid; D001241:Aspirin; D000077333:Telmisartan; D007213:Indomethacin