Synthesis of detomidine and medetomidine metabolites: 1,2,3- Trisubstituted arenes with 4'(5')-imidazolylmethyl groups

Article abstract of DOI:10.1002/jhet.5570300631

Two synthetic strategies permitted the synthesis of various metabolites of detomidine (1) and medetomidine (4), potent α-2 adrenoceptor agonists that undergo rapid oxidative metabolism at the aromatic methyl group distal to the imidazole ring. In the detomidine series, the addition of a Grignard reagent prepared from 2-((3',4'-dimethoxyphenyl)methoxy)methyl-6-bromotoluene (13) to imidazole-4(5)-carboxaldehyde (7) provided 2-(((3',4'- dimethoxyphenyl)methoxy)methyl)-6-(1'-hydroxy-1'-(5''- imidazolyl)methyl)toluene (14). In a subsequent reduction, it was possible to differentiate between the secondary benzylic hydroxyl group and the primary benzylic hydroxyl group protected as a 3,4-dimethoxybenzyl ether. Removal of the protecting group provided 3-(hydroxymethyl)detomidine (3-HD) (2) and an oxidation furnished 3-carboxydetomidine (3-CD) (3). However, in the medetomidine series, a similar hydrogenolysis of 2-(((3',4'- dimethoxyphenyl)methoxy)methyl)-6-(1'-hydroxy-1'-methyl-1'-(5''- imidazolyl)methyl)toluene (17) failed, and an alternate, longer route involving dehydration and reduction was necessary to secure 3- (hydroxymethyl)medetomidine (3-HM) (5) and following an oxidation, 3- carboxymedetomidine (3-CM) (6). Finally, an expeditious route to 3-CM (6) involved the addition of the Grignard reagent prepared from 2-(3-bromo-2- methylphenyl)-4,4-dimethyl-2-oxazoline (22) to 4-acetyl-1H-imidazole and the hydrogenolysis and hydrolysis of 2-(1-(4,4-dimethyl-2-oxazolyl))-6-(1'-oxo- 1'-(5'-imidazolyl)methyl)toluene (23).