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

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)tolulene ( 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 ).