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‐1 H ‐imidazole and the hydrogenolysis and hydrolysis of 2‐(1‐(4,4‐dimethyl‐2‐oxazolyl))‐6‐(1′‐oxo‐1′‐(5′‐imidazolyl)methyl)toluene ( 23 ).