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).
|Number of pages||7|
|Journal||Journal of Heterocyclic Chemistry|
|State||Published - Dec 1993|
ASJC Scopus subject areas
- Organic Chemistry