SYNTHESIS OF DETOMIDINE AND MEDETOMIDINE METABOLITES - 1,2,3-TRISUBSTITUTED ARENES WITH 4'(5')-IMIDAZOLYLMETHYL GROUPS

Two synthetic strategies permitted the synthesis of various metabolite s of detomidine (1) and medetomidine (4), potent alpha-2 adrenoceptor agonists that undergo rapid oxidative metabolism at the aromatic methy l group distal to the imidazole ring. In the detomidine series, the ad dition of a Grignard reagent prepared from ',4'-dimethoxyphenyl)methox y)methyl-6-bromotoluene (13) to imidazole-4(5)-carboxaldehyde (7) prov ided )-6-(1'-hydroxy-1'-(5''-imidazolyl)methyl)tolulene (14). In a sub sequent reduction, it was possible to differentiate between the second ary benzylic hydroxyl group and the primary benzylic hydroxyl group pr otected as a 3,4-dimethoxybenzyl ether. Removal of the protecting grou p provided 3-(hydroxymethyl)detomidine (3-HD) (2) and an oxidation fur nished 3-carboxydetomidine (3-CD) (3). However, in the medetomidine se ries, a similar hydrogenolysis of ydroxy-1'-methyl-1'-(5''-imidazolyl) methyl)toluene (17) failed, and an alternate, longer route involving d ehydration and reduction was necessary to secure 3-(hydroxymethyl)mede tomidine (3-HM) (5) and following an oxidation, 3-carboxymedetomidine (3-CM) (6). Finally, an expeditious route to 3-CM (6) involved the add ition of the Grignard reagent prepared from -(3-bromo-2-methylphenyl)- 4,4-dimethyl-2-oxazoline (22) to 4-acetyl-1H-imidazole and the hydroge nolysis and hydrolysis of zolyl))-6-(1'-oxo-1'-(5'-imidazolyl)methyl)t oluene (23).