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

Ivan Stoilov, David S. Watt, Jack P. Goodman, Jan S.T. Pyrek

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

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).

Original languageEnglish
Pages (from-to)1645-1651
Number of pages7
JournalJournal of Heterocyclic Chemistry
Volume30
Issue number6
DOIs
StatePublished - Dec 1993

ASJC Scopus subject areas

  • Organic Chemistry

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