An Easy, Convenient, and Safe Process for the Synthesis of Lofexidine Hydrochloride

A very efficient, cost-effective, and easily scalable process for the synthesis of lofexidine hydrochloride (1), an alpha 2-adrenergic receptor agonist used for treating opioid withdrawal is presented. Process development allows the preparation of lofexidine hydrochloride (1) through a one-pot amida...

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Bibliographic Details
Published in:Organic process research & development 2021-08, Vol.25 (8), p.1816-1821
Main Authors: Donnola, Monica, Airoldi, Annalisa, Barozza, Alessandro, Roletto, Jacopo, Paissoni, Paolo
Format: Article
Language:English
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Summary:A very efficient, cost-effective, and easily scalable process for the synthesis of lofexidine hydrochloride (1), an alpha 2-adrenergic receptor agonist used for treating opioid withdrawal is presented. Process development allows the preparation of lofexidine hydrochloride (1) through a one-pot amidation/imidazoline ring formation reaction, starting from ethyl 2-(2,6-dichlorophenoxy)­propionate (13) and ethylenediamine (5) by the action of titanium isopropoxide. The required intermediate ethyl 2-(2,6-dichlorophenoxy)­propionate (13) can efficiently be obtained through O-alkylation of 2,6-dichlorophenol (2) with ethyl 2-chloropropionate (12) using potassium carbonate as an acid-scavenger agent.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.0c00453