- An Easy, Convenient, and Safe Process for the Synthesis of Lofexidine Hydrochloride
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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.
- Donnola, Monica,Airoldi, Annalisa,Barozza, Alessandro,Roletto, Jacopo,Paissoni, Paolo
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- PROCESS FOR THE SYNTHESIS OF LOFEXIDINE
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The present invention relates to an improved process for the synthesis of lofexidine, or a pharmaceutically acceptable salt thereof, using an aluminium alkoxide as Lewis acid.
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Page/Page column 15-16
(2021/10/22)
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- A PROCESS FOR THE SYNTHESIS OF LOFEXIDINE
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Disclosed is a process for the synthesis of lofexidine of formula (I) and the hydrochloride salt thereof (II), from ethyl 2-(2,6-dichlorophenoxy)propionate (III) and ethylenediamine in the presence of tetravalent titanium alkoxides, preferably titanium isopropoxide, in an apolar solvent such as toluene. A further object of the present invention is a process for the preparation of the intermediate ethyl 2-(2,6-dichlorophenoxy)propionate (III) from 2,6-dichlorophenol and ethyl 2-chloropropionate in the presence of a polar aprotic solvent and an alkali or alkaline earth carbonate salt, preferably potassium carbonate. Both processes are more cost-effective and more easily industrially scalable than the known procedures, thus enabling the active ingredient to be obtained with high yields at a limited cost.
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Page/Page column 4; 13-14
(2021/01/22)
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- Chemistry of Lofexidine
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The systematic syntheses and pharmacological studies of numerous imidazolines aryloxyalkyl-substituted in the 2-position show that substitution of the aryl residue in the 2,6-position by halogen and addition of a side-chain to the alkyl residue results in compounds with marked antihypertensive activity. 2-[1-(2,6-Dichlorphenoxy)-ethyl]-2-imidazoline hydrochloride (lofexidine, Lofetesin and Loxacor) exhibits the most marked hypotensive activity. The synthesis and physico-chemical properties of lofexidine are described.
- Betzing,Biedermann
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p. 916 - 918
(2007/10/02)
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