Liquid Assisted Grinding for the N-Demethylation of Alkaloids

Abstract

A mechanochemical approach has been demonstrated for the selective cleavage of nitrogen–carbon bonds in the N-demethylation of various alkaloids relevant in the pharmaceutical industry. This methodology employs a range of so-called “liquid additives” used in microliter quantities in liquid assisted grinding rather than “solvents” used in solution phase reactions. Green liquid additives such as alcohols, water, PEG and ionic liquids as well as a nonchemical, mechanical approach for the generation of nanoscale Fe0 dust significantly improve the green attributes of the N-demethylation process.

Liquid‐Assisted Grinding Mechanochemistry in the Synthesis of Pharmaceuticals

“…All yields refer to isolated product, characterized by melting point 1 H NMR 13 C NMR and mass. In 2017, Singer and co-workers developed a liquid assisted grinding (LAG) promoted nonclassical Polonovski reaction for the N-demethylation of various alkaloids [120] (Scheme 18b). Dextromethorphan (DXM) 122 a and other alkaloids were first treated by mCPBA and HCl to give N-oxide hydrochloride derivatives, then converted into their N-nor derivatives by Fe 0 dust catalyzed selective cleavage of nitrogen-carbon bonds under mechanochemical ball-milling conditions.…”

N-Dealkylation of Amines

“…An interesting iron-based modified-Polonovski reaction using liquid assisted grinding (LAG) mechanochemistry was developed by Awalt et al [ 96 ]. As organic solvents constitute 80–90% of nonaqueous waste produced in pharma industries, any attempt to reduce the consumption of solvent usage can drastically reduce the environmental footprint of chemical processes.…”

ElectrochemicalN-demethylation of tropane alkaloids

“…13 Over the past decade, modifications of the reaction based on iron cata-lysts have been developed for the N-demethylation of tropane and opiate alkaloids. 2,3,6,8,[14][15][16][17][18][19] These reactions are based on a multi-step process, comprising the oxidation of the tertiary amine using m-chloroperbenzoic acid (m-CPBA) or H 2 O 2 to the corresponding N-oxide, which is then isolated as the HCl salt. The N-oxide salt is N-demethylated with iron-based catalysts such as FeSO 4 •7H 2 O, FeCl 2 •4H 2 O, or Fe(NH 4 SO 4 ) 2 , 14,15 iron porphyrin complex, 16,17 ferrocene, 8 and iron powder 2 which need to be separated from the reaction mixture by chelating with EDTA or TPPS (meso-tetra(4-sulfophenyl)porphyrin) 14,15 or by filtration.…”

“…† Previous methods use either toxic organic solvents, require powerful oxidants or necessitate chromatographic purification or filtration to remove catalysts, all of which add to the overall cost of the procedure and increase the impact on the environment notably for large-scale production processes. 2,3,6,8,[14][15][16][17][18][19] Concerted N-demethylation/N-acylation strategies based on palladium catalysts have been reported for atropine and opiate alkaloids. [21][22][23][24] Although these methods have been applied for the synthesis of the semi-synthetic opiates naltrexone 22 and buprenorphine, 23 the reaction is not selective for atropine, since the hydroxyl group is dehydrated, leading to the formation of apoatropine.…”