An Improved Process for the N‐Demethylation of Opiate Alkaloids using an Iron(II) Catalyst in Acetate Buffer

Abstract

An improved process to N-demethylate opiate alkaloids utilising a solution of the ferrous porphyrin, tetrasodium 5,10,15,20-tetra(4-sulfophenyl)porphyrinatoiron(II) [ = Fe(II)-TPPS (8)], in acetate buffer is described. This method provided the corresponding N-demethylated opiates in good yield with high reproducibility.

ElectrochemicalN-demethylation of tropane 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. [16][17][18] Recent works have focused on using greener solvents such as ethanol and isopropanol, instead of chloroform, in the N-demethylation of N-oxides.…”

“…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. [16][17][18] Recent works have focused on using greener solvents such as ethanol and isopropanol, instead of chloroform, in the N-demethylation of N-oxides. 3,6,18,20 In one approach, iron nanoparticles have been studied as catalyst for the N-dealkylation of various alkaloids reporting a yield of 85% for the synthesis of noratropine.…”

“…† 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.…”

A Multi-Step Continuous Flow Process for the N-Demethylation of Alkaloids

“…The non-classical Polonovski reaction has been used for the N-demethylation of a range of opiate alkaloids, [12][13][14][15][16][17][18][19][20] some of which are important precursors of semi-synthetic pharmaceuticals such as buphrenorphine, naltrexone and naloxone. For example, the oxidation of thebaine 2 to thebaine N-oxide followed by reaction with two molar equivalents of FeSO 4 •7H 2 O afforded N-northebaine in 74% yield.…”

“…[14] This reaction proved most reliable when the air sensitive catalyst was maintained in an acetate buffer. [15] It was later found that the relatively inexpensive and air stable iron complex, ferrocene, was also an effective catalyst for this reaction; affording N-northebaine in 84% yield. [16,18] More recently, it was discovered that iron(0) in the form of iron powder as well as stainless steel can also serve as effective catalysts for Polonovski-type reactions.…”