Electrochemical N-Demethylation of 14-Hydroxy Morphinans: Sustainable Access to Opioid Antagonists

Article abstract of DOI:10.1021/acs.orglett.0c02424

The most challenging step in the preparation of many opioid antagonists is the selective N-demethylation of a 14-hydroxymorphinan precursor. This process is carried out on a large scale using stoichiometric amounts of hazardous chemicals like cyanogen bromide or chloroformates. We have developed a mild reagent- and catalyst-free procedure for the N-demethylation step based on the anodic oxidation of the tertiary amine. The ensuing intermediates can be readily hydrolyzed to the target nor-opioids in very good yields.

Full text of DOI:10.1021/acs.orglett.0c02424

pubs.acs.org/OrgLett
Letter
Electrochemical N‑Demethylation of 14-Hydroxy Morphinans:
Sustainable Access to Opioid Antagonists
Gabriel Glotz, C. Oliver Kappe,* and David Cantillo*
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ABSTRACT: The most challenging step in the preparation of
many opioid antagonists is the selective N-demethylation of a 14-
hydroxymorphinan precursor. This process is carried out on a large
scale using stoichiometric amounts of hazardous chemicals like
cyanogen bromide or chloroformates. We have developed a mild
reagent- and catalyst-free procedure for the N-demethylation step
based on the anodic oxidation of the tertiary amine. The ensuing
intermediates can be readily hydrolyzed to the target nor-opioids in very good yields.
he ongoing opioids crisis, which is causing nearly 1000
T
overdose-related deaths per week in the United States,1
has dramatically increased the demand for opioid antagonists
like naloxone or naltrexone.2 The need for these lifesaving
antidotes for drug overdose treatment has, unfortunately, also
led to a significant rise in their price,3 which reduces their
availability to less favored communities.4 Decreasing the cost
of production for opioid antagonists via more efficient
synthetic routes is therefore highly desired and a very active
field of research.5,6 The most challenging step in the
preparation of these 14-hydroxy morphinans is the selective
removal of the N-methyl group from the relatively complex
morphine precursor (Figure 1A). The resulting nor-derivative
(i.e., the ensuing secondary amine) is a key intermediate from
which a range of essential medicines, including naloxone or
naltrexone, can be synthesized by simple realkylation with the
corresponding alkyl bromide.5,6 The N-demethylation process
is currently carried out using excess amounts of harmful
electrophilic reagents like cyanogen bromide (via the von
Braun reaction)7 or chloroalkyl formates.8 The combination of
stoichiometric amounts of peroxides and acylating agents
(classical Polonovski reaction) or metal reductants (non-
classical Polonovsky reaction) has also been applied (Figure
1B).9 Not surprisingly, more benign alternatives have been
actively investigated during the past two decades, including
palladium-catalyzed10 and photochemical11 aerobic oxidations
as well as chemoenzymatic procedures.12 However, these
methods have not been adopted by industry.12
Figure 1. Importance and strategies for the N-demethylation of 14-
hydroxy opioids for the preparation of overdose antidotes.
Notably, all N-demethylation reactions previously men-
tioned entail either an oxidation of the N−CH3 group or
withdrawal of the nitrogen electron pair by an electrophilic
reagent to initiate the demethylation process. Indeed, iminium
cation intermediates have been invoked for the palladium
catalyzed10 and photochemical routes11 as well as for the
nonclassical Polonovsky reaction.6 We hypothesized that,
under suitable electrochemical conditions, the N-methyl
Received: July 21, 2020
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group could be anodically oxidized to the corresponding
iminium cation in a two-electron process. Trapping of the
iminium cation by the 14-hydroxy group or acyl transfer from
the same position would generate intermediates that can be
readily hydrolyzed to the target nor-derivative (Figure 1C).10
This electrochemical strategy would not require any external
oxidant and, ideally, could be carried out in benign solvents
under mild conditions, delivering a highly convenient,
sustainable,13 and inexpensive N-demethylation method-
ology.14
At the onset of our investigation, cyclic voltammograms of
the 14-hydroxy precursor oxycodone (1a) and its O-acetyl-
protected derivative 14-acetyloxycodone (1b) were recorded
to assess whether the target tertiary amine could be selectively
oxidized (Figure 2A). The presence of a highly activated
aromatic ring can cause undesired oxidations, leading to the
formation of biaryl dimers.15 Analogous voltammograms were
obtained for both compounds. The oxidation of the amine was
observed at ca. Ep/2 = 1.1 V vs SCE, following the typical
irreversible pattern for tertiary amines.16 The second oxidation
peak, corresponding to the oxidation of the aromatic ring,
appeared at Ep/2 = 1.6 V vs SCE. In this case, the reversibility
of the electron transfer could be observed by increasing the
scan rate (Figure S1), indicating a relatively slow degradation
(i.e., dimerization) of the oxidized species at the low
concentrations utilized for the recording of the voltammo-
grams. Most notably, the difference in oxidation potentials
between the two moieties (ca. 0.5 V) pointed to a selective
reaction, probably even under galvanostatic conditions.
An initial screening of the reaction conditions was carried
out using the electrolysis of oxycodone (1a) as a model, which
was expected to provide oxazolidine 2a upon the formation of
an iminium cation (Figure 2B).17 All reactions were performed
in an undivided cell (IKA Electrasyn) at room temperature. To
our delight, the first attempt using graphite as the anode and
stainless steel as the cathode material in acetonitrile, using
LiClO4 as the supporting electrolyte, provided 29% conversion
to 2a and very good selectivity after 2 F/mol of charge (96
min) had been applied (Figure 2B, entry 1). The main side
products observed were the expected biaryl dimers.15 (See
Figure S3.) Dimerization can take place for both the starting
oxycodone (1a) and the oxazolidine electrolysis product (2a),
and thus the generation of small amounts of dimers in a late
stage of the reaction was expected. A screen of several solvent
systems and supporting electrolytes (entries 2−8) revealed that
the utilization of quaternary ammonium salts had a significant
beneficial influence on the reaction (entries 2 and 3). The
poorer performance of the lithium salt could be ascribed to the
formation of a complex with the tertiary amine.18 As expected,
the addition of protic solvents had a positive effect, providing a
source of protons for the concurrent cathodic reduction
(entries 6 and 8). The utilization of pure methanol as a solvent
resulted in a lower conversion (entry 5), with a 4:1
combination of MeCN and MeOH being the best solvent
system (entry 8). Several electrode materials were also
evaluated. (See Table S1.) None of the electrode combinations
provided significant improvements with respect to graphite/
stainless steel. Indeed, the utilization of platinum as an anode
material, for example, resulted in lower conversion under
otherwise identical conditions (entry 8 vs 9). Excellent results
were achieved by applying a 20% excess of electricity (2.4 F/
mol, 116 min) under a current of 5 mA in MeCN/MeOH with
Et4NBF4 as the supporting electrolyte (entry 10).
With the optimal conditions in hand, several key 14-hydroxy
and 14-acetyl opioid precursors were electrolyzed, leading to
cyclization to oxazolidines or O,N-acyl transfer, respectively
(Figure 3A). The optimal reaction parameters were directly
utilized without further reoptimization. The very good
conversions and selectivities obtained for all cases enabled a
simple workup procedure entailing the evaporation of solvent
followed by purification by short-path column chromatography
over neutral alumina. In addition to oxycodone (1a) and O-
acetyloxycodone (1b), O-acetyl codeinone (1c) was also
successfully subjected to the electrochemical oxidation,
resulting in a highly selective O,N-acyl transfer (vide infra).10c
Opioid antagonists such as naloxone or naltrexone generally
feature a 3-hydroxy group (cf. Figure 1), which is generated by
O-demethylation of the naturally occurring 3-methoxy opiates,
at either an early19 or a late20 stage of the synthetic route. The
Figure 2. (A) Cyclic voltammograms of opioid precursors 1a,b and
(B) optimization of the electrolysis conditions using 1a as the model.
aGeneral conditions: undivided cell; 0.15 mmol of substrate in 3 mL
of solvent; 5 mL of IKA Electrasyn vial; (+)C: graphite anode; (−)Fe:
stainless steel cathode. bDetermined by HPLC peak area percent (205
nm). cPercent of product with respect to all peaks except the substrate
(HPLC peak area percent, 205 nm).
B
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Figure 3. (A) Electrochemical oxazolidination and N-demethylative acyl transfer of several opioid precursors (isolated yields are given). (B)
Transfer of the electrochemical reaction to a flow cell and “one-pot” transformation to the nor-derivative.
presence of phenols is particularly problematic during anodic
oxidations due to their relatively low oxidation potentials.16
Indeed, the cyclic voltammetry of 3,14-dihydroxy opioids
typically shows product degradation starting at ca. 0.6 V vs
SCE.21 Gratifyingly, the selective electrochemical N-demethy-
lation of 14-hydroxymorphinone was enabled by first
generating its 3,14-O-diacetyl derivative (1d) (Figure 3A).
Cyclic voltammograms of the opioid precursor and the diacetyl
derivative showed a clear differentiation between the amine
and aryl oxidation peaks upon protection, pointing to a
selective electrochemical reaction. (See Figure S2.) Indeed,
electrochemical N-demethylative acyl transfer under the
optimal conditions resulted in 2d in 78% isolated yield.
Notably, this compound can be easily transformed to
noroxymorphone by acidic workup.10e
To improve the scalability of our electrochemical protocol,
the reaction was transferred to a flow electrolysis cell22 using as
a model the electrolysis of oxycodone (1a) (Figure 3B). The
flow cell consisted of a parallel plate arrangement, with the two
electrodes separated by a 0.3 mm chemically resistant Mylar
film incorporating a reaction channel.23 (The flow electrolysis
cell is described in the Supporting Information.) The reaction
mixture was pumped through the cell and recirculated at a flow
rate of 2 mL/min until the desired amount of charge had been
passed. Using an identical reaction mixture as in batch mode
and a current of 10 mA, the outcome of the reaction was
analogous. Nearly identical conversion and selectivity to the
oxazolidine intermediate as that in batch was obtained. It is
worth noting that direct treatment of the crude electrolysis
reaction mixture with HCl delivered the target nor-derivative
3a in 75% overall isolated yield. Furthermore, it should be
mentioned that no inert atmosphere or anhydrous solvents
were required to perform this transformation. This N-
demethylation, which generally is executed using rather
hazardous reagents in stoichiometric quantities (cf. Figure
1B), here is driven simply by electricity via inexpensive
electrode materials, producing hydrogen as a byproduct.
The proposed mechanism for the reaction (Figure 4A) starts
with a two-electron oxidation of the tertiary amine with the
release of one proton, generating the key iminium cation
intermediate. In the case of the 14-hydroxy opioids, rapid
intramolecular 1,5-cyclization, with the release of a second
proton, generates the oxazolidine intermediate. The two
protons released during the process are reduced at the
cathode, producing hydrogen gas. In the case of the O-
acetyl-protected derivatives, with no hydroxy group available
for an intramolecular cyclization, the iminium cation
intermediate is trapped by the methanol present as a cosolvent.
The resulting N,O-acetal intermediate reacts with a second
molecule of methanol, releasing the N-methyl carbon as
dimethoxymethane via a cyclic intermediate. Alternatively, the
release of dimethoxymethane may directly provide the free
secondary amine, which then undergoes rapid O,N-acyl
C
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Figure 4. (A) Proposed mechanism for the electrochemical oxazolidination and demethylative O,N-acyl transfer of opioids and (B−D) experiments
carried out to gain mechanistic insights.
transfer. This mechanism is analogous to the pathway
proposed for palladium-promoted acyl-transfer reactions.10c
To gain further insights into the reaction mechanism, several
experiments were performed. The kinetic isotope effect (KIE)
was evaluated using oxycodone-d3 (1a-d3) in a parallel single-
component experiment (Figure 4B). A moderate KIE (kH/kD =
1.5) was observed, suggesting that the second oxidation event,
with the release of a proton, is the rate-determining step of the
reaction. The KIE value is in agreement with a proton-coupled
electron transfer (PCET) in which the proton donor is close to
the acceptor (the solvent in this case).24 The intermediacy of
the iminium cation could be confirmed by its trapping with
cyanide and diphenylamine (Figure 4C). This was achieved by
generating the iminium ion in a “cation pool”25 at −45 °C
using a divided cell (lower temperatures could not be reached
in acetonitrile) and adding the nucleophile after the electricity
had been turned off. (See the Supporting Information for
details.) The trapping products were obtained in low amounts,
indicating that the temperature was not sufficiently low to
permit accumulation of the cation. To ensure that the observed
products were the result of trapping of the iminium cation and
not of ring opening of the oxazolidine, the latter was treated
with excess amounts of the nucleophilic reagents. No reaction
was observed. Finally, direct observation of the iminium ion by
infrared spectroscopy was also attempted, again using the
“cation pool” methodology (Figure 4D). In this case, an FTIR
probe was immersed in the anodic chamber of the divided
cell.26 Oxycodone derivative 6-oxyodol (1e), with the ketone
group reduced to an alcohol, was used as the substrate to
eliminate interference of the carbonyl signal from the IR.
Gratifyingly, under electrolysis, a weak peak appeared at ca.
1657 cm−1 that could be ascribed to the CN stretch of the
intermediate.27 The weak signal observed supported the
hypothesis that the iminium cation is not sufficiently stable
at −45 °C.
In summary, we have designed a catalyst- and reagent-free
electrochemical methodology for the N-demethylation of 14-
hydroxy opioids, the crucial step in the synthesis of important
opioid antagonists such as naloxone or naltrexone. The
synthetic strategy is based on the two-electron anodic
oxidation of the tertiary amine, generating an iminium ion
that rapidly undergoes intramolecular oxazolidination or
demethylative O,N-acyl transfer. The procedure has been
evaluated for several important opioid API (active pharma-
ceutical ingredient) precursors including oxycodone and 3,14-
diacetylmorphinone. The protocol has been transferred to a
flow electrolysis cell, enabling its scale-up. Notably, the key
nor-derivatives could be prepared in one pot by simply adding
hydrochloric acid to the crude electrolysis reaction mixture.
This strategy avoids the use of stoichiometric amounts of
hazardous electrophilic reagents and provides the target
compounds in good yields.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02424.
Experimental details, HPLC derivatization procedure,
cyclic voltammetry, kinetic isotope effect and chemical
trapping experiments, FTIR detection of the iminium
ion, details of the flow electrolysis cell and setup, and
copies of NMR spectra (PDF)
D
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AUTHOR INFORMATION
Corresponding Authors
■
David Cantillo − Institute of Chemistry, University of Graz,
8010 Graz, Austria; Center for Continuous Flow Synthesis and
Processing (CC FLOW), Research Center Pharmaceutical
Engineering GmbH (RCPE), 8010 Graz, Austria;
orcid.org/0000-0001-7604-8711; Email: david.cantillo@
uni-graz.at
C. Oliver Kappe − Institute of Chemistry, University of Graz,
8010 Graz, Austria; Center for Continuous Flow Synthesis and
Processing (CC FLOW), Research Center Pharmaceutical
Engineering GmbH (RCPE), 8010 Graz, Austria;
orcid.org/0000-0003-2983-6007; Email: oliver.kappe@
uni-graz.at
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Containing Halogen in the Aromatic Ring. Synth. Commun. 1994, 24,
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Gabriel Glotz − Institute of Chemistry, University of Graz, 8010
Graz, Austria; Center for Continuous Flow Synthesis and
Processing (CC FLOW), Research Center Pharmaceutical
Engineering GmbH (RCPE), 8010 Graz, Austria
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02424
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The CC FLOW Project (Austrian Research Promotion Agency
FFG No. 862766) is funded through the Austrian COMET
Program by the Austrian Federal Ministry of Transport,
Innovation and Technology (BMVIT), the Austrian Federal
Ministry of Science, Research and Economy (BMWFW), and
the State of Styria (Styrian Funding Agency (SFG)).
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