An Integrated Continuous-Flow Synthesis of a Key Oxazolidine Intermediate to Noroxymorphone from Naturally Occurring Opioids

Article abstract of DOI:10.1002/ejoc.201700811

A telescoped procedure for the direct preparation of an advanced intermediate towards noroxymorphone from the naturally occurring alkaloids oripavine and thebaine is presented. The reaction procedure involves an intensified continuous-flow hydroxylation, followed by a continuous solvent switch and hydrogenation in a packed-bed hydrogenator (H-Cube). The obtained reaction mixture, containing oxymorphone as intermediate in excellent yield and purity, can be then directly converted into the desired noroxymorphone oxazolidine intermediate through palladium catalyzed N-methyl oxidation.

Full text of DOI:10.1002/ejoc.201700811

A Journal of
Accepted Article
Title: An Integrated Continuous Flow Synthesis of a Key Oxazolidine
Intermediate to Noroxymorphone from Naturally Occurring
Opioids
Authors: Alejandro Mata, David Cantillo, and C. Oliver Kappe
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700811
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700811
Supported by

European Journal of Organic Chemistry
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An Integrated Continuous Flow Synthesis of a Key Oxazolidine
Intermediate to Noroxymorphone from Naturally Occurring
Opioids
[
a,b]
[a,b]
[a,b]
Alejandro Mata,
David Cantillo* and C. Oliver Kappe*
Abstract: A telescoped procedure for the direct preparation of an
advanced intermediate towards noroxymorphone from the naturally
occurring alkaloids oripavine and thebaine is presented. The
reaction procedure involves an intensified continuous flow
conditions. Palladium(0) particles of high catalytic activity were
generated by heating Pd(OAc) in DMA/AcOH. With the 14- N-
2
hydroxy opioids dissolved in this solution, a rapid and selective
methyl oxidation to 1,3-oxazolidines ensued in the presence of
[
6-8]
hydroxylation, followed by
a
continuous solvent switch and
O .
2
The reaction, based on the original method developed by
[
9]
hydrogenation in packed-bed hydrogenator (H-Cube). The
a
Hudlicky et al. in 2008, consumes only O
2
as stoichiometric
obtained reaction mixture, containing oxymorphone as intermediate
in excellent yield and purity, can be then directly converted to the
desired noroxymorphone oxazolidine intermediate via palladium
catalyzed N-methyl oxidation.
reagent and produces as the only by-product. A
H
2
O
hydrogenation/oxidation sequence allows employing the same
palladium catalyst for the transformation directly from 14-
hydroxymorphinone, consuming only hydrogen and oxygen in
[
6]
the process.
The missing link toward a process which enables the
preparation of noroxymorphone (4) from the naturally occurring
oripavine (1) and thebaine (1’) is therefore the C14 hydroxylation
reaction to 14-hydroxymorphinone. This reaction is typically
performed using hydrogen peroxide and formic or acetic acid
Introduction
Naltrexone and naloxone are arguably some of the most
[
1]
important substances used as opioid antagonists. Naloxone is
on the World Health Organization's List of Essential Medicines
and it is used since the 1960s as a treatment of acute opioid
overdose. It is normally administered to the patient in parenteral
form, although more recently intranasal formulations have also
[10]
mixtures, generating reactive peracids that rapidly oxidize the
diene group of the opioid. This method was adapted to
[11]
continuous flow conditions by scientists from Siegfried AG.
Unfortunately, the high amounts of water and acid present in the
performic acid reaction mixture make a direct telescoped
process towards noroxymorphone (4) virtually impossible.
[
2]
become available.
Naltrexone is a longer-acting opioid
antagonist primarily used in the management of opioid and
alcohol dependence. Naloxone and naltrexone are prepared
from oxymorphone (3) following an N-demethylation and N-
alkylation sequence (Scheme 1) via noroxymorphone (4).
Indeed, noroxymorphone, the direct product of the N-
demethylation of oxymorphone is the key intermediate in the
synthesis of various opioid antagonists apart from naloxone and
Isolation
of
the
reaction
intermediates
(i.e.,
14-
hydroxymorphinone (2), oxymorphone (3)) is usually required,
which inevitably reduces reaction yield and increases the
amount of solvent waste generated. Due to the increasing
demand of opioid antagonists based on N-alkylated
noroxymorphones,
preparation of the N-demethylated derivative from oripavine is
highly desirable. In this context, continuous flow processing has
demonstrated to be an ideal tool for the development of
uninterrupted multistep reactions.
sequential steps can be readily achieved via continuous
quenching, liquid-liquid extraction or even filtration stages
enabling genuine fully integrated processes. With this in mind,
we envisaged a modular continuous flow reactor set-up which
combines the (i) performic acid-mediated C14-hydroxylation, (ii)
hydrogenation, and (iii) aerobic oxidation steps into a single
telescoped process. We envisaged that the hydrogenation and
aerobic oxidation steps, which require a non-protic polar solvent
[1,2]
a suitable telescoped process for the
[
3-5]
naltrexone, including nalmefene (Scheme 1).
Oxymorphone,
in turn, can be prepared from the naturally occurring opioids
oripavine (1) and thebaine (1’) via C-14 hydroxylation and
subsequent hydrogenation pathways (Scheme 1).
[12]
The integration of several
Recently, our group has developed a series of strategies
for the generation of noroxymorphone (4) from 14-
[
6-8]
hydroxymorphinone under continuous flow conditions.
The
crucial reaction step towards the generation of 4 was an
unprecedented aerobic N-methyl oxidation using palladium(0) as
catalyst, which generates oxazolidine
5
as intermediate
(Scheme 1). Hydrolysis of 5 readily provides 4 under mild
[
6-8]
(DMA) and anhydrous conditions,
could be combined with the
initial C14-hydroxylation after a sequential continuous flow
liquid-liquid extraction, phase separation and solvent exchange
process (Figure 1). Herein, we report on the details of the
individual reaction steps and the developments of an integrated,
telescoped continuous flow process.
[
[
a]
b]
Institute of Chemistry, University of Graz, NAWI Graz
Heinrichstrasse 28, 8010 Graz, Austria
E-mail: david.cantillo@uni-graz.at, oliver.kappe@uni-graz.at
http://goflow.at
Research Center Pharmaceutical Engineering (RCPE)
Inffeldgasse 13, 8010 Graz, Austria
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201700811
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RO
RO
O
RO
hydrogenation
RO
N-demethylation
C14-
hydroxylation
O
O
O
NMe
NMe
OH
NMe
OH
NH
OH
MeO
O
O
O
R = H:
noroxymophone (4)
R = Me:
R = H: oripavine (1)
R = Me: thebaine (1')
isolated from
R = H: 14-hydroxy
morphinone (2)
R = Me: 14-hydroxy
codeinone (2')
R = H: oxymorphone (3)
R = Me: oxycodone (3')
noroxycodone (4')
papaver somniferum
(opium poppy)
HO
HO
HO
O
HO
O
O
O
N
N
N
OH
N
OH
OH
O
O
O
H C
O
2
naloxone
naltrexone
nalmefene
5
Scheme 1. Synthetic route for the preparation of semisynthetic opiates from naturally occurring oripavine
1
and thebaine 1’.
[
14-16]
reactor, as it is generated and consumed in situ.
In this
Results and Discussion
context, generation of hazardous percarboxylic acids in
[
17]
microreactor environments has also been described.
therefore decided to explore the reaction of oripavine with H
We
Batch and Continuous Flow C14 Hydroxylation
2 2
O
The preparation of 14-hydroxymorphinone (2) by C14
hydroxylation of oripavine (1) is a well-developed process
in HCOOH at higher temperatures. Initial batch experiments in
sealed vessels using very small amounts of reagents (Table 1)
revealed that the process can indeed be further intensified. At
temperatures of 100 and 110 °C full conversion of the starting
material was observed after 7 min and 2 min reaction time,
respectively. A mixture of the desired 14-hydroxymorphinone (2)
and small amounts of the corresponding N-oxide (2b) (5-10%)
were observed in all reactions. Formation of 2b as side product
is irrelevant as its hydrogenation over Pd/C in the next step also
leads to oxymorphone 3. Excellent selectivities were observed at
temperatures up to 100 °C (Table 1, entry 2). At 110 °C
unsatisfactory selectivity (94%) was observed and therefore
100 °C was chosen as optimal temperature for the process.
typically carried out using a combination of HCOOH and H
2 2
O ,
which generates in situ performic acid as the key reactive
[
10]
intermediate. Due to the explosive character of performic acid,
which can detonate at temperatures of 80-85 °C at certain
[
13]
concentrations,
the reaction is normally carried out at room
temperature or under moderate heating for several hours. The
continuous process for the C14-hydroxylation of oripavine and
thebaine developed by Siegfried AG was performed at
[
11]
temperatures of 80 °C (reaction time 15 min),
which is
essentially the detonation limit of the reactive intermediate.
Continuous flow reactors can operate within the explosive
regime minimizing risks due to the small channel dimensions
and the small amounts of hazardous material accumulated in the
Figure 1. Proposed concept for the continuous telescoped synthesis of noroxymorphone from oripavine.
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European Journal of Organic Chemistry
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The flow rates for the liquid feeds were set to 389 μL/min
and 41 μL/min for Feed A and B, respectively, to obtain the
desired reagent stoichiometry (1 equiv) and residence time
within the reactor (7 min). Without further optimization 4 mmol of
oripavine (1’) were processed using the continuous flow setup.
HPLC monitoring of the crude reaction mixture collected from
the output revealed excellent conversion (99%) and selectivity
HO
HO
HO
H O (1 equiv)
2
2
O
O
+
O
O-
HCOOH
N+
OH
N
N
OH
O
O
O
1
2
2b
(99%) for the desired products (the HPLC chromatogram of the
crude reaction mixture is shown in Figure S1 of the Supporting
Information). The 2:2b ratio was 95:5 in the continuous flow run.
Due to the high selectivity achieved, the product (containing 5%
N-oxide, which results in the same product after hydrogenation
in the next step) could be isolated after simple evaporation of the
solvent under reduced pressure as the formate salt (94%
2 2
Scheme 2. C14-hydroxylation of oripavine 1 with H O in HCOOH.
[
a]
Table 1. Batch intensification of the C14-hydroxylation of oripavine (1).
1
[
b]
[b,c]
isolated yield, 97% purity by H NMR).
Temp (°C)
80
Time (min)
Conv (%)
2:2b
9:1
Select (%)
Using the same continuous flow setup and conditions
thebaine (1’) could be also successfully C14-hydroxylated to the
corresponding 14-hydroxycodeinone (2’) (cf. Scheme 1). As for
oripavine (1), excellent conversion and selectivities were
achieved, and a 93% isolated yield for the desired 14-hydroxy
1
2
3
15
7
99
99
99
99
98
94
100
9:1
110
2
9:1
1
derivative 2’ was obtained (purity 98% by H NMR).
[
a] Conditions: sealed vessel, 0.5 mmol substrate in 0.5 mL HCOOH, 1
equiv H (30% aqueous solution). [b] Determined by HPLC peak area
integration (215 nm) after derivatization with Ac O (see Experimental
Section). [c] Relative amount of 2+2b with respect to other side products.
2
O
2
C14 Hydroxylation/Hydrogenation Sequence
2
Hydrogenation
of
the
7,8-olefine
group
of
14-
hydroxymorphinone (2) is the common route for the preparation
[[ 10a,c]
of oxymorphone (3) in batch.
The reaction has been
extensively described in batch as well as under continuous flow
With the optimal conditions in hand we translated the C14
hydroxylation process to continuous flow conditions (Figure 2).
The flow setup consisted of two feeds containing the substrate
[6-8,10]
conditions using Pd/C as catalyst.
Our group has described
in previous reports the hydrogenation of 14-hydroxymorphinone
[6-8]
2
using polar non-protic solvents such as DMA.
Protic solvent
(
1) in HCOOH (Feed A) and H
pumping system (Uniqsis binary pumping module) was fed with
HCOOH (A) and water (B), and the substrate and H were
2 2
O (Feed B), respectively. The
mixtures like iPrOH/HCOOH are commonly used as well in batch
procedures.
The third step in the route towards noroxymorphone, i.e.,
the aerobic oxidation of oxymorphone to oxazolidine 5, has been
2 2
O
introduced via sample loops. The liquid streams were mixed
using a T-mixer (0.5 mm id) before entering a residence time
unit (PFA tubing, 3 mL, 0.8 mm id) at 100 °C. The system was
pressurized using an adjustable back-pressure regulator
shown in our previous work to be sensitive to protic solvents
[6-8]
(DMA being the solvent of choice).
A solvent switch from the
HCOOH/H
2
O mixture from the C14-hydroxylation to DMA is
(Vapourtec) at 4 bar.
therefore needed enabling a telescoped process from 1 to 5 (or
’ to 5’). To decide whether this solvent swap is more beneficial
1
HO
O
to be performed prior or after the hydrogenation, we performed
some preliminary batch experiments to evaluate the
performance of the hydrogenation in DMA and HCOOH/H O
2
N
(with the second solution being the crude reaction mixture
O
obtained from the previous step). Thus, mmol 14-
hydroxymorphinone 2 and 1 mol% Pd/C 10% were placed in a
1
1
in HCO
2
H (1M)
4
mL
round bottom flask and DMA or HCOOH were added. The
reaction mixtures were stirred under H atmosphere (1 bar) and
2
HCO
A
2
H
HO
HO
100 °C, 7 min
389 L/min
monitored by HPLC. Surprisingly, the reduction of the alkene
was much faster in DMA as solvent. Full conversion to
oxymorphone 3 was achieved after 1 h reaction, while in
HCOOH ca. 3 h were required.
Continuous flow hydrogenation experiments were carried
out using a commercially available hydrogenator (H Cube,
ThalesNano) equipped with a packed bed reactor containing
O
+
NH
O
O
4
bar
N
OH
4
1 L/min
OH
H
2
O
O
O
B
2
2b
3
mL
H
2
O
2
(9.8M)
Figure 2. Schematic view of the continuous flow setup for the C14
hydroxylation of oripavine (1).
10% Pd/C. To evaluate the potential process integration with the
previous step starting solutions were prepared using the crude
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European Journal of Organic Chemistry
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reaction mixture obtained from the C14-hydroxylation flow setup
visually observed inside of the tubing. The gas liquid separation
was performed in a vessel which was kept at 80 °C to avoid
condensation of the DCM on the walls. Optimal flow rates for the
liquid streams are shown in Figure 3. The DCM/aqueous mixture
ratio was 8:1 and the DCM/DMA proportion 10:1 using these
(see above). The samples were diluted with DMA to a 0.2 M
concentration and directly subjected to continuous
hydrogenation with the H Cube. Due to the short residence
times obtained within the packed bed reactor (< 1 min) the
reaction temperature and hydrogen pressure were gradually
increased to obtain full conversion to the desired oxymorphone
conditions.
The
remaining
liquid
contained
14-
hydroxymorphinone (2) in DMA and was suitable to be pumped
further to the next synthetic step. Thus, 2 in DMA, obtained
using this solvent switch module, was directly pumped into the
continuous flow hydrogenator using the optimal conditions
(Table 2, entry 5). Notably, excellent conversion and selectivity
was obtained for the desired oxymorphone (3). Evaporation of
the solvent under reduced pressure yielded the crystalline
product (86% yield over three steps, purity 90% by 1H NMR).
(
3) (Table 2). Thus, using 20 bar and room temperature as initial
set of conditions only 20% conversion was achieved (entry 1). At
0 °C and 60 bar (entry 5) H pressure more than 95% was
6
2
obtained maintaining excellent selectivity towards the desired
product 3. Under intensified conditions a 91% isolated yield of
oxymorphone (with respect to the initial oripavine) was obtained
after simply evaporating the solvent under reduced pressure
(purity 90% by 1H NMR).
aq. wa ss te
2
in HCO
2
H/H
2
O
Table 2. Continuous flow hydrogenation of 14-hydroxymorphinone 2 to
oxymorphone 3 in an H-Cube reactor (Thalesnano).
357 L/min
GG ravity-based
separator
[a]
DCM (g)
NH OH
4
6
% in H O
2
232 L/min
95°C
80°C
DCM
DCM (gas)
DMA (liquid)
4.7 L/min
2
in DMA
D MM A
[
b]
[b]
Figure 3. Schematic view of the cont ii nuous flow setup for the liqud-liquid
extraction, phase separation and DCM- DD MA solvent exchange.
Temp (°C)
Pressure (bar)
Conv (%)
Select (%)
1
2
3
4
5
rt
20
20
30
60
60
35
40
50
90
95
99
99
99
99
99
50
50
50
60
C14 Hydroxylation/Hydrogenation/Aerobic Oxidation
The aerobic N-methyl oxidation of oxymorphone using
palladium(0) as catalyst in continuous flow mode has been
[
6-8]
extensively studied in our group.
The optimal reaction
conditions for this transformation consist of generating
palladium(0) particles of high catalytic activity by heating
[
a] Conditions: 0.2 M substrate in DMA/HCOOH, 0.3 mL/min. [b] Determined
by HPLC peak area integration (215 nm) after derivatization with Ac
Experimental Section).
2
Pd(OAc) in DMA/AcOH. The colloidal Pd(0) is then mixed with
2
O (see
the 14-hydroxy opioids giving 1,3-oxazolidines 5 after a rapid
[
6-8]
and selective N-methyl oxidation with
O .
2
As this
transformation had been thoroughly investigated and optimized
in batch and flow conditions, we did not attempt to further modify
the conditions for the aerobic oxidation in this work, which
focuses in the integration of the 3-step telescoped process.
Thus, a 0.2 M solution of oxymorphone (3) in DMA was
prepared after a sequential continuous flow C14 hydroxylation,
quench, liquid-liquid-extraction, phase separation, solvent switch
and hydrogenation (Figure 4) following the procedures described
in detail above on a 3 mmol scale. The solution was mixed with
a freshly prepared colloidal suspension of Pd(0) from Pd(OAc)2
and DMA/AcOH. Heating of the reaction mixture under O2
atmosphere was carried out in batch and monitored by HPLC.
The aim of the continuous flow setup for the liquid-liquid
extraction/phase separation/solvent exchange was to develop a
continuous procedure which enabled the integration of the initial
C14 hydroxylation step with both the subsequent hydrogenation
and aerobic oxidation. Thus, the solution containing 14-
hydroxymorphinone in HCOOH/H
suitable base (aq. NH OH) releasing the opioid in its basic form,
which was then extracted into an organic solvent (DCM) (Figure
). Continuous separation of the organic and aqueous phases
2
O was quenched with a
4
3
[
18]
could be readily achieved by a gravity-based separator. Such
gravitational separation techniques are state-of-the-art and have
been used in many continuous flow setups,
Gratifyingly, the desired 1,3-oxazolidine
5 rapidly formed
[
19]
including
The (low
attaining 85% HPLC yield after 2 h. This result is in strong
contrasts to the rather poor results for aerobic oxidations that
have been obtained without applying the liquid-liquid extraction
and solvent switch to the reaction mixture (see above). The
[
20]
continuous end-to-end manufacturing examples.
boiling) organic solvent was then mixed with DMA using a T-
mixer and the mixture heated in a residence time unit (PFA, 1.6
mm id, 14 mL). Rapid vaporization of the volatile DCM could be
telescoped
process
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European Journal of Organic Chemistry
10.1002/ejoc.201700811
FULL PAPER
HO
HO
O
NMe
O
NMe
MeO
OH
aq. waste
O
1M in HCOOH
0.2M in DMA
1
00 °C, 7 min
(89% over 3-steps)
H
2
O
2
Gravity-based
separator
DCM (g)
NH
in H
4
OH
H-Cube
HO
HO
O2
2
O
95°C
1
0% Pd/C
Pd(OAc)
2
DCM/H
2
O 8:1
O
O
80°C
6
0 bar
NMe
batch
N
6
0 °C
DCM
OH
O
<
1 min
DCM (gas)
O
O
DMA (liquid)
H
2
in DD MA
83%
DMA
(86% ov ee r 4-steps)
(HPLC)
Figure 4. Telescoped continuous process for the generation of 1,3-oxazolidine 5 from oripavine 1.
developed herein could therefore be seen as a method to
integrate reaction steps where reagents or solvents present
problems of compatibility.
The same process, applied to thebaine (1’), yielded a
solution of 14-hydroxycodone (3’) in DMA that could also be
by using mobile phases A [water/acetonitrile, 90:10 (v/v) + 0.1ꢀ% TFA]
and B (MeCN + 0.1ꢀ% TFA) at a flow rate of 1.5 mL/min (the following
gradient was applied: linear increase from 3ꢀ% B to 100ꢀ% B in 17 min).
MW heated reaction were performed in a single-mode Biotage Initiator+
instrument.
2
oxidized in the presence of Pd(0) under an O atmosphere to the
corresponding 1,3-oxazolidine 5’.
HPLC Samples Preparation - Ac
mixture (50 µL) and Ac O (200 µL) were added to a HPLC vial containing
a saturated aqueous solution (1 mL) of NaHCO . The vial was capped,
2
O derivatization: The crude reaction
2
3
the septum perforated with a needle, and the mixture stirred vigorously at
room temperature for 10 min. The content of the vial was then directly
analyzed by HPLC–UV/Vis with the method described above in the
General section.
Conclusions
We have developed a telescoped continuous flow process which
enables the generation of 1,3-oxazolidines 5 and 5’, precursors
to noroxymorphinone (4), a key intermediate in the synthesis of
several opioid antagonists. Integration of the 3-step synthetic
route (i.e., C14-hydroxylation/hydrogenation/aerobic oxidation)
has been enabled via a continuous flow acid quench with
C14 Hydroxylation of Oripavine (1) in Batch: Oripavine (150 mg) and
formic acid (0.5 mL) were placed in a microwave vial and stirred until the
substrate was fully dissolved. Then, 51 μL of H O (30% in water, 1
2 2
equiv) were added under stirring. The vial was capped and heated at the
desired temperature (Table 1) in a dedicated microwave reactor. After
the desired reaction time was comp ll eted the vial was cooled to 50 °C
with compressed air. Method 2 was used for HPLC analysis.
aqueous NH
4
OH followed by
a
sequential liquid-liquid
extraction/phase separation/solvent switch protocol. Thus, the
C14-hydroxylation reaction mixture, consisting of the
C14 Hydroxylation in Flow: The flow set-up depicted in Figure 2 was
used. Flow rates for Feeds A and B were set to 389 μL/min and 41
μL/min, respectively. The GC-oven temperature was set to 100 °C. A 1 M
solution of the substrate (3 mmol) (or ii pavine 1 or thebaine 1’) in HCOOH
corresponding 14-hydroxy-opioid
2
in HCOOH/H
2
O
is
transformed into a DMA solution of the intermediate, suitable for
the hydrogenation/aerobic oxidation steps. The telescoped
process has been applied to the naturally occurring oripavine (1)
and thebaine (1’) alkaloids to generate oxazolidines (5) and (5’)
in clean, high yielding processes.
2 2
was introduced in the Feed A sample loop. 30% H O in water was
introduced in Feed B loop. When the system was stable reagent samples
were simultaneously injected into the ll iquid streams. The reaction mixture
collected from the reactor output was immediately analyzed by HPLC
and/or evaporated under reduced pressure to obtain the corresponding
1
4-hydroxy-opioid as the formate salt.
Experimental Section
1
Hydrogenation in Batch: 1 ml of the crude reaction mixture obtained
from the C14 hydroxylation flow reactor (see above) was diluted with
DMA to obtain a 0.1 M solution. 1 mol% of 10% Pd/C was added. The
General: H NMR spectra were recorded with a Bruker 300 MHz
13
spectrometer. C NMR spectra were recorded with the same instrument
at 75 MHz. Chemical shifts (δ) are expressed in ppm downfield from TMS
as internal standard. The letters s, d, t, q, and m are used to indicate
singlet, doublet, triplet, quadruplet, and multiplet. Analytical HPLC–
UV/Vis (Shimadzu LC20) analysis was carried out with a C18 reversed-
phase (RP) analytical column (150ꢀ×ꢀ4.6 mm, particle size 5 µm) at 37 °C
reaction mixture was stirred at room temperature under H
The reaction was stopped after HPLC analysis showed >95% conversion
1 hour). Method 1 was used for HPLC analysis.
2
atmosphere.
(
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European Journal of Organic Chemistry
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1
Hydrogenation in Flow: The starting solution was prepared by diluting
the crude reaction mixture from the C14 hydroxylation flow reactor (see
above) with DMA to a concentration of 0.2 M. The hydrogen level of the
H-Cube was set to “full H2” mode; the reactor containing a Pd/C cartridge
was preheated at 60 °C, the pressure to 60 bar, and the flow rate to 0.1
mL/min. When the reactor was stable the reaction mixture was
processed. The mixture collected from the output was evaporated under
Oxycodone (3’): H NMR (300 MHz, D
2
O) δ = 6.83 – 6.64 (m, 2H), 4.84
(s, 1H), 3.71 – 3.64 (m, 3H), 3.60 – 3.54 (m, 1H), 3.28 (d, J = 20.1 Hz,
1H), 3.11 – 3.04 (m, 1H), 2.96 (dd, J = 20.2, 6.1 Hz, 1H), 2.84 (dd, J =
14.9, 5.2 Hz, 1H), 2.76 (s, 3H), 2.66 – 2.43 (m, 2H), 2.11 (dt, J = 14.9,
13
3.0 Hz, 1H), 1.98 (d, J = 19.7 Hz, 1H), 1.87 (m, 1H), 1.53 (m, 2H).
C
NMR (75 MHz, D O): δ = 211.3, 143.9, 142.6, 126.8, 122.6, 121.0, 114.0,
2
89.3, 70.5, 66.2, 56.5, 48.5, 46.7, 40.7, 34.3, 30.4, 26.9, 22.9 ppm.
1
reduced pressure yielding oxymorphone (91%, purity 90% by H NMR).
Aerobic N-Methyl Oxidation: Pd(OAc)
μL, 3 equiv.) were dissolved in DMA (1 mL). The mixture was heated for
2
(2.3 mg, 5% mol) and AcOH (23
Acknowledgements
0
15 min at 120 °C. A deep-black solution of colloidal Pd was obtained.
We acknowledge support from ThalesNano Inc. for providing the
H-Cube catalyst cartridges, and Bernhard Gutmann for his
scientific contribution to this work.
The mixture was cooled down to 110 °C. 1 mL of the solution obtained
from the hydrogenation module (see Figure 4) was added. The solution
was stirred at 110 °C under O atmosphere and monitored by HPLC.
2
End-to-End Generation of Oxazolidine 5 from Oripavine. A solution
containing oripavine 1 in HCOOH (1 M, 3 mmol) was loaded in the feed A
sample loop of the C14-hydroxilation setup depicted in Figure 2. 30%
Keywords: continuous flow • telescoped synthesis • opioid
antagonists • microreactors • demethylation
2 2
H O in water was introduced in Feed B loop. Flow rates for feeds A and
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1
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4
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1
4
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1
1
1
1
4-Hydroxy-codeinone (2’): H NMR (300 MHz, D
2
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2
=
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Entry for the Table of Contents (Please choose one layout)
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Opioids
Alejandro M
Oliver Kapp
Page No. –
An Integrat
Synthesis o
Intermediat
from Natur
From poppy towards API: A telescoped continuous flow procedure for the
preparation of an advanced intermediate for the synthesis of various opioid
antagonists from oripavine and thebaine is presented.
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