Synthesis of Naltrexone and (R)-Methylnaltrexone from Oripavine via Direct Oxidation of Its Quaternary Salts

Article abstract of DOI:10.1055/s-0034-1378808

(R)-Methylnaltrexone and naltrexone were each prepared in four steps from oripavine in practical yields. The procedure involved quaternization of oripavine with cyclopropylmethyl halides, singlet oxygen oxidation of the quaternary salts, and the reduction of endo peraoxides to 14-hydroxyketone functionalities. (R)-Methylnaltrexone was prepared from the corresponding R-diastereomer of the oripavine salt. All diastereomeric mixtures of the quaternary salts were subjected to N-demethylation with sodium thiolate to yield cyclopropyl methylnororipavine, which was converted into naltrexone by peracid oxidation and hydrogenation according to established procedures.

Full text of DOI:10.1055/s-0034-1378808

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2101–2108
letter
2101
A. Machara et al.
Letter
Synlett
Synthesis of Naltrexone and (R)-Methylnaltrexone from Oripavine
via Direct Oxidation of Its Quaternary Salts
Ales Macharaa
HO
HO
HO
Lukas Wernerb
Hannes Leischb
Robert J. Carrollb
David R. Adamsb
D. Mohammad Haqueb
D. Phillip Coxc
O
O
O
Br
Br
Br
N
O
O
N
N
OH
Me
Me
Me
O
MeO
HO
MeO
HO
(R)-methylnaltrexone
HO
Tomas Hudlicky*b
O
O
O
a Faculty of Science, Charles University in Prague, Hlavova 8, Prague 2, 128
43, Czech Republic
N
N
Me
N
OH
O
MeO
oripavine
MeO
macharaa@natur.cuni.cz
cyclopropylmethyl nororipavine
naltrexone
b Chemistry Department and Centre for Biotechnology, Brock University,
500 Glenridge Avenue, St. Catharines, Ontario, L2S 3A1, Canada
thudlicky@brocku.ca
c Noramco, Inc., 503 Carr Road, Suite 200, Wilmington, DE 19809, USA
PCox2@its.jnj.com
Received: 12.05.2015
2
HO
3
Accepted after revision: 05.07.2015
Published online: 10.07.2015
DOI: 10.1055/s-0034-1378808; Art ID: st-2015-s0360-l
HO
1
A
11
4
10
B
15
16
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13
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E
O
9
D
Abstract (R)-Methylnaltrexone and naltrexone were each prepared in
four steps from oripavine in practical yields. The procedure involved
quaternization of oripavine with cyclopropylmethyl halides, singlet oxy-
gen oxidation of the quaternary salts, and the reduction of endo per-
oxides to 14-hydroxyketone functionalities. (R)-Methylnaltrexone was
prepared from the corresponding R-diastereomer of the oripavine salt.
All diastereomeric mixtures of the quaternary salts were subjected to
N-demethylation with sodium thiolate to yield cyclopropyl methylnorori-
pavine, which was converted into naltrexone by peracid oxidation and
hydrogenation according to established procedures.
N
5
N
14
OH
17
C
OH
7
8
6
O
O
naltrexone (1)
naloxone (2)
HO
HO
HO
O
N
O
MeO
N
OH
HO
Key words photochemical oxidation, singlet oxygen, naltrexone syn-
thesis, (R)-methylnaltrexone synthesis, N-demethylation of oripavine
quaternary salts
buprenorphine (4)
nalbuphine (3)
HO
OH
O
The major constituents of the opium poppy, such as
morphine, codeine, thebaine, and oripavine, serve as start-
ing materials for the synthesis of important medicinal
agents. Naltrexone (1, Figure 1) is an opioid antagonist (μ-
and κ-receptors) used for long-term treatment of opioid or
alcohol dependence. Naloxone (2) is used primarily in treat-
ing overdose of other opiates or opiate-derived products in
an emergency. Nalbuphine (3) is used as an analgesic, as is
buprenorphine (4), which at higher dosage can be used to
treat addiction. Suboxone®, a combination of buprenor-
phine and naloxone is used for the latter purpose. (R)-
Methylnaltrexone (5), or (Relistor®) is a peripherally acting
μ-receptor antagonist that is effective in reducing side ef-
fects, such as constipation, associated with the use of opioid
analgesic agents. As it does not cross the blood–brain barri-
er it does not diminish analgesic effects.
O
O
Br
Br
N
N
OH
Me
O
Me
OH
(R)-methylnaltrexone (5)
Figure 1 Medicinally useful opiate-derived products
Manufacturing of these opiate-derived medicinal agents
requires effective and large-scale solutions to two funda-
mental problems: the introduction of C-14 hydroxyl group
and the replacement of N-methyl group with other alkyl
functionalities, such as allyl, cyclopropylmethyl-, or cy-
clobutylmethyl groups. The first of these problems has
been solved effectively in the industrial preparation of oxy-
codone and oxymorphone by oxidation of thebaine or ori-
pavine, respectively.1 The second problem usually involves
N-demethylation by harsh methods such as the von Braun
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2101–2108

2102
A. Machara et al.
Letter
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HO
HO
HO
X
O
O
O
for (R,S)-7b:
X
N
Me
X
N
Me
N
precipitation
Me
a X = Cl
b X = Br
MeO
MeO
MeO
(R)-7b
oripavine (6)
[R/S = 7:1 to 10:1] for 7a
[R/S = 1:2 to 1:3] for 7b
7a,b
1. oxidation
2. hydrogenation
N-demethylation
HO
HO
O
HO
O
O
N
X
N
N
OH
Me
MeO
O
MeO
HO
buprenorphine (4)
(R)-methylnaltrexone (5b)
8
1. oxidation
2. hydrogenation
MeX
HO
O
N
OH
O
naltrexone (1)
Scheme 1 General design for naltrexone, methylnaltrexone, and buprenorphine from a common intermediate
reaction or chloroformate-mediated dealkylation.2 Recent-
ly, new methods of N-demethylation have emerged and in-
clude palladium-catalyzed demethylation/acylation,3 iron-
catalyzed demethylation of N-oxides,4 demethylation cata-
lyzed by fungal cytochromes,5 and other methods.6 In 2011
we reported an improved synthesis of buprenorphine from
oripavine via N-demethylation of the quaternary salts with
thiolates7 to yield N-cyclopropylmethyl nororipavine 88
(Scheme 1). This intermediate was converted into bu-
prenorphine by known procedures. The most significant
improvement was the avoidance of the use of cyanogen
bromide in the demethylation protocol. The entire se-
quence from oripavine to buprenorphine was shortened by
three steps and performed in four operations (seven chemi-
cal steps) in 32% overall yield.8
clobutylmethyl noroxymorphinone,9 reduction to nalbu-
phone, and further stereoselective reduction of the C-6 ke-
tone functionality led to nalbuphine.
The ease of preparation of N-cyclopropylmethyl norori-
pavine 8 prompted us to consider a general approach to
naltrexone by oxidation of 8 and to methylnaltrexone by di-
rect oxidation of the quaternary salts 7. Naltrexone, pre-
pared from oxymorphone in several steps, is converted into
(R)-methylnaltrexone10 by alkylation with iodomethane,
bromomethane, or dimethyl sulfate, followed by multiple
crystallizations to pure (R)-methylnaltrexone (MNTX). Al-
though direct methylations of naltrexone have been report-
ed10,11 it is more customary to protect the C-3 phenol with
benzyl,12 acyl,13 ethyloxycarbonyl,14 or silyl15 protecting
groups (Scheme 2). After deprotection the NMTX salt is
carefully deprotonated to obtain zwitterion 10, which, be-
cause of its limited solubility, is easily filtered off and later
dissolved in aqueous HBr. This protocol improves product
purity and more importantly allows for feasible anion ex-
change on an industrial scale.
Nalbuphine (3) was synthesized in an analogous fash-
ion. The quaternary salt derived from oripavine by alkyla-
tion with cyclobutylmethyl bromide was N-demethylated.
Oxidation of the N-cyclobutylmethyl nororipavine to N-cy-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2101–2108

2103
A. Machara et al.
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obtained as mixtures of R- and S-diastereomers (configura-
tion at N-17, morphine numbering) in varying ratios de-
pending on the conditions used. The isomers were separa-
ble by chromatography to provide standard samples that
were then used to determine the ratios of these diastereo-
mers in the reaction mixtures by HPLC analysis. The quater-
nary chloride salt was transformed into the corresponding
bromide by passing its solution through an ion-exchange
resin.
BnO
HO
1. BnCl, K2CO3,
acetone
2. Me2SO4, NaHCO3,
acetone
O
O
O
MeSO4
N
N
OH
OH
Me
O
naltrexone (1)
[R/S = 97:3]
9
1. H2, Pd(C)
2. Na2CO3, H2O
Chloride salt 7a was obtained by heating oripavine with
cyclopropylmethyl chloride in N-methylpyrrolidone at
120 °C for more than 24 hours. Under these conditions 7a
was produced in ca. 55% as a mixture of R/S diastereomers
(7:1). The mixtures could be further enriched in the R-iso-
mer by heating at elevated temperatures for 48 hours as it
was found that the S-isomer was slowly degraded. This pro-
cedure led to improved ratios of R/S isomers (ca. 10:1 to ca.
20:1) at the expense of isolated yield. Whereas this method
could ultimately produce the pure R-isomer, it was not ef-
fective because of the dramatic depletion of useful mass.
Bromide salt 7b was obtained by heating oripavine with
cyclopropylmethyl bromide in anhydrous DMF at 80 °C for
more than 12 hours. In order to attain full conversion the
crude mixture was subjected to a second cycle with 0.5
equivalents of cyclopropylmethyl bromide to provide 7b in
94% yield as a mixture of R/S diastereomers (1:3). From this
reaction mixture we were able to precipitate pure (R)-7b in
the approximate yield of ca. 20%. Separation of pure (R)-7b
was accomplished by simple filtration of cold reaction mix-
ture of 7b and was possible only in the case of the bromide
salt.
O
HO
O
O
1. HBr, MeOH, H2O
2. purification
Br
N
N
OH
OH
Me
Me
O
O
(R)-methylnaltrexone (5b)
10
Scheme 2 Example of a synthetic route towards MNTX12
Because the quaternization of naltrexone is not ste-
reospecific and the undesired S-isomer is usually present in
less than 5% yield, the final product must be recrystallized
several times to meet FDA requirements. Alkylation of oxy-
morphone with cyclopropylmethyl bromide furnished (S)-
methyl naltrexone. The reaction is very slow hence this
method is not viable for preparation of a potential active
pharmaceutical ingredient (API).16 Here we report the de-
tails of the singlet-oxygen oxidation of the quaternary salts
and compare the efficiency of preparing (R)-methylnaltrex-
one either directly from 7 or from 8 via oxidation to nal-
trexone (1) and subsequent methylation.
Quaternary salts 7a and 7b were prepared by heating
oripavine with cyclopropylmethyl chloride or bromide in
55% and 94% yield, respectively (Scheme 3). The salts were
The pure R-isomer was to be used eventually in direct
oxidation while the filtrates from the filtrations/precipita-
tions would be subjected to N-demethylation with thiolate
HO
HO
HO
Cl
TPP, 1O2
H2, Pd/C
O
O
Cl
O
Cl
Cl
N
NMP, 120 °C
55–58%
70– 71%
CH2Cl2, MeOH
85–92%
N
N
O
O
Me
OH
Me
Me
MeO
MeO
O
HO
7a
R/S = 7:1 to 10:1
11a
5a
R/S = 10:1
Note: These ratios are the result of slow decomposition
of the S-isomer under the conditions of the reaction
O
Dowex, HBr
90–97%
NMe
Dowex, HBr
90–98%
MeO
HO
6
HO
HO
TPP, 1O2
CH2Cl2, MeOH
Br
O
H2, Pd/C
61–74%
O
Br
Br
O
N
N
Br
NMP, 80 °C
94%
86–93%
O
O
N
Me
Me
OH
Me
MeO
MeO
O
7b
R/S = 1:2 to 1:3
11b
5b
R/S = 1:2 to 1:3 [from 7b]
R/S = 10:1 [from 5a]
Scheme 3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2101–2108

2104
A. Machara et al.
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Synlett
to produce cyclopropylmethyl nororipavine (8), which can
serve as a convenient precursor to buprenorphine and nal-
trexone. In this fashion, the total mass of the quaternary
salts can be used to access three useful products.
The oxidation of salt 7b with peracids, performed with
pure isomers as well as R/S mixtures, was not successful
primarily because of low yields of the desired product and
the formation of a large number of side products, in con-
trast to the results obtained with conversion of oripavine to
oxymorphone by such established procedures.17
We therefore turned to singlet-oxygen oxidation of 7a,b
as means of introduction of the C-14 hydroxyl group, as
shown in Scheme 3. We were inspired by an earlier report
that described the oxidation of thebaine salts with singlet
oxygen.18 Irradiation of a solution of 7a,b (of varying iso-
meric composition) in dichloromethane and methanol in
the presence of oxygen and tetraphenylporphyrin (TPP)
produced high yields of the corresponding endo-peroxides
11a,b, whose hydrogenation led directly to methylnaltrex-
one chloride or bromide 5a or 5b, respectively.
The experiments shown in Scheme 3 were initially con-
ducted with isomeric mixtures, some of which were en-
riched with the desired R-diastereomer (R/S ratio = ca. 7:1
to 10:1). As we were able to obtain pure (R)-7b from the
crude mixtures we turned to investigations of more effec-
tive mass management in the synthesis of (R)-methylnal-
trexone bromide (5b) from pure (R)-7b by oxidation and
subsequent hydrogenation. (R)-Methylnaltrexone bromide
(5b) can also be prepared from 8 by known oxidation and
quaternization protocols. The two routes were then com-
pared for the best overall mass yield. The summary and de-
tails of these transformations are shown in Scheme 4.
Pure R-diastereomer 7b, obtained as described above,
was subjected to oxidation with singlet oxygen, which led
to endo-peroxide 11b in 93% yield. Direct hydrogenation of
11b provided (R)-methylnaltrexone bromide (5b); however,
the product contained 10–15% of the C-6 alcohol resulting
from overreduction. This problem was solved by partial re-
duction of 11b to 12b accomplished by the use of the Pd/C
catalyst poisoned with thiourea (1% by weight). The
hydroxyenone 12b was then cleanly hydrogenated to
(R)-methylnaltrexone bromide (5b).
To approach the synthesis of naltrexone we utilized all
isomeric mixtures of 7a or 7b that were produced by quat-
ernization or resulting from purification of 7b. These mix-
tures, containing varying ratios of R- and S-diastereomers,
were subjected to N-demethylation conditions with sodium
thiolate, as previously reported,7 to produce N-cyclopropyl-
methyl nororipavine (8) in 60–70% yields. In this manner all
oripavine mass committed to the initial quaternization was
used either to produce (R)-methylnaltrexone bromide (5b)
or 8, from which naltrexone is made by reliable oxidation
HO
O
HO
HO
O
O
Br
H2, Pd/C
O2, TPP, CH2Cl2–MeOH
N
Br
Br
N
O
O
N
OH
Me
thiourea
93%
Me
Me
MeO
O
MeO
(R)-11b
(R)-12b
7b [pure R]
H2, Pd/C
74% (2 steps)
tert-dodecanethiol, t-BuONa, DMSO
77%
HO
80 °C, 30 min
HO
HO
1.AcO2H, AcOH, H2O
2. H2, Pd/C
O
O
O
Br
N
N
N
OH
OH
95%
Me
MeO
O
O
8
1
(R)-5b
tert-dodecanethiol, t-BuONa, DMSO
80 °C, 45 min
60–70%
HO
O
X
N
X = Cl, Br
Me
MeO
[R/S: varying ratios]
7a,b
Scheme 4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2101–2108

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HO
OH
O
OH
O
MeI, N-methylpyrrolidone, –8 °C
I
O
+
N
I
Me
OMe
OMe
N
N
MeO
Me
8
(S)-7c
(R)-7c
Scheme 5
protocols. Naltrexone (1) can also be converted into (R)-
methylnaltrexone bromide (5b) by alkylation with methyl
iodide according to established protocols.10–12
Finally, we examined the quaternization of N-cyclopro-
pylmethyl nororipavine (8) in order to determine if a more
favorable ratio of R- and S-diastereomers of salts 7 may be-
come available. This compound was prepared from ori-
pavine for the first time in 2009 during our studies on the
synthesis of buprenorphine.8a
reomers in each case was found to be highly dependent on
the conditions of the reaction as well as on the nature of the
halide. The pure R-diastereomer of the quaternary salt
yielded (R)-methylnaltrexone by singlet-oxygen oxidation
followed by hydrogenation. All residual material containing
varying ratios of R- and S-diastereomers was subjected to
N-demethylation with sodium thiolate to provide N-cyclo-
propylmethyl nororipavine, which was converted into nal-
trexone by known procedures. Naltrexone can be converted
into (R)-methylnaltrexone by alkylation. Thus the reported
process provides for a very efficient conversion of oripavine
to either naltrexone or (R)-methylnaltrexone, with all of the
mass of the starting material committed to either product.
At four steps, the procedure reported here is much shorter
than some of the commercially used processes, which are
ten steps or more.
It should be noted that large-scale industrial processes
that employ photochemistry are not common because of
safety and efficiency issues on scale-up. An exception was
recently reported by the Sanofi group: Photochemically
generated singlet oxygen was used in a large-scale synthe-
sis of artemisinin (370 kg obtained from 600 kg of artemis-
inic acid).21 In addition, the efficiency (as well as safety) is-
sues may be solved further by employing continuous-flow
reactors, as was recently demonstrated by the conversion of
α-pinene to pinocarvone.22
Oripavine, thebaine, and N-cyclopropylmethyl norori-
pavine (8) have been shown to be good substrates for quat-
ernization, in contrast to other morphinans and analogues
such as oxymorphone or intermediates used in the synthe-
sis of buprenorphine. Madyastha made this observation in
1983,7 reporting that thebaine is converted into its quater-
nary salts in 12 hours (95% yield) in contrast to codeine (48
hours, 90%) and morphine (72 hours, 60%). He also rea-
soned that the unique conformation of these substrates, im-
parted by the methoxydiene moiety and lacking 1,3-inter-
actions between the C-14 sp3 substituent and the incoming
electrophile is responsible for the enhanced reactivity in
oripavine or thebaine derivatives. Alkylation of 8 with
methyl iodide in N-methylpyrrolidone at –8 °C led to diaste-
reomeric mixtures of 7c in which the R-isomer was pre-
ferred (R/S = 3.6:1.0), as shown in Scheme 5. This observa-
tion implies that the incoming electrophile will preferen-
tially occupy the axial position in the quaternary salt and
that alkylation of 8 provides essentially the opposite ratio of
diastereoisomers than that obtained by alkylation of ori-
pavine with cyclopropylmethyl halides at higher tempera-
tures (R/S = 1:3, at 80 °C for cyclopropylmethyl bromide).
The use of the quaternary salts 7a or 7b in N-demethyl-
ation has proven to be superior to analogous experiments
with N-demethylation of salts derived from thebaine. While
such salts were formed in good yields their treatment with
sodium thiolate led to complex mixtures and decomposi-
tion, presumably as a result of competing O-demethylation,
which can also be problematic when applied to thebaine as
a free base.7,19
Acknowledgement
The authors are grateful to the following agencies for the financial
support of this work: Noramco, Inc.; Natural Science and Engineering
Council of Canada (NSERC) (Idea to Innovation and Discovery Grants);
Canada Research Chair Program, Canada Foundation for Innovation
(CFI); TDC Research, Inc.; TDC Research Foundation; Ontario Partner-
ship for Innovation and Commercialization (OPIC); and the Advanced
Biomanufacturing Centre (Brock University). One of us (AM) is grate-
ful to the University Centre of Excellence of Charles University,
Prague, Czech Republic for support of part of this work.
Supporting Information
We have provided an efficient four-step conversion of
oripavine to naltrexone and/or (R)-methylnaltrexone via
quaternary salts derived from oripavine by alkylation with
cyclopropylmethyl halides.20 The ratio of R- and S-diaste-
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378808. Experimentals for com-
pounds 5a, 7a, 7c, 11a, 11b, 12b and NMR spectra (1H and 13C) of 1,
(R)-5b, (R)-7b, (S)-7b, 8, 11a (1H NMR only), (R)-12b are included.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
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References and Notes
(19) (a) Lawson, J. A.; DeGraw, J. I. J. Med. Chem. 1977, 20, 165.
(b) Murphy, B.; Snajdr, I.; Machara, A.; Endoma-Arias, M.;
Stamatatos, T. C.; Cox, D. P.; Hudlicky, T. Adv. Synth. Catal. 2014,
356, 2679.
(1) References to oxycodone/oxymorphone preparation by peracid
oxidation of thebaine or oripavine: (a) Freund, M.; Speyer, E. J.
Prakt. Chem. 1916, 94, 135. (b) Gates, M.; Boden, R. M.;
Sundararaman, P. J. Org. Chem. 1989, Oxidation of 5-alkyl the-
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Neumeyer, J. L. Org. Lett. 2005, 7, 3239.
(2) Cyanogen bromide: (a) von Braun, J. Ber. Dtsch. Chem. Ges. 1900,
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(3) Carroll, R. J.; Leisch, H.; Scocchera, E.; Hudlicky, T.; Cox, D. P.
Adv. Synth. Catal. 2008, 350, 2984.
(20) Key Experimental Procedures
N-Cyclopropylmethyl Nororipavine Methyl Bromide (7b)
A. From Chloride Salt 7a
Compound 7a (0.150 g, 0.39 mmol) was dissolved in
a
minimum amount of aq MeOH (H2O–MeOH, 3:1). The solution
was filtered through a column packed with Dowex®-1 resin
(Sigma, strongly basic bromine loaded, 50–100 mesh) and
eluted with distilled H2O (500 mL). The majority of the solvent
was removed under reduced pressure. The residue was lyo-
philized to give the title compound 7b as a white solid (0.16 g,
95%). 1H NMR and 13C NMR spectra were identical to the spectra
of compound 7a. MS–FAB+: m/z = 785 [(C22H26NO3)2Br]+.
B. From Oripavine and Cyclopropylmethyl Bromide
A flame-dried, argon-purged round-bottomed flask with an
attached reflux condenser was charged a suspension of ori-
pavine (1.84 g, 6.18 mmol) in anhydrous DMF (10 mL). Cyclo-
propylmethyl bromide (1.8 mL, 18.5 mmol, 3.0 equiv) was
added to the vigorously stirred suspension of oripavine in one
portion and at r.t. The flask was immersed in an 80 °C oil bath,
and the mixture was stirred under argon atmosphere for 12 h.
After cooling, an aliquot was analyzed by HPLC (285 nm) and
determined to contain approximately 3.6% (integration, area
under curve) oripavine (as the HBr salt). NaHCO3 (0.02 g, 0.24
mmol, 4 mol%) was added to the reaction mixture, which was
stirred for 1 h prior to the addition of additional cyclopropyl-
methyl bromide (0.30 mL, 3.1 mmol, 0.5 equiv) at r.t. The reac-
tion mixture was immersed in the 80 °C oil bath for an addi-
(4) (a) Scammels, P. J.; Orbell, G. WO 2011032214, 2011.
(b) McCamley, K.; Ripper, J. A.; Singer, R. D.; Scammells, P. J.
J. Org. Chem. 2003, 68, 9847. (c) Thavaneswaran, S.; Scammells,
P. J. Bioorg. Med. Chem. Lett. 2006, 16, 2868.
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D. P.; Hudlicky, T. Collect. Czech. Chem. Commun. 2009, 74, 1179.
(6) Other methods of N- and O-demethylation, for thioethoxide:
see: (a) Feutrill, G. I.; Mirrington, R. N. Tetrahedron Lett. 1970,
16, 1327. Thioethoxide under microwave irradiation:
(b) Cvengros, J.; Neufeind, S.; Becker, A.; Schmaltz, H.-G. Synlett
2008, 1993. Thiopropoxide: (c) Lawson, J. A.; DeGraw, J. I. J. Med.
Chem. 1977, 20, 165. Thiopropoxide: (d) Hutchins, C. W.;
Cooper, G. K.; Purro, S.; Rapoport, H. J. Med. Chem. 1981, 24, 773.
Thiopropoxide: (e) Michne, W. F. J. Med. Chem. 1978, 21, 1322.
BBr3: (f) Rice, K. C. J. Med. Chem. 1977, 20, 164. NbCl6: (g) Sudo,
Y.; Arai, S.; Nishida, A. Eur. J. Org. Chem. 2006, 752.
(7) For demethylation of morphine alkaloids by thiolate anions,
see: Manoharan, T. S.; Madyastha, K. M.; Bali Singh, B.;
Bhatnagar, S. P.; Weiss, U. Synthesis 1983, 809.
(8) (a) Werner, L.; Machara, A.; Adams, D. R.; Cox, D. P.; Hudlicky, T.
J. Org. Chem. 2011, 76, 4628. (b) Hudlicky, T.; Carroll, R.; Leisch,
H.; Machara, A.; Werner, L.; Adams, D. R. WO 2010121369 A1,
2010.
(9) Machara, A.; Cox, D. P.; Hudlicky, T. Heterocycles 2012, 84, 615.
(10) Goldberg, L. I.; Merz, H.; Stockhaus, K. US 4171186-A, 1979.
(11) Cantrell, G. L.; Halvachs, R. E. WO 2004043964 A2, 2004.
(12) Dlubala, A. WO 2008034973, 2008; US 20080214817, 2008
(13) (a) Wang, P. X.; Cantrell, G. L.; Halvachs, R. E.; Roesch, K. R.;
Buehler, H. J.; Haar, J. P. Jr. US 8669366-B2, 2014. (b) Doshan, H.
D.; Perez, J. WO 2006127899, 2006.
(14) Weigl, U.; Schar, P.; Stutz, A. US 20100168427 A1, 2010; WO
2008138605, 2008
(15) Sun, H.; Dan, C.; Luo, J.; Ye, W.; Lin, B.; Zhang, D.; Liao, W. WO
2012010106, 2012.
tional
8 h. Analysis by HPLC (285 nm) revealed that
approximately 1% oripavine remained in the reaction mixture.
The reaction mixture (fine beige slurry) was cooled to r.t. and
filtered through a fine-fritted funnel. The residue was washed
with MeOH (1.5 mL), and the product precipitated after slow
addition of the filtrate to a vigorously stirred volume of toluene
(ca. 100 mL). After the precipitate was filtered and washed with
toluene (2 × 10 mL), it was dried under vacuum to provide a
slightly off-white solid in greater than quantitative yield. This
material was stirred in acetone (50 mL) at r.t. for 2 h prior to a
second filtration. The solid was collected and dried under
vacuum to yield 2.60 g (94% yield) of N-cyclopropylmethyl ori-
pavine ammonium bromide salt (7b) as a white, free-flowing
solid; mp 194–200 °C; isomeric ratio determined by HPLC (S/R =
2.6:1).
R-Isomer
20
Mp 219–221 °C (EtOH); Rf = 0.30 (CH2Cl2–MeOH, 5:1); [α]D
–109.38 (c 1, MeOH). H NMR (600 MHz, DMSO): δ = 9.37 (s, 1
1
H), 6.62 (d, J = 8.1 Hz, 1 H), 6.55 (d, J = 8.1 Hz, 1 H), 6.01 (d,
J = 6.6 Hz, 1 H), 5.42 (s, 1 H), 5.29 (d, J = 6.6 Hz, 1 H), 4.67 (d,
J = 7.2 Hz, 1 H) 3.71 (m, 1 H), 3.70 (m, 1 H), 3.61 (s, 3 H), 3.45
(dd, J = 13.5, 4.6 Hz, 1 H), 3.39 (dd, J = 13.7, 7.6 Hz, 1 H), 3.29
(ddd, J = 13.2, 13.2, 4.0 Hz, 1 H) 3.19 (s, 3 H), 3.06 (dd, J = 19.4,
7.2 Hz, 1 H), 2.59 (ddd, J = 14.1, 14.1, 5.1 Hz, 1 H), 1.86 (dd,
J = 14.2, 2.9 Hz, 1 H), 1.21 (m, 1 H), 0.75 (m, 2 H), 0.51 (m, 1 H),
0.44 (m, 1 H). 13C NMR (150 MHz, DMSO): δ = 154.6, 143.5,
140.4, 132.6, 124.1, 122.5, 120.2, 119.8, 117.6, 96.1, 87.2, 68.1,
67.1, 55.6, 54.0, 46.1, 44.2, 31.5, 30.4, 5.1, 4.4, 4.2.
(16) For the synthesis of (S)-methylnaltrexone, see: Wagoner, H.;
Sanghvi, S. P.; Boyd, T. A.; Verbicky, C.; Andruski, S. WO
2006127898, 2006.
(17) Wang, P. X.; Jiang, T.; Cantrell, G. L.; Bereberich, D. W. WO
2008118654 A1, 2008.
(18) For related work on thebaine, see: (a) López, D.; Quiñoá, D.;
Riguera, R. Tetrahedron Lett. 1994, 35, 5727. (b) Lopez, D.;
Quinoa, E.; Riguera, R. J. Org. Chem. 2000, 65, 4671.
S-Isomer
Mp 195–197 °C (MeOH–i-PrOH); Rf = 0.28 (CH2Cl2–MeOH, 5:1);
[α]D20 –43.73 (c 1.0, MeOH). 1H NMR (600 MHz, DMSO): δ = 9.37
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2101–2108

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(s, 1 H), 6.63 (d, J = 8.0 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 5.98 (d,
J = 6.6 Hz, 1 H), 5.39 (s, 1 H), 5.26 (d, J = 6.6 Hz, 1 H), 4.75 (d,
J = 6.9 Hz, 1 H), 3.77 (d, J = 19.6 Hz, 1 H), 3.64 (dd, J = 13.4, 6.1
Hz, 1 H), 3.60 (s, 3 H), 3.49 (dd, J = 13.4, 3.2 Hz, 1 H), 3.35 (m, 1
H), 3.29 (s, 3 H), 3.28 (m, 1 H), 3.06 (dd, J = 19.5, 7.0 Hz, 1 H),
2.56 (ddd, J = 14.0, 14.0, 4.5 Hz, 1 H), 1.79 (d, J = 11.9 Hz, 1 H),
1.21 (m, 1 H), 0.72 (m, 2 H), 0.52 (m, 1 H), 0.39 (m, 1 H). 13C
NMR (150 MHz, DMSO): δ = 154.6, 143.4, 140.4, 132.6, 124.1,
122.6, 120.2, 119.7, 117.6, 96.0, 87.3, 68.6, 63.9, 55.6, 54.0, 48.6,
for 10 min prior to warming to r.t. Monitoring of the reaction by
TLC (MeOH–EtOAc = 1:10) showed consumption of starting
material 35 min after addition of peracetic acid. The reaction
mixture at r.t. was diluted with i-PrOH (2.5 mL), then Pd/C (0.05
g, 10 wt%) was added, and the reaction mixture was subjected
to a hydrogen atmosphere (Parr shaker, 3.45 bar) for 15 h. The
mixture was filtered through a pad of Celite, which was subse-
quently washed with i-PrOH. AcOH was removed as an azeo-
trope with toluene prior to concentration to dryness. Naltrex-
one (0.51 g, 95% yield) was obtained after further drying under
vacuum; Rf = 0.55 (CHCl3–MeOH, 92:8); mp 167–169 °C [CHCl3,
lit.23 174–176 °C (acetone)]; [α]D20 –84.8 (c 1.0, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 6.73 (d, J = 7.6 Hz, 1 H), 6.59 (d, J = 7.6 Hz,
1 H), 5.66 (s, 2 H), 4.76 (s, 1 H), 3.22 (d, J = 5.6 Hz, 1 H), 3.12–
3.03 (m, 2 H), 2.73 (dd, J = 4.1, 11.6 Hz, 1 H), 2.58 (dd, J = 5.8,
18.6 Hz, 1 H), 2.52–2.30 (m, 4 H), 2.16 (td, J = 5.9, 3.0 Hz, 1 H),
1.92 (d, J = 12.0 Hz, 1 H), 1.75–1.50 (m, 3 H), 0.87 (m, 2 H), 0.56
(d, J = 7.4 Hz, 2 H), 0.16 (d, J = 4.4 Hz, 2 H).
43.7, 31.3, 30.6, 4.9, 4.6, 4.3. MS–FAB+: m/z (%) = 55 (31), 98 (24),
+
112 (38), 239 (12), 352 (100). HRMS: m/z calcd for C22H26N03
352.1907; found: 352.1898.
:
N-Cyclopropylmethyl Nororipavine (8)
To a slurry of NaOt-Bu (0.88 g, 9.20 mmol) in freshly distilled
DMSO (6 mL) was added tert-dodecanethiol (1.86 g, 9.20 mmol,
distilled) in one portion. The vigorously stirred mixture was
purged with argon for 3 min. The flask was immersed in a 90 °C
oil bath for 10 min, then the oil bath (and the mixture) was
allowed to cool to 80 °C. A solution of N-cyclopropylmethyl ori-
pavine ammonium bromide (7b, 1.32 g, 3.07 mmol; R/S ratio =
66:34) in DMSO (6 mL) at r.t. was added to the preformed
mixture of tert-dodecanethiolate in DMSO at 80 °C over 10 min.
A sharp color change from a clear, slightly yellow solution to a
black-colored mixture occurred after the addition of the first
few drops of the N-cyclopropylmethyl oripavine ammonium
bromide solution. The reaction mixture was stirred at 80 °C for
45 min following the addition and monitored by HPLC (285
nm). After complete consumption of starting material the reac-
tion mixture was allowed to cool to r.t. with stirring, then it was
poured into H2O (80 mL). The pH of the aqueous mixture was
adjusted to pH 2 with HCl (6 M) and washed with hexanes
(1 × 20 mL, 1 × 10 mL). The pH of the aqueous mixture (milky
yellow suspension) was readjusted to pH 8 with NaOH (aq, 15%).
The fine, white precipitate was observed upon pH adjustment
and dissolved upon extraction with EtOAc (1 × 20 mL, 1 × 15
mL). The pH of the aqueous phase was adjusted again to pH 8
(white precipitate was observed) and extracted with EtOAc
(3 × 10 mL). The organic layers were combined and washed
with H2O (1 × 10 mL) and brine (1 × 10 mL), then dried over
MgSO4, filtered, and concentrated to provide crude material,
which was crystallized from acetone–cyclohexane mixture
(1:1) to afford 0.61 g (59% yield) of N-cyclopropylmethyl norori-
pavine (8) as a pale-yellow crystalline solid. Column chroma-
tography (MeOH–EtOAc, 1:5) of mother liquor afforded 0.07 g
(6% yield) of title compound. Rf = 0.25 (MeOH–EtOAc, 1:5); mp
General Procedure for the Photooxygenation Reactions18
To a solution of the quaternized morphine alkaloid (0.25–0.30
mmol) in CH2Cl2–MeOH (4:1, 8 mL) in a double-glass wall mini
reactor was added tetraphenylporphyrin (0.02 g). Oxygen was
bubbled through the reaction mixture for 4 h, while irradiated
from a distance of 30 cm with a street lamp (500 W) at a reac-
tion temperature of 5–15 °C. The strongly colored solution was
transferred to an Erlenmeyer flask, and the corresponding
endoperoxide was precipitated by the addition of Et2O. The
slightly purple solid was dissolved in MeOH and precipitated
with Et2O to afford the endoperoxide as slightly colored solid.
Because of the instability of the endoperoxide intermediates,
only 1H NMR data were obtained.
General Procedure for the Reduction of Endoperoxide Inter-
mediates
To a solution of the endoperoxide intermediate (0.20–0.30
mmol) dissolved in a mixture of H2O–i-PrOH–formic acid
(1:1:1, 2.4 mL) was added Pd/C (10%, 10 wt%). The reaction
mixture was flushed three times with H2 and then stirred at 1
atm of H2 for 24 h. The suspension was filtered through a short
plug of Celite, and the plug was washed with MeOH. The filtrate
was concentrated in vacuo, and the residue was lyophilized.
Flash column chromatography on silica (eluent CH2Cl2–MeOH,
9:1) provided the corresponding product.
Methylnaltrexone Bromide (5b)
A. From Chloride Salt by Ion Exchange
Compound 5a (0.05 g, 0.13 mmol) dissolved in a minimum
amount aq MeOH (H2O–MeOH, 3:1), and the solution was fil-
tered through a column packed with Dowex®-1 resin (Sigma,
strongly basic bromine loaded, 50–100 mesh) and eluted with
distilled H2O (400 mL). The majority of the solvent was removed
under reduced pressure, then the residue was lyophilized to
give the title compound 5b as a white solid (0.054 g, 98%). 1H
NMR and 13C NMR spectra were identical to the spectra
20
165–166 °C (CH2Cl2), 166–167 °C (MeOH); [α]D –168.60 (c 1,
CHCl3). IR (KBr): ν = 3445, 2908, 1630, 1458, 1234, 1046, 1016,
926, 868 cm–1. 1H NMR (600 MHz, CDCl3): δ = 6.65 (d, J = 8.4 Hz,
1 H), 6.55 (d, J = 8.4 Hz, 1 H), 5.59 (d, J = 6.6 Hz, 1 H), 5.29 (s, 1
H), 5.07 (d, J = 6.6 Hz, 1 H), 4.02 (d, J = 6.6 Hz, 1 H), 3.61 (s, 3 H),
3.29 (d, J = 18.0 Hz, 1 H), 3.00 (dd, J = 12.6, 4.2 Hz, 1 H), 2.90 (m,
1 H), 2.76 (dd, J = 18.0, 7.2 Hz, 1 H), 2.55 (m, 2 H), 2.24 (m, 1 H),
1.71 (d, J = 11.4 Hz, 1 H), 0.97 (m, 1 H), 0.56 (d, J = 8.4 Hz, 2 H),
0.19 (d, J = 8.4 Hz, 2 H). 13C NMR (150 MHz, CDCl3): δ = 152.2,
143.1, 138.8, 133.2, 132.6, 126.7, 119.7, 116.5, 112.1, 96.4, 89.4,
58.6, 58.6, 55.0, 46.8, 43.8, 36.2, 31.2, 9.2, 3.9 (2 × CH2). MS (EI+):
m/z (%) = 43 (100), 58(19), 84 (56), 227 (8), 282 (12), 337 (41).
HRMS: m/z calcd for C21H23NO3: 337.1678; found: 337.1681.
Naltrexone (1)
of 5b obtained from compound 11b. MS–FAB+: m/z
= 793
[(C21H26NO4)2Br]+.
B. By Reduction of Endoperoxide 11b
Following the general procedure for the reduction of endoper-
oxide intermediates, compound 11b (0.10 g, 0.22 mmol) yielded
methylnaltrexone bromide salt 5b as a colorless solid (0.08 g,
74%). MS–FAB+: m/z = 793 [(C21H26NO4)2Br]+.
A solution of N-methylcyclopropyl nororipavine (8, 0.52 g, 1.52
mmol) in H2O–AcOH (1:1 v/v) was chilled to 5 °C with stirring.
A solution of peracetic acid (0.40 g, 1.67 mmol; 32 wt%) in AcOH
was added dropwise over 2 min. The mixture was stirred at 5 °C
C. By Reduction of Enone 12b
To a solution of the enone 12b (0.20 g, 0.46 mmol) dissolved in
MeOH (3 mL) was added Pd/C (0.02 g; 10 wt%). The reaction
mixture was hydrogenated in Parr shaker at 40 psi for 12 h. The
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suspension was filtered through a short plug of Celite, and the
plug was washed with MeOH. The evaporation of MeOH fur-
nished 0.19 g of essentially pure product (checked by HPLC and
by 1H NMR).
(22) (a) Loponov, K. N.; Lopes, J.; Barlog, M.; Astrova, E. V.; Malkov, A.
V.; Lapkin, A. A. Org. Process Res. Dev. 2014, 18, 1443.
(b) Levesque, F.; Seeberger, P. H. Org. Lett. 2011, 13, 5008.
(23) Valiveti, S.; Paudel, K. S.; Hammel, D. C.; Hamad, M. O.; Chen, J.;
Crooks, P. A.; Stinchcomb, L. A. Pharmaceut. Res. 2005, 22, 981.
(21) (a) Turconi, J.; Griolet, F.; Guevel, R.; Oddon, G.; Villa, R.; Geatti,
A.; Hvala, M.; Roen, K.; Göller, R.; Burgard, A. Org. Process Res.
Dev. 2014, 18, 417. For an older report on the use of photochem-
istry in industry, see: (b) Fischer, M. Angew. Chem., Int. Ed. Engl.
1978, 17, 16.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2101–2108