Unexpected N-demethylation of oxymorphone and oxycodone N-oxides mediated by the burgess reagent: Direct synthesis of naltrexone, naloxone, and other antagonists from oxymorphone

Article abstract of DOI:10.1002/adsc.201200676

N-Oxides derived from oxycodone and O-acyloxymorphone were treated with the Burgess reagent to provide the corresponding oxazolidines in excellent yields. Oxazolidines derived from Oacyloxymorphone were further hydrolyzed to noroxymorphone, whose alkylation furnished naltrexone, naloxone, and nalbuphone, which can be converted to nalbuphine, the mixed agonist-antagonist analgesic. The entire sequence from oxymorphone to the various antagonists was reduced to three one-pot operations, proceeding in excellent overall yields. In addition, quaternary salts of the oxazolidines with allyl or cyclopropylmethyl groups in fixed equatorial configurations were synthesized. Complete spectral and experimental data are provided for all compounds.

Full text of DOI:10.1002/adsc.201200676

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DOI: 10.1002/adsc.201200676
Unexpected N-Demethylation of Oxymorphone and Oxycodone
N-Oxides Mediated by the Burgess Reagent: Direct Synthesis
of Naltrexone, Naloxone, and Other Antagonists from
Oxymorphone
Lukas Werner,a Martina Wernerova,a Ales Machara,a Mary Ann Endoma-Arias,a
Jan Duchek,a David R. Adams ,a D. Phillip Cox,b and Tomas Hudlickya,*
a
Chemistry Department and Centre for Biotechnology, Brock University, 500 Glenridge Avenue, St. Catharines, Ontario
L2S3A1, Canada
E-mail: thudlicky@brocku.ca
Noramco, Inc., 503 Carr Road, Suite 200, Wilmington, DE 19809, USA
b
Received: July 30, 2012; Published online: October 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200676.
Abstract: N-Oxides derived from oxycodone and
O-acyloxymorphone were treated with the Burgess
reagent to provide the corresponding oxazolidines
in excellent yields. Oxazolidines derived from O-
acyloxymorphone were further hydrolyzed to nor-
oxymorphone, whose alkylation furnished naltrex-
one, naloxone, and nalbuphone, which can be con-
verted to nalbuphine, the mixed agonist-antagonist
analgesic. The entire sequence from oxymorphone
to the various antagonists was reduced to three
one-pot operations, proceeding in excellent overall
yields. In addition, quaternary salts of the oxazoli-
dines with allyl or cyclopropylmethyl groups in
fixed equatorial configurations were synthesized.
Complete spectral and experimental data are pro-
vided for all compounds.
Various morphine antagonists[1] such as naltrexone
(1),[2] naloxone (2),[3,4] and nalbuphone (3) are avail-
able by semi-synthesis from the natural opiates such
as morphine (4), codeine (5), thebaine (6), or oripa-
vine (7), (see Figure 1). These compounds are used
extensively in medicine as antagonists (naltrexone
and naloxone) and mixed agonists/antagonists (nalbu-
phine). Naltrexone has long been used for the treat-
ment of alcoholism,[5,6] and is the active ingredient in
Vivitrolꢀ, an extended release injectable suspension
for the treatment of alcoholism and opioid depend-
ence.[7] Naloxone is the active ingredient in Narcanꢀ
for the reversal of opioid overdose[8,9] and is used to
mitigate side effects in combination with buprenor-
phine[10] (Suboxoneꢀ)[11] for the treatment of opioid
addiction, with tilidine[12] (Valoron Nꢀ) for the treat-
ment of pain and with oxycodone[13] (Targinꢀ)[14] for
the prophylaxis and/or treatment of opioid-induced
bowel dysfunction during the treatment of pain. Nal-
buphine[15] is the active ingredient in Nubainꢀ and is
used for the treatment of pain in very low doses par-
ticularly in women.
Keywords: Burgess reagent; N-demethylation of
oxycodone and oxymorphone; N-oxides of oxyco-
done and oxymorphone; synthesis of naltrexone,
naloxone, and nalbuphone
Figure 1. Semi-synthetic opiate derivatives and their natural progenitors.
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Unexpected N-Demethylation of Oxymorphone and Oxycodone N-Oxides
Their synthesis from naturally occurring opiates re- tested in a variety of ways with other functional
quires several steps consisting of the oxidation of the groups. The synthesis of cis-fused sulfamidates was ac-
C-14 position and the eventual, seemingly trivial oper- complished by the reaction of the Burgess reagent
ation, the replacement of an N-methyl group with cy- with epoxides[25] and 1,2-diols.[26] The Burgess reagent
clopropylmethyl, allyl, or cyclobutylmethyl and other was shown to oxidize thiols to disulfides in high
alkyl groups, respectively.
yields.[27] New applications[28] as well as more thermal-
The introduction of the C-14 hydroxy into various ly stable forms of this reagent[29] are being reported,
natural morphinans to produce oxycodone (8) and including its chiral auxiliary version,[30] and the re-
oxymorphone (9) has been reduced to practice on agent has been used extensively in natural product
large scales with high degrees of efficiency by oxida- syntheses.[31]
À
tion of thebaine or oripavine. Methods for direct C
We examined the reaction of oxycodone N-oxide
H oxidation at C-14 for compounds such as codeine, 10, derived from oxycodone, with the Burgess reagent
morphine, or hydrocodone have been reported but and found a clean conversion to oxazolidine 12 in sig-
are not very efficient or practical at this time. On the nificantly higher yield than that quoted in the Smith
other hand, N-demethylation of natural opiates still procedure, as shown in Scheme 1.
represents a challenge, especially in terms of efficien-
Presumably, the intermediate iminium species 11 is,
cy or the focus on environmentally benign procedures in the absence of a nucleophile, trapped, by the C-14
and reagents. Many methods have been employed for hydroxy group to form the oxazolidine. Such a process
the demethylation; these include the use of cyanogen would represent the (formally) forbidden 5-endo-trig
bromide (von Braun reaction),[17] methyl or ethyl closure. An alternative to this closure would be trap-
chloroformate,[18] 1-chloroethyl chloroformate (ACE- ping of the iminium species with triethylamine and
Cl),[19] and microbial protocols,[20] including a recently a subsequent SN2-type alkylation, as shown below in
published procedure employing fungal biotransforma- Scheme 2.[32]
tions.[21] The biotransformations of several morphine
This was a somewhat unexpected result, especially
alkaloids with the strain Cunninghamella echinulata in view of the recent report by Scammells, in which
and several others produced the free amines in rea- 11 was proposed as an intermediate in the ferrocene-
sonable yields and purity. Such processes, when scaled catalyzed demethylation of N-oxide 10.[33] In that
up and improved, would have great potential as envi- report nor-oxycodone was produced in 32% yield
ronmentally benign N-demethylation protocols.
with 23% recovery of oxycodone. No oxazolidine for-
Recently, iron(II)- as well as iron(0)-catalyzed N- mation was mentioned and formaldehyde was as-
demethylation of several morphinan N-oxides was re- sumed to be the by-product of hydrolysis of 11. The
ported by Scammells.[22] Smith et al.[23] developed oxazolidine should have been observed under the
a method to convert N-methylated 6-oxo-14-hydroxy- conditions of the reaction, corresponding to the re-
morphinanes to the corresponding nor compounds by sults reported by Smith but perhaps it was hydrolyzed
treating the N-oxide with an Fe(II)-based reducing in situ and hence escaped detection.
agent in the presence of formic acid to form an oxa-
Presumably, with the Burgess reagent the initial sul-
zolidine. Conversion of the N-oxide to the corre- fonation occurs at the site of N-oxide and not at the
sponding oxazolidine works equally well irrespective C-14 hydroxy group, which then serves to either trap
of whether the 7,8 carbon bond is unsaturated or satu-
rated. Despite a host of methods available in the liter-
ature and in patents to accomplish this task there still
exists the need for an efficient conversion of various
morphinans to the medicinally important antagonists
as well as to other N-alkyl derivatives some of which
also have increased agonist activities.
Because the conversion of natural opiates to their
C-14 hydroxy derivatives is well established it would
be convenient to provide a direct conversion of oxy-
morphone to the corresponding antagonists via N-de-
methylation and alkylation. In this paper we report
a rather unexpected reaction of the Burgess reagent[24]
with N-oxides derived from oxymorphone and oxyco-
done to the corresponding oxazolidines and a high-
yielding conversion of the former compound to nal-
trexone, naloxone, and other antagonists.
The reactivity of the Burgess reagent, long associat-
ed only with the dehydration of alcohols, has been Scheme 1.
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Scheme 2.
the iminium ion or displace the triethylammonium used) and the protected material was converted to N-
salt as shown above. However, the C-14 hydroxy oxides 13a and 13b, whose exposure to the Burgess
group may play some role in anchimeric assitance or reagent provided in high overall yields oxazolidines
delivery of the reagent to the N-oxide. Attempts to 15a (89–93%, 78% after crystallization) and 15b
generate the iminium species of type 11 (and thus no- (84%), Scheme 3.
rhydrocodone) from hydrocodone N-oxide with the
Hydrolysis of the acetate or carbonate-protected
Burgess reagent were not successful. The procedure is products 15a, b under either acidic or basic buffered
easily reduced to a one-pot protocol providing 12 as conditions furnished cleanly the free phenol (noroxy-
a hygroscopic solid that can be used without further morphone) 16, which was alkylated to the known an-
purification.
tagonists as shown in Scheme 4. The entire process
The same protocol was applied to oxymorphone from oxymorphone to naltrexone or naloxone can be
(9), a more convenient starting material for the pro- performed in just three operations (without purifica-
duction of various antagonists and other N-alkyl de- tion of intermediates) in an overall yield of 55–65%.
rivatives. The phenol was protected as either acetate
Finally, we have converted oxazolidine 12, derived
(Ac2O was used) or ethyl carbonate (EtOCOCl was from oxycodone, to the quaternary salts 17 and 18
(allyl and cyclopropylmethyl, respectively). The prep-
aration of the cyclopropylmethyl salt 18 required ele-
vated temperature and DMF as the solvent. Oxazoli-
dine 15a was converted to the quaternary salts 19, 20,
and 21, respectively, as shown in Scheme 4. The alky-
lation with allyl bromide was carried out in nitrome-
thane and produced the quaternary salts 17 and 19 in
high yields. When cyclopropylmethyl bromide was
employed under these conditions only 22, the product
resulting from the opening of the oxazolidine ring
with nitromethane, was observed. The corresponding
derivative 20, containing the cyclopropylmethyl
group, was obtained in ca. 50% yield when the reac-
tion was carried out at elevated temperature in DMF
instead of nitromethane. The remaining mass balance
likely consisted of the hydrobromide of oxazolidine
15a. The cyclobutylmethyl derivative 21 could, in
principle, be obtained by a similar protocol.
Mild hydrolysis of 19 and 20 in aqueous methanol
or on wet silica gel furnished the corresponding oxa-
Scheme 3.
Scheme 4.
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Unexpected N-Demethylation of Oxymorphone and Oxycodone N-Oxides
Scheme 5.
zolidine quaternary salts 23 and 24 in ca. 80% yield. hydrolysis of the salt 20 (Scheme 5). The results of
The compounds appeared to be bromide salts (vide these and other endeavors will be reported in due
mass spectral analysis) although the possibility, during time.
the basic hydrolysis of the acetates, of ion exchange
We have demonstrated that a high-yielding method
for hydroxide and hence the equilibrium formation of for the N-demethylation of oxycodone and oxymor-
the inner salts of type 26 should be considered. All of phone N-oxides becomes available by the reaction of
the salts have the alkyl substituent fixed in the equa- the N-oxides with the Burgess reagent. Several other
torial position, as, for example, in the conformation of potential N-demethylating agents were examined for
(R)-methylnaltrexone. To the best of our knowledge this purpose but none were found to be more effec-
compounds of this type in which the C-14 hydroxy is tive than the Burgess reagent. Thus oxycodone N-
alkylated have not been investigated in detail for an- oxide yielded oxazolidine 12 also on treatment with
tagonist/agonist activity. Further exploitation of the TsCl (30%), CrO3 (44%) and DCC (50%). Treatment
chemistry described in this paper will involve the con- of the N-oxide with CS2 or SeO2 resulted only in its
version of quaternary salts such 20 or 24 directly into re-conversion to oxycodone.
(R)-methylnaltrexone by a reduction of the oxazoli-
dine bridge to a methyl group.
The potential of this newly discovered reactivity of
the Burgess reagent in an improved manufacture of
In preliminary experiments we attempted the re- opiate antagonists was demonstrated with the high-
duction of the quaternary salt 20 under a variety of yielding synthesis of naloxone and naltrexone from
conditions, including the activation of the C-14 oxymorphone. Finally, this work provides a unique
oxygen with Lewis acids. We observed only the C-14 opportunity for the future exploration of biological
methyl ether 27 rather than (R)-methylnaltrexone, as properties of the quaternary salts derived from the
shown in Scheme 5. Clearly additional, and more de- oxazolidines.
tailed, investigation is required in order to elicit the
cleavage of 20 to produce the desired quaternary salt.
Finally, we should compare the efficacy of this nal-
trexone synthesis by hydrolysis of oxazoline 15b and
alkylation of 16 versus the quaternization of 15a and
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1H NMR (CDCl3, 600 MHz): d=6.90 (d, 1H, J=8.2 Hz),
6.76 (d, 1H, J=8.4 Hz), 4.73 (d, 1H, J=6.0 Hz), 4.70 (d,
1H, J=6.0 Hz), 4.69 (s, 1H), 3.37 (d, 1H, J=19.2 Hz), 3.27
(d, 1H, J=7.8 Hz), 3.17 (dd, 1H, J=7.8, 19.2 Hz), 2.89
(ddd, 1H, J=4.8, 14.4, 14.4 Hz), 2.80 (m, 2H), 2.45–2.30 (m,
5H), 1.98 (ddd, 1H, J=3.3, 4.2, 13.8 Hz), 1.67 (ddd, 1H, J=
3.1, 14.4, 14.4 Hz), 1.56 (m, 1H); 13C NMR (CDCl3,
150 MHz): d=206.36, 168.57, 147.49, 132.45, 129.76, 128.65,
123.49, 119.97, 91.25, 86.53, 77.00, 63.95, 52.40, 44.23, 37.09,
34.09, 30.28, 27.13, 20.83; MS (+EI): m/z (%)=341 (8), 299
(100), 243 (7); HR-MS (+EI): m/z=341.12606, calcd. for
C19H19N1O5: 341.12632.
Experimental Section
3-Acetyloxymorphone N-Oxide (13a)
Oxymorphone (9) (600 mg, 1.99 mmol) was dissolved in tet-
rahydrofuran (8 mL). Solid K2CO3 (275 mg, 1.99 mmol) and
acetic anhydride (188 mL, 1.99 mmol) were then added and
reaction mixture was stirred at room temperature for 1.5 h.
TLC analysis (DCM/MeOH 95:5, double development)
showed only traces of starting material. The crude material
was subjected to the oxidation protocol without isolation
and furnished N-oxide 13a as a solid: [a]2D0: À189.33 (c 1,
CHCl3); mp 1608C (CHCl3); IR (KBr): n=3449, 2968, 2938,
1764, 1726, 1685, 1654, 1627, 1495, 1444, 1373, 1287, 1219,
Noroxymorphone (16)
1193, 1161, 1111, 1044, 931, 629 cmÀ1; H NMR (CDCl3, 300
1
Mhz): d=12.25 (bs, 1H) 6.91 (d, 1H, J=8.4 Hz), 6.72 (d,
1H, J=8.1 Hz), 4.80 (s, 1H), 3.60 (d, 1H, J=5.1 Hz), 3.36–
3.03 (m, 9H), 2.31 (s, 3H), 2.23 (td, 1H, J=3.0, 14.7 Hz),
1.96 (ddd, 1H, J=3.0, 4.8, 12.6 Hz), 1.71 (dd, 1H, J=3.9,
11.4 Hz), 1.58 (ddd, 1H, J=3.6, 14.1, 14.1 Hz); 13C NMR
(CDCl3, 75 MHz): d=206.97, 168.31, 148.23, 133.53, 129.93,
125.90, 124.10, 119.84, 90.15, 75.44, 72.14, 61.51, 59.49, 49.77,
34.84, 32.62, 28.94, 25.82, 20.74; MS (FAB+): m/z (%)=360
(100), 342 (20); HR-MS (FAB+): m/z=360.14441, calcd.
for C19H22N1O6: 360.14471.
A. Acetic acid buffer: Oxazolidine 15a (0.1 g, 0.29 mmol)
was suspended in AcOH/NH3 buffer (pH 9, 10% w/w,
1.5 mL) and heated for 16 h at 508C. The reaction mixture
was then cooled to room temperature and stirred for an ad-
ditional 2 h. A light brown precipitate was filtered off and
dried to afford noroxymorphone 16 as a brownish solid;
yield: 69 mg (82%); mp>3008C (lit>3008C).[34]
B. Ammonium carbonate buffer: Oxazolidine 15a (0.2 g,
0.57 mmol) was suspended in NH4HCO3/NH3 buffer (pH 9,
10% w/w, 1 mL) and heated for 16 h at 508C. The reaction
mixture was then cooled to room temperature and stirred
for an additional 2 h. The light brown precipitate was fil-
tered and dried to afford noroxymorphone 16 as a brownish
solid; yield: 131 mg (78%); mp>3008C.
(5aR,8aS,11aR,11bS)-2-Acetoxy-5,5a,9,10-tetrahydro-
6,11b-ethano-7H-furo[2’,3’,4’,5’:4,5]phenanthro
ACHTUNGTRNE[NUNG 9,8a-
d]oxazol-11(11aH)-one (15a): One-Pot Protocol
ACHTUNGTRENNUNG
Naltrexone (1)
Oxymorphone (9) (600 mg, 1.99 mmol) was dissolved in tet-
rahydrofuran (8 mL). Solid K2CO3 (275 mg, 1.99 mmol) and
acetic anhydride (188 mL, 1.99 mmol) were then added and
the reaction mixture was stirred at room temperature for
1.5 h. TLC analysis (DCM/MeOH 95:5, double develop-
ment) showed only traces of starting material. The reaction
mixture was then cooled to approximately 48C (ice bath)
and a cold (48C) solution of mCPBA (446 mg, 1.99 mmol;
77% purity) in dichloromethane (6 mL) was added dropwise
over a period of 1 min. [The solution of mCPBA was pre-
pared by dissolving 669 mg mCPBA (77%) in dichlorome-
thane (9 mL) and adding MgSO4 (670 mg). The mixture was
agitated several times over a period of 30 min and cooled in
an ice-bath to 48C]. After stirring for 1 h a white precipitate
of N-oxide formed and the reaction mixture was cooled to
À208C. Burgess reagent (593 mg, 2.49 mmol) in dichlorome-
thane (7 mL) was then cannulated at À208C into the reac-
tion mixture over a period of 2 min. The reaction mixture
was allowed to warm to 108C (3 h total reaction time) and
then diluted with ethyl acetate (100 mL) and washed with
an aqueous NaHCO3 solution (2ꢂ20 mL). The combined
aqueous layer was re-extracted with ethylacetate (2ꢂ20 mL)
and the combined organic layers were dried over MgSO4,
filtered, and concentrated to afford of reasonably pure (92–
95%) 15a; yield: 636 mg (93%). Crystallization of the prod-
uct from a mixture of EtOH/i-PrOH (1:1, 2 mL) from 258C
to 5–108C, afforded 520 mg (76%) of 15a. Repetition of the
experiment on a 1-g scale yielded 15a (78%) as a solid. Rf =
0.7 (DCM/MeOH/NH4OH 90:8:2); [a]2D0: À84.1 (c 1,
CHCl3); mp 179–1828C (i-PrOH); IR (KBr): n=2954, 2892,
2864, 2834, 1765, 1722, 1624, 1494, 1445, 1370, 1339, 1317,
Cyclopropylmethyl bromide (64 mg, 0.479 mmol) and Et3N
(45 mL, 0.327 mmol) were added to a suspension of noroxy-
morphone 16 (100 mg, 0.348 mmol) in a mixture of N-
methyl-2-pyrrolidinone/H2O (10:1 v/v, 0.35 mL). The reac-
tion vessel was purged with argon and the mixture stirred at
708C for 2 h. After 2 h additional Et3N (45 mL, 0.327 mmol)
was added and the mixture was stirred for additional 6 h at
708C. The reaction mixture was then cooled to room tem-
perature, diluted with dichloromethane (15 mL) and washed
with aqueous saturated NaHCO3 (3ꢂ3 mL). The aqueous
layer was re-extracted with dichloromethane (5 mL) and the
combined organic layers were dried over MgSO4. Column
chromatography of the residue (DCM/MeOH 4:1) afforded
naltrexone (1) as a white solid; yield: 103 mg (87%); mp
173–1758C (acetone); mp 159–1618C (MeOH). [lit. mp 174–
1768C (acetone)[35]]; the material was identical in all re-
spects to the material described in the literature.[36] Rf =0.42
(EtOAc/MeOH 4:1); [a]2D0: À207.00 (c 1, CHCl3); IR
(CHCl3): n=3568, 3359, 3010, 2931, 2834, 1723, 1620, 156,
1
1317, 1146, 1058, 943 cmÀ1; H NMR (600 MHz, CDCl3): d=
6.74 (d, J=8.1 Hz, 1H), 6.60 (d, J=8.1 Hz, 1H), 5.82 (bs,
1H, OH), 4.74 (s, 1H), 3.21 (d, J=5.9 Hz, 1H), 3.11–3.03
(m, 2H), 2.72 (dd, J=12.0, 4.8 Hz, 1H), 2.58 (dd, J=18.4,
6.0 Hz, 1H), 2.49–2.39 (m, 3H), 2.34 (ddd, J=14.5, 3.0,
3.0 Hz, 1H), 2.18 (ddd, J=12.2, 3.8, 3.8 Hz, 1H), 1.91 (m,
1H), 1.66 (ddd, J=14.2, 14.2, 3.3 Hz, 1H), 1.59 (ddd, J=
12.8, 2.7 Hz, 1H), 0.88 (m, 1H), 0.57 (m, 2H), 0.16 (m, 2H);
13C NMR (150 MHz, CDCl3): d=210.02, 142.51, 138.80,
129.05, 124.25, 119.90, 117.91, 90.60, 70.32, 62.01, 59.21,
51.07, 43.60, 36.21, 31.36, 30.65, 22.62, 9.42, 4.02, 3.81; MS
(+EI): m/z (%)=47 (15), 55 (41), 84 (100), 110 (12), 202
1216, 1201, 1185, 1158, 1073, 1009, 958, 930, 889, 781 cmÀ1
;
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Unexpected N-Demethylation of Oxymorphone and Oxycodone N-Oxides
(5), 256 (12), 286 (7), 300 (15), 341 (64); HR-MS: m/z=
Acknowledgements
341.16320, calcd. for C20H23NO4: 341.1627.
The authors are grateful to the following agencies for finan-
cial support of this work: Noramco, Inc., Natural Sciences
and Engineering Research Council of Canada (NSERC)
(Idea to Innovation and Discovery Grants), Canada Research
Chair Program, Canada Foundation for Innovation (CFI),
Research Corporation, TDC Research, Inc., TDC Research
Foundation, Brock University, and the Ontario Partnership
for Innovation and Commercialization (OPIC). We also
thank Dr. Thomas Bader, Dr. Alfred Stutz, Dr. Harald Hof-
meier, and Dr. Hansueli Bichsel, Labor fuer Prozess For-
schung, University of Zurich, for providing their procedure
for N-alkylation of nor-morphinans.
Naloxone (2)
Allyl bromide (56 mg, 0.463 mmol) and Et3N (45 mL,
0.327 mmol) were added to a suspension of noroxymor-
phone 16 (100 mg, 0.348 mmol) in a mixture of N-methyl-2-
pyrrolidone/H2O (10:1 v/v, 0.35 mL). The reaction vessel
was purged with argon and the mixture was stirred at 708C
for 2 h. At that time additional Et3N (45 mL, 0.327 mmol)
was added and the mixture was stirred for additional 7.5 h
at 708C. The reaction mixture was then cooled to room tem-
perature, diluted with dichloromethane (15 mL), and
washed with aqueous saturated NaHCO3 (3ꢂ3 mL). The
aqueous layer was re-extracted with dichloromethane
(5 mL) and the combined organic layers were dried over
MgSO4. Column chromatography of the crude material
(DCM/MeOH 4:1) afforded naloxone (2) as a white solid;
yield: 96 mg (84%); mp 181–1828C (ethyl acetate). [lit. mp
173-À1758C,[37] 179.58C (toluene)[38]]. The material was
identical in all respects to the material described in the liter-
ature.[39]
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Nalbuphone (3)
A slurry of noroxymorphone 16 (220 mg, 0.766 mmol),
sodium hydrogen carbonate (77 mg, 0.92 mmol), cyclobutyl-
methyl bromide (160 mg, 1.07 mmol) and N-methyl-2-pyrro-
lidone (1 mL) was stirred under a nitrogen atmosphere at
908C for 19 h. The reaction mixture was cooled and
quenched with water (10 mL). The quenched reaction mix-
ture pH was adjusted to pH 9 and the product was extracted
with dichloromethane (3ꢂ5 mL). The combined organic
layers were washed with water, brine and dried over
MgSO4. Column chromatography afforded nalbuphine (3)
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1
8.0 Hz, 1H), 6.61 (d, J=8.0 Hz, 1H), 5.64 (bs, 1H, OH),
4.72 (s, 1H), 3.11 (d, J=18.4 Hz, 1H), 3.04 (ddd, J=14.4,
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m/z (%)=41 (27), 69 (9), 98 (5), 300 (88), 355 (38), 356
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Adv. Synth. Catal. 2012, 354, 2706 – 2712