A simple and practical method for the oxidation of thebaine to 14-hydroxycodeinone by V2O5-H2O2

Article abstract of DOI:10.1055/s-0028-1088007

An efficient, practical and expeditious method has been developed for the oxidation of thebaine to 14-hydroxycodeinone in excellent yield by employing 20 mol% of V₂O₅ in the presence of 30% H₂O ₂ in aqueous medium. The method provides a clean technological process for the preparation of a key drug intermediate, 14-hydroxycodeinone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088007

1062
SHORT PAPER
A Simple and Practical Method for the Oxidation of Thebaine to
14-Hydroxycodeinone by V2O5–H2O2
Oxidation of
T
a
hebaine to
i
14-H
y
k
ane t Das Sharma, Dilip Konwar*
Synthetic Organic Chemistry Division, North East Institute of Science & Technology (Formerly Regional Research Laboratory, Jorhat),
Jorhat 785006, Assam, India
Fax +91(376)2370011; E-mail: dkonwar@yahoo.co.uk
Received 10 November 2008; revised 26 November 2008
HO
HO
MeO
Abstract: An efficient, practical and expeditious method has been
developed for the oxidation of thebaine to 14-hydroxycodeinone in
excellent yield by employing 20 mol% of V2O5 in the presence of
30% H2O2 in aqueous medium. The method provides a clean tech-
nological process for the preparation of a key drug intermediate, 14-
hydroxycodeinone.
O
O
O
N
N
NMe
OH
OH
OH
O
O
O
Key words: 14-hydroxycodeinone, thebaine, vanadium pentoxide,
hydrogen peroxide, catalytic oxidation
oxycodone (1)
naltrexone (2)
naloxone (3)
MeO
MeO
O
The development of efficient methods for the synthesis of
opioid derivatives which have pain-relieving properties
and are devoid of side effects, such as addiction, has been
a strong challenge to organic chemists.1 The introduction
of the 14-hydroxyl group onto the morphine alkaloid
structure improves its pharmacological properties. Many
such derivatives are clinically used as analgesic and anti-
tussive agents, and for the treatment of opiate abuse, opi-
ate overdose and alcohol addiction. For example,
oxycodone (Eucodal; 1) is finding increasing application
as an analgesic and antitussive agent,2a whereas naltrex-
one (2) and naloxone (3) are used to treat opiate abuse,2b
opiate overdose2c and alcohol addiction.2d 14-Hydroxyco-
deinone (4) is the key 14-hydroxylated intermediate for
the synthesis of these drug molecules (Figure 1).
O
NMe
NMe
OH
MeO
O
14-hydroxycodeinone (4)
thebaine (5)
Figure 1
deinone salt in 61% yield.4e 14-Hydroxycodeinone can
also be obtained in high yield (90%) from thebaine bi-
tartrate monohydrate, but the preparation of the starting
material from codeine phosphate hemi-hydrate requires
multi-step reacions.4f The synthesis of 14-hydroxyco-
deinone can also be achieved by the oxidation of codein-
one or codeine. For example, the oxidation of codeinone
by Co(OAc)3 in AcOH furnished 14-hydroxycodeinone in
51% yield,4g whereas oxidation by MnSO4 in the presence
of sodium thiosulfate afforded 14-hydroxycodeinone in
85% yield.4h In addition to these methods, Madyastha et
al.4i carried out a microbial transformation of codeine into
14-hydroxycodeinone by employing Bacillus sp. in 53%
yield accompanied by the formation of 14-hydroxyco-
deine as a side product (yield 9%).
These reported methods suffer from low yields,4a–e,g,i
harsh reaction conditions,4a–c use of toxic4a and stoichio-
metric amount of reagents,4b–d,f,g formation of byprod-
ucts,4a–c,i use of acids,4a–g long reaction times4a–c,f–h and the
need for extensive chromatography in order to purify the
final product.4i It is therefore desirable to develop a prac-
tical, efficient, environmentally acceptable and catalytic
method for the oxidation of thebaine to 14-hydroxyco-
deinone, which eliminates the drawbacks stated above.
Thebaine (5, Figure 1), a minor opium alkaloid found in
the poppy Papaver somniferum, has no direct medicinal
application.3 However, thebaine has been widely used as
the starting material for the synthesis of many 14-hydrox-
ylated opiates. In this context, a number of improved
methods have been reported in the literature for the oxida-
tion of thebaine to 14-hydroxycodeinone. Rapoport et al.4a
accomplished the oxidation of thebaine to 14-hydroxyco-
deinone in very low yield (25%) by employing a cold
H2CrO4/H2SO4 mixture as the oxidizing agent. Hauser et
al.4b reported the oxidation of thebaine by m-chloroper-
oxybenzoic acid in a mixture of AcOH–TFA in 74%
yield. But, Iijima et al.4c reported that this reaction did not
give reproducible yields and furnished only 24.3% of the
desired product along with many undesirable side prod-
ucts. Kraßnig et al.4d oxidized thebaine by using the H2O2/
HCO2H/H2SO4 system in 74.7% yield. Photooxidation of
thebaine in TFA/CH2Cl2 produced the 14-hydroxyco-
Recently, the combination of V2O5–H2O2 has emerged as
a powerful oxidizing system for the oxidation of various
organic substrates under mild conditions.5 This system is
SYNTHESIS 2009, No. 7, pp 1062–1064
Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1088007; Art ID: Z23808SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
9

SHORT PAPER
Oxidation of Thebaine to 14-Hydroxycodeinone
1063
cheap, non-toxic and easy to handle. In a continuation of
our efforts to develop clean and environmentally friendly
synthetic methods6 for various organic transformations
we wish to report herein an efficient, practical and eco-
friendly method for the oxidation of thebaine (5) to 14-hy-
droxycodeinone (4) by employing 20 mol% V2O5 in the
presence of 30% H2O2 in a refluxing THF–H2O mixture in
excellent yield (Scheme 1).
Table 1 Oxidation of Thebaine to 14-Hydroxycodeinone Using
V2O5 and H2O2 in a Range of Solvents under Reflux
MeO
MeO
oxidant
solvent
O
O
NMe
NMe
OH
MeO
O
Entry Oxidizing system Solvents
V2O5 H2O2
Time Yield
(h)
MeO
MeO
(%)a
V2O5 (20 mol%)
30% H2O2 (1.5 equiv)
(mol%) (equiv)d
O
O
H2O–THF (1:1)
reflux, 30 min
NMe
NMe
1
2
50
50
50
25
20
15
10
5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0
H2O
6.0
14.0
0.3
0.3
0.3
0.4
1.0
1.3
4.0
4.0
0.3
0.3
2.3
0.4
0.4
0.35
n.r.b
20c
86
OH
THF + H2O (1:1)
THF + H2O (1:1)
THF + H2O (1:1)
THF + H2O (1:1)
THF + H2O (1:1)
THF + H2O (1:1)
THF + H2O (1:1)
THF + H2O (1:1)
THF + H2O (1:1)
THF + H2O (2:1)
THF + H2O (1:2)
THF
MeO
O
5
4
3
Scheme 1
4
86
5
86
In order to carry out the oxidation of thebaine in aqueous
medium, we initiated our studies by adding 50 mol% of
V2O5 and 1.5 equivalents of 30% H2O2 to a flask contain-
ing thebaine in water. Unfortunately, no reaction was ob-
served even after six hours reflux (entry 1, Table 1). Since
the reason may be due to the insolubility of the thebaine
in water, the solubility problem was addressed by using a
mixture of organic solvent (THF) and water. However, the
resulting yield was very poor after 14 hours of stirring at
room temperature (entry 2, Table 1). But under reflux
conditions, the desired 14-hydroxycodeinone was ob-
tained in excellent yield in a much shorter reaction time
(entry 3, Table 1). The reaction conditions were then op-
timized by employing a range of catalyst loadings and sol-
vent systems. The results are documented in Table 1. It
was established that either V2O5 or H2O2 alone were not
able to oxidize thebaine (entries 9 and 10, Table 1); the
presence of both was indispensable for this oxidation pro-
cess. The best result was achieved by carrying out the re-
action with 20 mol% of V2O5 in the presence of 1.5
equivalents of H2O2 in a THF–H2O (1:1) mixture under
reflux (entry 5, Table 1).
6
84
7
81
8
76
9
20
0
n.r.b
n.r.b
86
10
11
12
13
14
15
16
1.5
1.5
1.5
1.5
1.5
1.5
1.5
20
20
20
20
20
20
83
72
MeCN + H2O (1:1)
MeOH + H2O (1:1)
EtOH + H2O (1:1)
83
79
80
a Isolated yield.
b No reaction. No spot detected by TLC.
c Reaction was carried out at 25 °C.
d 30% H2O2 was used for every reaction.
We then turned our attention to the effects of different ox-
idizing agents on the oxidation of thebaine. To this end, a
series of metal oxidants were tried. Among those tested,
only Ce(SO4)2·4H2O afforded the desired product (7%
yield). Other oxidants [MnO2, Mg(ClO4)2, FeCl3,
with peracid (A)5b to form 14-hydroxycodeinone
(Scheme 2).
In conclusion, a practical, straightforward and environ-
mentally acceptable clean technological process has been
developed for the preparation of a key drug intermediate,
14-hydroxycodeinone, from thebaine by employing 20
mol% of V2O5 in the presence of 30% H2O2 (1.5 equiv) in
a refluxing H2O–THF (1:1) mixture, in excellent yield.
The oxidizing system is inexpensive, stable and environ-
mentally acceptable. The method does not involve any
acid and the mild reaction conditions, easy work-up, clean
reaction profiles, lower catalyst loading, cost efficiency
and excellent yield render this approach an interesting al-
ternative to the existing methods.
Cu(OAc)2·H2O,
CuCl2·2H2O,
KIO3,
KMnO4,
Fe(NO3)3·9H2O and NaNO2] were completely ineffective
in this transformation as no product was detected in any
case. The experimental procedure is very simple: thebaine
(1 mmol) was mixed with 20 mol% of V2O5 and 30%
H2O2 (1.5 equiv) in a mixture of H2O–THF (1:1, 10 mL).
The reaction mixture was then refluxed for 30 min, then
worked-up to produce 14-hydroxycodeinone in excellent
yield (Scheme 1). The reaction was very clean and no
side-product was formed.
Though it is difficult to speculate on the mechanism of the
reaction at this stage, it is envisaged that thebaine reacts
Synthesis 2009, No. 7, 1062–1064 © Thieme Stuttgart · New York

1064
S. Das Sharma, D. Konwar
SHORT PAPER
Acknowledgment
OH
O
OH
O
The authors acknowledge the Director, and the analytical division
of NEIST for their help. Also, S.D.S. thanks CSIR, New Delhi for
the fellowship.
+
+ 1/2 O2
2
V2O5
3 H2O2
V
HO
A
MeO
References
MeO
(1) (a) Lenz, G. R.; Evans, S. M.; Walters, D. E.; Hopfinger, A.
J.; Hammond, D. L. Opiates; Academic Press: Orlando,
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(c) Bentley, K. W. In The Alkaloids, Chemistry and
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1–159; and references therein.
O
O
NMe
OH
NMe
OH
Me
O
O
O
OH
O
V
HO
A
Scheme 2 Plausible mechanism for the oxidation of thebaine to 14-
hydroxyodeinone by V2O5–H2O2
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are uncorrected. 1H NMR spectra were recorded on an Avance DPX
300 MHz FT-NMR spectrometer. Chemical shifts are expressed in
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were recorded on an FT-IR-system-2000 Perkin–Elmer spectrome-
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C.; Schmidhammer, H. Arch. Pharm. Med. Chem. 1996,
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14-Hydroxycodeinone (4)
Tetrahedron Lett. 1994, 35, 5727. (f) Lin, Z.; Francis, C. A.;
Kaldahl, C. A.; Antczak, K. G.; Kumar, V. US Patent
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In a 50 mL two-necked round-bottom flask, thebaine 5 (2 mmol)
was mixed with V2O5 (20 mol%) and 30% H2O2 (1.5 equiv) in a
mixture of H2O–THF (1:1, 10 mL). The reaction mixture was then
refluxed for 30 min. After the reaction was complete (progress mon-
itored by TLC), the mixture was neutralized through dropwise ad-
dition of aq NH4OH and extracted with EtOAc (3 × 10 mL). The
organic layer was washed with brine (1 × 10 mL), dried over
Na2SO4 and concentrated under vacuum to give the crude product,
which was recrystallized (MeOH) to afford pure 14-hydroxyco-
deinone 4.
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Yield: 0.538 g (86%); off-white crystals; mp 274–275 °C (Lit.4c
275 °C); [a]D31 –109.0 (c 0.76, 10% AcOH).
FT-IR (KBr): 1674.3, 3423.9 cm–1.
1H NMR (CDCl3, 300 MHz): d = 1.67–1.71 (m, 1 H), 2.57 (dd,
J = 18.4, 4.8 Hz, 1 H), 2.17–2.63 (m, 3 H), 2.44 (s, 3 H), 3.03 (d,
J = 6.2 Hz, 1 H), 3.13 (d, J = 18.4 Hz, 1 H), 3.84 (s, 3 H), 4.71 (s,
1 H), 5.14 (br s, 1 H), 6.17 (d, J = 9.96 Hz, 1 H), 6.68 (d, J = 8.2 Hz,
1 H), 6.61 (d, J = 8.2 Hz, 1 H), 6.63 (d, J = 10.1 Hz, 1 H).
ESI-MS: m/z = 315.0 [M+ + 2].
Anal. Calcd for C18H19O4N: C, 69.00; H, 6.11; N, 4.47. Found: C,
69.08; H, 6.17; N, 4.40.
Synthesis 2009, No. 7, 1062–1064 © Thieme Stuttgart · New York