The first synthesis of 3-deoxyoripavine and its utilization in the preparation of 10-deoxyaporphines and cyprodime

Article abstract of DOI:10.2478/s11532-013-0256-x

The synthesis of 3-deoxyoripavine (7) was realized as a novel and promising intermediate towards the synthesis of the important class of dopaminergic and/or serotonergic 10-deoxyaporphines and the special pharmacological tool μ opioid antagonist cyprodime

Full text of DOI:10.2478/s11532-013-0256-x

Cent. Eur. J. Chem. • 11(8) • 2013 • 1278-1285
DOI: 10.2478/s11532-013-0256-x
Central European Journal of Chemistry
The first synthesis of 3-deoxyoripavine
and its utilization in the preparation
of 10-deoxyaporphines and cyprodime#
Research Article
Attila Sipos1*, Antal Udvardy2,
Attila C. Bényei1,2, Sándor Berényi3
1Department of Pharmaceutical Chemistry,
Medical and Health Science Centre,
University of Debrecen, H-4010 Debrecen, Hungary
2Department of Physical Chemistry,
University of Debrecen, H-4010 Debrecen, Hungary
3Department of Organic Chemistry,
University of Debrecen, H-4010 Debrecen, Hungary
Received 14 January 2013; Accepted 19 March 2013
Abstract:
The synthesis of 3-deoxyoripavine (7) was realized as a novel and promising intermediate towards the synthesis of the important class of
dopaminergic and/or serotonergic 10-deoxyaporphines and the special pharmacological tool µ opioid antagonist cyprodime. Generally,
the preparation of these valuable biologically active compounds was achieved in remarkable yields.
Keywords: Oripavine • Cyprodime • 10-deoxyaporphines • Reduction • Acid-catalyzed rearrangement
© Versita Sp. z o.o.
removal of the (phenyltetrazolyl)oxy moiety from the
1. Introduction
aporphines was reported to be ‘erratic and capricious’ in
both catalytic hydrogenolysis reactions and in catalytic
hydrogen-transfer reactions [8,9].
The
synthesis
and
neuropharmacological
characterization of 10-deoxyapomorphine derivatives
are a new and important direction in the development
of potent and subtype selective dopaminergic and/or
serotonergic ligands [1-6]. Currently all the synthetic
methods towards deoxyapomorphines are based
on the preparation of 3-O-(trifluoromethyl)sulfonyl-
morphine (2) or -oripavine (5), the acid-catalyzed
rearrangement of these morphinans into aporphinoids
and further manipulations on the sensitive aporphine
backbone. Earlier procedures involved the synthesis
and transformation of 3-(1-phenyltetrazoyl)morphine (3)
[7,8], however the rearrangement of this compound gave
rise to a mixture of aporphines and the hydrogenolytic
Here we report a new, efficient and versatile route
to 10-deoxyaporphines based on hitherto unknown
3-deoxyoripavine (7). The practical significance of
this procedure is even higher due to the fact that the
starting derivative of our procedure, oripavine (4), is
now one of the major industrial poppy alkaloids [10-12];
especially since the discovery and growing cultivation
of the poppy mutant known as top1 (for ‘thebaine
oripavine poppy 1’) which led the island state of
Tasmania to produce the major part of the world’s licit
thebaine and oripavine directly from natural sources
[10].
* E-mail: sipos.attila@pharm.unideb.hu
#This paper is dedicated to the memory of Prof. Sándor Makleit who passed away on 27.09.2012
1278

A. Sipos et al.
R
H
OH
OCH3
1
2
3
4
5
6
morphine
oripavine
H
Tf
T
N
N
H3C
H3C
O
O
H
Tf
T
OR
OR
4-6
N
N
1-3
N
N
Tf: SO2CF3 T:
Figure 1. Structure of morphinans currently used for the synthesis of 10-deoxyapomorphines.
2. Experimental procedure
J
1-2=8.1), 5.88 (dd, 1H, H7, J7-6, 7-8α =10.9, 1.8), 5.63 (dd,
1H, H6, J6-7, 6-5α =10.9, 2.1), 5.09 (d, 1H, H5β, J5β-6=2.4),
4.09 (m, 1H, H8α), 3.12 (dd, 1H, H10α, J10α-10β, 10α-9=18.1,
<2), 2.98 (d, 1H, J=4.1), 2.60 (dd, 1H, J =4.2, <2), 2.51
(s, 3H, NCH3), 1.98 (m, 2H, H15β, H14), 1.84 (ddd, 1H,
H15α, J =5.2, <2, <2). 13C-NMR (DMSO-d6) δ=144.4,
140.1, 138.3, 129.4, 126.1, 125.4, 120.0, 118.2, 85.8,
63.5, 58.1, 47.5, 45.8, 45.1, 43.8, 32.8, 21.1.
Neomorphine (9)
Physical data were fully in agreement with previously
published data [23].
Calculated for free base C17H19NO3:C, 71.56; H, 6.61;
found: C, 71.51; H, 6.79; MS (ESI) m/z 285.2 (M+H+),
calculated for C17H20NO3+: 285.2; H-NMR (DMSO-d6)
δ=9.21 (s, 1H, phenolic OH), 6.69 (dd, 2H, H1, H2, J1-
2=7.8), 5.48 (dd, 1H, H8, J7α-8, 7β-8=3.4, 2.2), 4.64 (d, 1H,
H5, J5β-6β=5.3), 4.26 (dd, 1H, H6β, J6β-5β, 7β-5β=5.1, <2),
3.69 (m, 1H, H9), 3.19-2.82 (m, 3H, H10α, H10β, H16α),
2.44 (s, 3H, NCH3), 2.42-2.21 (m, 3H, H7α, H7β, H16β),
1.96 (ddd, 1H, H15β, J=5.2, >2, >2), 1.81 (ddd, 1H,
H15α, J =5.2, >2, >2). 13C-NMR (DMSO-d6) δ=146.4,
142.1, 137.7, 131.2, 127.3, 124.7, 119.2, 113.4, 87.4,
66.8, 56.0, 49.1, 47.0, 43.4, 41.0, 35.4, 20.1.
Melting points were determined with a Kofler hot-stage
apparatusandareuncorrected.Thinlayerchromatography
was performed on pre-coated Merck 5554 Kieselgel 60
F254 foils using dichloromethane:methanol = 8:2 mobile
phase. The spots were visualized with Dragendorff’s
1
reagent. H and 13C NMR spectra were recorded on a
Varian Gemini 200 MHz spectrometer; chemical shifts
are reported in parts per million (δ) from internal TMS
and coupling constants (J) are measured in hertz. Mass
spectral measurements were performed with a Bruker
micrOTOF-Q instrument in the ESI mode. Elemental
analyses (C, H) were obtained on a Carlo Erba EA1108
analyzer.
1
Procedure
for
the
formation
of
3-O-
[(trifluoromethyl)sulfonyl]morphinans
A suspension of the alkaloid (9.20 mmol) and Et3N
(1.92 mL, 13.8 mmol) in CH2Cl2 (150 mL) kept under
nitrogen was stirred for 1 h at room temperature.
N-Phenyl-trifluoromethanesulfonimide
(3.94
g,
11.0 mmol) was added, and after being stirred for 48 h,
the reaction mixture was extracted with 10% aqueous
NaHCO3. The organic layer was dried (K2CO3), filtered,
and concentrated in vacuo. The oily residue was
subjected to column chromatography.
6,7-Didehydro-8β-hydroxy-17-methyl-3-O-
[(trifluoromethyl)sulfonyl]-4,5-epoxy-morphinan
(10)
3-O-[(Trifluoromethyl)sulfonyl]morhpine (2)
Physical and spectral data were fully in agreement
with previously published data [1].
3-O-[(Trifluoromethyl)sulfonyl]oripavine (5) \
Physical and spectral data were fully in agreement
with previously published data [2].
γ-Isomorphine (8)
Physical data were fully in agreement with previously
published data [22].
Calculated for free base C17H19NO3: C, 71.56; H,
6.61; found: C, 71.49; H, 6.71; MS (ESI) m/z 285.1
(M+H+), calculated for C17H20NO3+: 285.2; 1H-NMR
(DMSO-d6) δ=9.33 (s, 1H, OH), 6.62 (dd, 2H, H1, H2,
Yield: 87%; colourless oil; calculated for free base
C18H18N5F3O5S: C, 51.80; H, 4.35; found: C, 51.61;
H, 4.61; MS (ESI) m/z 418.1 (M+H+), calculated for
C18H19N5F3O5S+: 418.1; 1H-NMR (CDCl3) δ=6.75 (d, 1H,
H1, J1-2=8.1), 6.67 (d, 1H, H2, J1-2=8.1), 5.79 (dd, 1H,
H7, J7-6, 7-8α =11.4, 2.0), 5.60 (dd, 1H, H6, J6-7, 6-5α =11.4,
2.1), 5.12 (d, 1H, H5β, J5β-6=2.2), 3.99 (m, 1H, H8α),
3.17 (dd, 1H, H10α, J10α-10β, 10α-9=16.8, <2), 2.71-2.09 (m,
7H, H10β, H9, H16α, H16β, NCH3), 1.91 (m, 2H, H15β,
H14), 1.80 (ddd, 1H, H15α, J =5.2, <2, <2). 13C-NMR
(CDCl3) δ=145.1, 140.1, 137.1, 128.6, 127.2, 125.1,
120.7, 119.4 (q, JC-F=318 Hz), 113.5, 84.9, 63.3, 57.6,
47.1, 46.0, 45.2, 43.8, 32.6, 21.2.
1279

The first synthesis of 3-deoxyoripavine and its utilization
in the preparation of 10-deoxyaporphines and cyprodime
8,14-Didehydro-6α-hydroxy-17-methyl-3-O- onto 100 mL of water. After extraction with CH2Cl2 (4 x
[(trifluoromethyl)sulfonyl]-4,5-epoxymorphinan (11)
15 mL), the combined organic layers were washed with
Yield: 84%. white foam; calculated for free base water (3 x 25 mL), dried (sodium sulfate), filtered, and
C18H18NO5F3S: C, 51.80; H, 4.37; found: C, 51.66; evaporated. Treatment with boiling ethanol provided the
H, 4.47; MS (ESI) m/z 417.1 (M+H+), calculated for 3-deoxymorphinan.
C18H19NO5F3S +: 417.1; 1H-NMR (CDCl3) δ=7.01 (d, 1H,
H2, J1-2=7.9), 6.88 (d, 1H, H1, J1-2=7.9), 5.43 (dd, 1H,
3-Deoxyoripavine (7)
Yield:92%;whitepowder;Mp.:136-138oC;calculated
H8, J7α-8, 7β-8=3.5, 2.0), 4.67 (d, 1H, H5, J5β-6β=5.1), 4.26 for free base C18H19NO2: C, 76.84; H, 6.81; found: C,
(dd, 1H, H6β, J6β-5β, 7β-5β=5.1, <2), 3.55 (m, 1H, H9), 3.13- 76.88; H, 6.88; MS (ESI) m/z 282.2 (M+H+), calculated
2.80 (m, 3H, H10α, H10β, H16α), 2.51-2.17 (m, 6H, H7α, for C18H20NO2+: 282.1; H-NMR (CDCl3) δ=7.06 (t, 1H,
1
H7β, H16β, NCH3), 1.92 (ddd, 1H, H15β, J=5.1, >2, >2), H2, J1-2=7.3, J2-3=7.3), 7.06 (t, 2H, H1, H3, J1-2=7.3, J2-
1.80 (ddd, 1H, H15α, J =5.1, >2, >2). 13C-NMR (CDCl3) 3=7.3), 5.60 (d, 1H, H8, J7-8=6.4), 5.60 (s, 1H, H5), 5.05
δ=147.2, 139.9, 137.7, 131.7, 127.3, 120.7, 119.7 (q, (d, 1H, H7,
J
7-8=6.4), 3.68 (m, 1H, H9), 3.64 (s, 3H,
JC-F=321 Hz), 114.2, 113.6, 88.0, 66.7, 58.1, 49.1, 46.5, OCH3), 3.38 (1H, d, H10α, J10α-10β= 16.1) , 2.97-2.62
43.7, 41.0, 35.1, 23.1.
(m, 3H, H10β, H16α, H16β), 2.52 (s, 3H, NCH3), 2.24
Procedure for the formation of 3-(O-1- (ddd, 1H, H15β, J=5.2, >2, >2), 1.78 (ddd, 1H, H15α
phenyltetrazol-5-yl)morphinans
J=5.2, >2, >2). 13C-NMR (CDCl3) δ=157.7 (C4), 153.2
A suspension of the alkaloid (35.1 mmol) in 500 mL (C6), 136.2 (C11), 134.1 (C14), 132.2 (C12), 128.8 (C2),
of acetone was allowed to reflux with 5-chlor-l-phenyl- 119.3 (C1), 112.8 (C8), 107.8 (C3), 96.5 (C7), 89.0 (C5),
1H-tetrazole (6 .33 g, 35.1 mmol) and K2CO3 (10.53 g, 61.6 (C9), 55.7 (OCH3), 46.6 (C16), 45.9 (C13), 42.8
76.3 mmol) for 24 h. The reaction mixture was cooled, (N-CH3), 37.1 (C15), 31.1 (C10).
diluted with H2O (500 mL), and extracted with CH2Cl2.
7,8-Didehydro-6α-hydroxy-17-methyl-4,5-
The extract was washed with H2O, dried over MgSO4, epoxymorphinan (12)
and filtered. The filtrate, on evaporation to dryness
Yield: 87%. Physical and spectral data were fully in
and trituration with ether, gave the 3-O-protected agreement with previously published data [1].
alkaloid.
3-(O-1-Phenyltetrazol-5-yl)morphine (3)
Physical and spectral data were fully in agreement
with previously published data [1].
6,7-Didehydro-8β-hydroxy-17-methyl-4,5-
epoxymorphinan (13)
Yield:85%;whitepowder;Mp.:127-128oC;calculated
for free base C17H19NO22: C, 75.81; H, 7.11; found: C,
3-(O-1-Phenyltetrazol-5-yl)oripavine (6)
75.68; H, 7.20; MS (ESI) m/z 270.2 (M+H+), calculated
Yield: 92%; white crystals; Mp.: 183-185oC, for C17H20NO2+: 270.1; H-NMR (CDCl3) δ=6.81 (t, 1H,
calculated for free base C25H23N5O3: C, 68.01; H, 5.25; H2, J1-2=7.2, J2-3=7.2), 6.59 (t, 1H, H3, J2-3=7.2), 6.48 (t,
found: C, 68.10; H, 5.27; MS (ESI) m/z 442.2 (M+H+), 1H, H1, J1-2=7.2), 5.84 (dd, 1H, H7, J7-6, 7-8α =10.3, <2),
calculated for C25H24N5O3+: 442.2; 1H-NMR (CDCl3) 5.56 (dd, 1H, H6, J6-7, 6-5α =10.4, 2.0), 5.10 (d, 1H, H5β,
1
δ=7.67-7.42 (m, 5H, Ph), 6.62 (dd, 2H, H1-H2, J1-2=8.2),
J5β-6=2.7), 4.04 (m, 1H, H8α), 3.17 (dd, 1H, H10α, J10α-
5.61 (d, 1H, H8, J7-8=6.1), 5.40 (s, 1H, H5), 5.10 (d, 1H, 10β, 10α-9=18.6, <2), 2.56-2.20 (m, 7H, H10β, H9, H16α,
H7, J7-8=6.1), 3.67 (m, 1H, H9), 3.62 (s, 3H, OCH3), 3.34 H16β, NCH3), 1.93 (m, 2H, H15β, H14), 1.87 (ddd, 1H,
(1H, d, H10α, J10α-10β= 16.4), 2.84-2.52 (m, 3H, H10β, H15α, J =5.4, <2, <2). 13C-NMR (CDCl3) δ=157.9, 134.3,
H16α, H16β), 2,47 (s, 3H, NCH3), 2.23 (ddd, 1H, H15β, 133.0, 131.4, 129.4, 126.1, 120.0, 109.2, 85.4, 63.5,
J=5.2, >2, >2), 1.76 (ddd, 1H, H15α J=5.2, >2, >2). 59.4, 47.3, 46.0, 45.3, 43.3, 32.9, 21.6.
13C-NMR (CDCl3) δ=160.4, 154.7. 154.0, 152.4, 132.7,
131.2, 130.0, 128.7, 128.4, 127.8, 124.7, 123.4, 120.8, epoxymorphinan (14)
8,14-Didehydro-6α-hydroxy-17-methyl-4,5-
119.2, 112.5, 96.4, 91.0, 69.8, 56.5, 48.1, 46.8, 42.4,
37.2, 29.1.
Yield:91%;whitepowder;Mp.:144-145oC;calculated
for free base C17H19NO2: C, 75.81; H, 7.11; found: C,
Optimized procedure for the hydrogenolysis of 78.72; H, 7.29; MS (ESI) m/z 270.1 (M+H+), calculated
for C17H20NO2+: 270.1; H-NMR (CDCl3) δ=7.02 (t, 1H,
1
3-O-[(trifluoromethyl)-sulfonyl]morphinans
1,1’-Bis(diphenylphosphino)-ferrocene (399 mg, H2, J1-2=7.2, J2-3=7.2), 7.06 (t, 2H, H1, H3, J1-2=7.2, J2-
0.72 mmol) and palladium acetate (114 mg, 0.48 mmol) 3=7.2), 5.46 (dd, 1H, H8, J7α-8, 7β-8=3.6, 2.3), 4.67 (d, 1H,
wereaddedtoastirredmixtureofthe3-O-[(trifluoromethyl) H5, J5β-6β=5.4), 4.19 (dd, 1H, H6β, J6β-5β, 7β-5β=5.4, <2),
sulfonyl]morphinan (4.80 mmol), triethylamine (2.56 mL, 3.58 (m, 1H, H9), 3.21-2.69 (m, 3H, H10α, H10β, H16α),
18.24 mmol), and formic acid (0.48 mL, 12.00 mmol) in 2.39-2.15 (m, 6H, H7α, H7β, H16β, NCH3), 1.91 (ddd,
DMF (8 mL) at 60 oC under argon for 12 h. After cooling 1H, H15β, J=5.4, >2, >2), 1.81 (ddd, 1H, H15α, J =5.4,
to room temperature, the reaction mixture was poured >2, >2). 13C-NMR (CDCl3) δ=159.8, 138.7, 134.5, 131.6,
1280

A. Sipos et al.
refluxed in acetone in the presence of K2CO3, resulted
in white crystals allowing us to perform X-ray analysis
(Fig. 2, CCDC 860893) of the 3-etheral region of the
molecule as described in a previous study [13]. The C3-O
bond length is 1.413 Ǻ, and the C3-O-C bond angle was
116.6o, which are close to the average values determined
by Johnstone et al. [13] for a series of tetrazoyl ethers
used for the removal of phenolic OH function.
This study confirmed that compound 6 is a promising
starting derivative for the synthesis of 3-deoxyoripavine
(7) on the basis of the determining parameters deduced
by Johnstone’s group [14-17]. The alternative starting
compound of the aimed deoxygenated oripavine 7 was
the 3-O-[(trifluoromethyl)sulfonyl]oripavine (5) prepared
according to the literature procedure in 75% yield [2].
There were several potential hydrogenolytic
conditions identified in the literature, however, as it was
of mentioned, finding the appropriate reductive capacity
Figure 2. X-ray structure of compound 6, showing 50% probability
displacement ellipsoids (H atoms omitted for clarity).
127.3, 119.2, 113.4, 107.6, 87.2, 67.1, 57.5, 48.5, 47.1,
43.5, 41.0, 35.4, 20.1.
Acid-catalyzed
rearrangement
3-deoxyoripavine (7) in the presence of alcohols or and acidity of the applied conditions was the real task
thiols
of this complex optimization procedure. This procedure
Amixture of 7 (200 mg, 0.71 mmol), methanesulfonic is summarized in Table 1 focusing on the most relevant
acid (1 mL) and alcohol/thiol (200 μL) was stirred for steps.
o
30 min at 90 C. Then the reaction mixture was added
The hydrogenolysis of the tetrazoyl ethers is usually
dropwise, with stirring and external ice-cooling, to a achieved by catalytic hydrogenation; however this route
solution of potassium hydrogen carbonate (2 g) in was ruled out as a potential method on the basis of
water (10 mL). After extraction with dichloromethane literature reports[20]. The hydrogenolysis of morphine-
(3×15 mL), the combined extracts were washed with 3-tetrazoyl ether resulted in 3-deoxydihydromorphine
saturated brine, dried (MgSO4), and concentrated and it is well known that the reductive stability of
under reducer pressure. The purification of morphine-type alkaloids is considerably higher than the
10-deoxyapomorphines
means of column chromatography (Kieselgel 40, several attempts were made for the selective transfer
dichloromethane:methanol= 8:2). hydrogenation of tetrazoyl moiety with different hydrogen
was
performed
by same for oripavine-type diene structures. Therefore,
Thecharacterizationsofthenovelmorphinansrelated donors. As it can be concluded from Table 1, these
to the synthesis of cyprodime and new aporphines are methods gave rise to the expected compound in poor
presented in the supplementary document.
yields (Entries 1 & 2). In the case of hydrazine the crude
reaction mixture contained fully and partially saturated
morphinans without 3-OH function besides the aimed
compound 7. The application of sodium hypophosphite
led to a very complex mixture with partially saturated
morphinans. The most promising attempts were made
with 1,4-cyclohexadiene as H-donor. Besides 17%
of target 3-deoxyoripavine (7) the mixture of partially
saturated morphinans with unprotected 3-OH functions
were also obtained. Generally the procedures based
on 3-O-[(trifluoromethyl)sulfonyl]oripavine (5) proved
to be a promising starting compound in view of the Pd-
catalyzed deoxygenating methods. The application of
formic acid in the presence of Pd(OAc)2, triethylamine
and triphenylphosphine led to compound 7 in 37% yield
(Entry 4), however the use of sterically more demanding
dppf resulted in a higher yield (49%), probably due
to a steric hindrance towards ring C of the skeleton.
Palladium-on-charcoal with magnesium metal in
3. Results and discussion
Towards the synthesis of 3-deoxyoripavine (7) we
identified in the literature two potential starting materials;
either the 3-O-(trifluoromethyl)sulfonyl- 5 or 3-O-(1-
phenyltetrazoyl)-derivatives 6 of the parent alkaloid
4. The challenge in the preparation of the 3-deoxy
derivative was to find an appropriate hydrogenolytic
procedure active enough to remove the 3-etheral moiety
but keep unaffected the conjugated diene system of ring
C known to be especially sensitive to reductive and
acidic conditions [11]. The phenyltetrazoyl ether 6 was
prepared in excellent yields (94%) from oripavine (4)
according to the protocol used for the synthesis of the
similar morphine ether [7]. The procedure, in which the
free base of 4 and 5-chloro-1-phenyl-1H-tetrazole was
1281

The first synthesis of 3-deoxyoripavine and its utilization
in the preparation of 10-deoxyaporphines and cyprodime
Table 1. Results of the hydrogenolysis reactions aimed at 3-deoxyoripavine (7) production.
OCH3
OCH3
H-donor + catalyst
N
N
H3C
H3C
O
O
(+ base + ligand)
OR
7
5 or 6
Reactions
Starting
diene
H-donor
Catalyst
Base
Ligand
Isolated yield Reference to
(%) of 7
the procedure
1
2
3
4
5
6
7
8
6
6
6
5
5
5
5
5
NH2NH2•H2Oa
NaH2PO2b
10% Pd/C
10% Pd/C
10% Pd/C
Pd(OAc)2
Pd(OAc)2
-
-
5
[14], [15]
[15]
-
-
7
1,4-cyclohexadienec
HCOOHd
-
-
17
37
49
15
43
92
[15]
Et3N
Et3N
-
PPh3
dppf
-
[18]
HCOOHd
[18]
(MeOH)e
10% Pd/C - Mg
10% Pd/C - Mg
Pd(OAc)2
[19]
HCOONH4, (MeOH)e
HCOOH+Et3Nf
-
-
[19]
Et3N
dppf
[18]
aTwo-phase system of toluene:ethanol:water=7:3:2, r.t., 1.5 h, under argon. b0.4M aquoeous solution of NaH2PO2, toluene:ethanol=7:3, reflux (ca.
70oC) under argon, 1 h. cRefluxing methanol under argon, 1.5 h; d0.2 eq. Pd(OAc)2, 3 eq. Et3N, 0.4 eq. phosphine [dppf=1,1’-bis(diphenylphosphino)-
ferrocene], 2 eq. 99% HCOOH, DMF, 60oC, under argon, 1h. e1 eq. HCOONH4, 1.2 eq. Mg in carefully deoxygeneted abs. MeOH under argon, r.t., 2 h.
f2.5 eq. HCOOH, 3.8 eq. Et3N, 0.1 eq. Pd(OAc)2, 0.15 eq. dppf, DMF under argon, 60oC, 12 h.
methanol gave rise to a low amount of product besides hydroxylated metabolites of morphine (1) itself [24]. The
a mixture of saturated morphinans. It was suggested triflate formation of alkaloids 1, 8 and 9 (Scheme 1) was
that the application of ionic additives could improve performed in excellent yields (84-91%).
efficacy and shorten required reaction time [19]. In the
The previously presented methodology (Table 1,
course of those experiments ammonium acetate was Entry8)forthehydrogenolysisof3-O-triflatefunctionwas
found to be the best; however in our hands the use of successfully applied for compounds 2, 10, 11 giving rise
ammonium formate resulted in the highest conversion to the expected 3-deoxygenated morphinans 12-14 in
into the desired compound. It is interesting to note that 85-91% yields. The formation of products with saturated
according to the plausible mechanism suggested by ring C of the morphinan skeleton was not observed.
Mori et al. methanol is an indirect H-donor interacting Therefore it can be stated that the substitution pattern
with magnesium [19]. The most efficient procedure for and the position of the double bond in ring C are not
the synthesis of targeted product 7 (92%, Entry 8) was limiting factors of the application of the 3-deoxygenation
the one using formic acid and an excess of triethylamine of morphinans.
in the presence of Pd(OAc)2 and dppf. This latter method
As it was referred to previously, one of the main areas
is considered as a specifically optimized version of the for the utilization of new 3-deoxyoripavine (7) was the
original procedure of Cacchi and co-workers [18]. The acid-catalyzed rearrangement into 10-deoxyaporphines
replacement of dppf with PPh3 gave rise to considerably exploiting all the accumulated knowledge regarding this
lower yields.
In order to further investigate the performance
procedure [25].
The data summarized in Scheme 2 suggest that
and conformity of our best conditions with different the acid-catalyzed rearrangement could be realized
electronic systems in ring C, we synthesized the starting from deoxymorphinandiene 7 rather than from
corresponding triflates of morphine (1), γ-isomorphine morphine (1) or oripavine (4), as in this new method
(8) and neomorphine (9) according to the method no catechol system is involved. This catechol system
described for the synthesis of (-)-3-O-[-(trifluoromethyl) often leads to the appearance of oxidized by-products
sulfonylmorphine (2) [1]. On the basis of the difference [29]. These side-products make the work-up procedure
in the substitution pattern and electronic structure of difficult and contribute to the decrease of isolated yields.
the ring C of γ-isomorphine (8) [21] and neomorphine In these cases the average isolated yields of three
(9) [22,23] these compounds are considered as runs were found to be good to excellent. Taking into
1282

A. Sipos et al.
R3
R3
R4
R2
R1
R3
R4
R2
R1
R2
R1
7
R4
8
6
N
HCOOH, Et3N
Pd(OAc)2, dppf
(CF3SO2)2NPh, Et3N
N
N
H3C
H3C
H3C
O
O
O
CH2Cl2
OH
OTf
1, 8, 9
12-14
2, 10, 11
R1
R2
H
R3
R4
H
Position of C=C
C7-C8
1, 2, 12
OH
H
H
OH
H
8, 10, 13
9, 11, 14
H
H
C6-C7
OH
H
H
C8-C14
Scheme 1. Synthesis of 3-deoxymorphinans.
R-X
Yield (%)
Ref.
15
16
17
18
19
20
OH
74
89
86
78
91
84
26, 27
3
4
OCH3
X-R
OH
5
OCH3
3, 28
2
1
N
6a
OCH2CH3
O(CH2)2F
SCH2CH3
28
6
-
N
R-XH, CH3SO2OH
90oC, 30 min
H3C
H3C
H
O
7
8
10
9
S(CH2)2CH3
-
15-20
7
Scheme 2. Synthesis of 2-substituted-11-hydroxyaporphines, the isolated yields for products 15-20 and the literature references for known
compounds.
OCH3
O
O
HO
HO
10% Pd-C/40 psi H2
N
N
H2O2/HCOOH
Zn/NH4Cl, ref. MeOH
N
AcOH
H3C
H3C
H3C
O
O
O
87%
84%
91%
7
21
22
O
O
OCH3
OCH3
O
H3CO
N
HO
H3CO
N
H3CO
N
NaH/(CH3)2SO4
cc. HCl/MeOH
82%
N
H3C
H3C
H3C
OCH3
59%
OH
OCH3
cyprodime
23
25
24
Scheme 3. New route to key intermediate 25 of the synthesis of cyprodime.
consideration the high yielding 3-O-triflation of oripavine preparation of key intermediate 25 from oxymorphone,
and 3-deoxygenation of compound 5, the overall yields an expensive semi-synthetic major analgesic, in
for this series of 10-deoxyaporphines 15-20 were in the 6 steps [30,32]. The structure of compound 7 offers
range of 51-62%.
the shortening of this procedure as it is presented in
Scheme 3.
Cyprodime [30] is
a prototypical, selective µ
opioid antagonist, which is still the target of intense
All these standard synthetic steps were performed
pharmacological research in part because of the in accordance with a previous report on the alternative
availability of its tritium-labeled derivative [31]. The synthesis of cyprodime [33]. The overall yield for
original synthesis of the cyprodime was based on the key intermediate 25 was 32% in the present 5-step
1283

The first synthesis of 3-deoxyoripavine and its utilization
in the preparation of 10-deoxyaporphines and cyprodime
study. Interestingly, it was possible to obtain the 10-deoxyaporphines and the special pharmacological
trimethoxymorphinan 24 in average yield (59%) under tool µ opioid antagonist cyprodime.
usual O-methylation conditions [31] in the presence of
5 equivalents of NaH and (CH3)2SO4. The position of the
double bond in ring C was established on the basis of Acknowledgement
the coupling constants of H7.
The authors are indebted for the support of the
Hungarian Science Fund (NKTH-OTKA K101372) and
4. Conclusion
the Austrian Science Fund (15481 and TRP 19-B18).
The research was supported by the EU and co-financed
Inconclusion,theefficientpreparationof3-deoxyoripavine by the European Social Fund under the project ENVIKUT
(7) was achieved starting from the 3-O-triflate of (TÁMOP-4.2.2.A-11/1/KONV-2012-0043).
oripavine 5. The optimization of the hydrogenolitic
conditions resulted in a procedure yielding 92% of the
desired compound 7. The methodology was extended for Supplementary data
morphine(1)anditsisomersandfoundtobeausefulroute
to 3-deoxymorphinans without change in the electronic Supplementary data associated with this article can
system of ring C. It was recognized that 3-deoxyoripavine be found in the online version. This file includes
(7) was a valuable starting product towards the synthesis crystallographic and spectral information of new
of the important class of dopaminergic and serotonerg compounds.
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