First synthesis and utilization of oripavidine - A concise and efficient route to important morphinans and apomorphines

Article abstract of DOI:10.1002/hlca.200800438

The synthesis and transformation of oripavidine (8) offer an efficient and simple route to highly active dopamine agonist apomorphines and a variety of important 14β-hydroxy-morphinan derivatives. Natural origin thebaine (6), the starting compound of the

Full text of DOI:10.1002/hlca.200800438

Helvetica Chimica Acta – Vol. 92 (2009)
1359
First Synthesis and Utilization of Oripavidine – AConcise and Efficient Route
to Important Morphinans and Apomorphines
a
a
a b
by Attila Sipos* ), S a´ ndor Ber e´ nyi ), and S a´ ndor Antus ) )
a) Department of Organic Chemistry, University of Debrecen, P.O. Box 20, HU-4010 Debrecen
(
fax: þ 36-52-512836, e-mail: asipos@puma.unideb.hu)
b) Research Group for Carbohydrates of the Hungarian Academy of Sciences, P.O. Box 55,
HU-4010 Debrecen
The synthesis and transformation of oripavidine (8) offer an efficient and simple route to highly
active dopamine agonist apomorphines and a variety of important 14b-hydroxy-morphinan derivatives.
Natural origin thebaine (6), the starting compound of the procedure, was converted into its N-{[1,2-
bis(ethoxycarbonyl)hydrazinyl]methyl} counterpart. l-Selectride was found to be an efficient agent to
perform a one-pot O- and N-deprotection at positions 3 and 17, respectively.
Introduction. – The synthesis of high affinity dopamine agonists is one of the main
directions of the chemistry of aporphines. It is a general observation that the N-
substitution of potent compounds could further improve their binding affinities and
1
selectivities to D or D receptor subtypes ). In the Figure, the structure and D affinity
1
2
2
of some important apomorphines, 1 – 5, are presented.
Figure. Some important D agonists
2
Apomorphine hydrochloride (1 · HCl) is the active drug substance of some
pharmaceutical products acting via its dopaminergic potency. Compounds 2 – 4 are
frequently used in the pharmacological studies associated with the activation of the
dopamine system.
These N-substituted derivatives are traditionally prepared with the acid-catalyzed
rearrangement of previously N-substituted morphinans. Our research group explored
the opportunities of a one-step synthesis of 2-O- and 2-S-substituted aporphines from
appropriate morphinandienes [2]. This shortened methodology still comprises at least
five steps from natural thebaine (6), and 19 – 23% of overall yields were achieved. In
1)
For recent reviews, see [1].
ꢀ
2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 92 (2009)
comparison, the traditional synthesis of N-Pr-2-MeO-norapomorphine (4) consists of
seven steps with an overall yield of 10% [3].
Results. – In this work, we present a novel strategy for the synthesis of several
important dopamine D agonists and the successful extension of the method for the
2
preparation of 14b-hydroxy-6-ketomorphinan derivatives. Coop and Rice developed
the first one-pot O- and N-deprotection procedure applying the previously formed N-
(carbomethoxy)normorphinans [4]. The only restriction of this method is that in
morphinans having a C(8)¼C(14) bond the formation of corresponding N-methoxy-
carbonyl derivative is always accompanied with the cleavage of the C(9)ꢀN(17) bond
[
5].
In order to circumvent this issue in the case of thebaine (6), we applied the
formation of a N-nor-N-{[1,2-bis(ethoxycarbonyl)hydrazinyl]methyl} derivative [3a]
and tried the l-Selectride-mediated O- and N-deprotection to obtain oripavidine (8,
Scheme 1).
Scheme 1. Novel Synthesis of Highly Potent Dopamine D Agonists
2
We found that, with the application of the method described by Coop and Rice,
compound 8 was isolated in 44% yield as a HCl salt [4]. However, the optimization of

Helvetica Chimica Acta – Vol. 92 (2009)
1361
the reaction time and cooling period had a significant effect on the conversion
Table 1).
(
Table 1. Time Optimization of One-Pot O- and N-Deprotection
a
Run
Reflux period [h]
Cooling period [h]
Yield after isolation ) [%]
1
2
3
4
4.5
6.0
9.0
9.0
0.5
0.5
0.5
2.0
44
49
59
64
a) Reported yields are averages of 3 runs.
Analytical data for oripavidine (8) were found to be in accordance with previously
published data of the natural origin compound [6]. The regioselective propylation of
compound 8 was found to be an unpredicted issue in the synthesis route as it was
realized that the usual propylation procedure with PrI and K CO in refluxing EtOH
2
3
yielded a mixture of N- and O-alkylated products (Table 2).
Table 2. Selective N-Alkylation of Oripavidine 8
Time [h] Temp. [8] Yields after isolation ) [%]
N-Pr product 9 N- and O-Pr product
47 12
a
Reagents/Conditions
PrI/K CO /thermal
20
5
77
77
2
3
PrI/K CO /thermal
29
75
70
4
0
0
2
3
b
PrOH/[Cp*IrCl ] /NaHCO /thermal ) 17
110
140
2
2
3
b
PrOH/[Cp*IrCl ] /NaHCO /MW )
0.5
2
2
3
a) Reported yields are averages of 3 runs. ) 1 Equiv. of amine, 1 equiv. of PrOH, 1 mol-% of catalyst, and
b
2
mol-% base in toluene.
To perform the selective N-alkylation of the valuable oripavidine 8 in the highest
possible yield in a mild procedure, our attention turned to the catalytic method of Fujita
et al. applying a pentamethylcyclopentadienyliridium(III) chloride/sodium hydrogen-
carbonate {[Cp*IrCl ] /NaHCO } reagent combination and PrOH as alkylating agent
2
2
3
2
[
7a] ). To reduce the reaction time and the applied temperature, the conventional
thermal activation was replaced with microwave-activation also providing high
conversion (Table 2).
The acid-catalyzed rearrangement was performed with and without the presence of
nucleophiles in line with literature methods [2][3c], giving rise to the aimed
apomorphines 3 – 5 in high yield (Scheme 1).
Due to the fact that the structure of compound 8 includes the same ring C motif as
thebaine (6), we studied the transformation of this skeleton into pharmaceutically
determining 14b-hydroxy-6-ketomorphinans. There are two well-established methods
for the conversion of thebaine-like ring C into this substitution pattern; one of them
2)
The applied catalyst, [Cp*IrCl ] , was prepared in accordance with the procedure described in [7b].
2 2

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Helvetica Chimica Acta – Vol. 92 (2009)
utilizes a HCOOH/H O reagent combination, the other uses MCPBA and oxalic acid
2
2
in glacial AcOH [8].
After testing both procedures, it was realized that the unprotected phenolic OH
group is a major concern according to the obtained analytical data of the crude product
mixtures. Therefore, N(17) and the phenolic OH group were protected with an easily
removable benzyl group prior to the oxidative transformation of ring C (Scheme 2).
The MeOH/H O solution of compound 8, 2.5 equiv. of BnBr, and 3 equiv. of NaOH was
2
stirred for 4 h. The benzylation product was removed by CH Cl extraction and
2
2
chromatographed on silica gel.
Scheme 2. Concise and Efficient Route to 14b-Hydroxy Derivatives
The reaction of 3,17-dibenzylnormorphinandiene 10 with a HCOOH/H O reagent
2
2
mixture gave rise to the desired diprotected 14b-hydroxy derivative 11 in average yield.
The catalytic hydrogenation to 12 was carried out in a Parr hydrogenator at room
temperature in the presence of acid for 50 h and was found to be appropriate for both
the saturation of the C¼C bond in ring C and the removal of benzyl protecting groups
[
9]. The structure of the hydrochloride salt of noroxymorphone (12) offers the chance
of easy transformation into important pharmaceutical compounds (naltrexone,
naloxone, oxycodone, etc.) [8] or into frequently used diagnostic and experimental
derivatives (naltrindole, norBNI, IOXY, and other N-labelled PET or SPECT
radiotracers) [10].
Discussion. – The first synthesis of oripavidine (8) opened up new transformation
possibilities to both pharmacologically useful, highly active, and selective apomor-
phines and medically and diagnostically important 14b-hydroxymorphinan derivatives
on the basis of the diene motif in its ring C. Among the applied methods, there are two
novel methodologies besides well-established morphinan transformations. One of them

Helvetica Chimica Acta – Vol. 92 (2009)
1363
is the l-Selectride-mediated O- and N-deprotection of a N-nor-N-{[1,2-bis(ethoxycar-
bonyl)hydrazinyl]methyl} derivative, and the other one is the catalytic, chemoselective
alkylation of a secondary amine in the presence of a free phenolic OH moiety.
Experimental Part
M.p.: Kofler hot-stage apparatus. Thin layer chromatography (TLC): pre-coated Merck 5554
Kieselgel 60 F254 foils using CHCl /MeOH 8 :2 as the mobile phase. The spots were visualized with
3
1
13
Dragendorffꢂs reagent. [a] : Perkin-Elmer Model 241 polarimeter. H- and C-NMR spectra: Bruker
D
DMX 400 spectrometer, chemical shifts are reported in ppm [d] from internal TMS, and coupling
constants J are measured in Hz. HR-MS: Bruker micrOTOF-Q instrument in the ESI mode.
1
7-{[1,2-bis(ethoxycarbonyl)hydrazino]methyl}northebaine (¼ Diethyl 1-{[(5a)-6,7,8,14-Tetradehy-
dro-3,6-dimethoxy-4,5-epoxymorphinan-17-yl]methyl}hydrazine-1,2-dicarboxylate; 7). Despite several
references to the preparation of compound 7, its detailed characterization has not been presented. The
title compound was prepared from thebaine (6, 1000 mg, 3.21 mmol) according to the procedure
described in [4] with 9 h of refluxing and 2 h of cooling periods (Table 1). Pale yellow solid. Yield:
2
5
1
1
(
011 mg (67%). M.p. 168 – 1708. R (CHCl /MeOH 8 :2): 0.43. [a]
D
¼ 321 (c ¼ 0.1, CHCl ). H-NMR
f
3
3
400 MHz, CDCl ): 11.23 (br. s, NH); 6.69, 6.58 (2d, J(1,2) ¼ 8.0, HꢀC(1), HꢀC(2)); 5.80 (d, J(7,8) ¼ 5.1,
3
HꢀC(8)); 4.94 (d, J(7,8) ¼ 5.2, HꢀC(7)); 4.71 (s, H ꢀC(5)); 4.29 – 4.21 (m, 2 COOCH Me); 4.08 (s,
b
2
NꢀCH
2
ꢀN); 3.87 (s, MeOꢀC(3)); 3.62 – 3.58 (m, H
a
ꢀC(9), MeOꢀC(6)); 2.87 – 2.09 (m, H ꢀC(10),
a
H ꢀC(10), H ꢀC(15), H ꢀC(16), H ꢀC(16)); 1.98 (td, J(15,16) ¼ 11.4, J(15a,15b) ¼ 4.5, H ꢀC(15));
b
b
a
b
a
13
1
.24 – 1.17 (m, 2 COOCH Me). C-NMR (100 MHz CDCl ): 157.12, 156.89 (2 COOCH ); 151.12 (C(6));
2 3 2
1
45.01 (C(4)); 143.76 (C(3)); 135.40 (C(14)); 131.31 (C(12)); 126.39 (C(11)); 120.44 (C(1)); 115.07
(
5
(
C(2)); 110.62 (C(8)); 96.73 (C(7)); 90.42 (C(5)); 71.18 (NꢀCH ꢀN); 62.69, 62.14 (2 COOCH Me);
2
2
7.94 (MeOꢀC(6)); 55.46 (MeOꢀC(3)); 54.04 (C(9)); 49.93 (C(16)); 43.99 (C(13)); 35.61 (C(15)); 32.11
þ
þ
C(10)). ESI-HR-MS: 486.2266 ([M þ H] , C H N O ; calc. 486.2240).
25
32
3
7
Oripavidine Hydrochloride (¼(5a)-6,7,8,14-Tetradehydro-6-methoxy-4,5-epoxymorphinan-17-ium-
3
-ol Chloride; 8 · HCl). The title compound was prepared from compound 7 (1000 mg, 2.06 mmol) in line
with the previously described procedure [4], however, the reflux period was 9 h, and the cooling period
was 2 h (Table 1). The yield for the HCl salt was found to be 64% (422 mg). All the physical and spectral
data of this semi-synthetic product were in accordance with those reported for natural origin oripavidine
(
8) [6].
N-Propylnororipavine Hydrochloride (¼(5a,17S)-6,7,8,14-Tetradehydro-6-methoxy-17-propyl-4,5-
epoxymorphinan-17-ium-3-ol Chloride; 9 · HCl). In a pressurized glass vial under an atmosphere of N
2
were suspended oripavidine base (8, 566 mg, 2 mmol), PrOH (120 mg, 2 mmol), [Cp*IrCl2]2 (8 mg,
.01 mmol), and NaHCO (2 mg, 0.02 mmol) in toluene (2 ml). The vial was inserted into the microwave
0
3
cavity of the CEM Discover microwave reactor, irradiated at the 1308 target temp. for 30 min hold time
and subsequently cooled by rapid gas-jet cooling (Table 2). The product mixture was allowed to cool to
r.t. in the microwave cavity. After cooling, the pH of the mixture was set to 10 by concentrated NH soln.
3
and extracted with CHCl
3
(3 ꢁ 15 ml). The org. layers were collected, washed with sat. NaCl soln., dried
over anh. MgSO , and evaporated. The residue was subjected to SiO CC. Elution with CHCl /MeOH
4
2
3
1
:1 gave morphinan 9. The crystalline product was precipitated by addition of abs. Et O and converted
2
into the hydrochloride salt with 1m HCl in EtOH. 456 mg (70%). Yellow, cubic crystals. M.p. 212 – 2148.
2
5
1
[
(
a] ¼ ꢀ199 (c ¼ 0.1, DMSO). R of the free base (CHCl /MeOH 8 :2) 0.63. H-NMR (400 MHz,
D
f
3
D )DMSO): 6.63, 6.54 (2d, J(1,2) ¼ 8.1, HꢀC(1), HꢀC(2)); 5.83 (d, J(7,8) ¼ 6.0, HꢀC(8)); 4.80 (d,
6
J(7,8) ¼ 6.1, HꢀC(7)); 4.66 (s, H ꢀC(5)); 3.61 – 3.58 (m, H ꢀC(9), MeOꢀC(6)); 2.69 – 2.12 (m,
b
a
H ꢀC(10), H ꢀC(10), H ꢀC(15), H ꢀC(16), H ꢀC(16), NꢀCH ); 1.81 – 1.74 (m, H ꢀC(15),
a
b
b
a
b
2
a
13
NꢀCH ꢀCH ); 0.92 (t, J ¼ 7.5, CH ꢀMe). C-NMR (100 MHz, (D )DMSO): 154.42 (C(6)); 148.62
2
2
2
6
(
C(4)); 144.26 (C(3)); 133.11 (C(14)); 130.52 (C(12)); 123.90 (C(11)); 118.34 (C(1)); 114.57 (C(2));
1
13.61 (C(8)); 95.54 (C(7)); 88.15 (C(5)); 59.09 (C(9)); 54.76 (NꢀCH ); 53.43 (MeOꢀC(6)); 49.38
2
(
C(16)); 43.72 (C(13)); 35.61 (C(15)); 30.19 (C(10)); 24.61 (NꢀCH ꢀCH ); 18.67 (CH ꢀMe). ESI-HR-
2
2
2
þ þ
MS: 326.1777 ([M þ H] , C H NO ; calc. 326.1751).
20
24
3

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Helvetica Chimica Acta – Vol. 92 (2009)
N-Propyl-2-hydroxynorapomorphine Hydrochloride (¼(6aR)-5,6,6a,7-Tetrahydro-2,10,11-trihy-
droxy-6-propyl-4H-dibenzo[de,g]quinolinium Chloride; 3 · HCl). The title compound was prepared in
accordance with the procedure described earlier for its N-methyl derivative [2a]. The synthesis was
started from the HCl salt of compound 9 (500 mg, 1.38 mmol). The yield for the HCl salt was found to be
7
4% (356 mg). All the physical and spectral data were in line with the previously reported results [3c].
N-Propyl-2-methoxynorapomorphine Hydrochloride (¼(6aR)-5,6,6a,7-Tetrahydro-10,11-dihydroxy-
-methoxy-6-propyl-4H-dibenzo[de,g]quinolinium Chloride; 4 · HCl). The title compound was prepared
2
in accordance with the procedure described earlier for its N-methyl derivative [2c]. The synthesis was
started from the HCl salt of compound 9 (500 mg, 1.38 mmol). The yield for the HCl salt was found to be
7
9% (395 mg). All the physical and spectral data were in line with the previously reported results [3c].
N-Propyl-2-methylthionorapomorphine Hydrochloride (¼(6aR)-5,6,6a,7-Tetrahydro-10,11-dihy-
droxy-2-(methylsulfanyl)-6-propyl-4H-dibenzo[de,g]quinolinium Chloride; 5 · HCl). The title compound
was prepared in accordance with the procedure described earlier [2b]. The synthesis was started from the
HCl salt of compound 9 (500 mg, 1.38 mmol). The yield for the HCl salt was found to be 68% (356 mg).
All the physical and spectral data were in line with the previously reported results [2b].
3
,17-Dibenzylnororipavine (¼(5a)-17-Benzyl-3-(benzyloxy)-6,7,8,14-tetradehydro-6-methoxy-4,5-
epoxymorphinan; 10). The MeOH/H O soln. of compound 8 · HCl (639 mg, 2 mmol), 2.5 equiv. of
2
benzylbromide, and 3 equiv. of NaOH was stirred for 4 h. The volatile org. part of the soln. was removed
in vacuo, and the residual slurry was extracted with AcOEt (3 ꢁ 15 ml). The org. layers were collected,
washed with sat. NaCl soln., dried over anh. MgSO , and evaporated. The residue was subjected to SiO
4
2
CC in order to separate the diprotected product from monoprotected by-products (eluent: CHCl /
3
2
5
MeOH 8 :2). Yield: 71% (619 mg). Yellow solid. M.p. 110 – 1128. [a] ¼ ꢀ68 (c ¼ 0.1, CHCl ). R
D
3
f
1
(
CHCl /MeOH ¼ 8/2) 0.54. H-NMR (400 MHz, CDCl ): 7.18 – 7.04 (m, 10 arom. H); 6.51, 6.43 (2d,
3
3
J(1,2) ¼ 8.3, HꢀC(1), HꢀC(2)); 5.78 (d, J(7,8) ¼ 5.8, HꢀC(8)); 5.11 (s, CH ꢀO); 4.85 (d, J(7,8) ¼ 5.9,
2
HꢀC(7)); 4.62 (s, H ꢀC(5)); 3.64 – 3.51 (m, H ꢀC(9), CH ꢀN(17), MeOꢀC(6)); 2.77 – 2.05 (m,
b
a
2
H ꢀC(10), H ꢀC(10), H ꢀC(15), H ꢀC(16), H ꢀC(16)); 1.90 (td, J(15,16) ¼ 11.1, J(15a,15b) ¼ 4.6,
a
b
b
a
b
13
H ꢀC(15)). C-NMR (100 MHz, CDCl ): 156.72 (C(6)); 147.11 (C(3)); 146.59 (C(4)); 140.39, 138.21
a
3
(
(
(
C(1’), C(1’’)); 134.72 (C(14)); 129.52 – 112.47 (14 arom. C, C(8)); 95.10 (C(7)); 89.82 (C(5)); 72.06
CH ꢀO); 59.91 (C(9)); 57.32 (CH ꢀN(17)); 53.15 (MeOꢀC(6)); 49.27 (C(16)); 44.16 (C(13)); 36.92
2
2
þ
þ
3
C(15)); 27.06 (C(10)). ESI-HR-MS: 464.2231 ([M þ H] , C H NO ; calc. 464.2220).
31
30
3
,17-Dibenzyl-14-hydroxynormorphinone (¼(5a)-17-Benzyl-3-(benzyloxy)-7,8-didehydro-14-hy-
droxy-4,5-epoxymorphinan-6-one; 11). A soln. of compound 10 (500 mg, 1.08 mmol), HCOOH
0.5 ml), H O (350 mg, 30%, 3.24 mmol), and H O (1.2 ml) was heated at 458 for 6 h and cooled to
(
2
2
2
r.t. for 2 h. The pH of the soln. was adjusted to 9 with conc. NH Cl and extracted with AcOEt (3 ꢁ 10 ml).
4
The combined org. layers were washed with brine, dried over MgSO , and evaporated to dryness. The
4
remaining brown gum was subjected to CC to give the title compound. Yield: 60% (301 mg). All the
physical and spectral data were in line with the previously reported results [8].
1
4-Hydroxydihydronormorphinone Hydrochloride (¼(5a)-3,14-Dihydroxy-4,5-epoxymorphinan-
7-ium-6-one Chloride; 12 · HCl). A mixture of compound 11 (300 mg, 0.65 mmol), glacial AcOH
60 mg, 1 mmol), and Pd/C (5%, 560 mg) in EtOH (35 ml) was hydrogenated in a Parr hydrogenator
1
(
with H gas at r.t. for 50 h. The mixture was filtered through Celite. The filtrate was evaporated in vacuo,
2
and the residual slurry was dissolved in H O (20 ml). The pH of the soln. was adjusted to 9 with conc.
2
NH Cl and extracted with AcOEt (3 ꢁ 10 ml). The combined org. layers were washed with brine, dried
4
over MgSO , and evaporated to dryness. The crude 12 was converted into the hydrochloride salt with 1m
4
HCl/EtOH and recrystallized from AcOEt/MeOH 9 :1. The yield for the HCl salt was found to be 84%
(
175 mg). All the physical and spectral data were in line with the previously reported results [8].
Naltrexone Hydrochloride (¼(5a,17S)-17-(Cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxymorphin-
an-17-ium-6-one Chloride). Title compound was synthesized in line with the procedure presented for the
preparation of N-propylnororipavine hydrochloride (9 · HCl). The synthesis was started from the HCl
salt of compound 12 (200 mg, 0.62 mmol), cyclopropylmethanol (45 mg, 0.62 mmol), and NaHCO3
(
53 mg, 0.63 mmol). The yield for the HCl salt of the title compound was 52% (117 mg). The physical
and spectral data were identical with that of the authentic sample of naltrexone · HCl.

Helvetica Chimica Acta – Vol. 92 (2009)
1365
The authors are grateful for the financial support to the National Science Foundation (Grant OTKA
reg. No. T049436, PD77327 and NI61336). We thank the P e´ ter P a´ zm a´ ny Programme (NKTH, RET006/
2
004) to allow us the use of microwave reactor and Szabolcs Fekete for the valuable technical help. A. S. is
indebted to the Centre for International Mobility, Finland, for financial support.
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Received December 9, 2008