Synthesis of pharmacologically active apomorphines by direct N-substitution on the aporphine backbone

Article abstract of DOI:10.1055/s-2008-1078494

A method has been developed for the direct N-substitution of aporphines comprising the N-oxidation-N-deprotection-N-alkylation sequence. This methodology was found to be insensitive to the change in the substitution pattern of rings A or D, therefore it is presumed to be applicable also for aporphines derived from total synthesis and natural sources. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1078494

LETTER
1703
Synthesis of Pharmacologically Active Apomorphines by Direct
N-Substitution on the Aporphine Backbone
S
ynthesis of Pharm
t
acolog
t
ically
ictive
l
A
pomo
a
rphines Sipos,* Sándor Berényi*
Department of Organic Chemistry, University of Debrecen, P. O. Box 20, 4010 Debrecen, Hungary
Fax +36(52)512836; E-mail: asipos@puma.unideb.hu
Received 1 April 2008
Table 1 Some Important D2 Agonists
Abstract: A method has been developed for the direct N-substitu-
tion of aporphines comprising the N-oxidation–N-deprotection–N-
alkylation sequence. This methodology was found to be insensitive
to the change in the substitution pattern of rings A or D, therefore it
is presumed to be applicable also for aporphines derived from total
synthesis and natural sources.
3
4
R
5
2
6a
N
1
Alk
H
OH
OH
7
11
10
Key words: alkaloids, transition metals, protecting groups, me-
dicinal chemistry, oxidations
8
9
1–10
R
Compd
Alk
Me
Pr
D2 Binding affinity (nM)
Aporphines are isolated in increasing number from natu-
ral sources.1 This group of isoquinoline alkaloids can be
prepared by total synthesis,2 and by semisynthesis from
natural-occurring morphinans via acid-catalyzed rear-
rangement of the morphinan ring.3
1
2
H
11.1
0.80
0.38
0.05
1.12
0.17
6.45
0.071
17.7
0.89
H
3
OH
OH
Me
Pr
Aporphines display a variety of interesting pharmacolog-
ical properties.4 The SAR studies indicate that in particu-
lar substituents at N-6 influences binding affinity and
selectivity to dopamine D1- and D2-agonist receptors.5
Selected D2-receptor agonists are shown in Table 1.
4
5
OMe
OMe
F
Me
Pr
6
7
Me
Pr
Apomorphine (1) itself displays dopaminergic properties
and it is used in certain pharmaceuticals. Compounds 2, 4,
6, 8, and 10 are even more potent.
8
F
9
Br
Me
Pr
N-Methyl aporphines can be prepared by acid-catalyzed
rearrangement of N-methyl morphinandienes.6 Other N-
alkyl groups can be introduced by demethylation followed
by re-alkylation. However, the N-demethylation requires
so harsh conditions that a C8=C14 bond in the morphinan-
diene skeleton usually does not survive.7
10
Br
dative behavior of apomorphine in aqueous media giving
raise to some norapomorphines as a result of anodic oxi-
dation.10 This investigation aimed the better understand-
ing of the biological interactions of apomorphine rather
than providing some practical procedure for the N-substi-
tution.
Hence, there is a demand for a more efficient approach.
The present paper describes a new protocol, which gives
access to a series of important N-alkylated aporphines by
demethylation of N-methylaporhines followed by re-alky-
lation.
We explored the possibilities of adoption of the oxida-
tion–cleavage-alkylation sequence of Scammells et al.,
originally developed for morphinans, to aporphine back-
bone to obtain pharmacologically more interesting N-pro-
pyl congeners.11
There has been no practical method for the direct N-de-
methylation and consequent N-alkylation of aporphines,8
however, some successful attempts were published re-
garding the synthesis of noraporphines. Begtrup’s group
applied the cleavage of N–Bn bond by catalytic hydroge-
nation.9 They performed N-deprotection of an aporphine
obtained by the rearrangement of the previously N-benzy-
lated morphinan. Garrido and co-workers studied the oxi-
Table 2 Oxidation of 2-Bromoapocodeine (14)
Procedure
Temp (°C) Time (h)
Yield (%)a
H2O2
r.t.
60
60
r.t.
18
7
11
6
MCPBA
H2O2, Mg(OH)2, PhCN
H2O2, Na2WO4
24
36
61
SYNLETT 2008, No. 11, pp 1703–1705
x
x
.x
x
.2
0
0
8
3.5
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078494; Art ID: G11608ST
© Georg Thieme Verlag Stuttgart · New York
a Isolated yields after column chromatography, averages of three runs.

1704
A. Sipos, S. Berényi
LETTER
R2
R2
R2
R1
R1
R1
(i)
(ii)
O
(iii)
N
N
HN
Me
Me
H
H
H
OH
OH
OH
R3
R3
R3
OMe
OMe
OMe
31–40
R1
R2
R3
21–30
11–20
11, 21, 31, 41, 4
12, 22, 32, 42, 6
13, 23, 33, 43, 8
14, 24, 34, 44, 10
15, 25, 35, 45, 51
16, 26, 36, 46, 52
17, 27, 37, 47, 53
18, 28, 38, 48, 54
19, 29, 39, 49, 55
20, 30, 40, 50, 56
OH
OMe
F
Br
Ph
H
H
H
H
H
H
H
H
H
H
Cl
Br
Ph
H
H
H
H
H
H
H
H
H
Cl
Br
R2
R2
R1
R1
N
N
(iv)
Pr
Pr
H
H
OH
OH
OH
R3
R3
OMe
H
41–50
4, 6, 8, 10, 51–56
Scheme 1 Direct N-substitution of aporphines. Reagents and conditions: (i) H2O2, Na2WO4, 52–67%; (ii) FeSO4·7H2O, 82–91%;
(iii) PrI/K2CO3, 75–82%; (iv) MeSO2OH, methionine, 77–87%.
The main concern regarding the oxidative N-deprotection oxides (Table 3) leading either to previously highlighted
of aporphine skeleton was its sensitivity to this kind of N-propyl norapomorphines 4, 6, 8, and 10 or other, hith-
chemical effect. It is well known that the nondegradative erto unknown, apomorphines 51–56 (Scheme 1) with po-
oxidation of aporphines leads to 7-oxoaporphines with tential pharmacological interest.16,17
several oxidizing agents ranging from chromium trioxide
The HCl salts of N-oxides 21–30 were N-deprotected ac-
in pyridine12a to manganese(III) acetate.12b Since the mod-
cording to Scammells’ procedure applying FeSO4·7H2O
ification of the N-substituent was planned on apocodeines
having semiprotected catechol motifs, the oxidation of
ring D was considered a minor issue under mild condi-
tions. Scammells’ method offered the choice between the
application of large excess of hydrogen peroxide (11
equiv) and almost quantitative amount of m-chloroper-
in methanol at 0 °C.11 Noraporphine hydrochlorides 31–
40 were then re-alkylated with propyl iodide in the pres-
ence of three equivalents of potassium carbonate in meth-
anol. Finally, the O-demethylation of norapocodeines 41–
50 into the pharmacologically more interesting norapo-
morphines 4, 6, 8, 10, and 51–56 was carried out by meth-
benzoic acid (MCPBA, 1.1 equiv). Both oxidizing agents
anesulfonic acid and methionine18 reagent mixture. The
were tested according to the original methods11 in terms of
neuropharmacological characterization of the stable HCl
the potency of formation of the desired N-oxide and unfa-
salts of novel apomorphines 51–56 is still in progress.
vorable oxidation products. In these test reactions and fur-
ther optimization steps 2-bromoapocodeine (14) was
used.13 It was found that these long-term oxidation proce-
Table 3 Yields of the N-Deprotection Steps
dures produced N-oxide in low yield and considerable
amount of side product was obtained in the form of insol-
Compd
Isolated yield (%)a
uble dark tar in the crude product mixture (Table 2).
N-Oxide formation
N-Deprotection
After reviewing recent literature we identified two prom-
ising catalytic procedures offering significantly milder
conditions. The first one suggested the application of het-
erogeneous catalysis with H2O2, basic minerals, and ben-
zonitrile as an additive in water–methanol solvent.14
During workup it was noted that the amount of the dark,
overoxidized side product decreased, however, the isolat-
ed yield for N-oxide remained under 40%. Therefore our
attention turned to the application of a shorter, room-tem-
perature procedure utilizing Na2WO4 as a catalyst.15 In or-
der to increase the solubility of our apocodeine 14 the
11
12
13
14
15
16
17
52
54
63
61
67
55
59
63
60
59
85
82
87
82
90
91
82
84
87
84
original aqueous media was changed to water–1,4-diox- 18
ane (1:2). The yield of the reaction remarkably increased
and the amount of the side product remained at an accept-
able level.
19
20
a Reported yields are averages of 3 runs.
After this optimization step the method was expanded to
a variety of apocodeines 11–20 in order to synthesize N-
Synlett 2008, No. 11, 1703–1705 © Thieme Stuttgart · New York

LETTER
Synthesis of Pharmacologically Active Apomorphines
1705
A.; Debreceni, Sz.; Szabó, R.; Gyulai, Zs.; Berényi, S. Synth.
Commun. 2007, 37, 2549. (e)Berényi, S.; Kiss, B.; Schmidt,
É.; Greiner, I. Bioorg. Med. Chem. 2008, 16, 3773.
(17) General Procedure for the N-Substitution of Aporphines
Apocodeine base (2.92 mmol) and Na2WO4 (300 mg, 1.02
mmol) was dissolved in H2O–1,4-dioxane (1:2, 10 mL) and
cooled to 0 °C for the dropwise addition of H2O2 (30% w/v,
12 mmol). The reaction mixture was stirred at r.t. for 3.5 h.
The excess H2O2 was quenched by addition of small portions
of MnO2 at 0 °C and the presence of the peroxide determined
by KI-starch paper. The reaction mixture, containing some
overoxidized product as dark precipitation, was then vacuum
filtered through a short pad of Celite. Solvent was removed
in vacuo to give the crude product as a pale brown solid. It
was immediately turned into hydrochloride salt by
dissolving in a few drops of CHCl3 and dropping some EtOH
sat. with HCl gas. After filtration, the mixture of minor
apocodeine·HCl and major apocodeine N-oxide·HCl was
dissolved in MeOH (10 mL) followed by the addition of
FeSO4·7H2O (2 equiv) at 0 °C. The reaction mixture was
then left to stir at r.t. for 1 h. Conversion was followed by
TLC (80% CH2Cl2–20% MeOH). The reaction solvent was
removed in vacuo and the residue redissolved in a 0.1 M
EDTA solution adjusted to pH 10 by addition of NH3 (70
mL). The aqueous phase was then extracted with CHCl3
(3 × 30 mL). The combined organic phase was dried over
MgSO4, filtered, and the solvent removed in vacuo to give
dark brown mixture of apocodeine and norapocodeine.
Norapocodeine was isolated by means of silica column
chromatography (eluent: 80% CH2Cl2–20% MeOH).
Physical and spectral data of the products of the synthetic
route from (–)-(R)-2-bromoapocodeine (14) to (–)-(R)-N-
propyl-2-bromonorapomorphine (10) are detailed to
represent the described method.
In conclusion we have presented a procedure for direct N-
substitution of aporphines comprising the N-oxidation–N-
deprotection–N-alkylation sequence. This methodology
was found to be insensitive to the change in the substitu-
tion pattern of rings A or D, therefore it is presumed to be
applicable for aporphines also from total synthesis and
natural sources.
Acknowledgment
The authors are grateful for substantial discussions with Prof. Sán-
dor Antus and for the financial support to the National Science
Foundation (Grant OTKA reg. No. T049436 and NI61336). A.S. is
indebted to Centre for International Mobility, Finland for financial
support.
References and Notes
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(–)-(R)-2-Bromoapocodeine N-Oxide Hydrochloride
(24·HCl)
25
Off-white, plate-shape crystals; mp >250 °C (Et2O); [a]D
–168 (c 0.1, DMSO); Rf base = 0.21 (CHCl3–MeOH, 8:2).
+
HRMS (EI): m/z (%) calcd for C18H18BrNO3 : 375.0470
[M+]; found: 375.0482 (100) [M+]. 1H NMR (400 MHz,
DMSO-d6): d = 7.44 (1 H, s, C1–H), 7.14 (1 H, s, C3–H),
6.77–6.70 (2 H, 2 d, C8–H, C9–H, J8-9 = 8.1 Hz), 6.14 (1 H,
br s, OH), 5.32 (1 H, td, C6a–H, J6a-7a 9.4 Hz, J6a-7b 2.7 Hz),
3.77 (3 H, s, C10–OCH3), 3.70–2.94 (6 H, m, C4–Ha, C4–
Hb, C5–Ha, C5–Hb, C7–Ha, C7–Hb), 2.91 (3 H, s, NCH3).
13C NMR (100 MHz, DMSO-d6): d = 146.61 (C10), 144.43
(C9), 136.19–114.78 (10 C, arom.), 75.09 (C6a), 60.56 (C5),
56.23 (C10–OCH3), 54.51 (N–CH3), 37.39 (C7), 25.81 (C4).
(–)-(R)-2-Bromonorapocodeine Hydrochloride (34·HCl)
White, cubic crystals; mp >250 °C (Et2O); [a]D25 –78 (c 0.1,
DMSO); Rf base = 0.17 (CHCl3–MeOH, 8:2). HRMS (EI):
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+
m/z (%) calcd for C17H17BrNO2 : 346.0437 [M+ + 1]; found:
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346.0444 (100) [M+ + 1]. 1H NMR (400 MHz, DMSO-d6):
d = 7.41 (1 H, s, C1–H), 7.07 (1 H, s, C3–H), 6.69–6.62 (2
H, 2 d, C8–H, C9–H, J8-9 = 8.0 Hz), 6.09 (1 H, br s, OH),
4.13 (1 H, td, C6a–H, J6a-7a = 9.1 Hz, J6a-7b = 2.5 Hz), 3.83 (3
H, s, C10–OCH3), 3.09–2.18 (7 H, m, C4–Ha, C4–Hb, C5–
Ha, C5–Hb, C7–Ha, C7–Hb, NH). 13C NMR (100 MHz,
DMSO-d6): d = 147.12 (C10), 144.76 (C9), 137.28–113.19
(10 C, arom.), 56.47 (C10–OCH3), 53.71 (C6a), 43.56 (C5),
37.18 (C7), 26.66 (C4).
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Synlett 2008, No. 11, 1703–1705 © Thieme Stuttgart · New York