Synthesis and dopamine receptor affinities of N-Alkyl-11-hydroxy-2- methoxynoraporphines: N-Alkyl substituents determine D1 versus D2 receptor selectivity

Article abstract of DOI:10.1021/jm701045j

We developed a procedure to synthesize a series of N-alkyl-2-methoxy-11- hydroxynoraporphines from thebaine and evaluated their binding affinities at dopamine D₁ and D₂ receptors in rat forebrain tissue. At D₂ receptors, the most potent 10,11-catechol-aporphine was (R)-(-)-2-methoxy-N-n-propylnorapomorphine (D₂, K_i = 1.3 nM; D₁, K_i = 6450 nM), and the most selective and potent 11-monohydroxy aporphine was (R)-(-)-2-methoxy-11-hydroxy-N-n-propylnoraporphine (D₂, K_i = 44 nM; D₁, K_i = 1690 nM). In contrast, the N-methyl congeners (R)-(-)-2-methoxy-11-hydroxy-N-methyl- aporphine (D₁ vs D₂, K_i = 46 vs 235 nM) showed higher D₁ than D₂ affinity, indicating that N-alkyl substituents have major effects on D₂ affinity and D ₂/D₁ selectivity in such 2-methoxy-11-monohydroxy- substituted aporphines.

Full text of DOI:10.1021/jm701045j

J. Med. Chem. 2008, 51, 983–987
983
Synthesis and Dopamine Receptor Affinities of N-Alkyl-11-hydroxy-2-methoxynoraporphines:
N-Alkyl Substituents Determine D1 versus D2 Receptor Selectivity
Yu-Gui Si, Matthew P. Gardner, Frank I. Tarazi, Ross J. Baldessarini, and John L. Neumeyer*
Alcohol & Drug Abuse Research Center and Mailman Research Center, McLean Hospital, HarVard Medical School, 115 Mill Street, Belmont,
Massachusetts 02478-9106 USA
ReceiVed August 22, 2007
We developed a procedure to synthesize a series of N-alkyl-2-methoxy-11-hydroxynoraporphines from
thebaine and evaluated their binding affinities at dopamine D
1
and D
receptors, the most potent 10,11-catechol-aporphine was (R)-(-)-2-methoxy-N-n-propylnorapomorphine
, K ) 1.3 nM; D , K ) 6450 nM), and the most selective and potent 11-monohydroxy aporphine was
R)-(-)-2-methoxy-11-hydroxy-N-n-propylnoraporphine (D , K ) 44 nM; D , K ) 1690 nM). In contrast,
vs D , K ) 46 vs 235
affinity, indicating that N-alkyl substituents have major effects on D affinity
selectivity in such 2-methoxy-11-monohydroxy-substituted aporphines.
2
receptors in rat forebrain tissue. At
D
2
(
(
D
2
i
1
i
2
i
1
i
the N-methyl congeners (R)-(-)-2-methoxy-11-hydroxy-N-methyl-aporphine (D
nM) showed higher D than D
and D /D
1
2
i
1
2
2
2
1
Introduction
R)-(-)-Apomorphine (APO) is a 10,11-catecholaporphine
apomorphine to provide active (R)-(-)-11-monohydroxyapor-
phines. Our earlier investigations indicated that the 11-hydroxy
group (analogous to the m-hydroxy group of DA) plays a crucial
role in DA receptor affinity and that 10,11-dihydroxy substitu-
tion is not required for dopaminergic activity. These earlier
investigations led to the preparation and neuropharmacological
(
with dopamine (DA) receptor agonist activity that has been used
as a pharmacological probe of DA receptors in a variety of
central nervous system disorders. APO has been used success-
fully in the treatment of Parkinson’s disease and erectile
4g
evaluation of (R)-(-)-11-hydroxy-N-n-propylnoraporphine [(R)-
1
dysfunction (Figure 1). For hydroxylated aporphines, the
(
-)-11-OH-NPa, 2b], a compound displaying high affinity and
configuration at the 6a asymmetric carbon atom, the number
and location of the hydroxyl groups, and the size of N-alkyl
substituents at the nitrogen atom all appear to contribute to the
7
selectivity for the D2 receptor.
Based on these findings, we investigated the synthesis of a
series of 11-monohydroxy (R)-(-)-aporphines with a 2-methoxy
substituent, and various alkyl groups at the 6N position
2
affinity at D1 and D2 DA receptors. The absolute configuration
is critically important for interactions at DA receptors. Only
the (R)-(-) enantiomer of apomorphine, obtained by the acid-
catalyzed rearrangement of (-)-morphine, but not the (S)-(+)-
(
compounds 3a-d), and evaluated their DA receptor affinities
in rat forebrain tissue.
3
Chemistry. We considered several approaches to the prepa-
enantiomer, possesses DA-agonist activity. Total synthesis of
8
ration of (R)-(-)-N-alkyl-11-hydroxy-2-methoxyaporphines and
racemic R,S-apomorphine followed by resolution has led to the
synthesis and neuropharmacological assessment of a number
of dihydroxy noncatechol, masked catecholic, mono- and
trihydroxyaporphines, with or without C2 subsituents, as well
developed a facile procedure using the Pd/C-catalyzed reduction
of N-alkyl-2-methoxy-10-O-[(trifluoromethyl)sulfonyl]-11-hy-
droxyaporphines 8 with Mg metal in MeOH at room temperature
2
(RT) in the presence of NH OAc (Scheme 1). Thebaine 5a was
4
as aporphines with various N-alkyl substituents.
O-demethylated with L-Selectride using the procedure reported
2
-Substituted (R)-(-)-apomorphine analogues have also been
9
4,5
by Rice to obtain oripavine 6a. Thebaine 5a was also converted
prepared in several laboratories including ours (Figure 1). We
found that substituents in the 2-position of aporphines modulate
dopaminergic receptor potency and D2/D1 selectivity and that
most of these compounds display relatively high D2 potency
and D2/D1 receptor selectivity. DA receptor affinity and
functional activity studies found that (R)-(-)-2-methoxyapo-
morphine [(R)-(-)-2-OMe-APO, 1d], (R)-(-)-2-methoxy-N-n-
propylnorapomorphine [(R)-(-)-2-OMe-NPA, 1c], and 2-fluoro-
N-n-propylnorapomorphine [(R)-(-)-2-F-NPA] were among the
4
f
to northebaine 4. N-Alkylnororipavines 6b-d were obtained
by N-alkylation of northebaine 4, followed by 3-O-demethyla-
tion with L-Selectride. 3-O-Triflation of oripavine 6a and its
N-alkyl derivatives 6b-d with PhNTf2, followed by acid
4
h
catalyzed rearrangement, led to the aporphine triflates 8a-d.
Further Pd/C-catalyzed reduction with Mg metal in MeOH at
RT in the presence of NH4OAc provided the target N-alkyl-
8
,10
1
1-hydroxy-2-methoxyaporphines 3a-d
(Scheme 1).
4
most potent and highly selective agonists for the D2 receptor.
,
Results and Discussion
APO has efficacy in the treatment of Parkinson s disease, but
its poor oral bioavailability induced by susceptibility to oxidation
of the 10,11-catechol moiety greatly limits its clinical utility
and encourages development of aporphines with greater oral
bioavailability and longer action than are provided by APO.
One means of enhancing oral bioavailability without losing DA
agonist activity, is to eliminate the 10-hydroxy group in
We obtained the in Vitro affinities of compounds 1a-d and
a-d at DA D1 and D2 receptors in rat striatum tissue using
6
3
competitive binding assays with membrane homogenates of rat
striatum tissue, following procedures reported in detail previ-
7
ously. The data show that the 2-methoxy-substituted analogues
of (R)-(-)-APO and (R)-(-)-NPA led to >2857-fold and 4862-
fold D2 over D1 receptor selectivity, respectively (Table 1).
Introduction of a 2-methoxy substituent into (R)-(-)-11-OH-
NPa increased D2-over-D1 selectivity from 24.5-fold to 38.4-
*
To whom correspondence should be addressed. Tel: 617-855-3388.
Fax: 617-855-2519. E-mail: jneumeyer@mclean.harvard.edu
1
0.1021/jm701045j CCC: $40.75

2008 American Chemical Society
Published on Web 02/06/2008

9
84 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
Si et al.
Figure 1. Structures of potent aporphine analogues.
Scheme 1. Synthesis of N-Alkyl-11-hydroxy-2-methoxynoraporphines 3
a
Table 1. Affinities (Ki) for Rat Forebrain D1 and D2 Receptors
Ki (nM)
1
compd
a APO
b NPA
c 2-OMe-NPA
d 2-OMe-APO
a 11-OH-aporphine
b 11-OH-NPa
a
b
c
d
3
R
R
X
D1
D2
D2/D1 potency ratio
1
1
1
1
2
2
3
3
3
3
Me
Pr
Pr
Me
Me
Pr
Me
Et
OH
OH
OH
OH
H
H
H
OMe
OMe
H
1010 ( 105
3410 ( 300
6450 ( 130
>10000
26.5 ( 1.0
699 ( 118
46.0 ( 2.8
130 ( 20
1690 ( 130
>10000
1.9 ( 0.5
0.9 ( 0.3
1.3 ( 0.4
3.5 ( 0.8
108 ( 11
28.5 ( 12.8
235 ( 32
28.0 ( 6.0
44.0 ( 8.3
>10000
532
3789
4862
>2857
b
b
0.24
24.5
0.19
4.60
b
b
H
H
H
H
H
OMe
OMe
OMe
OMe
Pr
Bu
38.4
H
a
3
b
Radioligands: D1, [ H]SCH23390; D2, [ H]nemonapride. From ref 7b.
fold. As with 10,11-dihydroxy (catechol) aporphines (1a-d)
with or without a 2-methoxy substituent, switching the N-methyl
to N-propyl increased D2 selectivity. However, N-methyl-11-
monohydroxyaporphines showed preferential affinity at D1 over
D2 DA receptors, with or without a 2-methoxy substituent (Table
(3b) was D2 selective, whereas the N-n-butyl analogue (3d) was
inactive at both D1 and D2 receptors. Our findings therefore
indicate that the N-alkyl substituent in 11-monohydroxyapor-
phines greatly affects their selective interactions at D1 or D2
receptors.
1
). To further understand the affect of N-alkyl substituents on
Conclusion
D1/D2 selectivity, we also synthesized the N-ethyl- (3b) and N-n-
butyl-2-methoxy-11-hydroxynorapophines (3d) and evaluated
their D1 and D2 receptor binding affinities. The N-ethyl analogue
The present findings support the following tentative conclu-
sions: (1) The presence of a single hydroxyl group in 11-

Synthesis of N-Alkyl-11-hydroxy-2-methoxynoraporphines
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 985
1
hydroxyaporphines is sufficient to confer affinity and activity
at DA receptors; (2) introduction of a 2-methoxy moiety on
the A-ring of catechol aporphines increases D2-over-D1 selectiv-
ity; (3) for 11-monohydroxy aporphines, the N-substituent
determines dopamine receptor selectivity: D1 is preferred with
N-methyl, and D2 is preferred with an N-n-propyl substituent;
N-Butylnorthebaine (5d): oil (65%); H NMR (300 MHz,
CDCl
3
) δ 6.65 (d, J ) 8.2 Hz, 1H), 6.59 (d, J ) 8.2 Hz, 1H), 5.54
d, J ) 6.4 Hz, 1H), 5.29 (s, 1H), 5.03 (d, J ) 6.4 Hz, 1H), 3.84
s, 3H), 3.71 (d, J ) 6.9 Hz, 1H), 3.59 (s, 3H), 3.28 (d, J ) 18.0
(
(
Hz, 1H), 2.85–2.66 (m, 3H), 2.57–2.52 (m, 2H), 2.18 (m, 1H), 1.70
dt, J ) 12.3 and 2.7 Hz, 1H), 1.56–1.46 (m, 2H), 1.42–1.27 (m,
(
13
2
1
5
3
H), 0.94 (t, J ) 7.2 Hz, 3H); C NMR (75 MHz, CDCl ) δ 152.4,
(4) the combination of both N-propyl or N-ethyl and 2-methoxy
44.6, 142.7, 133.5, 132.6, 127.8, 119.1, 112.7, 111.5, 95.9, 89.2,
8.8, 56.3, 54.9, 53.9, 46.5, 44.2, 36.9, 30.4, 30.0, 20.8, 14.1.
substituents, as in (R)-(-)-2-methoxy-N-propyl-11-hydroxy-
noraporphine 3c or in (R)-(-)-2-methoxy-N-ethyl-11-hydroxy-
noraporphine 3b, produced high D2 affinity (44 nM for 3c and
General Procedure for the Synthesis of Oripavine (6a) and
N-Alkylnororipavines 6b-d. A mixture of thebaine (or N-
alkylnorthebaine, 9 mmol) and 18 mL L-Selectride (1.0 M in THF)
were heated under reflux for 30 min. After cooling to rt, the mixture
was poured into 50 mL of ice–water, and 10 mL of 1 N NaOH
2
8 nM for 3b, Table 1). Such monohydroxy aporphines are
expected to have higher chemical stability and oral bioavail-
ability than catechol-aporphines such as apomorphine and N-n-
propylnorapomorphine.
was added. The mixture was extracted with CH
At 0–5 °C, the aqueous phase was acidified to pH ) 1–2 with 10%
vol) HCl and then made basic to pH 9–10 with NH OH. The
mixture was extracted with CH Cl
2
Cl
2
(50 mL × 3).
(
4
Experimental Section
2
2
(50 mL × 3). The combined
1
13
General Synthetic Methods. H and C NMR spectra were
recorded at 300 and 75 MHz, respectively, using CDCl as solvent,
except compounds 8a, 8b, 8c, and 3d were in DMSO-d , on a
Bruker AC300 spectrometer. Chemical shifts are given as δ value
ppm) downfield from tetramethylsilane as an internal reference.
organic layer was washed with brine (100 mL), dried with sodium
sulfate, and concentrated in vacuo. The residue was purified by
chromatography over a short column of silica gel eluting with
CH OH/CH Cl (1:20, vol) to provide N-alkylnororipavine.
3
6
3
2
2
1
(
Oripavine (6a): solid (28%); H NMR (300 MHz, CDCl ) δ
6.63 (d, J ) 8.0 Hz, 1H), 6.53 (d, J ) 8.0 Hz, 1H), 5.58 (d, J ) 6.4
3
Melting points were determined on a Thomas-Hoover capillary tube
apparatus and are reported uncorrected. GC-MS analyses were
performed with a Hewlett-Packard 5890 (Wilmington, DE) gas
chromatograph interfaced with a Hewlett-Packard 5972 mass
selective detector. Element analyses, performed by Atlantic Mi-
crolabs, Atlanta, GA, were within ( 0.4% of theoretical values.
Analytical thin-layer chromatography (TLC) was carried out on
Hz, 1H), 5.27 (s, 1H), 5.06 (d, J ) 6.4 Hz, 1H), 3.73 (d, J ) 7.2 Hz,
1H), 3.59 (s, 3H), 3.33 (d, J ) 18.3 Hz, 1H), 2.98–2.89 (m, 1H),
2.77–2.69 (m, 2H), 2.48 (s, 3H), 2.24 (m, 1H), 1.72 (dd, J ) 12.6
13
and 2.1 Hz, 1H); C NMR (75 MHz, CDCl ) δ 152.2, 143.1, 139.0,
132.7, 131.8, 126.2, 119.7, 116.6, 112.1, 96.2, 89.0, 60.6, 54.9,
3
46.2, 45.6, 41.6, 36.0, 30.4.
1
0
.2-mm Kieselgel 60F-254 silica gel plastic sheets (EM Science,
N-Ethylnororipavine (6b): solid (25%); mp 130–132 °C; H
Newark, NJ). Flash chromatography was used for the routine
purification of reaction products.
NMR (300 MHz, CDCl ) δ 6.63 (d, J ) 8.1 Hz, 1H), 6.53 (d, J )
3
8.1 Hz, 1H), 5.57 (d, J ) 6.4 Hz, 1H), 5.27 (s, 1H), 5.05 (d, J ) 6.4
Northebaine (4). A mixture of thebaine (12 g, 38.5 mmol) and
diethyl azodicarboxylate (DEAD) (8.7 g, 7.8 mL, 50 mmol) in dry
benzene (80 mL) was refluxed for 3 days. The mixture was
evaporated, and MeOH (100 mL) was added to the system followed
by pyridine hydrochloride (7.08 g, 61.6 mmol). The mixture was
stirred overnight. The solvent was evaporated in Vacuo to provide
a brown gum. MeOH (5 mL) and EtOAc (200 mL) were added to
the mixture and stirred for 2 days. The mixture was filtered to yield
northebaine hydrochloride as a white solid (4.8g, 37%): mp 270–272
Hz, 1H), 3.83 (d, J ) 6.9 Hz, 1H), 3.59 (s, 3H), 3.29 (d, J ) 18.3 Hz,
1H), 2.88–2.66 (m, 5H), 2.20 (m, 1H), 1.70 (d, J ) 12.3 Hz, 1H),
1
3
1.14 (t, J ) 7.2 Hz, 3H); C NMR (75 MHz, CDCl ) δ 152.2, 143.0,
3
138.8, 133.0, 132.3, 126.5, 119.7, 116.5, 111.9, 96.2, 89.2, 58.3, 54.9,
47.4, 46.7, 43.3, 36.1, 30.9, 12.5.
N-Propylnororipavine (6c): foam (37%); H NMR (300 MHz,
1
CDCl ) δ 6.64 (d, J ) 8.1 Hz, 1H), 6.50 (d, J ) 8.1 Hz, 1H), 5.59
3
(d, J ) 6.4 Hz, 1H), 5.28 (s, 1H), 5.03 (d, J ) 6.4 Hz, 1H), 3.86
(d, J ) 6.9 Hz, 1H), 3.56 (s, 3H), 3.39 (d, J ) 18.3 Hz, 1H),
3.02–2.63 (m, 5H), 2.22 (m, 1H), 1.70–59 (m, 3H), 0.91 (t, J )
1
1
°
C (lit. mp 270–272 °C).
1
3
7
1
4
3
.5 Hz, 3H); C NMR (75 MHz, CDCl ) δ 152.2, 143.5, 139.4,
General Procedure for the Synthesis of N-Alkylnorthebaines
b-d. A mixture of RI (12 mmol), K CO (3.04 g, 22 mmol), and
2 3
33.0, 126.2, 119.9, 117.1, 113.3, 96.3, 89.0, 59.4, 55.4, 55.1, 53.6,
6.7, 43.7, 31.9, 28.6, 20.3, 12.2.
N-Butylnororipavine (6d): oil (15%); H NMR (300 MHz,
5
northebaine hydrochloride (3.30 g, 10 mmol) in EtOH (70 mL)
was refluxed overnight. Ethanol was removed in Vacuo. Water (50
mL) was added into the residue and extracted with EtOAc (30 mL
1
CDCl
3
) δ 6.64 (d, J ) 8.1 Hz, 1H), 6.53 (d, J ) 8.1 Hz, 1H), 5.57
(
(
2
d, J ) 6.4 Hz, 1H), 5.27 (s, 1H), 5.05 (d, J ) 6.4 Hz, 1H), 3.80
×
3). The combined organic layer was washed with brine (50 mL),
dried with Na SO , and evaporated in vacuo. The residue was
purified by chromatography over a short column of silica gel, eluting
with CH OH/CH Cl (1:100, vols).
N-Ethylnorthebaine (5b): oil (74%); H NMR (300 MHz,
CDCl ) δ 6.66 (d, J ) 8.2 Hz, 1H), 6.60 (d, J ) 8.2 Hz, 1H), 5.57
d, J ) 6.5 Hz, 1H), 5.30 (s, 1H), 5.03 (d, J ) 6.5 Hz, 1H), 3.85
s, 3H), 3.77 (d, J ) 7.2 Hz, 1H), 3.60 (s, 3H), 3.30 (d, J ) 17.7
d, J ) 6.6 Hz, 1H), 3.59 (s, 3H), 3.31 (d, J ) 18.0 Hz, 1H),
2
4
.90–2.58 (m, 5H), 2.21 (m, 1H), 1.70 (d, J ) 12.6 Hz, 1H),
.58–1.48 (m, 2H), 1.39–1.27 (m, 2H), 0.92 (t, J ) 7.5 Hz, 3H);
1
3
2
2
1
3
1
C NMR (75 MHz, CDCl ) δ 152.2, 143.0, 138.6, 132.9, 132.1,
3
1
3
26.6, 119.8, 116.4, 112.0, 96.3, 89.3, 58.9, 54.9, 53.5, 46.7, 43.8,
3
6.1, 31.0, 29.5, 20.8, 14.0.
(
(
General Procedure for the Synthesis of N-Alkyl-3-O-[(tri-
Hz, 1H), 2.82–2.74 (m, 3H), 2.70–2.62 (m, 2H), 2.19 (m, 1H), 1.74
fluoromethyl)sulfonyl]oripavines 7a–d. Under nitrogen, N-phe-
nyltrifluoromethanesulfonimide (11 mmol) was added to a mixture
of N-alkylnororipavine (10 mmol) and triethylamine (2.1 mL, 15
mmol) in CH Cl (50 mL). The resulting mixture was stirred at rt
2 2
for 3 h. The reaction mixture was washed with 30 mL of water
and 30 mL of brine. The organic layer was dried with anhydrous
1
3
(
(
1
3
dt, J ) 12.0 and 2.7 Hz, 1H), 1.16 (t, J ) 7.2 Hz, 3H); C NMR
75 MHz, CDCl ) δ 152.5, 144.6, 142.8, 133.4, 131.9, 127.5, 119.2,
12.7, 111.9, 95.8, 89.1, 58.4, 56.3, 54.9, 47.7, 46.4, 43.6, 36.6,
0.3, 12.8.
N-Propylnorthebaine (5c): solid (68%); mp 134–136 °C; H
NMR (300 MHz, CDCl ) δ 6.65 (d, J ) 8.2 Hz, 1H), 6.59 (d, J )
.2 Hz, 1H), 5.54 (d, J ) 6.4 Hz, 1H), 5.29 (s, 1H), 5.03 (d, J )
.4 Hz, 1H), 3.85 (s, 3H), 3.70 (d, J ) 6.9 Hz, 1H), 3.59 (s, 3H),
.28 (d, J ) 18.0 Hz, 1H), 2.81–2.66 (m, 3H), 2.54–2.49 (m, 2H),
.19 (m, 1H), 1.70 (m, 1H), 1.58–1.50 (m, 2H), 0.93 (t, J ) 7.2
3
1
3
2 4
Na SO , and the solvent was evaporated. The residue was dissolved
8
6
3
2
in ether (60 mL) and extracted with 1 M HCl (4 × 50 mL). The
combined acidic layer was basified with ammonium hydroxide, and
the mixture was extracted with CH
layer was washed with brine (80 mL) and dried with anhydrous
Na SO . The solvent was evaporated. The residue was purified by
chromatography over a short column of silica gel, eluting with
CH Cl /MeOH (20:1) to yield the product.
2
Cl
2
(3 × 50 mL). The organic
13
Hz, 3H); C NMR (75 MHz, CDCl
1
4
3
) δ 152.5, 144.6, 142.7, 133.5,
32.7, 127.8, 119.1, 112.7, 111.4, 95.9, 89.2, 58.8, 56.3, 56.2, 54.9,
6.5, 44.2, 36.9, 30.4, 21.0, 12.0.
2
4
2
2

9
86 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4
-O-[(Trifluoromethyl)sulfonyl]oripavine (7a): solid (75%); mp
Si et al.
3
(R)-(-)-N-Butyl-2-methoxy-10-O-[(trifluoromethyl)sulfonyl]-
11-hydroxynoraporphine (8d): solid (45%); mp 165–167 °C dec;
1
1
1
1
3
2
1
1
9
43–145 °C; H NMR (300 MHz, CDCl
3
) δ 6.94 (d, J ) 8.6 Hz,
1
H), 6.66 (d, J ) 8.6 Hz, 1H), 5.59 (d, J ) 6.4 Hz, 1H), 5.39 (s,
H), 5.06 (d, J ) 6.4 Hz, 1H), 3.64 (d, J ) 6.9 Hz, 1H), 3.61 (s,
H), 3.34 (d, J ) 18.6 Hz, 1H),2.82–2.63 (m, 3H), 2.46 (s, 3H),
.24 (ddd, J ) 12.6, 5.1 and 5.1 Hz, 1H), 1.75 (dd, J ) 12.6 and
3
H NMR (300 MHz, CDCl ) δ 7.55 (d, J ) 2.4 Hz, 1H), 7.07 (d,
J ) 8.4 Hz, 1H), 6.82 (d, J ) 8.4 Hz, 1H), 6.55 (d, J ) 2.4 Hz,
1H), 3.75 (s, 3H), 3.29–2.85 (m, 5H), 2.67 (m, 1H), 2.53–2.41 (m,
3H), 1.58–1.48 (m, 2H), 1.40–1.32 (m, 2H), 0.96 (t, J ) 7.5 Hz,
1
3
13
.8 Hz, 1H); C NMR (75 MHz, CDCl
3
) δ 152.0, 147.85, 136.0,
3
3H); C NMR (75 MHz, CDCl ) δ158.0, 138.0, 135.0, 131.5,
35.7, 131.2, 131.1, 121.5, 119.7, 118.7 (q, J ) 318 Hz), 112.2,
6.3, 90.8, 60.3, 55.0, 45.9, 45.7, 42.3, 36.6, 29.8.
130.6, 127.0, 126.6, 124.3, 120.3, 120.1, 118.3 (J ) 270.8 Hz),
112.6, 111.1, 58.6, 55.2, 53.4, 48.5, 34.5, 28.8, 27.9, 20.7, 14.0.
N-Ethyl-3-O-[(trifluoromethyl)sulfonyl]nororipavine (7b): oil
3 5
Anal. (C22H24NF O S) C, H, N.
1
(
73%); H NMR (300 MHz, CDCl
3
) δ 6.93 (d, J ) 8.6 Hz, 1H),
General Procedure for the Synthesis of N-Alkyl-2-methoxy-
1-hydroxynoraporphine 3a–d. Metallic Mg (36 mg, 1.5 mmol)
6
5
3
2
7
1
9
.65 (d, J ) 8.6 Hz, 1H), 5.56 (d, J ) 6.5 Hz, 1H), 5.38 (s, 1H),
.06 (d, J ) 6.5 Hz, 1H), 3.72 (d, J ) 7.2 Hz, 1H), 3.61 (s, 3H),
.30 (d, J ) 18.6 Hz, 1H), 2.77–2.68 (m, 3H), 2.53–2.49 (m, 2H),
.23 (m, 1H), 1.74–1.68 (m, 1H), 1.58–1.51 (m, 2H), 1.15 (t, J )
1
and NH
triflates 8a–d (0.5 mmol) and 10% (wt) Pd/C (44 mg) in MeOH
15 mL) at rt under nitrogen. The resulting mixture was stirred at
4
OAc (193 mg, 2.5 mmol) were added to a mixture of the
(
1
3
3
.2 Hz, 3H); C NMR (75 MHz, CDCl ) δ 152.0, 147.8, 136.1,
rt for 24 h and filtered with Celite. The residue was washed with
35.9, 131.2, 131.2 121.4, 119.7, 118.6 (J ) 319 Hz), 112.4, 96.3,
MeOH (2 × 20 mL). The filtrate was evaporated to dryness and
0.8, 58.0, 55.0, 47.7, 46.5, 43.4, 36.3, 30.7, 12.9.
2 2
dissolved in 100 mL of CH Cl . The solution was washed with 30
N-Propyl-3-O-[(trifluoromethyl)sulfonyl]nororipavine (7c):
mL of 10% (wt) ammonium hydroxide and 50 mL of brine. The
1
solid (72%); mp 105–107 °C; H NMR (300 MHz, CDCl
d, J ) 8.2 Hz, 1H), 6.64 (d, J ) 8.2 Hz, 1H), 5.56 (d, J ) 6.5 Hz,
3
) δ 6.93
organic layer was dried with anhydrous Na SO and evaporated in
2
4
(
Vacuo to dryness. The residue was purified by chromatography over
1
1
2
H), 5.38 (s, 1H), 5.06 (d, J ) 6.5 Hz, 1H), 3.72 (d, J ) 7.2 Hz,
H), 3.61 (s, 3H), 3.30 (d, J ) 18.6 Hz, 1H), 2.77–2.68 (m, 3H),
.53–2.49 (m, 2H), 2.23 (m, 1H), 1.74–1.68 (m, 1H), 1.58–1.51
a short column of silica gel, eluting with CH Cl /MeOH (100:1,
2
2
vol), and recrystallized from CH Cl to yield a colorless solid. The
2
2
free base was converted to HCl salt with 1 N HCl-ether.
1
3
(
3
m, 2H), 0.94 (t, J ) 6.9 Hz, 3H); C NMR (75 MHz, CDCl ) δ
(R)-(-)-2-Methoxy-11-hydroxyaporphine (3a): solid (75%);
1
1
3
2
51.9, 147.8, 136.2, 136.0, 131.6, 131.2, 121.4, 119.7, 118.6 (J )
mp (base) 214–215 °C; H NMR (base, 300 MHz, CDCl ) δ 7.61
3
19 Hz), 112.1, 96.3, 90.8, 58.5, 56.1, 55.0, 46.5, 43.8, 36.5, 31.0,
1.0, 11.9.
(d, J ) 2.7 Hz, 1H), 7.08 (dd, J ) 7.2 and 7.8 Hz, 1H), 6.85 (d, J
) 7.2 Hz, 1H), 6.76 (d, J ) 7.8 Hz, 1H), 6.61 (d, J ) 2.7 Hz, 1H),
3.80 (s, 3H), 3.25–3.02 (m, 4H), 2.76–2.49 (m, 3H), 2.55 (s, 3H);
N-Butyl-3-O-[(trifluoromethyl)sulfonyl]nororipavine (7d): oil
1
13
(
75%); H NMR (300 MHz, CDCl
3
) δ 6.93 (d, J ) 8.4 Hz, 1H),
C NMR (base, 75 MHz, CDCl ) δ 158.0, 152.8, 138.5, 134.5,
3
6
5
3
2
.65 (d, J ) 8.4 Hz, 1H), 5.57 (d, J ) 6.6 Hz, 1H), 5.38 (s, 1H),
.06 (d, J ) 6.6 Hz, 1H), 3.73 (d, J ) 7.2 Hz, 1H), 3.61 (s, 3H),
.30 (d, J ) 18.6 Hz, 1H), 2.77–2.68 (m, 3H), 2.57–2.52 (m, 2H),
.23 (m, 1H), 1.74–1.69 (m, 1H), 1.56–1.46 (m, 2H), 1.42–1.28
132.4, 128.2, 127.4, 121.1, 120.7, 115.6, 111.9, 111.1, 61.8, 55.2,
53.1, 43.9, 35.3, 29.4; MS (EI): m/z 281 (M ). Anal. (C H NO )
+
1
8
19
2
C, H, N.
(
R)-(-)-N-Ethyl-2-methoxy-11-hydroxynoraporphine (3b):
1
3
(
m, 2H), 0.94 (t, J ) 7.2 Hz, 3H); C NMR (75 MHz, CDCl
δ151.9, 147.8, 136.2, 136.0, 131.5, 131.2, 121.4, 119.7, 118.7 (J
322.5 Hz), 112.2, 96.3, 90.8, 58.4, 54.9, 53.9, 46.5, 43.9, 36.4,
3
)
1
solid (66%); mp (HCl salt) 214–215 °C; H NMR (base) (300 MHz,
CDCl
3
) δ 7.68 (d, J ) 2.5 Hz, 1H), 7.01 (t, J ) 7.8 Hz, 1H), 6.79
d, J ) 7.2 Hz, 1H), 6.70 (d, J ) 8.1 Hz, 1H), 6.58 (d, J ) 2.5 Hz,
)
3
(
1
0.9, 29.9, 20.7, 14.0.
H), 3.78 (s, 3H), 3.35 (d, J ) 13.5 Hz, 1H), 3.21–3.05 (m, 4H),
13
General Procedure for the Synthesis of N-Alkyl-2-methoxy-
0-O-[(trifluoromethyl)sulfonyl]-11-hydroxynoraporphines 8a–
d. The triflates 7a–d (5.6 mmol) were dissolved in 99% (vol)
methanesulfonic acid (15 mL, 232 mmol) under nitrogen at rt. The
resulting mixture was stirred for 30 min at 90 °C and then cooled
to rt. Ice–water (50 mL) was added, and the mixture was made
2.76–2.50 (m, 4H), 1.18 (t, J ) 6.9 Hz, 3H); C NMR (base, 75
1
MHz, CDCl ) δ 157.8, 153.0, 138.3, 134.4, 132.8, 128.1, 127.3,
3
121.2, 120.3, 115.6, 111.9, 111.4, 58.6, 55.2, 48.0, 47.7, 34.9, 29.1,
+
10.5; MS (EI) m/z 296 (M + H) . Anal. (C H NO ·HCl·0.9H O)
C, H, N.
19
21
2
2
(
R)-(-)-N-Propyl-2-methoxy-11-hydroxynoraporphine (3c):
basic with ammonium hydroxide and extracted with CH
0 mL). The organic layer was washed with brine (50 mL) and
dried with anhydrous Na SO . The solvent was evaporated. The
residue was purified by chromatography over a short column of
silica gel, eluting with CH Cl /MeOH (50:1, vol), and recrystalized
from methanol to yield compounds 8a-d.
R)-(-)-2-Methoxy-10-O-[(trifluoromethyl)sulfonyl]-11-hy-
2
Cl
2
(3 ×
1
solid (76%); mp (HCl salt) 188–190 °C dec; H NMR (base, 300
MHz, CDCl ) δ 7.68 (d, J ) 2.7 Hz, 1H), 7.01 (t, J ) 7.8 Hz,
H), 6.80 (d, J ) 7.5 Hz, 1H), 6.68 (d, J ) 8.1 Hz, 1H), 6.57 (d,
J ) 2.7 Hz, 1H), 3.78 (s, 3H), 3.35 (d, J ) 13.5 Hz, 1H), 3.21–3.05
m, 3H), 2.92–2.89 (m, 1H), 2.74–2.68 (m, 1H), 2.59–2.43 (m, 3H),
5
3
2
4
1
2
2
(
1
13
.65–1.57 (m, 2H), 0.95 (t, J ) 7.5 Hz, 3H); C NMR (base, 75
(
MHz, CDCl ) δ 157.8, 153.1, 138.5, 134.5, 132.8, 128.1, 127.6,
121.2, 120.3, 115.6, 111.9, 111.4, 59.2, 56.3, 55.2, 48.9, 35.1, 29.2,
19.0, 12.1; MS (EI) m/z 310 (M + H) . Anal. (C H NO ·HCl·
2
1.25H O) C, H, N.
3
1
droxyaporphine (8a): solid (56%); mp 168–170 °C; H NMR (300
MHz, DMSO-d ) δ 7.66 (br, 1H), 7.24 (d, J ) 8.1 Hz, 1H), 7.18
d, J ) 2.7 Hz, 1H), 6.95 (d, J ) 8.1 Hz, 1H), 6.71 (dd, J ) 12.9
and 2.7 Hz, 1H), 3.75 (s, 3H), 3.25–2.67 (m, 6H), 2.44 (s, 3H),
+
6
2
0
23
2
(
(
R)-(-)-N-Butyl-2-methoxy-11-hydroxynoraporphine (3d).
2
.38–2.16 (m, 1H). Anal. (C19
R)-(-)-N-Ethyl-2-methoxy-10-O-[(trifluoromethyl)sulfonyl]-
1-hydroxynoraporphine (8b): solid (42%); mp 178–180 °C dec;
H18NF
3
O
5
S) C, H, N.
1
solid (55%); mp (HCl salt) 218–220 °C dec; H NMR (HCl salt,
(
300 MHz, DMSO-d ) δ 11.02 (br, 1H), 10.16 (s, 1H), 7.91 (d, J )
6
1
2.4 Hz, 1H), 7.11 (t, J ) 7.8 Hz, 1H), 6.93 (d, J ) 7.8 Hz, 1H),
1
H NMR (300 MHz, DMSO-d
6
) δ 7.64 (s, br, 1H), 7.24 (dd, J )
.1 and 5.1 Hz, 1H), 7.16 (d, J ) 2.4 Hz, 1H), 6.94 (d, J ) 8.1 Hz,
H), 6.70 (dd, J ) 12.9 and 2.4 Hz, 1H), 3.74 (s, 3H), 3.23–2.88
6.86 (d, J ) 7.2 Hz, 1H), 6.76 (d, J ) 2.4 Hz, 1H), 4.29 (m, 1H),
3.82 (m, 1H), 3.77 (s, 3H), 3.53–3.27 (m, 3H), 3.16–2.88 (m, 4H),
1.80–1.72 (m, 2H), 1.45–1.33 (m, 2H), 0.95 (t, J ) 7.5 Hz, 3H);
8
1
(
1
3
m, 6H), 2.70 (m, 1H), 2.38–2.11 (m, 2H), 1.05 (t, J ) 5.7 Hz,
6
C NMR (HCl salt, 75 MHz, DMSO-d ) δ158.2, 154.8, 135.3,
3
H). Anal. (C20
H20NF
3
O
5
S) C, H, N.
133.2, 131.4, 128.7, 121.1, 119.5, 119.3, 115.9, 113.7, 110.7, 59.0,
(
R)-(-)-N-Propyl-2-methoxy-10-O-[(trifluoromethyl)sulfonyl]-
55.1, 52.6, 47.9, 31.1, 25.9, 24.7, 19.6, 13.6; MS (EI) m/z 324 (M
1
+
1
1-hydroxynoraporphine (8c): solid (44%); mp 173–175 °C; H
) δ 7.65 (br, 1H), 7.25 (t, J ) 8.1 Hz,
H), 7.18 (d, J ) 2.7 Hz, 1H), 6.95 (d, J ) 8.1 Hz, 1H), 6.72 (dd,
+ H) . Anal. (C21
H25NO
2
2
·HCl·1.25H O) C, H, N.
NMR (300 MHz, DMSO-d
6
Acknowledgment. This work was supported by the Bran-
fman Family Foundation. We thank Dr. Michael Decker for
the MS analysis. Morphine, thebaine, and oripavine were
generously supplied by Mallinckrodt, Inc.
1
J ) 12.3 and 2.7 Hz, 1H), 3.76 (s, 3H), 3.19–3.11 (m, 3H),
3
7
.00–2.65 (m, 3H), 2.35–2.26 (m, 3H), 1.52 (m, 2H), 0.92 (t, J )
.2 Hz, 3H).

Synthesis of N-Alkyl-11-hydroxy-2-methoxynoraporphines
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 4 987
Supporting Information Available: Results from elemental
analysis. This material is available free of charge via the Internet
at http://pubs.acs.org.
Zong, R.; Neumeyer, J. L. Synthesis of 2-fluoro-11-hydroxy-N-
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