Development of 3-phenyltropane analogues with high affinity for the dopamine and serotonin transporters and low affinity for the norepinephrine transporter

Article abstract of DOI:10.1021/jm801162z

Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine transporter (DAT) occupancy. In this study, a series of 3β-(substituted phenyl)tropane- 2β-carboxylic acid methyl esters (7a-g), 3β-(4-methoxyphenyl)tropane- 2β-carboxylic acid esters (8a-j), and 3β-(4-methoxyphenyl)-2β-[3- (4′-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoamine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities for both the DAT and 5-HTT and low affinity for the NET. 3β-(4-Methoxyphenyl) tropane-2β-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC50 value of 2.5 nM for the DAT and K_i values of 3.5 and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the DAT and 5-HTT relative to the NET in this study.

Full text of DOI:10.1021/jm801162z

8048
J. Med. Chem. 2008, 51, 8048–8056
Development of 3-Phenyltropane Analogues with High Affinity for the Dopamine and Serotonin
Transporters and Low Affinity for the Norepinephrine Transporter
Chunyang Jin, Herna´n A. Navarro, and F. Ivy Carroll*
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709-2194
ReceiVed September 16, 2008
Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-
administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine
transporter (DAT) occupancy. In this study, a series of 3ꢀ-(substituted phenyl)tropane-2ꢀ-carboxylic acid
methyl esters (7a-g), 3ꢀ-(4-methoxyphenyl)tropane-2ꢀ-carboxylic acid esters (8a-j), and 3ꢀ-(4-methox-
yphenyl)-2ꢀ-[3-(4′-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoam-
ine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT
relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities
for both the DAT and 5-HTT and low affinity for the NET. 3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic
acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC50 value of 2.5 nM for the DAT and Ki values of
3.5 and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the
DAT and 5-HTT relative to the NET in this study.
Introduction
monkeys with 3 produced a dose-dependent reduction in cocaine
maintained responding in all subjects trained to self-administer
cocaine under a multiple second-order schedule.19 Coadminis-
tration of the dose of 3 that reduced cocaine-maintained behavior
by 50% (ED50) with the selective serotonin transporter (5-HTT)
inhibitor fluoxetine (4) or citalopram (5) produced a more robust
reduction in cocaine self-administration compared with 3 alone
(Figure 1).
Studies in the low-to-mid 1980s established that cocaine (1)
blocks the uptake of dopamine (DAa), serotonin (5-HT), and
norepinephrine (NE).1,2 However, the behavioral stimulant and
reinforcing effects of cocaine associated with its abuse liability
have been linked more closely to inhibition of dopamine
uptake.3-5 The results from these studies led to the so-called
“dopamine hypothesis”, which proposed that the reinforcing
properties of cocaine were due to the inhibition of dopamine
uptake resulting in a buildup of dopamine in the synaptic cleft,
leading to significant potentiation of dopaminergic transmission.4,6
Numerous cocaine-discrimination and self-administration studies
in laboratory animals support this dopamine hypothesis.7
Importantly, neuroimaging studies in humans showed a signifi-
cant correlation between the level of dopamine transporter
(DAT) occupancy in the brain and the magnitude of the
subjective high reported following administration of cocaine8
and methylphenidate (2).9 Collectively, the results obtained in
behavioral and neuroimaging studies provide compelling evi-
dence that dopamine plays a major role in the neuropharma-
cology and addictive properties of cocaine. On the basis of the
importance of the DAT in the addictive properties of cocaine,
compounds that target the DAT and share some, but not all of
the pharmacological properties of cocaine, are of interest as
indirect dopamine agonist pharmacotherapies to treat cocaine
addiction and dependence.10-13
Other preclinical studies have also suggested that inhibition
of the 5-HTT can modulate the behavioral effects of psycho-
motor stimulants. For example, the early studies that reported
a positive correlation between compounds binding to the DAT
and their reinforcing effects in animals reported a negative
relationship between the potencies of several cocaine-like
compounds in self-administration studies and their binding
potencies to the 5-HTT.6,20
3ꢀ-(4-Chloro-3-methylphenyl)tropane-2ꢀ-carboxylic acid meth-
yl ester (6, RTI-112) is a 3-phenyltropane analogue that shows
subnanomolar affinity for inhibition of both the DAT and
5-HTT.21 In a study to characterize the effects of 6 in
pretreatment in rhesus monkeys trained to self-administer
cocaine under a second-order schedule of iv drug delivery, 6
possessed an ED50 of 0.03 mg/kg.22 Even though 6 showed
greater than 70% DAT occupancy at the highest dose tested,
DAT occupancy was below the limits of detection at the ED50
for reduction of cocaine self-administration.22 Compound 6,
which has about equal affinity for DAT and 5-HTT inhibition,
showed 84% occupancy of the 5-HTT at the ED50 dose.22
Importantly, 6 failed to maintain robust drug self-administration
in any of the three rhesus monkeys studied.22 In addition, 6 did
not exhibit any reinforcement effects in squirrel monkeys.23
Overall, these results suggest that mixed action inhibitors of
DAT and 5-HTT warrant consideration as potential pharmaco-
therapies for treating cocaine abuse.
Over the last several years, the DAT selective 3ꢀ-(4-
chlorophenyl)-2ꢀ-[3-(4′-methylphenyl)isoxazol-5-yl]tropane (3,
RTI-336) has been developed as an indirect dopamine agonist
(DAT inhibitor) as a potential pharmacotherapy for treating
patients addicted to cocaine.14-18 Pretreatment of rhesus
* To whom correspondence should be addressed. Phone: 919 541-6679.
Fax: 919 541-8868. E-mail: fic@rti.org. Address: Research Triangle
Institute, Post Office Box 12194, Research Triangle Park, NC 27709-2194.
a Abbreviations: DA, dopamine; 5-HT, serotonin; NE, norepinephrine;
DAT, dopamine transporter; 5-HTT, serotonin transporter; NET, norepi-
nephrine transporter; SAR, structure activity relationship; TFA, trifluoro-
acetic acid; NBS, N-bromosuccinimide; DMF, dimethylformamide; THF,
tetrahydrofuran; APCI, atmospheric pressure chemical ionization; ESI,
turbospray ionization; EI, electron impact.
The present study was undertaken to characterize the SAR
of 3ꢀ-phenyltropanes to develop novel compounds with high
affinities for both the DAT and 5-HTT while having low affinity
for the NET. In this paper, we describe the design, synthesis,
and monoamine transporter binding properties of several new
10.1021/jm801162z CCC: $40.75
2008 American Chemical Society
Published on Web 11/21/2008

3-Phenyltropane Analogues
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 8049
Figure 1. Structures of ligands.
Figure 2. 3ꢀ-Phenyltropanes.
Scheme 1a
3ꢀ-(substituted phenyl)tropane analogues 7a-g, 8a-j, and 9
(Figure 2). We report that 3ꢀ-(4-methoxyphenyl)tropane-2ꢀ-
carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) has
high-binding affinity at the DAT with an IC50 value of 2.5 nM
and the 5-HTT with a Ki value of 3.5 nM, respectively, and
good selectivity for the DAT and 5-HTT relative to the NET
(Ki ) 2040 nM).
Chemistry. All the compounds described in this study were
prepared starting from natural (-)-cocaine, and therefore, they
are optically active and possess the same absolute configuration
as (-)-cocaine. The synthesis of 3ꢀ-(substituted phenyl)tropane-
2ꢀ-carboxylic acid methyl esters 7a-g starting from anhydro-
ecgonine methyl ester (10) is outlined in Scheme 1. Conjugate
addition of 10 with the appropriate Grignard reagent at -45
°C in ethyl ether followed by trifluroacetic acid (TFA) afforded
7a-c in the range of 20-73% yield. Bromination of 3ꢀ-(4-
methoxyphenyl)tropane-2ꢀ-carboxylic acid methyl ester (7a)
with 1.1 equiv of bromine in the presence of tin(IV) chloride
gave the 3ꢀ-(3-bromo-4-methoxyphenyl)tropane 7d in 86%
yield. Treatment of 7a with 2.2 equiv of bromine provided a
67% yield of 3ꢀ-(3,5-dibromo-4-methoxyphenyl)tropane 7e.
Iodination of 7a with iodine chloride in acetic acid yielded the
3ꢀ-(3-iodo-4-methoxyphenyl)tropane 7f in 23% yield. The 3ꢀ-
(3,5-diiodo-4-methoxyphenyl) analogue 7g was synthesized in
94% yield by treatment of 7a with bis(pyridine)iodonium (I)
tetrafluoroborate and trifluoromethanesulfonic acid in dioxane.
Scheme 2 and Scheme 3 outline the synthesis of 3ꢀ-(4-
methoxyphenyl)tropane-2ꢀ-carboxylic acid esters 8a-j. Hy-
drolysis of 7a in aqueous dioxane gave the carboxylic acid 11
(Scheme 2). Treatment of 11 with oxalyl chloride afforded the
corresponding acid chloride, which was converted to the esters
8a-d in the range of 46-92% yield, by treatment with the
a Reagents: (a) ArMgBr, Et2O, -45 °C, 2 h, then -78 °C; (b) TFA; (c)
1.1 equiv Br2, 2.0 equiv SnCl4, 0 °C, 30 min for 7d; (d) 2.2 equiv Br2, 4.0
equiv SnCl4, room temperature, 3 h for 7e; (e) ICl, AcOH, room temperature,
24 h for 7f; (f) I(Py)2BF4, CF3SO3H, dioxane, room temperature, 3 h for
7g.
appropriate alcohol. Selective reduction of the p-nitrophenethyl
ester 8d by hydrogenation with catalytic platinum oxide in
methanol provided the amine 8e in 97% yield (Scheme 3).
Treatment of 8e with acetyl chloride and triethylamine gave
the amide 8f in 93% yield. Bromination of amine 8e with 1
equiv of N-bromosuccinimide (NBS) in dimethylformamide
(DMF) provided a 64% yield of 3-bromo-4-amino analogue 8g

8050 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24
Jin et al.
Scheme 2a
should further understanding of the mechanism of cocaine abuse
and lead to new pharmacotherapies for treatment.
Studies directed toward the 3-phenyltropane class of DAT
uptake inhibitors have provided valuable information about the
pharmacophore for the DAT as well as the 5-HTT and NET.18,30
SAR studies from our laboratory as well as others have shown
that the binding affinity for the monoamine transporters is highly
dependent on the nature and position of the substituents on the
3ꢀ-phenyl ring.18,30 In our original studies of 3ꢀ-phenyltropane
analogues, we reported that 3ꢀ-(4-methoxyphenyl)tropane-2ꢀ-
carboxylic acid methyl ester (7a) possessed an IC50 value of
6.5 nM at the DAT.24 Later, we found that 7a also exhibited
high affinity at the 5-HTT (Ki ) 4.3 nM), while having much
less affinity at the NET (Ki ) 1110 nM). In the present study,
we further explored the effect of adding additional substituents
to the 3ꢀ-(4-methoxyphenyl) ring of 7a (7b-g) or replacing
the 2ꢀ-carbomethoxy of 7a with other ester groups (8a-j) or
an isoxazole heterocyclic group (9) on DAT, 5-HTT, and NET
binding affinity. The ratio of Ki/IC50 values of NET/DAT and
the ratio of Ki values of NET/5-HTT were calculated as a
measure of the in vitro selectivity of the compounds for the
DAT relative to the NET and the 5-HTT relative to the NET,
respectively. The binding properties of 7a and the 3ꢀ-phenyl-
tropane analogues 7b-g with modifications on the 3ꢀ-phenyl
ring are presented in Table 1. Compound 7a with an IC50 value
of 6.5 nM at the DAT and a Ki value of 4.3 nM at the 5-HTT
is highly potent at both transporters. Importantly, it has a Ki
value of 1110 nM at the NET and thus is also highly selective
for the DAT and 5-HTT relative to the NET. Replacement of
the 4-methoxy group of 7a with the larger ethoxy substitution
afforded 7b with slightly increased affinity at the 5-HTT (4.3
nM vs 1.7 nM) but having 14-fold less affinity at the DAT (6.5
vs 92 nM). The addition of one halogen atom (F, Br or I) ortho
to the 4-methoxy group of 7a had a little effect on the binding
affinity at the 5-HTT with Ki values ranging from 3.1 to 4.8
nM (7c, 7d, and 7e). However, these compounds showed 4- to
7-fold increase of potency at the NET (160-270 nM vs 1100
nM of 7a) while having decreased affinity at the DAT (16-170
nM vs 6.5 nM of 7a). It is interesting to note that the addition
of dibromo or diiodo substitutions ortho to the 4-methoxy group,
which led to 7f and 7g resulted in approximately 4- to 5-fold
loss of binding affinity at the NET. Thus, 7f with NET/5-HTT
ratio of 1413 is the most selective compound for the
5-HTT relative to the NET in the series 7a-g. It appears that
the 5-HTT is more tolerant to steric substituents on the 3ꢀ-(4-
methoxyphenyl) ring than the NET. However, none of the 3ꢀ-
(substituted phenyl)-2ꢀ-carboxylic methyl ester analogues 7b-g
are as potent and selective for both the DAT and 5-HTT as the
parent compound 7a.
a Reagents: (a) 50% dioxane/H2O, reflux, 3 d; (b) (COCl)2, CH2Cl2, room
temperature, 1 h; (c) ROH, room temperature.
as the only isolated product. The dibrominated product was not
detected under this reaction condition. Alternately, treatment
of 8e with 2 equiv of bromine in acetic acid gave the
3,5-dibromo-4-amino compound 8h in 79% yield. Iodination
of 8e with 1.1 equiv of iodine chloride in acetic acid yielded
the 3-iodo-4-amino compound 8i in 31% yield as well as the
3,5-diiodo-4-amino analogue 8j in 17% yield. The 3ꢀ-(4-
methoxyphenyl)-2ꢀ-[3-(4′-methylphenyl)isoxazol-5-yl]tro-
pane (9) was synthesized using the procedure, outlined in
Scheme 4. Treatment of 4-methylacetophenone oxime with a
solution of n-butyl lithium in hexanes, followed by the addition
of 7a, yielded the ketoxime, which was cyclized with 3N
hydrochloric acid in tetrahydrofuran (THF) to give 9 in 68%
1
yield.14 The H NMR spectra of the target compounds are in
agreement with the assigned structures. The chemical shift and
coupling pattern of the C(2)-H and C(3)-H are consistent with
previously reported compounds that possess the 2ꢀ,3ꢀ-stereo-
chemistry.24-26
Biology. The binding affinities for the target compounds at
the DAT, 5-HTT, and NET were determined via competitive
binding assays using the previously reported procedures.27,28
The final concentration of radioligands in the assays were 0.5
nM [3H]-(-)-2ꢀ-carbomethoxy-3ꢀ-(4-fluorophenyl)tropane (12,
[3H]WIN 35,428)27,28 for the DAT, 0.5 nM [3H]-3-(2-methox-
yphenoxy)-N-methyl-3-phenylpropan-1-amine ([3H]nisoxetine)
for the NET, and 0.2 nM [3H]-(3S)-trans-3-[(1,3-benzodioxol-
5-yloxy)methyl]-4-(4-fluorophenyl)piperidine ([3H]paroxetine)
for the 5-HTT. The results of the binding studies, along with
binding data of cocaine and 629 for comparison are listed in
Tables 1 and 2. The DAT has two binding sites; thus, IC50 values
are reported. Because the 5-HTT and NET have only one
binding site, Ki values were calculated for inhibition of binding
at these two transporters.
A variety of functional groups and substituents are well
tolerated at 2-position of 3ꢀ-phenyltropanes without loss of high
affinity for the DAT, yet the nature of the substituents at
2-position has a profound effect on the monoamine transporter
selectivity.17,31-34 We previously reported that the methyl group
of the 2ꢀ- carbomethoxy substituent of cocaine can be replaced
with large groups (e.g., isopropyl, cyclopropyl, phenyl, phe-
nylethyl, etc.) without significant loss in binding affinity at the
DAT.35 Later determination of these ligands on binding at the
5-HTT and NET revealed that the isopropyl and phenyl esters
of cocaine analogues were reasonably selective for the DAT
relative to the 5-HTT and NET.21 Surprisingly, the phenylethyl
ester analogue showed increased potency at the 5-HTT com-
pared to cocaine. Accordingly, modification of the 2ꢀ-
cabomethoxy substituents of 7a was examined and the binding
Results and Discussion
Despite extensive efforts directed toward the development
of a pharmacotherapy for cocaine abuse, at present no clinically
approved drugs are available. Because the DAT is the critical
recognition site for cocaine and contributes to its abuse liability,
DAT inhibitors represent a promising approach in drug develop-
ment.17 Cocaine also inhibits 5-HT uptake. Animal behavior
studies have demonstrated that selective 5-HT uptake inhibitors
as well as dopamine uptake inhibitors can attenuate cocaine-
induced stimulant and reinforce effects.6 Thus, the synthesis
and pharmacological study of compounds having high affinities
for both the DAT and 5-HTT but with low affinity for the NET

3-Phenyltropane Analogues
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 8051
Scheme 3a
a Reagents: (a) PtO2, H2, MeOH, 3 h; (b) acetyl chloride, Et3N, CH2Cl2, 0 °C, 1 h; (c) 1 equiv NBS, DMF, room temperature, 1 h for 8g; (d) 2 equiv Br2,
AcOH, CH2Cl2, room temperature, 1 h for 8h; (e) 1.1 equiv ICl, AcOH, CH2Cl2, room temperature, 1 h for 8i and 8j.
Scheme 4a
selective compound for the DAT relative to the 5-HTT and NET,
which is analogous to the previously reported 2ꢀ-isoxazoltro-
panes.14
In summary, a series of 3ꢀ-(substituted phenyl)tropane-2ꢀ-
carboxylic acid methyl esters 7a-g, 3ꢀ-(4-methoxyphenyl)tro-
pane-2ꢀ-carboxylic acid esters 8a-j, and 2ꢀ-isoxazoltropane
a Reagents: (a) 4-methylacetophenone oxime/BuLi, room temperature,
16 h; (b) 3 N HCl, THF, 70 °C, 5 h.
analogue 9 were synthesized and evaluated for their monoamine
transporter binding affinities. A number of compounds (7a and
8e-i) exhibited high-binding affinities for both the DAT and
results are presented in Table 2. Changing the methyl ester of
5-HTT and low affinity for the NET. In this study, the most
7a to the larger isopropyl, cyclopropyl, or cyclobutyl groups to
give the esters 8a-c resulted in slightly decreased affinity for
potent and selective compound for both the DAT and 5-HTT
relative to the NET is 3ꢀ-(4-methoxyphenyl)tropane-2ꢀ-car-
the DAT (IC50 ) 6.0-14 nM) while having much larger loss
boxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i). Because
of affinities for both the 5-HTT and NET. Somewhat surpris-
the mixed action inhibitors of DAT and 5-HTT may provide
ingly, the 4-nitrophenethyl ester 8d led to increase of affinities
new pharmacotherapies for treating cocaine abuse, 7a, 8f, and
for both the 5-HTT and NET, with Ki values of 2.9 and 330
8i are promising candidates for further investigation.
nM, respectively, but exhibited 6-fold decreased affinity for the
DAT (IC50 ) 42 nM) as compared to 7a. In contrast, reduction
Experimental Section
of the 4-nitro group of 8d to give the 4-amino analogue 8e
Melting points were determined using a MEL-TEMP II capillary
melting point apparatus and are uncorrected. Nuclear magnetic
regained the high-binding affinity for the DAT (IC50 ) 7.0 nM)
while having much less affinity for the NET (Ki ) 2200 nM).
Thus, 8e is a potent and selective DAT/5-HTT ligand relative
to the NET. Acylation of the 4-amino group to give the
4-acetylamino analogue 8f had little effect on the binding
affinities for all three transporters. Further modifications on the
4-aminophenyl ring of 8e by addition of bromo or iodo groups
to the ortho position to give 8g and 8i, respectively, slightly
increased the binding affinities for both the DAT and 5-HTT,
making 8i more potent and selective DAT/5-HTT ligand relative
to the NET. The addition of dibromo or diiodo groups to the
ortho position led to 8h and 8j, respectively, resulting in even
better binding potency for the 5-HTT. Unfortunately, 8h and
8j had decreased affinity for the DAT with IC50 values of 15
and 100 nM, respectively. All the 4-aminophenethyl ester
analogues 8e-j possessed low-binding affinities at the NET,
with Ki values ranging from 1460-2600 nM. Thus, 3ꢀ-(4-
methoxyphenyl)tropane-2ꢀ-carboxylic acid 2-(3,5-diiodo-4-ami-
nophenyl)ethyl ester (8j) with Ki values of 1.0 nM at the 5-HTT
and 2600 nM at the NET, respectively, is the most potent and
selective compound for the 5-HTT relative to the NET in this
study. The most potent and selective compound for both the
DAT and 5-HTT is 3ꢀ-(4-methoxyphenyl)tropane-2ꢀ-carboxylic
acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with IC50 value
of 2.5 nM for the DAT and Ki values of 3.5 and 2040 nM for
the 5-HTT and NET, respectively. Finally, the 3ꢀ-(4-methox-
yphenyl)-2ꢀ-[3-(4′-methylphenyl)isoxazol-5-yl]tropane (9) is a
resonance (1H NMR and 13C NMR) spectra were obtained on a
Bruker Avance DPX-300 MHz NMR spectrometer or a Varian
Unity Inova 500 MHz NMR spectrometer. Chemical shifts are
reported in parts per million (ppm) with reference to internal solvent.
Mass spectra (MS) were run on a Perkin-Elmer Sciex API 150 EX
mass spectrometer equipped with APCI (atmospheric pressure
chemical ionization) or ESI (turbospray) sources or on a Hewlett-
Packard 5989A instrument by electron impact. Elemental analyses
were performed by Atlantic Microlab Inc., Atlanta, GA. Optical
rotations were measured on an AutoPol III polarimeter, purchased
from Rudolf Research. Analytical thin-layer chromatography (TLC)
was carried out using EMD silica gel 60 F254 TLC plates. TLC
visualization was achieved with a UV lamp or in an iodine chamber.
Flash column chromatography was done on a CombiFlash Com-
panion system using Isco prepacked silica gel columns or using
EM Science silica gel 60Å (230-400 mesh). Unless otherwise
stated, reagent-grade chemicals were obtained from commercial
sources and were used without further purification. All moisture-
and air-sensitive reactions and reagent transfers were carried out
under dry nitrogen.
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid Methyl
Ester (7a). Magnesium (1.44 g, 60.0 mmol) was weighed into a
500 mL round-bottom flask. A single crystal of iodine was added
and the flask was flushed with nitrogen and flame dried. After
cooling to room temperature, anhydrous Et2O (4 mL) was added.
A solution of 4-bromoanisole (6.26 mL, 50.0 mmol) in anhydrous
Et2O (40 mL) was prepared and 5 mL was added. After addition
of a catalytic amount of 1,2-dibromoethane, the orange iodine color

8052 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24
Jin et al.
Table 1. Monoamine Transporter Binding Properties of 3ꢀ-(Substituted phenyl)tropane-2ꢀ-carboxylic Acid Methyl Esters
5-HTT, Kib (nM)
NET, Kib (nM)
NET/DAT
ratioc
NET/5-HTT
ratiod
b
compda
X
Y
R
DAT, IC50 (nM) [3H]12
[3H]paroxetine
[3H]nisoxetine
cocaine
6
7a
7b
7c
7d
7f
89.1
95
1990
22
27
171
18
17
3
45
1
4
21
23
258
994
56
52
1413
51
0.82 ( 0.05
6.5 ( 1.3
92 ( 8
0.95 ( 0.04
4.3 ( 0.5
1.7 ( 0.4
4.8 ( 0.5
3.1 ( 0.1
2.9 ( 0.1
3.5 ( 0.4
7.5 ( 0.8
21.8 ( 0.6
1110 ( 64
1690 ( 50
270 ( 50
160 ( 20
4100 ( 400e
180 ( 20
>5000
H
H
F
Br
Br
I
H
H
H
H
Br
H
I
CH3
C2H5
CH3
CH3
CH3
CH3
CH3
16 ( 1
47 ( 15
92 ( 22
170 ( 60
1300 ( 200
7e
7g
I
667
a All compounds were tested as the HCl salt. b All values are means ( standard error of three or four experiments performed in triplicate. c NET/DA are
ratios of Ki/IC50 values. d NET/5-HTT are ratios of Ki values. e N ) 2.
disappeared, which indicated the initiation was successful. The rest
of the 4-bromoanisole solution was added slowly over 30 min while
the solution was kept refluxing. After addition, the reaction mixture
was refluxed for 1 h. The fleshly prepared Grignard solution was
then diluted with anhydrous Et2O (152 mL) and cooled to -45 °C.
A solution of anhydroecgonine methyl ester (10) (3.68 g, 20.0
mmol) in 1:1 mixture of CH2Cl2-Et2O (24 mL) was added slowly
and the reaction mixture was stirred at -45 °C for another 2 h.
After cooling to -78 °C, the reaction was quenched by slow
addition of a solution of TFA (9.24 mL, 120 mmol) in Et2O (24
mL). The mixture was warmed to room temperature and 6 N HCl
(80 mL) was added. The aqueous layer was separated, made basic
to pH 11 using NH4OH and extracted with EtOAc (3 × 100 mL).
The combined EtOAc extracts were washed with brine (3 × 50
mL), dried (Na2SO4) and concentrated under reduced pressure. Flash
column chromatography of the crude product on silica gel using 0
f 20% Et2O in hexanes with the addition of 5% Et3N afforded 7a
(4.10 g, 71%) as an oil. 1H NMR (300 MHz; CDCl3) δ 7.25-7.12
(m, 2H), 6.87-6.77 (m, 2H), 3.76 (s, 3H), 3.60-3.46 (m, 4H),
3.40-3.33 (m, 1H), 2.96 (ddd, J ) 12.6, 5.1, 5.1 Hz, 1H),
2.90-2.82 (m, 1H), 2.57 (ddd, J ) 12.6, 12.6, 3.0 Hz, 1H),
2.28-2.00 (m, 5H), 1.78-1.54 (m, 3H). 13C NMR (75 MHz;
CDCl3) δ 171.4, 157.2, 134.4, 127.8, 112.8, 64.8, 61.9, 54.5, 52.4,
50.4, 41.5, 33.8, 32.6, 25.4, 24.7. MS (APCI) m/z 290.2 (M + 1)+.
The free base was converted to the hydrochloride salt: mp 158-160
(75 MHz; CDCl3) δ 172.2, 152.2 (d, J ) 243 Hz), 145.7 (d, J )
11 Hz), 136.5 (d, J ) 5.8 Hz), 122.9 (d, J ) 3.5 Hz), 115.4 (d, J
) 18 Hz), 113.2 (d, J ) 2.0 Hz), 65.5, 62.4, 56.4, 52.9, 51.4, 42.1,
34.4, 33.2, 26.1, 25.4. MS (EI) m/z 308 (M+). The free base was
converted to the hydrochloride salt: [R]20 -103.3° (c 0.24,
D
CH3OH). Anal. (C17H23ClFNO3 ·1.25H2O) C, H, N.
3ꢀ-(3-Bromo-4-methoxyphenyl)tropane-2ꢀ-carboxylic Acid
Methyl Ester (7d). To a stirred solution of 7a (289 mg, 1.00 mmol)
in CH2Cl2 (5 mL) at 0 °C under nitrogen was added SnCl4 (0.23
mL, 2.00 mmol) followed by Br2 (0.06 mL, 1.10 mmol). After
stirring at 0 °C for 30 min, the reaction mixture was poured into a
mixture of NaHCO3-ice and extracted with CH2Cl2 (3 × 50 mL).
The combined CH2Cl2 extracts were dried (Na2SO4) and concen-
trated under reduced pressure. Flash column chromatography of
the crude product on silica gel using 0 f 5% Et2O in hexanes
with the addition of 5% Et3N afforded 7d (315 mg, 86%) as a solid:
1
mp 72-74 °C. H NMR (300 MHz; CDCl3) δ 7.39 (d, J ) 1.8
Hz, 1H), 7.19 (dd, J ) 8.4, 1.8 Hz, 1H), 6.82 (d, J ) 8.4 Hz, 1H),
3.85 (s, 3H), 3.60-3.50 (m, 4H), 3.42-3.33 (m, 1H), 2.93 (ddd, J
) 12.5, 5.1, 5.1 Hz, 1H), 2.88-2.81 (m, 1H), 2.51 (ddd, J ) 12.6,
12.5, 1.8 Hz, 1H), 2.32-2.02 (m, 5H), 1.77-1.54 (m, 3H). 13C
NMR (75 MHz; CDCl3) δ 172.0, 154.0, 136.9, 132.4, 127.4, 111.6,
111.1, 65.4, 62.3, 56.2, 52.8, 51.2, 42.0, 34.3, 33.0, 25.9, 25.3. MS
(ESI) m/z 368.5 (M + 1)+. The free base was converted to the
hydrochloride salt: mp 145-148 °C; [R]20 -89.6° (c 0.27,
D
°C; [R]20 -123.1° (c 0.29, CH3OH). Anal. (C17H24ClNO3 ·H2O)
D
CH3OH). Anal. (C17H23BrClNO3 ·0.75H2O) C, H, N.
C, H, N.
3ꢀ-(3,5-Dibromo-4-methoxyphenyl)tropane-2ꢀ-carboxylic Acid
Methyl Ester (7e). To a stirred solution of 7a (145 mg, 0.50 mmol)
in CH2Cl2 (5 mL) at 0 °C under nitrogen was added SnCl4 (0.23
mL, 2.00 mmol) followed by Br2 (0.056 mL, 1.10 mmol). After
stirring at room temperature for 3 h, the reaction mixture was poured
into a mixture of NaHCO3-ice and extracted with CH2Cl2 (3 × 30
mL). The combined CH2Cl2 extracts were dried (Na2SO4) and
concentrated under reduced pressure. Flash column chromatography
of the crude product on silica gel using 5% Et3N in hexanes afforded
7e (150 mg, 67%) as a solid: mp 145-147 °C. 1H NMR (300 MHz;
CDCl3) δ 7.37 (s, 2H), 3.84 (s, 3H), 3.63-3.52 (m, 4H), 3.42-3.31
(m, 1H), 3.00-2.83 (m, 2H), 2.46 (ddd, J ) 12.3, 12.3, 2.5 Hz,
1H), 2.30-2.02 (m, 5H), 1.78-1.54 (m, 3H). 13C NMR (75 MHz;
CDCl3) δ 171.9, 152.1, 142.3, 131.7, 117.7, 65.4, 62.2, 60.7, 52.5,
51.5, 42.0, 34.2, 33.2, 25.9, 25.4. MS (ESI) m/z 448.8 (M + 1)+.
The free base was converted to the hydrochloride salt: mp 183-185
3ꢀ-(4-Ethoxyphenyl)tropane-2ꢀ-carboxylic Acid Methyl Ester
(7b). The procedure for 7a was followed using 0.90 g (5.00 mmol)
of 10 to give 1.10 g (73%) of 7b as an oil. H NMR (300 MHz;
1
CDCl3) δ 7.20-7.11 (m, 2H), 6.83-6.75 (m, 2H), 3.99 (q, J )
6.5 Hz, 2H), 3.56-3.50 (m, 1H), 3.49 (s, 3H), 3.40-3.33 (m, 1H),
2.95 (ddd, J ) 12.5, 5.4, 5.4 Hz, 1H), 2.87-2.80 (m, 1H), 2.56
(ddd, J ) 12.3, 12.5, 2.7 Hz, 1H), 2.30-2.00 (m, 5H), 1.78-1.54
(m, 3H), 1.38 (t, J ) 6.5 Hz, 3H). 13C NMR (75 MHz; CDCl3) δ
172.0, 157.0, 134.7, 128.2, 113.9, 65.3, 63.1, 62.3, 52.9, 50.9, 41.9,
34.3, 33.1, 25.9, 25.1, 14.8. MS (EI) m/z 303 (M+). The free base
was converted to the hydrochloride salt: mp 164-165 °C; [R]20
D
-114.0° (c 0.34, CH3OH). Anal. (C18H26ClNO3 · 1.75H2O) C,
H, N.
3ꢀ-(3-Fluoro-4-methoxyphenyl)tropane-2ꢀ-carboxylic Acid
Methyl Ester (7c). The procedure for 7a was followed using 1.80 g
(10.0 mmol) of 10 to give 0.68 g (20%) of 7c as a solid: mp 74-76
°C; [R]20 -78.6° (c 0.29, CH3OH). Anal. (C17H22Br2ClNO3) C,
D
1
H, N.
°C. H NMR (300 MHz; CDCl3) δ 7.04-6.81 (m, 3H), 3.85 (s,
3H), 3.60-3.48 (m, 4H), 3.42-3.33 (m, 1H), 2.93 (ddd, J ) 12.6,
5.1, 5.1 Hz, 1H), 2.90-2.82 (m, 1H), 2.51 (ddd, J ) 12.6, 12.6,
2.7 Hz, 1H), 2.30-2.02 (m, 5H), 1.79-1.55 (m, 3H). 13C NMR
3ꢀ-(3-Iodo-4-methoxyphenyl)tropane-2ꢀ-carboxylic Acid Meth-
yl Ester (7f). To a stirred solution of 7a (289 mg, 1.00 mmol) in
1:1 mixture of AcOH-CH2Cl2 (10 mL) at room temperature under

3-Phenyltropane Analogues
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 8053
Table 2. Monoamine Transporter Binding Properties of 3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid Ester Analogues
a All compounds were tested as the HCl salt. b All values are means ( standard error of three or four experiments performed in triplicate. c NET/DAT
are ratios of Ki/IC50 values. d NET/5-HTT are ratios of Ki values. e N ) 2.
nitrogen was added ICl (0.10 mL, 2.00 mmol). After stirring at
room temperature for 24 h, the reaction mixture was poured into a
mixture of NaHCO3-ice and extracted with CH2Cl2 (3 × 50 mL).
The combined CH2Cl2 extracts were dried (Na2SO4) and concen-
trated under reduced pressure. Flash column chromatography of
the crude product on silica gel using 5% Et3N in hexanes afforded
added and the stirring was continued for another 3 h. The mixture
was diluted with EtOAc (50 mL), washed with NH4OH (10 mL),
brine (3 × 10 mL), and dried (Na2SO4). The solvent was
concentrated under reduced pressure. Flash column chromatography
of the crude product on silica gel using 5% Et3N in hexanes afforded
7g (255 mg, 94%) as a solid: mp 181-183 °C. 1H NMR (300 MHz;
CDCl3) δ 7.62 (s, 2H), 3.81 (s, 3H), 3.62-3.52 (m, 4H), 3.39-3.30
(m, 1H), 2.93-2.79 (m, 2H), 2.44 (ddd, J ) 12.0, 12.0, 2.7 Hz,
1H), 2.30-2.02 (m, 5H), 1.76-1.48 (m, 3H). 13C NMR (75 MHz;
CDCl3) δ 171.9, 156.9, 143.4, 139.0, 90.1, 65.4, 62.2, 60.8, 52.6,
51.5, 42.0, 34.3, 32.8, 25.9, 25.4. MS (ESI) m/z 542.2 (M + 1)+.
The free base was converted to the hydrochloride salt: mp 167-169
°C; [R]20D -62.1° (c 0.24, CH3OH). Anal. (C17H22ClI2NO3 ·0.5H2O)
C, H, N.
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid (11). A
mixture of 7a (1.90 g, 6.57 mmol) in 50% dioxane-H2O was
refluxed for 3 d. The solvent was removed under reduced pressure.
Recrystallization of the crude product from acetone-hexanes af-
forded 11 (1.65 g, 92%) as a solid: mp 132-134 °C. 1H NMR
(300 MHz; CDCl3) δ 7.22-7.12 (m, 2H), 7.90-7.80 (m, 2H), 3.76
(s, 3H), 3.61-3.46 (m, 2H), 3.21-3.08 (m, 1H), 2.70-2.51 (m,
1
7f (95.0 mg, 23%) as an oil. H NMR (300 MHz; CDCl3) δ 7.54
(d, J ) 2.1 Hz, 1H), 7.17 (dd, J ) 8.4, 2.1 Hz, 1H), 6.67 (d, J )
8.4 Hz, 1H), 3.76 (s, 3H), 3.52-3.42 (m, 4H), 3.35-3.28 (m, 1H),
2.85 (ddd, J ) 12.3, 5.4, 5.4 Hz, 1H), 3.38-3.26 (m, 1H), 2.46
(ddd, J ) 12.6, 12.3, 2.4 Hz, 1H), 2.22-1.94 (m, 5H), 1.71-1.48
(m, 3H). 13C NMR (75 MHz; CDCl3) δ 171.0, 155.2, 137.5, 136.3,
127.4, 109.5, 84.5, 64.3, 61.2, 55.3, 51.7, 50.2, 40.9, 33.2, 31.9,
24.9, 24.2. MS (APCI) m/z 416.5 (M + 1)+. The free base was
converted to the hydrochloride salt: mp 151-153 °C; [R]20D -82.3°
(c 0.22, CH3OH). Anal. (C17H23ClINO3 ·H2O) C, H, N.
3ꢀ-(3,5-Diiodo-4-methoxyphenyl)tropane-2ꢀ-carboxylic Acid
Methyl Ester (7g). To a stirred solution of I(Py)2BF4 (558 mg,
1.50 mmol) in dioxane (5 mL) at room temperature under nitrogen
was added CF3SO3H (0.18 mL, 2.00 mmol). After stirring for 10
min, a solution of 7a (145 mg, 0.50 mmol) in dioxane (1 mL) was

8054 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24
Jin et al.
2H), 2.48 (s, 3H), 2.38-2.21 (m, 2H), 2.03-1.90 (m, 2H),
1.82-1.70 (m, 1H). MS (ESI) m/z 306.5 (M + 1)+.
washed with ether (3 × 20 mL), made basic using NH4OH and
extracted with EtOAc (3 × 50 mL). The combined EtOAc extracts
were washed with brine (3 × 30 mL), dried (Na2SO4), and
concentrated under reduced pressure. Recrystallization of the crude
product from CH3OH afforded 8d (1.30 g, 84%) as a solid: mp
122-124 °C. 1H NMR (300 MHz; CDCl3) δ 8.11 (d, J ) 8.7 Hz,
2H), 7.26 (d, J ) 8.7 Hz, 2H), 7.14 (d, J ) 8.7 Hz, 2H), 6.80 (d,
J ) 8.7 Hz, 2H), 4.28-4.10 (m, 2H), 3.76 (s, 3H), 3.45-3.30 (m,
2H), 3.01-2.75 (m, 4H), 2.51 (ddd, J ) 12.6, 12.6, 2.7 Hz, 1H),
2.23-2.00 (m, 5H), 1.78-1.52 (m, 3H). 13C NMR (75 MHz;
CDCl3) δ 171.6, 157.8, 146.7, 146.2, 134.9, 129.7, 128.3, 123.6,
113.4, 65.3, 63.0, 62.4, 55.2, 52.9, 42.0, 34.8, 34.3, 33.1, 26.0, 25.2;
MS (APCI) m/z 425.5 (M + 1)+. The free base was converted to
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid Isopro-
pyl Ester (8a). To a stirred solution of 11 (138 mg, 0.50 mmol) in
anhydrous CH2Cl2 (5 mL) at 0 °C under nitrogen was added a 2 M
solution of oxalyl chloride in CH2Cl2 (0.5 mL, 1.00 mmol). After
stirring at room temperature for 1 h, the mixture was concentrated
under reduced pressure followed by vacuum drying to remove the
residual oxalyl chloride. The resultant acid chloride was dissolved
in anhydrous CH2Cl2 (5 mL) at room temperature under nitrogen
and isopropanol (0.12 mL, 1.50 mmol) was added. The reaction
mixture was stirred at room temperature for 16 h and quenched by
addition of NaHCO3. The CH2Cl2 phase was separated and the
aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The
combined CH2Cl2 extracts were dried (Na2SO4) and concentrated
under reduced pressure. Flash column chromatography of the crude
product on silica gel using 0 f 5% Et2O in hexanes with the
addition of 5% Et3N afforded 8a (145 mg, 92%) as a solid: mp
71-72 °C. 1H NMR (300 MHz; CDCl3) δ 7.24-7.15 (m, 2H),
6.88-6.78 (m, 2H), 4.97-4.80 (m, 1H), 3.77 (s, 3H), 3.60-3.50
(m, 1H), 3.41-3.33 (m, 1H), 2.94 (ddd, J ) 12.3, 5.1, 5.1 Hz,
1H), 2.86-2.78 (m, 1H), 2.57 (ddd, J ) 12.3, 12.3, 2.1 Hz, 1H),
2.28-2.02 (m, 5H), 1.80-1.54 (m, 3H), 1.09 (d, J ) 6.3 Hz, 3H),
1.04 (d, J ) 6.3 Hz, 3H). 13C NMR (75 MHz; CDCl3) δ 171.2,
157.7, 135.3, 128.4, 113.4, 66.5, 65.4, 62.4, 55.2, 52.9, 42.0, 34.3,
33.1, 26.0, 25.3, 21.8, 21.7. MS (APCI) m/z 318.1 (M + 1)+. The
free base was converted to the hydrochloride salt: mp 226-227
the hydrochloride salt: [R]20 -40.0° (c 0.27, CH3OH). Anal.
D
(C24H29ClN2O5 ·0.75H2O) C, H, N.
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid 2-(4-Ami-
nophenyl)ethyl Ester (8e). A mixture of 8d (150 mg, 0.35 mmol)
and PtO2 (15.0 mg) in MeOH was hydrogenated at 1 atmospheric
pressure for 3 h. Afterward, the mixture was filtered through a plug
of celite and the filtrate was concentrated under reduced pressure.
Flash column chromatography of the crude product on silica gel
using 0 f 2% MeOH in CH2Cl2 with the addition of 1% NH4OH
afforded 8e (135 mg, 97%) as an oil. 1H NMR (300 MHz; CDCl3)
δ 7.16 (d, J ) 8.7 Hz, 2H), 6.91 (d, J ) 8.7 Hz, 2H), 6.80 (d, J )
8.7 Hz, 2H), 6.58 (d, J ) 8.7 Hz, 2H), 4.21-4.10 (m, 1H),
4.04-3.91 (m, 1H), 3.75 (s, 3H), 3.52 (br s, 2H), 3.50-3.41 (m,
1H), 3.39-3.30 (m, 1H), 2.93 (ddd, J ) 12.6, 5.7, 5.7 Hz, 1H),
2.88-2.80 (m, 1H), 2.66 (t, J ) 6.9 Hz, 2H), 2.56 (ddd, J ) 12.8,
12.6, 2.7 Hz, 1H), 2.26-1.99 (m, 5H), 1.78-1.52 (m, 3H). 13C
NMR (75 MHz; CDCl3) δ 171.8, 157.8, 144.9, 135.2, 129.8, 128.5,
128.1, 115.3, 113.5, 65.4, 64.6, 62.5, 55.3, 53.0, 42.1, 34.4, 34.3,
33.2, 26.1, 25.4; MS (APCI) m/z 395.6 (M + 1)+. The free base
°C; [R]20 -93.7° (c 0.41, CH3OH). Anal. (C19H28ClNO3) C, H,
D
N.
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid Cyclopro-
pyl Ester (8b). The procedure for 8a was followed using 275 mg
(1.00 mmol) of 11 and 0.20 mL (3.00 mmol) of cyclopropanol to
was converted to the dihydrochloride salt: [R]20 -58.3° (c 0.24,
1
give 145 mg (46%) of 8b as a solid: mp 101-102 °C. H NMR
D
CH3OH). Anal. (C24H32Cl2N2O3 ·H2O) C, H, N.
(300 MHz; CDCl3) δ 7.24-7.13 (m, 2H), 6.89-6.78 (m, 2H),
4.01-3.92 (m, 1H), 3.77 (s, 3H), 3.54-3.45 (m, 1H), 3.42-3.32
(m, 1H), 2.94 (ddd, J ) 12.8, 5.7, 5.7 Hz, 1H), 2.86-2.78 (m,
1H), 2.54 (ddd, J ) 12.8, 12.6, 2.7 Hz, 1H), 2.30-2.02 (m, 5H),
1.80-1.54 (m, 3H), 0.67-0.42 (m, 3H), 0.41-0.28 (m, 1H). 13C
NMR (75 MHz; CDCl3) δ 172.9, 157.8, 135.1, 128.3, 113.5, 65.4,
62.5, 55.3, 52.8, 48.2, 42.1, 34.3, 33.0, 26.0, 25.3, 5.5, 4.9. MS
(ESI) m/z 316.4 (M + 1)+. The free base was converted to the
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid 2-(4-Acety-
laminophenyl)ethyl Ester (8f). To a stirred solution of 8e (65.0
mg, 0.16 mmol) in anhydrous CH2Cl2 (5 mL) at 0 °C under nitrogen
was added Et3N (0.07 mL, 0.48 mmol) followed by acetyl chloride
(0.02 mL, 0.32 mmol). After stirring at 0 °C for 1 h, the reaction
mixture was poured into a mixture of NaHCO3-ice and extracted
with CH2Cl2 (3 × 30 mL). The combined CH2Cl2 extracts were
dried (Na2SO4) and concentrated under reduced pressure. Flash
column chromatography of the crude product on silica gel using 0
f 2% MeOH in CH2Cl2 with the addition of 1% NH4OH afforded
hydrochloride salt: mp 190-192 °C; [R]20 -60.9° (c 0.32,
D
CH3OH). Anal. (C19H26ClNO3 ·1.25H2O) C, H, N.
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid Cyclobu-
tyl Ester (8c). The procedure for 8a was followed using 275 mg
(1.00 mmol) of 11 and 0.24 mL (3.00 mmol) of cyclobutanol to
give 270 mg (82%) of 8c as a solid: mp 90-91 °C. 1H NMR (300
MHz; CDCl3) δ 7.24-7.14 (m, 2H), 6.88-6.78 (m, 2H), 4.90-4.78
(m, 1H), 3.77 (s, 3H), 3.62-3.52 (m, 1H), 3.42-3.32 (m, 1H),
2.94 (ddd, J ) 12.6, 5.1, 5.1 Hz, 1H), 2.86-2.77 (m, 1H), 2.56
(ddd, J ) 12.6, 12.6, 2.4 Hz, 1H), 2.35-2.01 (m, 7H), 1.98-1.42
(m, 7H). 13C NMR (75 MHz; CDCl3) δ 171.1, 157.7, 135.2, 128.4,
113.4, 68.2, 65.4, 62.4, 55.3, 52.8, 42.1, 34.3, 33.1, 30.7, 29.8, 26.0,
25.3, 13.7; MS (ESI) m/z 330.1 (M + 1)+. The free base was
converted to the hydrochloride salt: mp 245-246 °C; [R]20D -75.9°
(c 0.29, CH3OH). Anal. (C20H28ClNO3) C, H, N.
1
8f (65.0 mg, 93%) as an oil. H NMR (300 MHz; CDCl3) δ 7.38
(d, J ) 7.5 Hz, 2H), 7.15 (d, J ) 8.4 Hz, 2H), 7.06 (d, J ) 7.5 Hz,
2H), 6.80 (d, J ) 8.4 Hz, 2H), 4.24-4.11 (m, 1H), 4.10-3.98 (m,
1H), 3.76 (s, 3H), 3.50-3.40 (m, 1H), 3.39-3.31 (m, 1H), 2.94
(ddd, J ) 12.3, 5.1, 5.1 Hz, 1H), 2.86-2.79 (m, 1H), 2.73 (t, J )
6.0 Hz, 2H), 2.54 (ddd, J ) 12.5, 12.3, 2.1 Hz, 1H), 2.22-2.00
(m, 8H), 1.75-1.56 (m, 4H). 13C NMR (125 MHz; CDCl3) δ 171.8,
168.4, 157.9, 136.4, 135.2, 134.4, 129.5, 128.6, 120.1, 113.6, 65.5,
64.2, 62.5, 55.4, 53.1, 42.1, 34.6, 34.4, 33.3, 26.1, 25.4, 24.8. MS
(ESI) m/z 437.7 (M + 1)+. The free base was converted to the
hydrochloride salt: [R]20 -62.7° (c 0.26, CH3OH). Anal.
D
(C26H33ClN2O4 ·1.5H2O) C, H, N.
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid 2-(4-Ni-
trophenyl)ethyl Ester (8d). To a stirred solution of 11 (1.00 g,
3.64 mmol) in anhydrous CH2Cl2 (10 mL) at 0 °C under nitrogen
was added a 2 M solution of oxalyl chloride in CH2Cl2 (3.64 mL,
7.28 mmol). After stirring at room temperature for 1 h, the mixture
was concentrated under reduced pressure followed by vacuum
drying to remove the residual oxalyl chloride. The resultant acid
chloride was dissolved in anhydrous CH2Cl2 (20 mL) at room
temperature under nitrogen, and 4-nitrophenylethyl alcohol (1.22
g, 7.28 mmol) and Et3N (2.05 mL, 14.6 mmol) were then added.
The reaction mixture was stirred at room temperature for 16 h,
poured into H2O, and extracted with CH2Cl2 (3 × 50 mL). The
combined CH2Cl2 extracts were dried (Na2SO4) and concentrated
under reduced pressure. The residue was partitioned between 6 N
HCl (20 mL) and Et2O (20 mL). The aqueous phase was separated,
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid 2-(3-Bromo-
4-aminophenyl)ethyl Ester (8g). To a stirred solution of 8e (150
mg, 0.38 mmol) in DMF (2.5 mL) at room temperature under
nitrogen was added NBS (67.6 mg, 0.38 mmol). After stirring at
room temperature for 1 h, the reaction mixture was poured into a
mixture of NaHCO3-ice and extracted with EtOAc (3 × 30 mL).
The combined EtOAc extracts were dried (Na2SO4) and concen-
trated under reduced pressure. Flash column chromatography of
the crude product on silica gel using 0 f 3% MeOH in CH2Cl2
with the addition of 1% NH4OH afforded 8g (115 mg, 64%) as an
oil. 1H NMR (500 MHz; CDCl3) δ 7.21 (d, J ) 2.0 Hz, 1H), 7.15
(d, J ) 9.0 Hz, 2H), 6.86 (dd, J ) 8.0, 2.0 Hz, 1H), 6.80 (d, J )
9.0 Hz, 2H), 6.65 (d, J ) 8.0 Hz, 1H), 4.14-4.08 (m, 1H),
4.02-3.96 (m, 3H), 3.76 (s, 3H), 3.48-3.44 (m, 1H), 3.36-3.32
(m, 1H), 2.93 (ddd, J ) 12.6, 5.5, 5.5 Hz, 1H), 2.84-2.80 (m,

3-Phenyltropane Analogues
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 24 8055
1H), 2.63 (dt, J ) 2.5, 7.0 Hz, 2H), 2.54 (ddd, J ) 12.8, 12.6, 3.0
Hz, 1H), 2.24-2.02 (m, 5H), 1.74-1.56 (m, 3H). 13C NMR (125
MHz; CDCl3) δ 171.5, 157.5, 142.3, 134.9, 132.7, 129.3, 128.7,
128.2, 115.6, 113.3, 109.1, 65.2, 64.1, 62.2, 55.1, 52.7, 41.8, 34.1,
33.6, 32.9, 25.8, 25.1. MS (APCI) m/z 475.8 (M + 1)+. The free
base was converted to the hydrochloride salt: [R]20D -53.3° (c 0.26,
CH3OH). Anal. (C24H30BrClN2O3 ·1.25H2O) C, H, N.
organic phase was separated and the aqueous phase was extracted
with EtOAc (3 × 30 mL). The combined organic phases were
washed with brine (3 × 30 mL), dried (Na2SO4), and concentrated
under reduced pressure. The residue was partitioned between Et2O
(20 mL) and 2 N HCl (20 mL). The aqueous phase was separated,
made basic using NaHCO3, and extracted with EtOAc (3 × 20
mL). The combined EtOAc extracts were then washed with brine
(3 × 30 mL), dried (Na2SO4), and concentrated under reduced
pressure. The resultant oil was dissolved in 1:1 mixture of 3 N
HCl-THF (20 mL) and refluxed for 5 h. After cooling to room
temperature, the mixture was made basic using NaHCO3 and
extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts
were washed with brine (3 × 30 mL), dried (Na2SO4), and
concentrated under reduced pressure. Flash column chromatography
of the crude product on silica gel using 0 f 10% Et2O in hexanes
with the addition of 5% Et3N afforded 9 (0.27 g, 68%) as a solid:
mp 154-156 °C. 1H NMR (300 MHz; CDCl3) δ 7.66 (d, J ) 8.1
Hz, 2H), 7.21 (d, J ) 8.1 Hz, 2H), 6.93 (d, J ) 8.7 Hz, 2H), 6.71
(s, 1H), 6.70 (d, J ) 8.7 Hz, 2H), 3.71 (s, 3H), 3.40-3.17 (m,
4H), 2.38 (s, 3H), 3.32-2.06 (m, 6H), 1.88-1.55 (m, 3H). 13C
NMR (75 MHz; CDCl3) δ 173.9, 161.6, 158.2, 139.5, 133.8, 129.5,
128.4, 127.2, 126.8, 113.7, 101.5, 65.6, 61.9, 55.1, 46.6, 42.1, 35.3,
35.2, 26.5, 25.2, 21.5. MS (ESI) m/z 389.8 (M + 1)+. The free
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid 2-(3,5-Di-
bromo-4-aminophenyl)ethyl Ester (8h). To a stirred solution of
8e (150 mg, 0.38 mmol) in 1:1 mixture of AcOH-CH2Cl2 (10 mL)
at room temperature under nitrogen was added Br2 (0.039 mL, 0.76
mmol). After stirring at room temperature for 1 h, the reaction
mixture was poured into a mixture of NaHCO3-ice and extracted
with CH2Cl2 (3 × 30 mL). The combined CH2Cl2 extracts were
dried (Na2SO4) and concentrated under reduced pressure. Flash
column chromatography of the crude product on silica gel using 0
f 10% MeOH in CH2Cl2 with the addition of 1% NH4OH afforded
1
8h (165 mg, 79%) as an oil. H NMR (500 MHz; CDCl3) δ 7.18
(s, 2H), 7.13 (d, J ) 8.0 Hz, 2H), 6.80 (d, J ) 8.0 Hz, 2H), 4.44
(s, 2H), 4.10-3.93 (m, 2H), 3.76 (s, 3H), 3.48-3.44 (m, 1H),
3.38-3.32 (m, 1H), 2.94 (ddd, J ) 11.5, 5.0, 5.0 Hz, 1H),
2.86-2.82 (m, 1H), 2.64-2.58 (m, 2H), 2.52 (ddd, J ) 11.0, 11.5,
3.0 Hz, 1H), 2.22-2.02 (m, 5H), 1.74-1.56 (m, 3H). 13C NMR
(125 MHz; CDCl3) δ 171.5, 157.5, 140.3, 134.8, 132.0, 129.7,
128.2, 113.3, 108.5, 65.2, 63.8, 62.2, 55.1, 52.8, 41.8, 34.1, 33.4,
32.9, 25.9, 25.1. MS (APCI) m/z 553.5 (M + 1)+. The free base
base was converted to the hydrochloride salt: [R]20 -107.0° (c
D
0.32, CH3OH). Anal. (C25H29ClN2O2 ·0.25H2O) C, H, N.
was converted to the hydrochloride salt: [R]20 -37.4° (c 0.27,
Acknowledgment. This research was supported by the
National Institute on Drug Abuse, grant no. DA05477.
D
CH3OH). Anal. (C24H29Br2ClN2O3 ·H2O) C, H, N.
3ꢀ-(4-Methoxyphenyl)tropane-2ꢀ-carboxylic Acid 2-(3-Iodo-
4-aminophenyl)ethyl Ester (8i) and 3ꢀ-(4-Methoxyphenyl)tro-
pane-2ꢀ-carboxylic Acid 2-(3,5-Diiodo-4-aminophenyl)ethyl Es-
ter (8j). To a stirred solution of 8e (158 mg, 0.40 mmol) in 1:1
mixture of AcOH-CH2Cl2 (10 mL) at room temperature under
nitrogen was added ICl (0.02 mL, 0.44 mmol). After stirring at
room temperature for 1 h, the reaction mixture was poured into a
mixture of NaHCO3-ice and extracted with EtOAc (3 × 30 mL).
The combined EtOAc extracts were dried (Na2SO4) and concen-
trated under reduced pressure. Flash column chromatography of
the crude product on silica gel using 0 f 5% MeOH in CH2Cl2
with the addition of 1% NH4OH afforded 8i (65.0 mg, 31%) and
8j (45.0 mg, 17%) as oil.
Supporting Information Available: Elemental analysis. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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8i: H NMR (300 MHz; CDCl3) δ 7.45 (d, J ) 1.5 Hz, 1H),
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The free base was converted to the hydrochloride salt: [R]20
D
-53.1° (c 0.26, CH3OH). Anal. (C24H30ClIN2O3 ·1.5H2O) C, H,
N.
8j: 1H NMR (300 MHz; CDCl3) δ 7.44 (s, 2H), 7.15 (d, J ) 8.0
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