Synthesis and monoamine transporter binding properties of 3β-(3′,4′-disubstituted phenyl)tropane-2β-carboxylic acid methyl esters

Article abstract of DOI:10.1021/jm040185a

3β-(3′-Methyl-4′-chlorophenyl)tropane-2-carboxylic acid methyl ester (Sb, RTI-112) is a 3-phenyltropane analogue that has high affinity for both the dopamine and serotonin transporters (DAT and 5-HTT, respectively). Compound 3b shows significant reduction

Full text of DOI:10.1021/jm040185a

J. Med. Chem. 2005, 48, 2767-2771
2767
Articles
Synthesis and Monoamine Transporter Binding Properties of
3â-(3′,4′-Disubstituted phenyl)tropane-2â-carboxylic Acid Methyl Esters
F. Ivy Carroll,*,† Bruce E. Blough,† Zhe Nie,† Michael J. Kuhar,‡ Leonard L. Howell,‡ and Hernan A. Navarro†
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, and
Yerkes National Primate Center of Emory University, 954 Gatewood Road NE, Atlanta, Georgia 30329
Received October 15, 2004
3â-(3′-Methyl-4′-chlorophenyl)tropane-2-carboxylic acid methyl ester (3b, RTI-112) is a 3-phe-
nyltropane analogue that has high affinity for both the dopamine and serotonin transporters
(DAT and 5-HTT, respectively). Compound 3b shows significant reduction of cocaine self-
administration in rhesus monkeys, yet fails to maintain robust drug self-administration. PET
studies revealed that unlike more DAT selective analogues such as GBR 12 909 and
3-(4-chlorophenyl)tropane-2-carboxylic acid phenyl ester (RTI-113), 3b shows no detectible DAT
occupancy when dosed at its ED50 for reduction of cocaine self-administration. In contrast, it
highly occupies the 5-HTT at this dose. In this study, we report the synthesis and monoamine
transporter binding potency of several new 3-(3′,4′-disubstituted phenyl)tropane-2-carboxylic
acid methyl esters (3c-k), which have binding properties very similar to 3b. With the exception
of the 3′,4′-dimethyl analogue 3k, all of the compounds possess subnanomolar IC50 and Ki values
at the DAT and 5-HTT, respectively. The 3′-chloro-4′-bromo analogue 3e (IC50 ) 0.12 nM) and
the 3′-bromo-4′-iodo analogue 3i (Ki ) 0.14 nM) are the most potent analogues at the DAT and
5-HTT, respectively. These compounds will be useful to further characterize the highly
interesting behavioral profile of 3b.
Introduction
Even though cocaine (1) binds to the dopamine,
serotonin, and norepinephrine transporters (DAT, 5-HTT,
NET, respectively) with similar affinities, the psycho-
motor stimulant and reinforcing effects in animals have
been attributed to its action at the DAT.1-4 The site
where cocaine binds to the DAT has been referred to as
the cocaine receptor.1,5 Much effort has been devoted to
the characterization of the pharmacophore for this site
(for reviews, see refs 6-9).6-9 For example, 3â-phenyl-
tropane-2â-carboxylic acid methyl ester (2), WIN 35,-
065-2 was a lead structure for conducting structure-
activity relationship (SAR) studies that provided insight
into the nature of this binding site on the DAT.6,7 Early
studies demonstated that in vitro binding affinity was
highly dependent on the nature of the substituents on
the 3â-aromatic ring.10,11 For example, the 3′,4′-disub-
stituted analogues such as the 3′,4′-dichloro (3a, RTI-
111) and 3′-methyl-4′-chloro (3b, RTI-112) compounds
were the first analogues reported to show subnanomolor
affinity at the DAT. Later reports showed that 3a and
3b also possessed subnanomolar affinity at the 5-HTT.12
Inhibiting 5-HT uptake may be an important charac-
teristic of these compounds since a number of reports
have suggested 5-HT indirectly modulates nucleus
accumbens DA release.13,14 Importantly, since animal
behavior studies have demonstrated that selective se-
rotonin uptake inhibitors as well as selective dopamine
uptake inhibitors can attenuate cocaine-induced stimu-
lant and reinforcing effects, compounds showing high
affinity for both the DAT and 5-HTT are of particular
interest.15-18 In this paper, we report the synthesis and
monoamine transporter binding properties of several
new 3â-(3′,4′-disubstituted phenyl)tropane-2â-carboxylic
acid methyl esters (3c-k). With the exception of the
3′,4′-dimethyl analogue 3k, all of the compounds showed
subnanomolor affinity at both the DAT and 5-HTT.
* To whom correspondence should be addressed. Research Triangle
Institute, P.O. Box 12194, Research Triangle Park, NC 27709-2194.
Phone: 919-541-6679. Fax: 919-541-8868. E-mail: fic@rti.org.
† Research Triangle Institute.
Chemistry
The synthesis of compounds 3c-j starting with the
appropriate 3-amino-4-halo compounds 4, 5, and 7 is
‡ Yerkes National Primate Center of Emory University.
10.1021/jm040185a CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/18/2005

2768 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 8
Carroll et al.
Table 1. Monoamine Transporter Binding Properties of 3â-(3′,4′-Disubstituted)tropane-2â-carboxylic Acid Methyl Esters
IC50, nM (Ki, nM)
compd
X
Y
DAT [3H]WIN 35 428
5-HTT [3H]paroxetine
NET [3H]nisoxetine
cocaine
2a
89.1
1050 (45)
3300 (1990)
23 ( 5
1060 ( 61 (178 ( 5.5)
3.13 ( 0.36 (0.29 ( 0.03)
10.5 ( 0.41 (0.95 ( 0.04)
0.78 ( 0.04 (0.19 ( 0.01)
1.39 ( 0.23 (0.34 ( 0.06)
0.94 ( 0.09 (0.23 ( 0.02)
0.71 ( 0.03 (0.18 ( 0.01)
1.14 ( 0.26 (0.25 ( 0.04)
1.04 ( 0.14 (0.63 ( 0.05)
0.58 ( 0.07 (0.14 ( 0.02)
2.0 ( 0.56 (0.19 ( 0.05)
9.88 ( 1.11 (2.42 ( 0.27)
920 ( 70 (550 (44)
3a
Cl
Cl
0.79 ( 0.08
0.82 ( 0.05
0.42 ( 0.02
0.41 ( 0.09
0.12 ( 0.04
0.27 ( 0.01
0.21 ( 0.06
0.26 ( 0.05
0.20 ( 0.04
0.98 ( 0.05
0.43 ( 0.07
18 ( 0.85 (11 ( 0.51)
36.2 ( 1.02 (21.8 ( 0.62)
7.24 ( 0.69 (3.62 ( 0.34)
15.1 ( 0.59 (7.74 ( 0.29)
1.31 ( 0.13 (0.65 ( 0.07)
2.80 ( 0.16 (1.10 ( 0.08)
10.4 ( 1.5 (5.12 ( 0.77)
1.26 ( 0.09 (0.63 ( 0.05)
1.96 ( 0.17 (0.98 ( 0.09)
40.4 ( 3.56 (24 ( 2.1)
107 ( 11 (44 ( 4.7)
3b
3c
3d
3e
3f
3g
3h
3i
Cl
Cl
Cl
Br
Br
Br
I
CH3
Br
I
Cl
Br
I
Cl
Br
I
I
I
3j
3k
CH3
CH3
Scheme 1a
Scheme 2a
a Reagents: (a) 3,4-dimethylphenylmagnesium iodide, (C2H5)2O,
-45 °C; (b) CF3CO2H, -78 °C.
Biology
The binding affinities of the target compounds 3c-j
along with reference compounds cocaine, 2a, and 3a-b
at the DAT, 5-HTT, and NET were determined via
competition binding assays using the previously re-
ported procedures.20 The results are listed in Table 1.
Some of the data was taken from previous reports.10,11
The final concentration of radioligands in the assays was
0.5 nM [3H]WIN 35,428 for the DAT, 0.2 nM [3H]-
paroxetine for the 5-HTT, and 1.0 nM [3H]nisoxetine for
the NET.
a Reagents: (a) NCS, CH3CN, reflux; (b) C4H9ONO, CuCl2,
CH3CN,65°C;(c)C4H9ONO,CuBr2,CH3CN,65°C;(d)(CH3)2CHCH2-
CH2ONO, CH2I2, 80 °C.
Results and Discussion
Despite extensive efforts directed toward the develop-
ment of pharmacotherapies to treat cocaine abuse, no
effective drug is currently in clinical use.21-24 Since the
DAT is the critical recognition site for cocaine and
contributes to its abuse liability, DAT inhibitors repre-
shown in Scheme 1. The 4′-amino-3′-iodo (4) and 4′-
amino-3′-bromo (5) starting materials were prepared as
previously reported.19 The 4′-amino-3′-chloro (7) mate-
rial was prepared by chlorination of the 4′-amino
compound 6 with N-chlorosuccimide in acetonitrile.
Diazotization of 4, 5, and 7 with butyl nitrite in
acetonitrile followed by treatment with the appropriate
copper(II) halide provided the compounds 3c-g. The 4′-
iodo analogues 3h-j were prepared by diazotization of
4, 5, and 7 with isoamyl nitrite in the presence of
diiodomethane. The 3′,4′-dimethyl analogue 3k was
obtained by the addition of 3,4-dimethylphenylmagne-
sium iodide to anhydroecgonine methyl ester (8) using
conditions similar to that used for the synthesis of other
analogues10 (Scheme 2).
sent a promising approach in drug development.21-23
A
number of preclinical studies in nonhuman primates
provide evidence that DAT inhibitors can effectively
attenuate cocaine self-administration.20,25-28 Recently,
we reported that 3b and 3â-(4′-chlorophenyl)tropane-
2â-carboxylic acid phenyl ester (9, RTI-113) were highly
effective in reducing cocaine self-administration in
rhesus monkeys and had no adverse behavioral ef-
fects.25,26 Positron emission tomography (PET) studies
in rhesus monkeys showed that doses of the relatively
DAT-selective 9 that decrease cocaine self-administra-
tion resulted in high occupancy of the DAT.26 In
contrast, even though 3b showed greater than 70% DAT
occupancy at the highest dose tested, DAT occupancy

Monoamine Transporter Binding of Phenyltropane Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 8 2769
carried out on plates precoated with silica gel GHLF (250 µm
thickness). TLC visualization was accomplished with a UV
lamp or in an iodine chamber. All moisture sensitive reactions
were performed under a positive pressure of nitrogen main-
tained by a direct line from a nitrogen source. Commercially
available ultralow water THF (J. T. Baker) was used.
was below the limit of detection at the ED50 for reduc-
tion of cocaine self-administration.25 Surprisingly, 3b,
which has about equal affinity for the DAT and 5-HTT,
showed 84% occupancy of the 5-HTT at the ED50 dose.25
Importantly, 3b failed to maintain robust drug self-
administration in any of the three rhesus monkeys
studied.25 These results strongly indicate that the
interesting behavioral profile of 3b may be due to its
interaction at both the DAT and 5-HTT. Compound 3b
also has high affinity for the NET (Table 1), and thus it
is possible that interaction at the NET may contribute
to 3b induced decrease in cocaine self-administration.
However, this seems unlikely since selective norepi-
nephrine uptake inhibitors such as desipramine failed
to reduce cocaine self-administration in nonhuman
primates.15,18 Thus, the synthesis and pharmacological
study of compounds possessing monoamine transporter
binding properties similar to 3b should lead to a better
understanding of the biochemical mechanism underly-
ing cocaine abuse and could lead to new pharmaco-
therapies for treatment.
The data listed in Table 1 show that compounds 3c-k
all have monoamine transporter binding properties very
similar to 3b. With the exception of the 3′,4′-dimethyl
analogue 3k, they all show subnanomolar IC50 and Ki
values at the DAT and 5-HTT, respectively. In addition,
similar to 3b, they have appreciable affinity for the
NET. The IC50 values at the DAT ranged from 0.12 to
0.98 nM with the 3′-chloro-4′-bromo analogue 3e (IC50
) 0.12 nM) possessing the highest affinity at the DAT.
The Ki values at the 5-HTT for 3c-j ranged from 0.14
to 0.63 nM. The 3′-bromo-4′-iodo analogue 3i with a Ki
of 0.14 nM possessed the highest affinity at the 5-HTT.
The Ki for the 3′,4′-dimethyl analogue 3k was 2.42 nM.
The compounds showed slightly higher Ki values at the
NET with a range of 0.98-44 nM. From an SAR
viewpoint, it is interesting to note that all of the
compounds possessed similar potency at the DAT and
5-HTT regardless of the size and electrostatic properties
of the compounds at either the 3′- or 4′- position. One
exception was the dimethyl analogue 3k, which had a
somewhat larger Ki value at the 5-HTT.
3â-(3′-Bromo-4′chlorophenyl)tropane-2â-carboxylic
Acid Methyl Ester (3c) Tartrate. Anhydrous copper(II)
chloride (250 mg, 1.88 mmol), butyl nitrite (272, µL, 2.3 mmol),
and anhydrous acetonitrile (8 mL) were added to a three-
necked round-bottom flask that was equipped with a reflux
condenser, additional funnel, and a gas outlet tub. The
resulting mixture was warmed to 65 °C. The amine (5, 550
mg, 2 mmol) in 2 mL of acetonitrile was added dropwise to
the reaction solution. Lots of precipitate appeared, followed
by the evolution of nitrogen. After 10 min the reaction mixture
was allowed to cool to room temperature, poured into 25 mL
of 20% aqueous HCl, and neutralized by the addition of
saturated sodium carbonate solution. The aqueous layer was
extracted by methylene chloride and dried (Na2SO4). Purifica-
tion by flash column (elution with 1:3 ethyl acetate-hexane
with1% TEA) gave 140 mg (24%) of product 3c as clear oil. 1H
NMR (CDCl3, 300 MHz) δ (ppm) 1.57-1.69 (m, 3H), 2.01-
2.21 (m, s, 5H, NCH3), 2.49 (dt, 1H, H-4), 2.87-2.91 (m, 2H),
3.35 (m, 1H), 3.51 (s, 3H, CO2CH3), 3.57 (m, 1H, H-1), 7.14
(dd, 1H, J ) 8.4 and 1.8 Hz, Ar H-6), 7.32 (d, 1H, J ) 8.4 Hz,
Ar H-5), 7.47 (d, 1H, J ) 2.1 Hz, Ar H-2); 13C NMR (CDCl3 75
MHz) δ 25.57, 26.18, 33.58, 34.31, 42.30, 51.59, 52.88, 62.45,
65.60, 122.24, 127.88, 129.85, 130.89, 133.07, 144.20, 172.14.
Tartrate salt had: mp 90-92 °C; [R]20 -90.2° (c 0.50, CH3-
D
OH); Anal. (C20H25BrClNO8): C, H, N.
3â-(4′-Chloro-3′iodophenyl)tropane-2â-carboxylic Acid
Methyl Ester (3d) Tartrate. Anhydrous copper(II) chloride
(81 mg, 0.6 mmol), butyl nitrite (88 µL, 0.75 mmol), and
anhydrous acetonitrile (4 mL) were added to a three-necked
round-bottom flask that was equipped with a reflux condenser,
additional funnel, and a gas outlet tube. The resulting mixture
was warmed to 65 °C. The amine (4, 200 mg, 0.5 mmol) in 1
mL of acetonitrile was added dropwise to the reaction solution.
Lots of precipitate appeared, followed by the evolution of
nitrogen. After 10 min, the reaction mixture was allowed to
cool to room temperature, poured into 25 mL of 20% aqueous
HCl, and neutralized by the addition of saturated sodium
carbonate solution. The aqueous layer was extracted with
methylene chloride and dried (Na2SO4). Purification by flash
column (elution with 3:1 ethyl acetate-hexane with1% TEA)
1
gave 150 mg (71%) of product 3d as light yellow oil. H NMR
(CDCl3, 300 MHz) δ (ppm) 1.58-1.75 (m, 3H), 2.04-2.16 (m,
s, 5H, NCH3), 2.49 (dt, 1H, H-4), 2.84-2.89 (m, 2H), 3.35 (m,
1H), 3.53 (s, 3H, CO2CH3), 3.57 (m, 1H, H-1), 7.20 (dd, 1H, J
) 9.0 and 3.0 Hz, Ar H-6), 7.32 (d, 1H, J ) 8.4 Hz, Ar H-5),
7.70 (d, 1H, J ) 2.1 Hz, Ar H-2); 13C NMR (CDCl3 75 MHz) δ
25.59, 26.21, 33.46, 34.34, 42.32, 51.68, 52.94, 62.47, 65.63,
98.02, 129.02, 136.07, 139.60, 144.07, 172.19. Tartrate salt
In summary, previous studies showed that the mixed
action monoamine transporter inhibitor 3b reduced
cocaine self-administration at a high level of 5-HTT
occupancy with no detectable DAT occupancy and
showed limited reinforcing effects. In this study, a
number of compounds possessing monoamine-binding
properties similar to but slightly different from that of
3b have been produced. All of the compounds showed
subnanomolar potency at the DAT and 5-HTT. These
compounds can serve as pharmacological tools to further
characterize the highly interesting behavioral profile
found for 3b and may lead to new pharmacotherapies
for treating cocaine abuse.
had: mp 118-120 °C; [R]19 -80.60° (c 0.50, CH3OH). Anal.
D
(C20H25ClINO8‚1.75H2O): C, H, N.
3â-(4′-Amino-3′-chlorophenyl)tropane-2â-carboxylic
Acid Methyl Ester (7). A 50 mL flask equipped with a reflux
condenser was charged with a solution of the 4-amino com-
pound 6 (550 mg, 2 mmol) in reagent grade acetonitrile (20
mL). The solution was heated to 60 °C and N-chlorosuccinim-
ide (NCS), 400 mg, 3 mmol) was added in one portion. The
mixture was heated to reflux. After 5 h, the reaction mixture
was allowed to cool to room temperature and concentrated
under vacuum to give a dark residue, which was dissolved in
methylene chloride, and washed by 10% aqueous ammonium
hydroxide and water. Organic layers were combined and dried
over sodium sulfate. Purification by flash chromatography
(elution with 3:1 ethyl acetate-hexane with 1% TEA) gave 250
Experimental Section
Nuclear magnetic resonance (1H NMR and 13C NMR)
spectra were recorded on a 300 MHz (Bruker AVANCE 300)
spectrometer. Chemical shift data for the proton resonances
were reported in parts per million (δ) relative to internal
(CH3)4Si (δ 0.0). Optical rotations were measured on an
AutoPol III polarimeter, purchased from Rudolf Research.
Elemental analyses were performed by Atlantic Microlab,
Norcross, GA. Analytical thin-layer chromatography (TLC) was
1
mg (40%) of the product. H NMR (CDCl3, 300 MHz) δ (ppm)
1.51-1.61 (m, 3H), 2.02-2.13 (m and s, 5H, NCH3), 2.42 (dt,
1H, H-4), 2.74-2.82 (m, 2H), 3.26 (m, 1H), 3.45 (s and m, 4H,
CO2CH3 and H-1), 3.83 (br s, 2H, NH2), 6.59 (d, 1H, J ) 6.0
Hz, Ar H-5), 6.90 (dd, 1H, Ar H-6), 7.03 (d, 1H, J ) 2.1 Hz, Ar

2770 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 8
Carroll et al.
H-2). The amine 7 was used for the synthesis of 3e and 3h
129.14, 132.40, 139.05, 144.65, 172.18. The tartrate salt had:
mp 120-122 °C; [R]19D -73.0° (c 0.50, CH3OH). Anal. (C20H25-
BrINO8‚0.5H2O): C, H, N.
without further purification.
3â-(4′-Bromo-3′-chlorophenyl)tropane-2â-carboxylic
Acid Methyl Ester (3e) Tartrate. Anhydrous copper(II)
bromide (139 mg, 0.70 mmol), butyl nitite (102 µL, 0.87 mmol),
and anhydrous acetonitrile (4 mL) were added to a three-
necked round-bottom flask that was equipped with a reflux
condenser, addition funnel, and a gas outlet tube. The resulting
mixture was warmed to 65 °C. The amine (7, 180 mg, 0.58
mmol) in 1 mL of acetonitrile was added dropwise to the
reaction solution. Lots of precipitate appeared, followed by the
evolution of nitrogen. After 0.5 h, the reaction mixture was
allowed to cool to room temperature, poured into 25 mL of 20%
aqueous HCl, and basified by the addition of saturated sodium
carbonate solution. The aqueous layer was extracted with
methylene chloride and dried. Purification by flash column
(elution with 1:1 ethyl acetate-hexane with 1% TEA) gave 120
3â-(3′-Chloro-4′-iodophenyl)tropane-2â-carboxylic Acid
Methyl Ester (3h) Tartrate. To a stirred solution of the
starting material, 3â-(4′-amino-3′-chlorophenyl)tropane-2â-
carboxylic acid methyl ester (7, 250 mg, 0.8 mmol), and
diiodomethane (5 mL) under an atmosphere of nitrogen was
added isoamyl nitrite (215 µL, 1.6 mmol) from a syringe. The
reaction mixture was stirred at room temperature for 1 h
under nitrogen and allowed to warm to 80 °C and continue to
stir for another 2 h. Since the evaporation of the solvent,
diiodomethane, was very difficult, the reaction mixture was
directly applied on a column and purified with a flash column
(elution with 1:1 ethyl acetate-hexane with 1% TEA) to give
110 mg (33%) of product 3h. 1H NMR (CDCl3, 300 MHz) δ
(ppm) 1.59-1.71 (m, 3H), 2.05-2.24 (m and s, 5H, NCH3), 2.49
(dt, 1H, H-4), 2.88-2.93 (m, 2H), 3.34 (m, 1H), 3.53-3.58 (s
and m, 4H, CO2CH3 and H-1), 6.87 (dd, 1H, J ) 8.2 and 1.8
Hz, Ar H-6), 7.32 (d, 1H, J ) 2.1 Hz, Ar H-2), 7.71 (d, 1H, J )
8.1 Hz, Ar H-5); 13C NMR (CDCl3 75 MHz) δ 25.18, 25.74,
33.31, 33.81, 41.91, 51.31, 52.20, 61.96, 65.18, 94.50, 126.43,
127.16, 127.95, 139.52, 145.60, 171.78. The tartrate salt had:
mp 120-122 °C; [R]19D -83.0° (c 0.50, CH3OH). Anal. (C20H25-
ClINO8‚H2O): C, H, N.
1
mg (55%) of product 3e. H NMR (CDCl3, 300 MHz) δ (ppm)
1.55-1.74 (m, 3H), 2.07-2.26 (m and s, 5H, NCH3), 2.51 (dt,
1H, H-4), 2.86-2.96 (m, 2H), 3.35 (m, 1H), 3.53 (s, 3H, CO2-
CH3), 3.58 (m, 1H, H-1), 7.03 (dd, 1H, J ) 8.4 and 1.8 Hz, Ar
H-6), 7.32 (d, 1H, J ) 1.8 Hz, Ar H-2), 7.48 (d, 1H, J ) 8.4 Hz,
Ar H-5); 13C NMR (CDCl3 75 MHz) δ 25.56, 26.19, 33.71, 34.26,
42.28, 51.67, 52.84, 62.44, 65.60, 119.77, 127.38, 129.80,
133.44, 134.22, 144.84, 172.15. Tartrate salt had: mp 95-97
°C; [R]19 -75.00° (c 0.50, CH3OH). Anal. (C20H25BrClNO8‚
D
3â-(3′-Bromo-4′-iodophenyl)tropane-2â-carboxylic Acid
Methyl Ester (3i) Tartrate. To a stirred solution of the
starting material, 3â-(4′-amino-3′-bromophenyl)tropane-2â-
carboxylic acid methyl ester (5, 320 mg, 0.9 mmol), and
diiodomethane (5 mL) under an atmosphere of nitrogen was
added isoamyl nitrite (242 µL, 1.8 mmol) from a syringe. The
reaction mixture was stirred at room temperature for 1 h
under nitrogen and allowed to warm to 80 °C and continue to
stir for another 2 h. Since the evaporation of the solvent,
diiodomethane was very difficult, the reaction mixture was
directly applied on a column and purified by flash column
(elution with 1:1 ethyl acetate-hexane with 1% TEA) to give
60 mg (14%) of product 3i. 1H NMR (CDCl3, 300 MHz) δ (ppm)
1.58-1.70 (m, 3H), 2.03-2.21 (m and s, 5H, NCH3), 2.49 (dt,
1H, H-4), 2.86-2.93 (m, 2H), 3.34 (m, 1H), 3.53-3.58 (s and
m, 4H, CO2CH3 and H-1), 6.92 (dd, 1H, J ) 8.1 and 2.0 Hz, Ar
H-6), 7.48 (d, 1H, J ) 1.8 Hz, Ar H-2), 7.72 (d, 1H, J ) 8.4 Hz,
Ar H-5); 13C NMR (CDCl3 75 MHz) δ 25.58, 26.20, 33.76, 34.20,
42.30, 51.71, 52.84, 62.45, 66.62, 97.96, 126.30, 128.12, 129.63,
140.00, 145.99, 172.17. The tartrate salt had: mp 100-102
H2O): C, H, N.
3â-(3′,4′-Dibromophenyl)tropane-2â-carboxylic Acid
Methyl Ester (3f) Tartrate. Anhydrous copper(II) bromide
(134 mg, 0.67 mmol), butyl nitrite (98 µL, 0.84 mmol), and
anhydrous acetonitrile (4 mL) were added to a three-necked
round-bottom flask that was equipped with a reflux condenser,
addition funnel, and a gas outlet tube. The resulting mixture
was warmed to 65 °C. The amine (5, 200 mg, 0.56 mmol) in 1
mL of acetonitrile was added dropwise to the reaction solution.
Lots of precipitate appeared, followed by the evolution of
nitrogen. After 10 min, the reaction was complete. The reaction
mixture was allowed to cool to room temperature, poured into
25 mL of 20% aqueous HCl, and neutralized by the addition
of saturated sodium carbonate solution. The aqueous layer was
extracted with methylene chloride and dried (Na2SO4). Puri-
fication by flash column (elution with 1:3 ethyl acetate-hexane
with 1% TEA) gave 85 mg (36% of product 3f as a clear oil. 1H
NMR (CDCl3, 300 MHz) δ (ppm) 1.57-1.69 (m, 3H), 2.01-
2.22 (m and s, 5H, NCH3), 2.50 (dt, 1H, H-4), 2.85-2.89 (m,
2H), 3.34 (m, 1H), 3.52-3.59 (s and m, 4H, CO2CH3 and H-1),
7.08 (dd, 1H, J ) 8.4 and 2.1 Hz, Ar H-6), 7.45-7.50 (d and d,
2H, Ar H-2 and H5, overlap); 13C NMR (CDCl3 75 MHz) δ
25.56, 26.18, 33.56, 34.26, 42.30, 51.70, 52.85, 62.33, 65.60,
112.10, 124.62, 128.07, 133.11, 134.40, 144.89, 172.15. The
tartrate salt had: mp 112-114 °C; [R]20D -82.4° (c 0.50, CH3-
OH). Anal. (C20H25BrNO8‚H2O): C, H, N.
3â-(4′-Bromo-3′-iodophenyl)tropane-2â-carboxylic Acid
Methyl Ester (3g) Tartrate. Anhydrous copper(II) bromide
(168 mg, 0.84 mmol), butyl nitrite (123 µL, 1.05 mmol), and
anhydrous acetonitrile (4 mL) were added to a three-necked
round-bottom flask that was equipped with a reflux condenser,
addition funnel, and a gas outlet tube. The resulting mixture
was warmed to 65 °C. The amine (4, 280 mg, 0.7 mmol) in 1
mL of acetonitrile was added dropwise to the reaction solution.
Lots of precipitate appeared, followed by the evolution of
nitrogen. After 10 min, the reaction mixture was allowed to
cool to room temperature, poured into 25 mL of 20% aqueous
HCl, and neutralized by the addition of saturated sodium
carbonate solution. The aqueous layer was extracted with
methylene chloride and dried (Na2SO4). Purification by flash
column (elution with 3:1 ethyl acetate-hexane with 1% TEA)
gave 250 mg (77%) of product 3g. 1H NMR (CDCl3, 300 MHz)
δ (ppm) 1.57-1.73 (m, 3H), 2.09-2.21 (m and s, 5H, NCH3),
2.49 (dt, 1H, H-4), 2.84-2.91 (m, 2H), 3.35 (m, 1H), 3.53 (s,
3H, CO2CH3), 3.57 (m, 1H, H-1), 7.12 (dd, 1H, J ) 8.6 and 2.1
Hz, Ar H-6), 7.48 (d, 1H, J ) 8.4 Hz, Ar H-5), 7.73 (d, 1H, J )
2.1 Hz, Ar H-2); 13C NMR (CDCl3 75 MHz) δ 25.56, 26.21,
33.52, 34.28, 42.32, 51.70, 52.88, 62.46, 65.63, 101.12, 127.09,
°C; [R]20 -81.6° (c 0.50, CH3OH). Anal. (C20H25BrINO8): C,
D
H, N.
3â-(3′, 4′-Diiodophenyl)tropane-2â-carboxylic Acid
Methyl Ester (3j) Hydrochloride. To a stirred solution of
3â-(4′-amino-3′-iodophenyl)tropane-2â-carboxylic acid methyl
ester (4, 1.32 g, 33.05 mmol) in 16.5 diiodomethane under N2
was added 0.888 mL (0.774 g, 66.01 mmol) of isoamyl nitrite
via syringe. The mixture was heated to 55 °C and stirred for
8 h. The solution was cooled and 150 mL of diethyl ether was
added. The organic layer was extracted with 1 M aqueous
hydrochloric acid (3×). The aqueous layers were basified with
ammonium hydroxide and extracted with methylene chloride
(3×). The combined organic layers were dried over sodium
sulfate, filtered, and concentrated under reduced pressure. The
crude dark yellow oil was purified by column chromatography
on silica gel. Elution with 1:1 ethyl acetate-hexane with 2%
TEA afforded 0.984 g (58%) of product 3j. 1H NMR (CDCl3,
300MHz) δ (ppm) 1.53-1.69 (m, 3H), 2.14-2.24 (m, 2H), 2.20
(s, 3H), 2.33 (t, 1H, J ) 8 Hz), 2.83-2.94 (m, 2H), 3.32 (bs,
1H), 3.34 (bs, 1H), 3.34 (s, 3H), 6.95 (dd, 1H, J ) 2.5 and 9.9
Hz), 7.71 (d, 1H, J ) 9.8 Hz), 7.71 (s, 1H). The hydrochloride
salt had: mp 174 °C; [R]20 -59.7° (c 0.03, CH3OH); Anal.
D
(C16H20ClI2NO2): C, H, N.
3â-(3′,4′-Dimethylphenyl)tropane-2â-carboxylic Acid
Methyl Ester (3k) Tartrate. Magnesium turnings (3.21 g,
0.132 mol) were stirred under argon for 2 weeks to activate.
The activated magnesium was covered with 20 mL of distilled
ether and a small iodine crystal added. About 1/3 of a solution
of 4-iodoxylene (17.05 mL, 0.120 mol) in 30 mL distilled ether

Monoamine Transporter Binding of Phenyltropane Analogues
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 8 2771
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was added under argon, and mixture was heated slightly to
initiate reaction. Addition continued at a dropwise rate to
maintain reflux. After the addition was completed, the mixture
was refluxed for 2-3 h and then stirred at room-temperature
overnight. The Grignard reagent prepared above was cannu-
lated into a (3 L) three-necked flask and rinsed in with 200
mL distilled ether. The flask was cooled to -45 °C in aceto-
nitrile/dry ice bath, and anhydroecogonine methyl ester (8, 88.1
g, 48.9 mmol) in 100 mL of distilled ether was added at a slow
dropwise rate over 1.5 h. After 3.5 h, the bath was exchanged
for an acetone/dry ice bath and the reaction was quenched by
the very slow addition of trifluoroacetic acid (37 mL, 0.48 mol)
in 80 mL of distilled ether over 2 h. The dry ice bath was
exchanged for ice/water bath and 200 mL of H2O added (pH
) 1.0).
The aqueous layer was separated and the ether was washed
with 1 N HCl (2 × 200 mL). The combined aqueous extracts
were basified with concentrated NH4OH and filtered through
a Celite pad to remove small amount of opaque material. The
aqueous filtrate was washed with the ethyl ether (2×) and once
with CH2Cl2. The combined organic extracts were washed with
brine, dried over Na2SO4, filtered, and evaporated to give 8.48
g of crude material as an orange oil. The crude material was
purified by flash chromatography using 15% (9:1 Et2O:Et3N)/
hexanes as eluent to give 0.68 g (5%) of the 3k. 1H NMR
(CDCl3, 300 MHz) δ (ppm) 1.62-1.72 (m, 3H), 2.22 (s, 3H and
s, 6H on top of m 2.16-2.25), 2.55 (dt, 1H, H-4), 2.90-2.91
(m, 2H), 3.47-3.68 (s and m, 4H, CO2CH3 and H-1), 6.97-
7.39 (m, 3H). The tartrate salt had: mp 122-124 °C; [R]20
D
-97.2° (c 0.50, CH3OH). Anal. (C22H31NO8‚0.5H2O): C, H, N.
Acknowledgment. This research was supported by
the National Institute on Drug Abuse Grants DA05477.
We thank Fluvanna Josephson for the synthesis of 3j.
Supporting Information Available: Elemental analysis.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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