4034 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Blough et al.
yl)nortropane-2â-carboxylic acid methyl ester (3b) was followed
with 0.212 g (0.462 mmol) of N-[(2,2,2-trichloroethyl)carbam-
oyl]-3â-(4′-propynylphenyl)nortropane-2â-carboxylic acid meth-
yl ester (14b) and 0.151 g (2.31 mmol) of activated zinc in 3
mL of glacial acetic acid affording 0.081 g (62% yield) of 3â-
(4′-propynylphenyl)nortropane-2â-carboxylic acid methyl ester
(4b): 1H NMR (CDCl3) δ 1.96 (s, 3H, CCH3), 7.02 (d, 2H, J )
8.2 Hz, aryl H), 7.23 (d, 2H, J ) 8.1 Hz, aryl H).
The free base was converted to the tartrate salt: mp 160-
162 °C; [R]27D -102.4° (c 0.62, MeOH). Anal. (C22H29NO8‚H2O)
C, H, N.
Ack n ow led gm en t. This work was supported in part
by the National Institute on Drug Abuse, Grant No.
DA05477.
The free base was converted to the tartrate salt: mp 168-
170 °C; [R]27 -106.0° (c 0.465, MeOH). Anal. (C22H27NO8‚
Refer en ces
D
0.75H2O) C, H, N.
(1) Madras, B. K.; Fahey, M. A.; Bergman, J .; Canfield, D. R.;
Spealman, R. D. Effects of cocaine and related drugs in nonhu-
man primates. I. [3H]Cocaine binding sites in caudate-putamen.
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3â-(4′-P r op ylp h en yl)n or t r op a n e-2â-ca r b oxylic Acid
Meth yl Ester (2b). To a solution of 0.1112 g (0.392 mmol) of
3â-(4′-propynylphenyl)nortropane-2â-carboxylic acid methyl
ester (4b) in 1.0 mL of ethyl acetate in a round-bottom flask
was added 0.1 g of 10% palladium on carbon (fire hazard). The
hydrogen atmosphere was added via a hydrogen-filled balloon,
and the slurry was stirred overnight. The slurry was filtered
through a plug of Celite to remove the palladium on carbon.
The solution was concentrated under reduced pressure. The
resulting oil was purified by flash chromatography on silica
gel. Elution with 3:1 ethyl acetate-hexane with 1% additional
triethylamine afforded 0.082 g (73% yield) of 3â-(4′-propylphen-
yl)nortropane-2â-carboxylic acid methyl ester (2b): 1H NMR
(CDCl3) δ 0.91 (t, 3H, J ) 7 Hz, CH2CH3), 2.54 (t, 2H, J ) 8
Hz, CH2CH2CH3), 7.09 (s, 4H, aryl H).
(2) Calligaro, D. O.; Eldefrawi, M. E. Central and peripheral cocaine
receptors. J . Pharmacol. Exp. Ther. 1987, 243, 61-67.
(3) Schoemaker, H.; Pimoule, C.; Arbilla, S.; Scattom, B.; J avoy-
Agid, F.; Langer, S. W. Sodium dependent [3H]cocaine binding
associated with dopamine uptake sites the rat striatum and
human putamen decrease after dopaminergic denervation and
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(4) Kennedy, L. T.; Hanbauer, I. Sodium-sensitive cocaine binding
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(5) Reith, M. E. A.; Sershen, H.; Lajtha, A. Saturable [3H]cocaine
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receptors on dopamine transporters are related to self-admin-
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(4′-substituted phenyl)tropane-2â-carboxylic acid esters and
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The free base was converted to the tartrate salt: mp 138-
140 °C; [R]27 -73.6° (c 0.46, MeOH). Anal. (C22H31NO8‚
D
0.5H2O) C, H, N.
(Z)-3â-(4′-P r op en ylp h en yl)n or t r op a n e-2â-ca r b oxylic
Acid Meth yl Ester (3d ). To a solution of 0.0812 g (0.286
mmol) of 3â-(4′-propynylphenyl)nortropane-2â-carboxylic acid
methyl ester (4b) in 3.0 mL of benzene in an ACE pressure
tube was added 1 small drop (7 µL) of quinoline followed by
183 mg of Lindlar’s catalyst. The gauge assembly was fitted
on top, and the tube was pressurized with 60 psi of hydrogen
gas. The slurry was stirred for 3.5 h. The tube was vented,
and the slurry was filtered through a plug of Celite to remove
the catalyst. The solution was concentrated under reduced
pressure. The resulting oil was purified by flash chromatog-
raphy on silica gel. Elution with 3:1 ethyl acetate-hexane
with 5% additional methanol and 1% additional triethylamine
afforded 0.0612 g (75% yield) of (Z)-3â-(4′-propenylphenyl)-
nortropane-2â-carboxylic acid methyl ester (3d ): 1H NMR
(CDCl3) δ 1.89 (d, 3H, J ) 7.2 Hz, CHCH3), 5.76 (dq, 1H, J )
7.2, 11.6 Hz, CHCH3), 6.38 (d, 1H, J ) 11.5 Hz, CHdCHCH3),
7.15 (d, 2H, J ) 8.3 Hz, aryl H), 7.22 (d, 2H, J ) 8.3 Hz, aryl
H).
The free base was converted to the tartrate salt: mp 107-
108 °C; [R]27 -104.2° (c 0.310, MeOH). Anal. (C22H29NO8‚
D
0.5H2O) C, H, N.
(E)-3â-(4′-P r op en ylp h en yl)n or t r op a n e-2â-ca r b oxylic
Acid Meth yl Ester (3c). To a stirred solution of 0.273 g (0.59
mmol) of N-[(2,2,2-trichloroethyl)carbamoyl]-3â-(4′-allylphen-
yl)nortropane-2â-carboxylic acid methyl ester (14c) in 7.0 mL
of ethanol was added 100 mg of rhodium(III) chloride. The
slurry was heated to reflux overnight and cooled. The slurry
was filtered through a plug of silica gel and concentrated under
reduced pressure affording 0.131 g (48% yield) of crude (E)-
N-[(2,2,2-trichloroethyl)carbamoyl]-3â-(4′-propenylphenyl)nor-
tropane-2â-carboxylic acid methyl ester (14d ).
To the crude carbamate in 1.4 mL of tetrahydrofuran and
1.4 mL of saturated aqueous ammonium acetate was added
0.160 g (1.42 mmol) of 10% PbO/Cd. The slurry was stirred
for 1 h and then filtered through Celite. The solution was
basified with saturated aqueous bicarbonate and extracted
with methylene chloride (5×). The combined extract was dried
over sodium sulfate, filtered, and concentrated under reduced
pressure. The crude oil was purified by flash chromatography
on silica gel. Elution with 3:1 ethyl acetate-hexane with 5%
additional methanol and 1% additional triethylamine afforded
0.0381 g (47% yield) of (E)-3â-(4′-propenylphenyl)nortropane-
2â-carboxylic acid methyl ester (3c): 1H NMR (CDCl3) δ 1.87
(d, 3H, J ) 6.1 Hz, CHCH3), 6.19 (dq, 1H, J ) 6.0, 15.8 Hz,
CHCH3), 6.36 (d, 1H, J ) 16.0 Hz, CHdCHCH3), 7.10 (d, 2H,
J ) 8.3 Hz, aryl H), 7.26 (d, 2H, J ) 8.9 Hz, aryl H).
(16) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Reactions of
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