Synthesis and Pharmacology of Potential Cocaine Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1207
extracted with 4 × 70 mL of 6 N HCl solution. The aqueous
layer was then made basic with 15% NaOH solution to a pH
of >11 and extracted with 3 × 200 mL of EtOAc; the organic
layer was washed with water and dried to give a mixture that
was crystallized from hexane/EtOAc (1:1) to yield 7.73 g
Meth yl er yth r o-(3-Ch lor op h en yl)(2-p ip er id yl)a ceta te
(11d ). A mixture of 0.25 g (0.87 mmol) of compound 6 (X )
3-Cl) and 10 mL of 6 N HCl solution was heated under reflux
for 6 h. The solution was evaporated to dryness to give 9 and
10 (14:86 by 1H NMR analysis), which were mixed with 11
mL of CH3OH and 0.5 mL of SOCl2. Using a procedure similar
to that used for 1 and 11 above, this gave 0.20 g (86%) of the
free base of 1 and 11 as a colorless oil which was dissolved in
MeOH, and excess concentrated HCl was then added; evapora-
tion to dryness gave a white solid, which was then recrystal-
lized with MeOH/EtOAc (1:2) to give 0.125 g (overall yield 47%)
of pure 11 (by 1H NMR analysis) as colorless crystals: mp
199.8-200.2 °C; 1H NMR (D2O) δ 7.34-77.25 (m, 3H), 7.14
(m, 1H), 3.82 (d, J ) 8.9 Hz, 1H), 3.68-3.62 (m, 1H), 3.56 (s,
1H), 3.16-3.11 (m, 1H), 2.83-2.75 (m, 1H), 1.92-1.36 (m, 6H);
MS-CI, m/z 268.1 (100, M + 1 - HCl). Anal. Calcd for
C14H19Cl2NO2: C, H, N, Cl.
Isola tion of Rep r esen ta tive Keton e 4 (X ) 3-OMe). A
45% yield of impure 3 (X ) 3-OMe) containing some 4 was
obtained from 3-methoxyphenylacetonitrile and 2-bromopyri-
dine according to the above general procedure (after removal
of unreacted 2-bromopyridine by distillation). Impure 3 was
mixed with concentrated HCl to give impure 5 (X ) 3-OMe)
containing 4. This mixture was placed on an alumina column
and eluted with EtOAc/hexane (2:1) which gave, in the early
fractions, a 9% yield of 4 as a yellow oil: 1H NMR (CDCl3) δ
8.73 (d, J ) 6.5 Hz, 1H), 8.03 (d, J ) 7.7 Hz, 1H), 7.91 (td, J
) 7.7, 1.5 Hz, 1H), 7.65-7.62 (m, 2H), 7.52-7.48 (m, 1H), 7.40
(t, J ) 8.2 Hz, 1H), 7.16 (dd, J ) 8.6, 2.6 Hz, 1H), 3.87 (s, 3H);
MS-EI m/z 213 (M+, 70), 135 (100).
1
(33.9%) of 3 as colorless crystals: mp 83.3-84.3 °C; H NMR
(CDCl3) δ 8.63 (dd, J ) 2.6, 1.5 Hz, 1H), 7.8 (td, J ) 7.8, 1.8
Hz, 1H), 7.45-7.26 (m, 6H), 5.29 (s, 1H); MS-CI m/z 229 (M +
1,100). Alternatively, 2-bromopyridine can be distilled out of
1
the mixture to give impure 3 (ca. 50%) containing 7% (by H
NMR analysis) of the ketone 4 (X ) 3-Cl).
(3-Ch lor op h en yl)(2-p yr id yl)a ceta m id e (5, X ) 3-Cl).
With stirring, 1.00 g (4.40 mmol) of 3 (X ) 3-Cl) was dissolved
in 10 mL of 12 N HCl, heated to 40 °C, and then stirred at
room temperature for 15 h. The solution was poured into 50
mL of ice-water and then adjusted to a pH of 10-11 with
15% NaOH solution. The mixture was extracted with 3 × 40
mL of CH2Cl2, washed with 50 mL of water, and dried to give
0.97 g (89%) of 5 as a colorless solid: mp 97.2-98.4 °C; 1H
NMR (D2O) δ 8.61 (d, J ) 5.0 Hz, 1H), 7.87 (s, br, 1H), 7.68
(td, J ) 7.8, 1.7 Hz, 1H), 7.44 (s, 1H), 7.34-7.23 (m, 5H), 6.21
(s, br, 1H), 4.98 (s, 1H); MS-EI m/z 246 (M+, 3.4), 203 (100),
167 (71).
er yth r o- a n d th r eo-(3-Ch lor op h en yl)(2-p ip er id yl)-
a ceta m id es (6 a n d 7, X ) 3-Cl). To a solution of 0.43 g (1.7
mmol) of 5 (X ) 3-Cl) in 15 mL of HOAc was added 0.14 g of
5% Pt/C. This mixture was treated with H2 gas at 30-40 psi
for 10 h. The catalyst was removed by filtration and the
filtrate evaporated to dryness. Excess concentrated HCl was
then added and the mixture again evaporated to dryness to
give 0.48 g (98%) of compounds 6 and 7 (83:17 by 1H NMR
analysis); washing with EtOH gave 0.29 g (60%) of pure 6 as
a white solid: mp 238.7-239.0 °C; 1H NMR (D2O) δ 7.34-
7.19 (m, 4H), 3.66-3.57 (m, 2H), 3.17-3.13 (m, 1H), 2.83-
2.79 (m, 1H), 1.96-1.92 (m, 1H), 1.74-1.70 (m, 2H), 1.47-
1.40 (m, 3H); MS-CI m/z 253.1 (91, M + 1 - HCl), 170.0 (100).
Nitr a tion of 1a . Com p ou n d 1v (X ) 4-NO2). To 30 mL
of fuming nitric acid at -10 °C, was added 3.9 g (0.015 mol) of
(()-threo-ritalinic acid. After stirring for 15 min, ice was added
and then ammonium hydroxide until pH ) 7. The solid was
collected, washed with water, and dried to give 3.1 g (71%) of
crude product. A portion (0.50 g) was converted to the methyl
ester in the standard manner to yield 0.46 g (87%) of crude
hydrochloride salt. Careful crystallization from acetone gave
er yth r o- a n d th r eo-(3-Ch lor op h en yl)(2-p ip er id yl)a cetic
Acid s (8, X ) 3-Cl). A mixture of 5.20 g (0.018 mol) of 6 and
7 (X ) 3-Cl) and 100 mL of 6 N HCl solution was heated under
reflux for 6 h. The solution was evaporated to dryness to give
compounds 8 (71:29 erythro:threo by 1H NMR analysis, con-
taining some NH4Cl): 1H NMR (D2O) δ 7.33-7.08 (m, 4H),
3.73 (d, J ) 8.9 Hz, 1H), 3.62-3.56 (m, 1H), 3.31-3.13 (m,
1H), 2.91-2.75 (m, 1H), 1.99-1.22 (m, 6H); MS-CI m/z 254.1
(57, M + 1 - HCl), 171.0 (100).
0.066 g of pure 1 (R ) 4-NO2). Anal. Calcd for C14H19
ClN2O4: C, H, N, Cl.
-
2-Am in o-3-(2-p yr id yl)in d ole (2). Using the same method
as for the synthesis of compound 3 above, 7.5 g (0.057 mol) of
2-aminophenylacetonitrile (prepared from Pd-catalyzed hy-
drogenation of 2-nitrophenylacetonitrile in EtOAc, mp 67-69
°C) yielded 1.9 g of 2 (16%, isolated by alumina chromatog-
1
raphy) as a green solid: mp 154-155 °C; H NMR (CDCl3) δ
th r eo- a n d er yth r o-(3-Ch lor op h en yl)(2-p ip er id yl)a cetic
Acid s (9 a n d 10, X ) 3-Cl). Under a N2 atmosphere, the
above mixture of compounds 8 (X ) 3-Cl, ca. 0.018 mol) were
mixed with 80 mL of 50% KOH solution and heated under
reflux for 4 days, in a Teflon cup. The top oily layer was
separated, dissolved in CH3OH, acidified with concentrated
HCl, and evaporated to dryness to give compounds 9 and 10
8.51 (H14, dd, J ) 5.0, 1.2 Hz, 1H), 7.79 (H6 and H9, d, J ) 8.3
Hz, 2H), 7.69 (H12, td, J ) 7.3, 1.5 Hz, 1H), 7.64 (H-N1, bs,
1H), 7.16 (H11, d, J ) 7.5 Hz), 7.16 (H7 or H8, t, J ) 7.8 Hz),
7.04 (H7 or H8, t, J ) 7.7 Hz, 1H), 6.93 (H13, t, J ) 7.5 Hz,
1H), ca. 2.5 (C2-NH2, vbs); MS-EI m/z 209 (M+, 100); IR (KBr)
3420 (m), 3276 (m), 1598 (s), 1512 (s), 782 (s), 736 cm-1 (s).
Dem eth yla tion of Meth oxy Com p ou n d s. Each pure (()-
threo-methoxy compound was mixed with excess 48% HBr and
refluxed for 4 h under N2. The solution was evaporated to
dryness and converted to methyl ester hydrochloride salts and
purified in the standard manner. The compound from 1 (X )
2-OCH3) gave a mixture of erythro and threo isomers (ca. 1:1)
which could not be separated.
1
(83:17 by H NMR analysis): 1H NMR (D2O) δ 7.31-7.08 (m,
4H), 3.84 (d, J ) 9.2 Hz), 3.74 (d, J ) 9.0 Hz), 3.63-3.56 (m,
1H), 3.32-3.17 (m, 1H), 2.96-2.85 (m, 1H), 1.73-1.18 (m, 6H).
Meth yl th r eo-(3-Ch lor oph en yl)(2-piper idyl)acetate (1k).
To a solution of the above mixture of 9 and 10 (X ) 3-Cl, ca.
0.018 mol) in 193 mL of absolute CH3OH was slowly added 8
mL of SOCl2, while cooling with an ice bath. The mixture was
stirred at room temperature for 1 day and evaporated, water
added, and the pH adjusted to ca. 11 with 15% NaOH solution.
The mixture was extracted with 3 × 120 mL of EtOAc and
the organic layer washed with H2O and dried. Removal of
solvent gave 3.53 g (74% from compounds 6 and 7) of the free
base of compounds 1 and 11 (91:9 by 1H NMR analysis) which
was dissolved in MeOH, and excess concentrated HCl was
added, and the mixture was evaporated to dryness to give a
white solid, which was washed with Et2O and EtOAc to give
P h a r m a cology: [3H]WIN 35,428 Bin d in g. The synthe-
sized compounds were screened for activity in a striatal tissue
preparation using a modification of the [3H]WIN 35,428
binding assay described by Reith and Selmeci.43
Male
Sprague-Dawley rats (Harlan Sprague-Dawley, Indianapolis,
IN) weighing 150-300 g were anesthetized using CO2 gas and
sacrificed by decapitation. (Preliminary experiments demon-
strated no difference in the KD or Bmax of [3H]WIN 35,428
binding in unanesthetized rats versus anesthetized rats; data
not shown.) Their brains were quickly removed and placed
in ice-cold 0.32 M sucrose. The striatal tissue was removed
and homogenized in 20 volumes of 0.32 M sucrose, using 10
up/down strokes of a motorized Potter-Elvejhm homogenizer.
The supernatant obtained after centrifugation for 10 min at 0
°C (S1 fraction) was removed and centrifuged for 20 min at
20000g and 0 °C to obtain the P2 fraction, which was then
resuspended in 50 volumes (original wet weight) of ice-cold
1
3.16 g (90%) of pure 1 (by H NMR analysis). The analytical
samples was recrystallized from MeOH: mp 197.0-197.9 °C;
1H NMR (D2O) δ 7.31-7.23 (m, 3H), 7.11-7.08 (m, 1H), 3.84
(d, J ) 9.4 Hz, 1H), 3.71-3.64 (m, 1H), 3.58 (s, 3H), 3.33-
3.27 (m, 1H), 2.93-2.89 (m, 1H), 1.69-1.22 (m, 6H); MS-CI
m/z 268.2 (100, M+ + 1 - HCl). Anal. Calcd for C14H19Cl2-
NO2: C, H, N, Cl.