4
94 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Perrone et al.
1
[R]20
endo CH
CH Cl), 5.00-5.30 (m, 1H, CH), 7.00-7.30 (m, 4H, aromatic),
1
H NMR 1.65-2.05 (m, 4H, endo CH
2
), 2.50-2.80 (m, 4H, CH
2
-
),
D
) -77.2° (c ) 1.0, CH
3
OH); H NMR 1.75-2.15 (m, 4H,
), 4.05 (s, 2H,
CN, benzyl CH
6
2
), 3.05-3.30 (m, 1H, CH), 3.80 (s, 3H, CH
3
2
CH ), 2.65-3.00 (m, 2H, benzyl CH
2
2
+
.65-7.30 (m, 3H, aromatic); GC/MS m/z 202 (M + 1, 4), 201
2
+
+
+
(
M , 30), 161 (100), 160 (21), 115 (22).
S)-(+)-5-Met h oxy-1,2,3,4-t et r a h yd r o-1-n a p h t h a len e-
a cetic Acid [(S)-(+)-10]. A mixture of nitrile (S)-(-)-9 (0.80
g. 4.0 mmol) and 40 mL of 50% H SO was refluxed for 4 h.
Then the cooled mixture was extracted with CHCl
(2 × 40
mL). The collected organic layers were dried over Na SO and
concentrated under reduced pressure. The crude residue was
chromatographed (CHCl as eluent) to give 0.18 g of the
6.80 (br s, 1H, NH); GC/MS m/z 225 (M + 2, 1), 224 (M + 1,
1), 223 (M , 4), 188 (23), 146 (37), 131 (21), 130 (100), 129 (43).
+
(
(
R)-(+)-N-(1,2,3,4-Tet r a h yd r on a p h t h a len -1-yl)ch lor o-
2
4
a ceta m id e [(R)-(+)-13]. As above, starting from (R)-(-)-
3
1
,2,3,4-tetrahydronaphthalenamine [(R)-(-)-12] (0.34 g, 2.3
2
4
mmol) and chloroacetyl chloride (0.19 mL, 2.4 mmol), com-
pound (R)-(+)-13 was obtained as a white semisolid in 93%
3
yield: [R]
20
3
) +71.4° (c ) 3.0, CH OH). H NMR and GC/MS
1
D
expected acid (20% yield). HPLC analyses on a Daicel Chiralcel
OD column using n-hexane/2-propanol/trifluoroacetic acid (98:
2
7
retention time of a pure sample of (-)-10 obtained by fractional
crystallization of its diastereomeric salt with (S)-(-)-1-phe-
nylethylamine.
spectra of this compound were identical to those of its
enantiomer.
:0.1), flow rate 1.0 mL/min, indicated that the sample was
0% ee of the acid (S)-10. This acid displayed the same
(
S)-(-)-4-(2-Meth oxyph en yl)-N-(1,2,3,4-tetr ah ydr on aph -
th a len -1-yl)-1-p ip er a zin oa ceta m id e [(S)-(-)-14]. The de-
rivative (S)-(-)-13 (0.43 g, 1.9 mmol) was refluxed overnight
with 1-(2-methoxyphenyl)piperazine (0.73 g, 3.8 mmol) and a
slight excess of NaHCO
3
in acetonitrile. After cooling, the
mixture was concentrated under reduced pressure, and the
(
R)- a n d (S)-4-[3-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)-n -p r op yl]-1-a r ylp ip er a zin e Der iva tives 2-4.
Gen er a l P r oced u r e. A stirred suspension of the appropriate
mesylate (2.0 mmol), 1-arylpiperazine (4.0 mmol), and K
residue was taken up with water and extracted with CHCl
The chloroform phase was dried over Na SO
evaporated, and the crude residue was chromatographed (CH
Cl
3
.
2
4
, the solvent was
2
CO
3
2
-
(2.0 mmol) in acetonitrile was refluxed overnight. After cooling,
2
/MeOH, 19:1, as eluent) to give (S)-(-)-14 as a white
2
the mixture was evaporated to dryness and H O was added
20
semisolid (0.60 g, 84% yield): [R]
D
3
) -13.8° (c ) 2.35, CHCl ).
to the residue. The aqueous phase was extracted twice with
CH Cl . The collected organic layers were dried over Na SO
and evaporated under reduced pressure. The crude residue was
chromatographed (CH Cl /MeOH, 19:1, as eluent) to yield
target compounds as pale-yellow oils. All compounds displayed
ee g 98% (HPLC analysis on a Daicel Chiralcel OD using
n-hexane/ethanol/diethylamine, 9:1:0.1, as the mobile phase,
flow rate 0.8 mL/min).
HPLC analysis on a Daicel Chiralcel OD using n-hexane/
ethanol/diethylamine (9:1:0.1) as the mobile phase (flow rate
.8 mL/min) indicated that the material was >98% ee:
2
2
2
4
1
0
H
2
2
NMR (300 MHz) 1.68-1.88 and 2.04-2.11 (m, 4H, endo CH
CH ), 2.70-2.88 [m, 6H, benzyl CH , CH N(CH ], 3.02 [br s,
H, (CH NAr], 3.13 [d, 2H, J ) 3.0 Hz, CH N(CH ], 3.84
s, 3H, CH ), 5.17-5.24 (m, 1H, CH), 6.82-7.25 (m, 8H,
aromatic), 7.42 (br d, 1H, NH, D O exchanged); GC/MS m/z
2
-
2
2
2
2 2
)
4
2
)
2
2
2 2
)
(
3
2
(
S)-(+)-4-[3-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
+
+
+
3
81 (M + 2, 1), 380 (M + 1, 7), 379 (M , 26), 205 (100), 190
26).
R)-(+)-4-(2-Meth oxyph en yl)-N-(1,2,3,4-tetr ah ydr on aph -
th a len -1-yl)p ip er a zin oa ceta m id e [(R)-(+)-14]. Title com-
pound was prepared as above starting from derivative (R)-
+)-13 (0.41 g, 1.8 mmol) and 1-(2-methoxyphenyl)piperazine
0.77 g, 4.0 mmol) in 84% yield: [R]20
) +13.3° (c ) 2.2,
). HPLC analysis on a Daicel Chiralcel OD using
n-hexane/ethanol/diethylamine (9:1:0.1) as the mobile phase
(flow rate 0.8 mL/min) indicated the material was >98% ee.
H NMR and GC/MS spectra of this compound were identical
1
-yl)-n -p r op yl]-1-p h en ylp ip er a zin e [(S)-(+)-2]. Starting
(
from (S)-(+)-3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-
n-propyl methanesulfonate [(S)-(+)-11] and 1-phenylpipera-
(
2
0
zine, the title compound was obtained in 92% yield: [R]
8.3° (c ) 1.3, CHCl ).
S)-(+)-1-(2-Met h oxyp h en yl)-4-[3-(5-m et h oxy-1,2,3,4-
t et r a h yd r on a p h t h a len -1-yl)-n -p r op yl]p ip er a zin e [(S)-
+)-3]. Starting from mesylate (S)-(+)-11 and 1-(2-methox-
yphenyl)piperazine, the title compound was obtained in 85%
D
)
+
3
(
(
(
D
CHCl
3
(
2
0
yield: [R]
S)-(+)-4-[3-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
-yl)-n -p r op yl]-1-(2-p yr id yl)p ip er a zin e [(S)-(+)-4]. Start-
ing from mesylate (S)-(+)-11 and 1-(2-pyridyl)piperazine, the
D
) +5.8° (c ) 1.6, CHCl
3
).
1
(
to those of its enantiomer.
1
R esolu t ion of 5-Met h oxy-1,2,3,4-t et r a h yd r o-1-n a p h -
th a len a m in e [(()-15]. To a solution of racemic amine (()-
15 (7.62 g, 43.0 mmol) and (S)-(+)-mandelic acid (3.27 g, 21.5
mmol) in MeOH (60 mL) was added diethyl ether (30 mL).
The solution was allowed to cool in the refrigerator until
crystallization occurred. The crystals were filtered and recrys-
tallized from MeOH/diethyl ether three times to afford 2.80 g
of (+)-mandelate salt. The salt was dissolved in water, the ice-
cooled solution made basic with 2 N NaOH, and the resulting
2
0
title compound was obtained in 80% yield: [R]
1.5, CHCl ).
R)-(-)-4-[3-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
D
) +9.6° (c
)
3
(
1
-yl)-n -p r op yl]-1-p h en ylp ip er a zin e [(R)-(-)-2]. Starting
from (R)-(-)-3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-
n-propyl methanesulfonate [(R)-(-)-11] and 1-phenylpipera-
2
0
zine, the title compound was obtained in 82% yield: [R]
8.6° (c ) 1.2, CHCl ).
R)-(-)-1-(2-Met h oxyp h en yl)-4-[3-(5-m et h oxy-1,2,3,4-
t et r a h yd r on a p h t h a len -1-yl)-n -p r op yl]p ip er a zin e [(R)-
-)-3]. Starting from mesylate (R)-(-)-11 and 1-(2-methox-
yphenyl)piperazine, the title compound was obtained in 91%
D
)
-
3
mixture extracted with CH
was dried over Na SO , and the solvent was evaporated to
dryness to give 1.48 g of pure (+)-15: [R]
2.8, MeOH). HPLC analyses on a Daicel Chiralcel OD-R
column using MeOH/H O (9:1) as the mobile phase (flow rate
2 2
Cl (40 mL). The organic phase
(
2
4
2
0
D
) +15.7° (c )
(
1
2
0
yield: [R]
R)-(-)-4-[3-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
-yl)-n -p r op yl]-1-(2-p yr id yl)p ip er a zin e [(R)-(-)-4]. Start-
ing from mesylate (R)-(-)-11 and 1-(2-pyridyl)piperazine, the
D
) -5.5° (c ) 1.85, CHCl
3
).
2
0
.4 mL/min) indicated the material was >98% ee. The collected
(
mother liquors containing the (-)-isomer of 15 were evapo-
rated, dissolved in 40 mL of MeOH, and treated with (R)-(-
)-mandelic acid (3.27 g, 21.5 mmol). The solution was treated
with 30 mL of diethyl ether and kept in the refrigerator
overnight. The crystals were filtered off and recrystallized from
MeOH/diethyl ether three times to afford 2.50 g of (-)-
mandelate salt which was treated as described above for its
1
2
0
title compound was obtained in 79% yield: [R]
1.5, CHCl ).
S)-(-)-N-(1,2,3,4-Tet r a h yd r on a p h t h a len -1-yl)ch lor o-
a ceta m id e [(S)-(-)-13]. Chloroacetyl chloride (0.23 mL, 2.9
mmol) in CH Cl was added dropwise to a stirred mixture of
the amine (S)-(+)-12 (0.33 g, 2.2 mmol) and NaHCO (0.25 g,
.0 mmol) in CH Cl , under cooling. The reaction mixture was
stirred for 1 h, and then it was washed with brine. The
separated organic phase was dried over Na SO and evapo-
rated under reduced pressure. The crude residue was chro-
matographed with CH Cl /ethyl acetate, 4:1, to give compound
S)-(-)-13 as a white semisolid in nearly quantitative yield:
D
) -9.7° (c
)
3
(
2
2
(
)
+)-isomer to give 1.25 g of amine (-)-15: [R]20
10.6, MeOH). HPLC analyses in the above condition
indicated that the material was >98% ee.
(S)-(-)-N-(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-
yl)br om oa ceta m id e [S-(-)-16]. This compound was ob-
tained as a semisolid in nearly quantitative yield from the
amine (S)-(+)-15 (0.18 g, 1.1 mmol) and bromoacetyl chloride
D
) -11.0° (c
3
3
2
2
2
4
2
2
(