702 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Calderon et al.
below) were purified by flash column chromatography and
recrystallized as for its enantiomer: mp 101-102 °C; 1H NMR
δ 0.99 (d, J ) 6.1 Hz, 3H), 1.11-1.26 (br d, 9H), 1.80-1.87
(m, 1H), 2.09-2.16 (m, 1H), 2.42-2.49 (br t, 1H), 2.56-2.60
(m, 2H), 2.78-2.88 (m, 2H), 3.29-3.38 (m, 3H), 3.50-3.58 (br
s, 2H), 5.13-5.25 (m, 3H), 5.78-5.92 (m, 1H), 6.85-6.97 (m,
2H), 7.28-7.32 (m, 4H), 7.44 (d, J ) 8.0 Hz, 2H); CIMS m/ z
26: 1H NMR (CDCl3) δ 0.99 (d, J ) 6.2 Hz, 3H), 1.15-1.23
(br d, 9H), 1.86-1.93 (m, 1H), 2.12-2.18 (m, 1H), 2.49-2.68
(m, 3H), 2.77-2.91 (m, 2H), 3.19-3.38 (m, 3H), 3.54 (br s, 2H),
5.13-5.26 (m, 3H), 5.80-5.93 (m, 1H), 7.21-7.42 (m, 9H);
[R]22D ) -23.9° (c 0.9, MeOH). Anal. (-)-26‚HCl lyophilizate
(C27H37N3O‚2HCl‚1.5H2O) C, H, N.
(+)-4-[(rS)-r-((2S,5R)-4-Allyl-2,5-dim eth yl-1-piper azin yl)-
3-flu or ob en zyl]-N,N-d iet h ylb en za m id e [(+)-27]. Com-
pound (+)-27 was obtained as a glass (0.58 g, 22%) during the
chromatography of (+)-23 with ethyl acetate: 1H NMR δ 0.99
(d, J ) 6.2 Hz, 3H), 1.18 (br d, 9H), 1.83-1.90 (m, 1H), 2.11-
2.17 (m, 1H), 2.48-2.63 (m, 4H), 2.77-2.90 (m, 2H), 3.30-
3.39 (m, 3H), 3.52 (br s, 2H), 5.14-5.25 (m, 3H), 5.69-5.93
(m, 1H), 6.89-6.95 (m, 1H), 7.07-7.10 (m, 1H), 7.18-7.26 (m,
438 (MH+); [R]22 ) -27.2° (c 0.7, MeOH). Anal. (C27H36N3-
D
OF) C, H, N.
(+)-4-[(rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-iodoben zyl]-N,N-dieth ylben zam ide [(+)-24]. A mix-
ture of 20 (3.25 g, 7.60 mmol), (-)-2 (1.17 g, 7.58 mmol),
anhydrous K2CO3 (3.15 g, 22.8 mmol), and tetrabutylammo-
nium iodide (0.28 g, 0.76 mmol) in 90 mL of anhydrous
acetonitrile was allowed to stir at reflux for 84 h under
nitrogen. The solution was filtered, and the volatiles were
evaporated under reduced pressure. The residue was dissolved
in 100 mL of a 1:1 mixture of ethyl acetate/water. The organic
layer was separated, washed with water (1 × 25 mL), and
dried. The volatiles were removed under reduced pressure to
give a mixture of (+)-24 and (+)-28 (4.06 g, crude). The crude
oil was purified by flash chromatography (silica gel, ethyl
acetate) to give 1.66 g of (+)-24 as an oil (40.2%) and (+)-28
(see below): 1H NMR (CDCl3) δ 0.98 (d, J ) 6.0 Hz, 3H), 1.16
(d, J ) 6.0 Hz, 3H), 1.05-1.30 (br s, 6H), 1.82 (dd, J )10.0
Hz, J ) 9.0 Hz, 1H), 2.12 (dd, J ) 10.0 Hz, J )9.0 Hz, 1H),
2.40-2.63 (br m, 3H), 2.76-2.89 (m, 2H), 3.29 (br s, 2H), 3.36
(dd, J ) 15.0 Hz, J ) 6 Hz, 1H), 3.53 (br s, 2H), 5.22-5.10 (m,
3H), 5.80-5.95 (m, 1H), 7.05 (d, J ) 8.0 Hz, 1H), 7.12 (t, J )
8.0 Hz, 1H), 7.32 (d, J ) 8.0 Hz, 2H), 7.43 (d, J ) 8.0 Hz, 2H),
7.53 (s, 1H), 7.62 (d, J ) 8.0 Hz, 1H); CIMS m/ z 545 (MH+);
HRMS (C27H36N3OI) requires 545.1903 (MH+), found 545.1910.
4H), 7.36 (d, J ) 8.0 Hz, 2H); CIMS m/ z 438 (MH+); [R]20
)
D
+24.2° (c 0.3, MeOH). Anal. (+)-27‚HCl lyophilizate (C27H36N3-
OF‚2HCl‚2H2O) C, H, N.
(-)-4-[(rR)-r-((2R,5S)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-flu or oben zyl]-N,N-dieth ylben zam ide [(-)-27]. Com-
pound (-)-27 (0.45 g, 17%) was obtained as an oil during the
chromatography of (-)-23 with ethyl acetate: 1H NMR δ 0.99
(d, J ) 6.5 Hz, 3H), 1.19 (br d, 9H), 1.83-1.90 (m, 1H), 2.11-
2.17 (m, 1H), 2.50-2.63 (m, 3H), 2.77-2.90 (m, 2H), 3.32-
3.39 (m, 3H), 3.54 (br s, 2H), 5.13-5.25 (m, 3H), 5.79-5.92
(m, 1H), 6.90-6.94 (m, 1H), 7.07-7.10 (br d, 1H), 7.18-7.24
(m, 4H), 7.36 (d, J ) 7.9 Hz, 1H); CIMS m/ z 438 (MH+); [R]20
D
) +24.0° (c 0.7, MeOH). Anal. (-)-27‚HCl lyophilizate
(C27H36N3OF‚2HCl‚3H2O) C, H, N.
(+)-4-[(rS)-r-((2S,5R)-4-Allyl-2,5-dim eth yl-1-piper azin yl)-
3-iod oben zyl]-N,N-d ieth ylben za m id e [(+)-28]. Compound
(+)-28 (1.50 g, 36.3%) was obtained as an oil described in the
synthesis and chromatographic purification of compound (+)-
24: 1H NMR (CDCl3) δ 1.00 (d, J ) 6.0 Hz, 3H), 1.18 (d, J )
6.0 Hz, 3H), 1.05-1.32 (br s, 6H), 1.87 (dd, J )10.0 Hz, J )
9.0 Hz, 1H), 2.14 (dd, J ) 10.0 Hz, J )9.0 Hz, 1H), 2.42-2.64
(br m, 3H), 2.75-2.92 (m, 2H), 3.20-3.40 (m, 3H), 3.53 (br s,
2H), 5.10-5.23 (m, 3H), 5.80-5.95 (m, 1H), 7.00 (t, J ) 8.0
Hz, 1H), 7.12-7.22 (m, 3H), 7.34 (d, J ) 8.0 Hz, 2H), 7.57 (d,
J ) 8.0 Hz, 1H), 7.80 (s, 1H); CIMS m/ z 545 (MH+); HRMS
(C27H36N3OI) requires 545.1903 (MH+), found 545.1915.
Compound (+)-24‚HCl lyophilizate, [R]22 ) +6.6° (c 0.84,
D
MeOH). Anal. (C27H36N3OI‚HCl‚2H2O) C, H, N.
(+)-4-[(rS)-r-((2S,5R)-4-Allyl-2,5-dim eth yl-1-piper azin yl)-
3-m eth oxyben zyl]-N,N-d ieth ylben za m id e [(+)-25]. After
separation of (+)-21 from the trituration mixture by filtration,
the volatiles were evaporated under reduced pressure. The
residue was purified by flash column chromatography eluted
with ethyl acetate to give 3.5 g (25%) of (+)-25 as a glass: 1H
NMR (CDCl3) δ 0.95 (d, J ) 6.1 Hz, 3H), 1.12-1.28 (br d, 9H),
1.85 (t, J ) 9.1 Hz, 1H), 2.15 (t, J ) 9.1 Hz, 1H), 2.45-2.70
(m, 3H), 2.75-2.90 (m, 2H), 3.22-3.39 (m, 3H), 3.55 (br s, 2H),
3.80 (s, 3H), 5.11-5.25 (m, 3H), 5.75-5.89 (m, 1H), 6.70-6.80
(m, 1H), 6.90-6.95 (m, 1H), 7.15-7.28 (m, 4H), 7.35 (d, J )
Compound (+)-28‚HCl lyophilizate, [R]22 ) +8.34° (c 0.73,
D
MeOH). Anal. (+)-28‚HCl lyophilizate (C27H36N3OI‚HCl.-
2H2O) C, H, N.
(+)-4-[(rS)-r-((2S,5R)-4-Allyl-2,5-dim eth yl-1-piper azin yl)-
3-h yd r oxyben zyl]-N,N-d ieth ylben za m id e [(+)-29]. Com-
pound (+)-29 was obtained as a glass (0.87 g, 50%) from (+)-
25, according to the procedure described for the synthesis and
purification of compound (+)-1. 1H NMR (CDCl3) δ 1.02 (d, J
) 6.1 Hz, 3H), 1.15-1.25 (m, 9H), 1.95 (br t, 1H), 2.18 (br t,
1H), 2.48-2.95 (m, 5H), 3.28-3.65 (m, 5H), 5.12-5.25 (m, 3H),
5.81-5.98 (m, 1H), 6.60-6.70 (m, 1H), 6.90-6.98 (m, 2H),
7.10-7.18 (m, 1H), 7.23 (d, J ) 8.1 Hz, 2H), 7.35 (d, J ) 8.1
Hz, 2H); CIMS m/ z 436 (MH+); [R]20D ) +19.3° (c 0.6, MeOH).
(+)-29‚Di-p-tolu yl-L-ta r tr a te: mp 145-147 °C; recrystallized
8.1 Hz, 2H); CIMS m/ z 450 (MH+); [R]20 ) +25.2° (c 1.0,
D
MeOH). (+)-25‚HCl lyophilizate, [R]22D ) +6.4° (c 0.5, MeOH).
Anal. (C28H39N3O2‚2HCl‚1.25H2O) C, H, N.
(-)-4-[(rR)-r-((2R,5S)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-m eth oxyben zyl]-N,N-d ieth ylben za m id e [(-)-25].
Compound (-)-25 was obtained as a glass (1.56 g, 24%)
according to the procedure described for the purification of
compound (+)-25: 1H NMR (CDCl3) δ 0.99 (d, J ) 6.3 Hz, 3
H), 1.16-1.28 (br d, 9 H), 1.85-1.90 (m, 1 H), 2.11-2.19 (m,
1 H), 2.45-2.65 (m, 3 H), 2.75-2.94 (m, 2 H), 3.28-3.39 (m, 3
H), 3.55 (br s, 2 H), 3.80 (s, 3 H), 5.12-5.25 (m, 3 H), 5.78-
5.93 (m, 1 H), 6.75-6.95 (m, 3 H), 7.08-7.35 (m, 3 H), 7.45 (d,
from ethanol/water; [R]22 ) -61.3° (c 1.0, MeOH). Anal.
D
(C47H55N3O10.0.75H2O) C, H, N.
(-)-4-[(rR)-r-((2R,5S)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)-3-h yd r oxyb en zyl]-N,N-d iet h ylb en za m id e [(-)-29].
Compound (-)-29 was obtained as a glass (0.42, 44%) from
(-)-25 according to the procedure described for the synthesis
and purification of (-)-1: 1H NMR (CDCl3) δ 0.98 (d, J ) 6.2
Hz, 3H), 1.16-1.27 (br d, 9H), 1.88 (dd, J ) 11.1 Hz, J ) 8.8
Hz, 1H), 2.14 (dd, J ) 11.1 Hz, J ) 8.8 Hz, 1H), 2.48-2.93
(m, 5H), 3.27-3.63 (m, 5H), 5.11-5.28 (m, 3H), 5.78-5.93 (m,
1H), 6.68-6.71 (m, 1H), 6.89-6.98 (m, 2H), 7.11-7.18 (m, 1H),
7.22 (d, J ) 8.2 Hz, 2H), 7.35 (d, J ) 8.2 Hz, 2H); CIMS m/ z
436 (MH+); [R]20D ) -17.9° (c 0.5, MeOH). (-)-29.Di-p-tolu yl-
D-ta r tr a te: recrystallized from ethanol/water; mp 135-138 °C;
J ) 8.0 Hz, 2 H); CIMS m/ z 450 (MH+); [R]20 ) -24.1° (c
D
1.8, MeOH). (-)-25‚HCl lyophilizate, [R]22 ) -6.4° (c 0.5,
D
MeOH). Anal. (C28H39N3O2‚2HCl‚0.5H2O) C, H, N.
(+)-4-[(rR)-r-((2S,5R)-4-Allyl-2,5-d im eth yl-1-p ip er a zi-
n yl)ben zyl]-N,N-d ieth ylben za m id e [(+)-26]. After separa-
tion of (+)-22 by filtration from the trituration mixture as
described above, the volatiles were evaporated under reduced
pressure and (+)-26 was purified by flash column chromatog-
raphy (ethyl acetate) to give 0.58 g of (+)-26 (21%) as an oil:
1H NMR (CDCl3) δ 0.99 (d, J ) 6.2 Hz, 3H), 1.17-1.19 (br d,
9H), 1.86-1.93 (m, 1H), 2.12-2.19 (m, 1H), 2.49-2.68 (m, 3H),
2.77-2.91 (m, 2H), 3.32-3.38 (m, 3H), 3.54 (br s, 2H), 5.13-
5.26 (m, 3H), 5.80-5.91 (m, 1H), 7.21-7.36 (m, 7H), 7.41 (d,
[R]22 ) +63.1° (c 0.5, MeOH). Anal. (C47H55N3O10.1.5H2O)
D
C, H, N.
J ) 7.6 Hz, 2H); [R]22 ) +23.5° (c 0.2, MeOH). Anal. (+)-
(+)-4-[(rR)-r-((2S,5R)-4-P r op yl-2,5-d im et h yl-1-p ip er -
a zin yl)ben zyl]-N,N-d ieth ylben za m id e [(+)-30]. A solution
of (+)-22 (0.07 mg, 0.17 mmol) in ethanol (10 mL) containing
10% Pd/C (0.025 g) was shaken for 1 h at room temperature
under 25 psig of H2. The solution was filtered, and the
volatiles were evaporated under reduced pressure to give 0.06
D
26‚HCl lyophilizate (C27H37N3O‚2HCl‚2H2O) C, H, N.
(-)-4-[(rS)-r-((2R,5S)-4-Allyl-2,5-dim eth yl-1-piper azin yl)-
ben zyl]-N,N-d ieth ylben za m id e [(-)-26]. Compound (-)-
26 was obtained as an oil (1.17g, 22%) according to the
procedure described for the synthesis and purification of (+)-