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B. Ghosh et al. / Bioorg. Med. Chem. 18 (2010) 5661–5674
5.14.5. Synthesis of 7-methoxy-N-propyl-N-(2-(4-(4-(pyridin-3-
yl)phenyl)piperazin-1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-
2-amine (21a)
5.14.10. Synthesis of (ꢀ)-7-(propyl(2-(4-(4-(pyridin-4-yl)-
phenyl)piperazin-1-yl)ethyl)amino)-5,6,7,8-tetrahydronaphth-
alen-2-ol (ꢀ)-22b
Compound 20a (0.61 g, 1.22 mmol) was reacted with LiAlH4
(0.23 g, 6.1 mmol) in THF (20 mL) by following the procedure F
to furnish 21a as oil (0.302 g, 51%). 1H NMR (400 MHz, CDCl3)
d ppm 0.80–0.84 (t, 3H, J = 8 Hz), 1.38–1.48 (m, 1H), 1.90–1.98
(m, 1H), 2.46–2.49 (t, 2H, J = 6 Hz), 2.62–2.76 (m, 4H), 2.82–
2.88 (m, 2H), 2.94–2.99 (br s, 1H), 3.16–3.18 (t, 4H, J = 4 Hz),
3.41 (s, 2H), 3.63–3.83 (m, 6H), 3.91 (s, 3H), 6.61 (s, 1H),
6.65–6.67 (d, 1H, J = 8 Hz), 6.82–6.85 (d, 1H, J = 12 Hz), 6.93–
6.95 (m, 2H), 7.266–7.299 (dd, 1H, J1 = 5.2 Hz, J2 = 8.4 Hz),
7.44–7.46 (d, 2H, J = 8 Hz), 7.77–7.80 (m, 1H), 8.45–8.46 (d, 1H,
J = 4 Hz), 8.75 (s, 1H).
Compound 21b (0.04 g, 0.083 mmol) was reacted with 1 M
BBr3/CH2Cl2 (0.41 mL, 0.41 mmol) in CH2Cl2 (10 mL) by following
the procedure G to furnish 22b (0.02 g, 59%). 1H NMR (400 MHz,
CDCl3) d ppm 0.94–0.96 (t, 3H, J = 4 Hz), 1.58–1.63 (m, 2H), 2.15–
2.18 (m, 1H), 2.61–2.94 (m, 12H), 3.12 (br s, 1H), 3.28–3.31 (t,
4H, J = 6 Hz), 6.60 (s, 1H), 6.66–6.68 (d, 1H, J = 8 Hz), 6.84–6.86
(d, 2H, J = 8 Hz), 6.98–7.00 (d, 1H, J = 8 Hz), 7.63–7.68 (m, 4H),
8.50–8.52 (d, 2H, J = 8 Hz). ½a D25
¼ ꢀ22:4, c = 0.5 in MeOH. The
ꢂ
product was converted into the corresponding tetrahydrochloride
salt as white solid; mp is 227–230 °C. Anal. Calcd for
(C30H42N4Cl4O, 2H2O) C, H, N.
5.14.6. Synthesis of (ꢀ)-7-methoxy-N-propyl-N-(2-(4-(4-(pyri-
din-4-yl)phenyl)piperazin-1-yl)ethyl)-1,2,3,4-tetrahydronaphth-
alen-2-amine (ꢀ)-21b
5.14.11. Synthesis of (ꢀ)-6-(propyl(2-(4-(4-(pyridin-4-yl)-
phenyl)piperazin-1-yl)ethyl)amino)-5,6,7,8-tetrahydrona-
phthalen-1-ol (ꢀ)-22c
Compound 20b (0.07 g, 0.15 mmol) was reacted with LiAlH4
(0.06 g, 1.5 mmol) in THF (20 mL) by following the procedure F
to furnish 21b as oil (0.041 g, 56.2%). 1H NMR (400 MHz, CDCl3) d
ppm 0.94–0.96 (t, 3H, J = 4 Hz), 1.58–1.63 (m, 2H), 2.15–2.18 (m,
1H), 2.61–2.94 (m, 12H), 3.12 (br s, 1H), 3.28–3.31 (t, 4H,
J = 6 Hz), 3.86 (s, 3H), 6.61 (s, 1H), 6.65–6.67 (d, 1H, J = 8 Hz),
6.84–6.86 (d, 2H, J = 8 Hz), 6.96–6.98 (d, 1H, J = 8 Hz), 7.63–7.68
(m, 4H), 8.50–8.52 (d, 2H, J = 8 Hz).
Compound 21c (0.07 g, 0.14 mmol) was reacted with 1 M BBr3/
CH2Cl2 (0.72 mL, 0.72 mmol) in CH2Cl2 (15 mL) by following the
procedure G to furnish 22c (0.05 g, 81%). 1H NMR (400 MHz, CDCl3)
d ppm 0.91–0.94 (t, 3H, J = 6 Hz), 1.48–1.65 (m, 3H), 2.08–2.13 (br
s, 1H), 2.46–3.03 (m, 15H), 3.26–3.30 (t, 4H, J = 8 Hz), 6.53–6.57 (m,
2H), 6.87–6.90 (t, 1H, J = 6 Hz), 7.03–7.05 (d, 2H, J = 8 Hz), 7.62–
7.67 (m, 4H), 7.45–8.47 (d, 2H, J = 8 Hz). ½a D25
¼ ꢀ37:5, c = 1 in
ꢂ
MeOH. The product was converted into the corresponding oxalate
salt as white solid; mp: 162–165 °C. Anal. Calcd for (C36H44N4O13
,
5.14.7. Synthesis of (ꢀ)-5-methoxy-N-propyl-N-(2-(4-(4-(pyri-
din-4-yl)phenyl)piperazin-1-yl)ethyl)-1,2,3,4-tetrahydrona-
phthalen-2-amine (ꢀ)-21c
0.5C4H10O) C, H, N.
5.14.12. Synthesis of (+)-7-(propyl(2-(4-(4-(pyridin-4-yl)-
phenyl)piperazin-1-yl)ethyl)amino)-5,6,7,8-tetrahydronaphth-
alen-2-ol (+)-22d
Compound 20c (0.125 g, 0.25 mmol) was reacted with LiAlH4
(0.095 g, 2.5 mmol) in THF (15 mL) by following the procedure F
to furnish 21c as oil (0.70 g, 72%). 1H NMR (400 MHz, CDCl3) d
ppm 0.91–0.93 (t, 3H, J = 4 Hz), 1.42–1.56 (m, 3H), 2.18 (br s,
1H), 2.46–3.12 (m, 15H), 3.32–3.34 (t, 4H, J = 4 Hz), 3.86 (s, 3H),
6.61–6.67 (m, 3H), 7.01–7.06 (m, 2H), 7.62–7.67 (m, 4H), 8.51–
8.53 (d, 2H, J = 8 Hz).
A solution of compound 21d (0.06 g, 0.12 mmol) in 48% aq.
HBr (3 mL) was refluxed for 2 h. The reaction mixture was
cooled to room temperature and evaporated to give a solid.
The resulting solid was neutralized by addition of saturated
NaHCO3 solution at 0 °C and extracted with dichloromethane,
and concentrated under reduced pressure. The crude material
was purified by column chromatography (DCM/MeOH, 9:1) to
give compound 22d (0.035 g, 60%). 1H NMR (400 MHz, MeOH-
5.14.8. Synthesis of (+)-7-methoxy-N-propyl-N-(2-(4-(4-(pyri-
din-4-yl)phenyl)piperazin-1-yl)ethyl)-1,2,3,4-tetrahydrona-
phthalen-2-amine (+)-21d
d4)
d ppm 0.96–1.00 (t, 3H, J = 7.2 Hz), 1.62–1.76 (m, 3H),
Compound 20d (0.12 g, 0.24 mmol) was reacted with LiAlH4
(0.09 g, 2.4 mmol) in THF (15 mL) by following the procedure F
to furnish 21d as oil (0.072 g, 62.1%). 1H NMR (400 MHz, MeOH-
d4) d ppm 0.93–0.96 (t, 3H, J = 7.2 Hz), 1.55–1.67 (m, 3H), 2.01–
2.15 (m, 1H), 2.57–2.91 (m, 16H), 3.00–3.07 (m, 2H), 3.57 (m,
1H), 3.73 (s, 3H), 6.64–6-67 (m, 2H), 6.94–6.96 (d, 1H, J = 8 Hz),
7.04–7.06 (d, 2H, J = 8.8 Hz), 7.63–7.68 (m, 4H), 8.46–8.48 (d, 2H,
J = 6 Hz).
2.12–2.15 (m, 1H), 2.66–2.97 (m, 14H), 3.06 (m, 2H), 3.28–3.34
(m, 3H), 6.55–6.58 (m, 2H), 6.88–6.90 (d, 1H, J = 8 Hz), 7.04–
7.06 (d, 2H, J = 8.8 Hz), 7.63–7.68 (m, 4H), 8.46–8.47 (d, 2H,
J = 5.6 Hz). 13C NMR (400 MHz, MeOH-d4) d ppm 10.65; 20.21;
25.39; 28.09; 30.92; 53.16; 53.54; 55.60; 59.34; 113.63;
115.19; 115.70; 120.79; 126.44; 127.53; 127.59; 129.28;
135.43; 149.08; 149.14; 152.31; 155.34. ½a D25
¼ þ27:2, c = 0.5 in
ꢂ
MeOH. The product was converted into the corresponding tetra-
hydrochloride salt; mp is 132–134 °C. Anal. Calcd for
(C30H42N4Cl4O, 2.3H2O) C, H, N.
5.14.9. Synthesis of 7-(propyl(2-(4-(4-(pyridin-3-yl)phenyl)-
piperazin-1-yl)ethyl)amino)-5,6,7,8-tetrahydronaphthalen-2-ol
(22a)
5.14.13. Synthesis of 2-(4-(4-iodophenyl)piperazin-1-yl)-N-(7-
methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propylacet-
amide (23)
Compound 21a (0.302 g, 0.62 mmol) was reacted with 1 M
BBr3/CH2Cl2 (2.5 mL, 2.5 mmol) in CH2Cl2 (20 mL) by following
the procedure G to furnish 22a (0.181 g, 62%). 1H NMR (400 MHz,
CDCl3) d ppm 0.87–0.91 (t, 3H, J = 8 Hz), 1.46–1.58 (m, 2H), 1.97–
2.00 (br s, 1H), 2.53–2.79 (m, 15H), 2.97 (br s, 1H), 3.27–3.30 (t,
4H, J = 6 Hz); 6.52 (s, 1H), 6.59–6.61 (d, 1H, J = 8 Hz), 6.88–6.90
(d, 1H, J = 8 Hz), 6.98–7.00 (d, 2H, J = 8 Hz), 7.316–7.349 (dd, 1H,
J1 = 5.6 Hz, J2 = 8.88 Hz), 7.48–7.50 (d, 2H, J = 8 Hz), 7.83–7.86 (m,
1H), 8.50–8.515 (d, 1H, J = 6 Hz), 8.81 (s, 1H).
This compound was prepared by following the N-alkylation
procedure N. Compound 13 (HCl salt, 0.50 g, 1.39 mmol) was re-
acted with 12c (0.61 g, 2.08 mmol) in CH3CN (50 mL) to furnish
23 as semisolid (0.51 g, 67.4%). 1H NMR (400 MHz, CDCl3) d ppm
0.87–0.89 (t, 3H, J = 4 Hz), 1.60–1.66 (m, 3H), 1.98–2.04 (br s,
1H), 2.48–2.52 (t, 2H, J = 8 Hz), 2.69–2.81 (m, 4H), 2.96–3.01 (m,
1H), 3.10–3.14 (t, 4H, J = 8 Hz), 3.44–3.45 (d, 2H, J = 4 Hz), 3.65–
3.86 (m, 4H), 3.91 (s, 3H), 6.61 (s, 1H), 6.65–6.66 (d, 1H, J = 4 Hz),
6.67–6.69 (d, 2H, J = 8 Hz), 6.96–6.98 (d, 1H, J = 8 Hz), 7.52–7.54
(d, 2H, J = 8 Hz).
The product was converted into the corresponding oxalate salt
as white solid; mp is 161–163 °C. Anal. Calcd for (C36H44N4O13
,
0.5H2O) C, H, N.