Journal of Medicinal Chemistry
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(hexane/EtOAc, 1:4) to give compound 5a (1.90 g, 80%). H NMR
(CDCl3, 400 MHz): δ 0.09 (s, 6H), 0.92 (s, 9H), 2.61 (t, J = 6.0 Hz, 2H),
2.72 (t, J = 5.0 Hz, 4H), 3.24 (t, J = 4.80 Hz, 4H), 3.80 (t, J = 6.4 Hz, 2H),
3.83 (s, 3H), 6.95 (d, J = 9.2 Hz, 2H), 6.98(d, J = 8.8 Hz, 2H), 7.46 (d, J =
8.8 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H).
(t, J = 4.0 Hz, 4H), 3.29 (t, J = 5.0 Hz, 4H), 3.70 (t, J = 5.6 Hz, 2H),
3.83 (s, 3H), 6.95−7.02 (m, 4H), 7.27−7.31 (m, 2H), 7.46 (d, J =
8.8 Hz, 2H).
2-(4-([1,1′-Biphenyl]-4-yl)piperazin-1-yl)ethanol (6d). Com-
pound 5d (2.5 g, 6.30 mmol) was reacted with n-tetrabutylammonium
fluoride (1.65 g, 6.30 mmol, 1.0 M solution in THF) in THF (50 mL) by
following procedure D to yield compound 6d (1.50 g, 80%). 1H NMR
(CDCl3, 400 MHz): δ 2.69 (t, J = 8.0 Hz, 4H), 2.78 (t, J = 4.0 Hz, 2H),
3.30 (t, J = 4.8 Hz, 4H), 3.72 (t, J = 5.6 Hz, 2H), 6.97−7.02 (m, 2H),
7.25−7.30 (m, 1H), 7.38−7.42 (m, 2H), 7.51−7.56 (m, 4H).
4-(4-(3′-Methoxy-[1,1′-biphenyl]-4-yl)piperazin-1-yl)butan-
1-ol (6e). Compound 5e (2.6 g, 5.72 mmol) was reacted with
n-tetrabutylammonium fluoride (1.50 g, 5.72 mmol, 1.0 M solution in
THF) in THF (40 mL) by following procedure D to yield compound 6e
(1.40 g, 72%). 1H NMR (CDCl3, 400 MHz): 1.62 (t, J = 8.0 Hz, 4H),
2.41 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 7.6 Hz, 4H), 3.27 (t, J = 6.8 Hz, 4H),
3.64 (t, J = 7.2 Hz, 2H), 3.85 (s, 3H), 6.85 (dd, J = 1.6 Hz, 8.0 Hz, 1H),
6.99 (d, J = 8.8 Hz, 2H), 7.09 (bs, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.32
(t, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H).
Procedure E. 2-(4-(4′-Methoxybiphenyl-4-yl)piperazin-1-yl)-
acetaldehyde (7a). Into a stirred solution of oxalyl chloride (0.324 mL,
2.56 mmol) in CH2Cl2 (40 mL) at −78 °C, DMSO (0.40 mL, 5.12 mmol)
was added. The reaction mixture was stirred for 10 min followed by
addition of compound 6a (400 mg, 1.28 mmol, dissolved in 5 mL of
CH2Cl2). The reaction mixture was stirred at the same temperature for
15 min. Then Et3N (0.78 mL, 7.68 mmol) was added next, and stirring
was continued for another 1 h and 20 min while allowing the reaction
mixture to reach at room temperature. The reaction mixture was
quenched by addition of water and extracted with CH2Cl2 (3 × 25 mL).
The combined organic layer was washed with brine and concentrated
to yield the compound 7a (321 mg, 81%), which was used without
purification in the next step.
1-(2-(t-Butyldimethylsilyloxy)ethyl)-4-(3′-methoxybiphenyl-
4-yl)piperazine (5b). Compound 4b (3.20 g, 11.94 mmol), was
reacted with (2-bromo-ethyl)-tert-butyldimethylsilane (3.42 g, 14.32
mmol), and K2CO3 (4.94 g, 35.74 mmol) in CH3CN (80 mL) by
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following the procedure C to furnish 5b (4.06 g, 80%). H NMR
(CDCl3, 400 MHz): δ 0.06 (s, 6H), 0.90 (s, 9H), 2.49 (t, J = 7.2 Hz, 2H),
2.63 (bs, 4H), 3.26 (t, J = 4.8 Hz, 4H), 3.68 (t, J = 4.0 Hz, 2H), 3.83 (s,
3H), 6.84 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 7.09 (t,
J = 2.4 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.51 (d,
J = 8.0 Hz, 2H).
1-(2-(t-Butyldimethylsilyloxy)ethyl)-4-(2′-methoxybiphenyl-
4-yl)piperazine (5c). Compound 4c (2.20 g, 8.20 mmol) was reacted
with (2-bromo-ethyl)-tert-butyldimethylsilane (2.34 g, 9.84 mmol),
and K2CO3 (3.39 g, 24.60 mmol) in CH3CN (30 mL) by following
procedure C to afford compound 5c (2.70 g, 80%). 1H NMR (CDCl3,
400 MHz): 0.06 (s, 6H), 0.90 (s, 9H), 2.58 (t, J = 5.6 Hz, 2H), 2.69
(bs, 4H), 3.24 (bs, 4H), 3.78 (t, J = 4.8 Hz, 2H), 3.83 (s, 3H), 6.95−7.06
(m, 4H), 7.24−7.27 (m, 2H), 7.44−7.46 (m, 2H).
1-([1,1′-Biphenyl]-4-yl)-4-(2-((tert-butyldimethylsilyl)oxy)-
ethyl)piperazine(5d). Compound 4d (2.1 g, 8.81 mmol) was reacted
with (2-bromo-ethyl)-tert-butyldimethylsilane (2.52 g, 10.58 mmol),
and K2CO3 (3.65 g, 26.43 mmol) in CH3CN (30 mL) by following
procedure C to afford compound 5d (2.79 g, 80%). 1H NMR (CDCl3,
400 MHz): δ 0.09 (s, 6H), 0.92 (s, 9H), 2.69 (t, J = 5.6 Hz, 2H), 3.18
(t, J = 6.8 Hz, 4H), 3.30 (t, J = 4.8 Hz, 2H), 3.72 (t, J = 5.6 Hz, 4H), 6.98
(d, J = 8.0 Hz, 2H), 7.25−7.30 (m, 1H), 7.40 (t, J = 8.0 Hz, 2H), 7.51−
7.56 (m, 4H).
2-(4-(3′-Methoxybiphenyl-4-yl)piperazin-1-yl)acetaldehyde
(7b). Compound 6b (2.6 g, 8.32 mmol) was reacted with oxalyl chloride
(1.43 mL, 16.65 mmol), DMSO (2.36 mL, 33.28 mmol), and Et3N
(6.91 mL, 49.92 mmol) in dichloromethane (50 mL) by following
procedure E to yield compound 7b (2.18 g, 85%).
2-(4-(2′-Methoxybiphenyl-4-yl)piperazin-1-yl)acetaldehyde
(7c). Compound 6c (500 mg, 1.60 mmol) was reacted with oxalyl
chloride (0.41 mL, 3.20 mmol), DMSO (0.50 mL, 6.40 mmol), and
Et3N (0.97 mL, 9.60 mmol) in dichloromethane (40 mL) by following
procedure E to yield compound 7c (372 mg, 75%).
2-(4-([1,1′-Biphenyl]-4-yl)piperazin-1-yl)acetaldehyde (7d).
Compound 6d (1.3 g, 4.60 mmol) was reacted with oxalyl chloride
(0.79 mL, 9.21 mmol), DMSO (1.30 mL, 18.4 mmol), and Et3N
(3.82 mL, 27.60 mmol) in dichloromethane (40 mL) by following
procedure E to yield compound 7d (1.0 g, 78%).
4-(4-(3′-Methoxy-[1,1′-biphenyl]-4-yl)piperazin-1-yl)butanal
(7e). Compound 6e (1.2 g, 3.52 mmol) was reacted with oxalyl chloride
(0.60 mL, 7.05 mmol), DMSO (1.00 mL, 14.08 mmol), and Et3N
(2.92 mL, 21.12 mmol) in dichloromethane (30 mL) by following
procedure E to yield compound 7e (0.89 g, 75%).
Procedure F. N6-(2-(4-(4′-Methoxybiphenyl-4-yl)piperazin-
1-yl)ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-
diamine ( )-(8a). Into a stirring solution of compound 7a (321 mg,
1.03 mmol) in CH2Cl2 (10 mL), ( )-pramipexole (219 mg, 1.03 mmol)
was added at room temperature. The reaction mixture was stirred for
1 h, and then NaBH(OAc)3 (393 mg, 1.85 mmol) was added into the
reaction mixture. After the reaction was stirred for 48 h, a saturated
solution of NaHCO3 was added into the reaction mixture, and it was
extracted with CH2Cl2 (3 × 50 mL). The combined organic layer was
washed with brine and finally purified by silica gel column chromato-
graphy (EtOAc/MeOH, 9:1) to yield compound ( )-8a (313 mg,
60%). 1H NMR (CDCl3, 400 MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.52−
1.56 (m, 2H), 1.76−1.79 (m, 1H), 2.06 (d, J = 8.8 Hz, 1H), 2.59−2.80
(m, 13H), 3.17−3.26 (m, 6H), 3.84 (s, 3H), 6.91−7.01(m, 4H), 7.42−
7.49 (m, 4H). The product was converted into corresponding hydro-
chloride salt, m.p. 268 °C. Anal. (C29H39N5OS·4.0HCl·2.0H2O): C, H, N.
N6-(2-(4-(3′-Methoxybiphenyl-4-yl)piperazin-1-yl)ethyl)-N6-
propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (( )-8b).
Compound 7b (250 mg, 0.80 mmol) was reacted with ( )-pramipexole
1-(4-((t-Butyldimethylsilyl)oxy)butyl)-4-(3′-methoxy-[1,1′-bi-
phenyl]-4-yl)piperazine (5e). Compound 4b (2.0 g, 7.45 mmol)
was reacted with (4-bromobutoxy)(tert-butyl)dimethylsilane (2.38 g,
8.94 mmol), and K2CO3 (3.08 g, 22.35 mmol) in CH3CN (40 mL) by
following procedure C to afford compound 5e (2.80 g, 85%).1H NMR
(CDCl3, 400 MHz): δ 0.09 (s, 6H), 0.92 (s, 9H), 1.62 (t, J = 8.0 Hz, 4H),
2.41 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 7.6 Hz, 4H), 3.27 (t, J = 6.8 Hz, 4H),
3.64 (t, J = 7.2 Hz, 2H), 3.85 (s, 3H), 6.85 (dd, J = 1.6 Hz, 8.0 Hz, 1H),
6.99 (d, J = 8.8 Hz, 2H), 7.09 (bs, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.32 (t,
J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H).
Procedure D. 2-(4-(4′-Methoxybiphenyl-4-yl)piperazin-1-yl)-
ethanol (6a). Into a stirring solution of compound 5a (1.5 g, 3.52
mmol) in anhydrous THF (30 mL), n-tetrabutylammonium fluoride
(0.92 g, 3.52 mmol, 1.0 M solution in THF) was added at 0 °C. The
reaction mixture was then stirred at room temperature for 1.5 h. THF
was evaporated in vacuo, and the residue was diluted with CH2Cl2
(50 mL) and washed with water. The water layer was extracted with
CH2Cl2 (3 × 75 mL). The combined organic layer was washed with
brine, dried over Na2SO4, and evaporated in vacuo. The crude product
was purified by silica gel column chromatography (EtOAc) to yield
compound 6a (1.04 g, 95%). 1H NMR (CDCl3, 400 MHz): δ 2.62 (t, J =
5.2 Hz, 2H), 2.70 (t, J = 4.8 Hz, 4H), 3.25 (t, J = 4.8 Hz, 4H), 3.67 (t, J =
5.4 Hz, 2H), 3.83 (s, 3H), 6.95 (d, J = 9.2 Hz, 2H), 6.98 (d, J = 8.0 Hz,
2H), 7.46 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 9.2 Hz, 2H).
2-(4-(3′-Methoxybiphenyl-4-yl)piperazin-1-yl)ethanol (6b).
Compound 5b (4.0 g, 9.39 mmol) was reacted with n-tetrabutylammo-
nium fluoride (2.44 g, 9.39 mmol, 1.0 M solution in THF) in anhydrous
THF (100 mL) by following procedure D to yield compound 6b (2.62 g,
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90%). H NMR (CDCl3, 400 MHz): δ 2.61 (t, J = 5.2 Hz, 2H), 2.69
(t, J = 4.0 Hz, 4H), 3.25 (t, J = 4.8 Hz, 4H), 3.67 (t, J = 6.0 Hz, 2H), 3.83
(s, 3H), 6.83 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H),
7.09 (bs, 1H), 7.15 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 8.2 Hz, 1H), 7.51
(d, J = 8.0 Hz, 2H).
2-(4-(2′-Methoxybiphenyl-4-yl)piperazin-1-yl)ethanol (6c).
Compound 5c (2.5 g, 5.87 mmol) was reacted with n-tetrabutylammo-
nium fluoride (1.53 g, 5.87 mmol, 1.0 M solution in THF) in anhydrous
THF (50 mL) by following procedure D to yield compound 6c (1.57 g,
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86%). H NMR (CDCl3, 400 MHz): δ 2.66 (t, J = 5.4 Hz, 2H), 2.74
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dx.doi.org/10.1021/jm401883v | J. Med. Chem. 2014, 57, 1557−1572