June 2008
767
NMR (CDCl3) d: 1.47 (9H, s), 1.71—1.93 (4H, m), 1.88 (3H, s), 3.28—3.38
(2H, m), 3.65—3.75 (2H, m), 4.41 (2H, d, Jꢁ5.5 Hz), 4.44—4.50 (1H, m),
6.32 (1H, dt, Jꢁ16.0, 5.5 Hz), 6.38 (1H, d, Jꢁ16.0 Hz), 6.91 (2H, d,
Jꢁ9.0 Hz), 7.07 (2H, d, Jꢁ9.0 Hz), 7.40 (1H, t, Jꢁ8.0 Hz), 7.51 (1H, d,
Jꢁ8.0 Hz), 7.55 (1H, d, Jꢁ8.0 Hz), 7.58 (1H, s).
give 33 (331 mg, 0.564 mmol, 78%) as a colorless amorphous solid. MS m/z:
514 (MꢃH)ꢃ. 1H-NMR (DMSO-d6) d: 1.68—1.79 (2H, m), 1.98—2.08
(2H, m), 2.29 (3H, s), 3.46—3.57 (2H, m), 3.68—3.76 (1H, m), 3.77—3.84
(1H, m), 4.18 (2H, s), 4.45 (2H, d, Jꢁ6.0 Hz), 4.66—4.74 (1H, m), 6.44
(1H, dt, Jꢁ16.5, 6.0 Hz), 6.55 (1H, d, Jꢁ16.5 Hz), 7.03 (2H, d, Jꢁ8.5 Hz),
7.40 (2H, d, Jꢁ8.5 Hz), 7.54 (1H, t, Jꢁ8.0 Hz), 7.68 (1H, d, Jꢁ8.0 Hz), 7.71
(1H, d, Jꢁ8.0 Hz), 7.87 (1H, s). IR (KBr) cmꢂ1: 1733, 1673, 1627. Anal.
Calcd for C25H31N5O5S·2.1HCl·1.7H2O: C, 48.37; H, 5.93; N, 11.28; Cl,
11.99; S, 5.16. Found: C, 48.20; H, 6.05; N, 11.29; Cl, 11.76; S, 5.47.
3-((E)-3-{4-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]phenylamino}-1-
propenyl)benzonitrile (34a) Molecular sieves 5A (15 g) was added to a
Similarly, compound 34g was prepared.
34g: 1H-NMR (CDCl3) d: 1.47 (9H, s), 1.68—1.99 (4H, m), 2.15 (3H, s),
3.28—3.40 (2H, m), 3.64—3.76 (2H, m), 4.32—4.53 (5H, m), 6.23—6.46
(2H, m), 6.93 (2H, d, Jꢁ9.0 Hz), 7.14 (2H, d, Jꢁ9.0 Hz), 7.35—7.59 (4H,
m).
N-{4-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]phenyl}-N-[(E)-3-(3-
cyanophenyl)-2-propenyl]-2-hydroxyacetamide (34h) To a solution of
N-{4-[1-(t-butoxycarbonyl)piperidin-4-yloxy]phenyl}-N-[(E)-3-(3-
cyanophenyl)-2-propenyl]-2-acetoxyacetamide 34g (1232 mg, 2.31 mmol) in
MeOH (20 ml) was added K2CO3 (640 mg, 4.63 mmol), and the resulting
mixture was stirred at room temperature for 1 h. H2O was added, and the
mixture was extracted with EtOAc. The organic layer was washed with
brine, dried and concentrated. The resulting residue was chromatographed
solution of 4-[1-(t-butoxycarbonyl)piperidin-4-yloxy]aniline
4 (11.3 g,
38.6 mmol) and 3-cyanocinnamaldehyde 6 (6.00 g, 38.2 mmol) in toluene
(30 ml), and the resulting suspension was refluxed for 2 h. The mixture was
filtered through a pad of celite and the filtrate was concentrated. The result-
ing residue was recrystallized from CH2Cl2 and Et2O to give an imine deriv-
ative (12.9 g). The imine derivative was suspended in EtOH (200 ml) and the
resulting mixture were treated with CeCl3·7H2O (catalytic amount) and
NaBH4 (1.13 g, 29.9 mmol). The reaction mixture was stirred at 0 °C for 1 h
and the mixture was concentrated. H2O was added, and the mixture was ex-
tracted with EtOAc. The organic layer was washed with brine, dried and
concentrated. The resulting residue was chromatographed on a silica gel col-
umn (hexane/EtOAcꢁ3/2) to give a yellow solid. The solid was washed with
i-Pr2O to give 34a (10.0 g, 23.1 mmol, 60%) as a pale yellow solid. 1H-NMR
(CDCl3) d: 1.46 (9H, s), 1.62—1.77 (2H, m), 1.81—1.93 (2H, m), 3.22—
3.35 (2H, m), 3.67—3.80 (2H, m), 3.93 (2H, dd, Jꢁ1.0, 5.5 Hz), 4.24—4.31
(1H, m), 6.39 (1H, dt, Jꢁ16.0, 5.5 Hz), 6.61 (1H, d, Jꢁ16.0 Hz), 6.61 (2H,
d, Jꢁ9.0 Hz), 6.81 (2H, d, Jꢁ9.0 Hz), 7.41 (1H, t, Jꢁ7.5 Hz), 7.51 (1H, d,
Jꢁ7.5 Hz), 7.57 (1H, d, Jꢁ7.5 Hz), 7.63 (1H, s).
3-[(E)-3-(N-{4-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]phenyl}-N-
methylamino)-1-propenyl]benzonitrile (34b) (Method C) To a suspen-
sion of 3-((E)-3-{4-[1-(t-butoxycarbonyl)piperidin-4-yloxy]phenylamino}-
1-propenyl)benzonitrile 34a (1.00 g, 2.31 mmol) and paraformaldehyde
(138 mg, 4.60 mmol) in CH2Cl2 (20 ml) were added AcOH (0.260 ml,
4.54 mmol) and NaBH3CN (144 mg, 2.29 mmol), and the resulting suspen-
sion was stirred overnight at room temperature. MeOH (20 ml) was added,
and the mixture was stirred at 30 °C for 5 h. H2O was added, and the mixture
was extracted with EtOAc. The organic layer was washed with brine, dried
and concentrated. The resulting residue was chromatographed on a silica gel
column (hexane/EtOAcꢁ3/2) to give 34b (761 mg, 1.70 mmol, 74%) as a
pale yellow oil. 1H-NMR (CDCl3) d: 1.47 (9H, s), 1.65—1.78 (2H, m),
1.82—1.93 (2H, m), 2.92 (3H, s), 3.21—3.34 (2H, m), 3.66—3.76 (2H, m),
4.02 (2H, d, Jꢁ5.0 Hz), 4.25—4.32 (1H, m), 6.32 (1H, dt, Jꢁ16.0, 5.0 Hz),
6.51 (1H, d, Jꢁ16.0 Hz), 6.72 (2H, d, Jꢁ9.0 Hz), 6.86 (2H, d, Jꢁ9.0 Hz),
7.39 (1H, t, Jꢁ7.5 Hz), 7.49 (1H, d, Jꢁ7.5 Hz), 7.56 (1H, d, Jꢁ7.5 Hz), 7.62
(1H, s).
on
a silica gel column (hexane/EtOAcꢁ1/2) to give 34h (977 mg,
1.99 mmol, 86%) as colorless amorphous solid. 1H-NMR (CDCl3) d: 1.47
(9H, s), 1.71—1.83 (2H, m), 1.88—1.99 (2H, m), 3.28—3.40 (3H, m),
3.60—3.78 (2H, m), 3.81 (2H, d, Jꢁ4.5 Hz), 4.46 (2H, d, Jꢁ6.5 Hz), 4.44—
4.51 (1H, m), 6.30 (1H, dt, Jꢁ16.0, 6.5 Hz), 6.44 (1H, d, Jꢁ16.0 Hz), 6.93
(2H, d, Jꢁ9.0 Hz), 7.07 (2H, d, Jꢁ9.0 Hz), 7.42 (1H, t, Jꢁ7.5 Hz), 7.53 (1H,
d, Jꢁ7.5 Hz), 7.56 (1H, d, Jꢁ7.5 Hz), 7.59 (1H, s).
3-((E)-3-{4-[1-(Acetimidoyl)piperidin-4-yloxy]phenylamino}-1-
propenyl)benzamidine Trihydrochloride (35a) 3-((E)-3-{4-[1-(t-Bu-
toxycarbonyl)piperidin-4-yloxy]phenylamino}-1-propenyl)benzonitrile 34a
was converted to 35a by the same procedure as that for 32. Compound 35a
was obtained (55%, 3 steps) as a yellow amorphous solid. MS m/z: 392
(MꢃH)ꢃ. 1H-NMR (DMSO-d6) d: 1.67—1.78 (2H, m), 1.99—2.10 (2H, m),
2.30 (3H, s), 3.40—3.95 (4H, m), 4.06 (2H, d, Jꢁ6.5 Hz), 4.65—4.72 (1H,
m), 6.56 (1H, dt, Jꢁ16.0, 6.5 Hz), 6.80 (1H, d, Jꢁ16.0 Hz), 7.10 (2H,
d, Jꢁ9.0 Hz), 7.35—7.55 (2H, m), 7.60 (1H, t, Jꢁ8.0 Hz), 7.70—7.80
(2H, m), 7.87 (1H, s). IR (KBr) cmꢂ1: 1672, 1625. Anal. Calcd for
C23H29N5O·3.0HCl·2.6H2O: C, 50.44; H, 6.85; N, 12.79; Cl, 19.42. Found:
C, 50.49; H, 6.97; N, 12.88; Cl, 19.27.
Similarly, compounds 35b—35f, 35h were prepared.
35b: MS m/z: 406 (MꢃH)ꢃ. 1H-NMR (DMSO-d6) d: 1.66—1.77 (2H,
m), 1.97—2.08 (2H, m), 2.31 (3H, s), 3.13 (3H, s), 3.40—3.70 (4H, m), 4.29
(2H, d, Jꢁ7.0 Hz), 4.71—4.78 (1H, m), 6.50 (1H, dt, Jꢁ16.0, 7.0 Hz), 6.76
(1H, d, Jꢁ16.0 Hz), 7.15 (2H, d, Jꢁ9.0 Hz), 7.58 (1H, t, Jꢁ7.5 Hz), 7.69
(1H, d, Jꢁ7.5 Hz), 7.70—7.85 (3H, m), 7.92 (1H, s). IR (KBr) cmꢂ1: 1672,
1625. Anal. Calcd for C24H31N5O·3.6HCl·2.9H2O: C, 48.94; H, 6.91; N,
11.89; Cl, 21.67. Found: C, 48.75; H, 6.77; N, 12.04; Cl, 21.90.
35c: MS m/z: 420 (MꢃH)ꢃ. 1H-NMR (DMSO-d6) d: 1.09 (3H, t,
Jꢁ7.0 Hz), 1.66—1.76 (2H, m), 1.98—2.09 (2H, m), 2.32 (3H, s), 3.50—
3.95 (6H, m), 4.24—4.36 (2H, m), 4.71—4.79 (1H, m), 6.49 (1H, dt,
Jꢁ16.0, 6.5 Hz), 6.73 (1H, d, Jꢁ16.0 Hz), 7.00—7.30 (2H, m), 7.58 (1H, t,
Similarly, compounds 34c—e were prepared.
34c: 1H-NMR (CDCl3) d: 1.16 (3H, t, Jꢁ7.0 Hz), 1.46 (9H, s), 1.67—
1.77 (2H, m), 1.82—1.93 (2H, m), 3.20—3.29 (2H, m), 3.36 (2H, q,
Jꢁ7.0 Hz), 3.66—3.76 (2H, m), 4.01 (2H, d, Jꢁ5.0 Hz), 4.23—4.29 (1H,
m), 6.31 (1H, dt, Jꢁ16.0, 5.0 Hz), 6.50 (1H, d, Jꢁ16.0 Hz), 6.69 (2H, d,
Jꢁ9.0 Hz), 6.84 (2H, d, Jꢁ9.0 Hz), 7.39 (1H, t, Jꢁ7.5 Hz), 7.49 (1H, d,
Jꢁ7.5 Hz), 7.55 (1H, d, Jꢁ7.5 Hz), 7.61 (1H, s).
Jꢁ7.5 Hz), 7.67 (1H, d, Jꢁ7.5 Hz), 7.75—7.90 (4H, m). IR (KBr) cmꢂ1
:
1673, 1623. Anal. Calcd for C25H33N5O·3.0HCl·2.1H2O: C, 52.98; H, 7.15;
N, 12.36; Cl, 18.77. Found: C, 52.83; H, 7.19; N, 12.44; Cl, 18.97.
35d: MS m/z: 434 (MꢃH)ꢃ. 1H-NMR (DMSO-d6) d: 1.17 (3H, d,
Jꢁ6.0 Hz), 1.43 (3H, d, Jꢁ6.0 Hz), 1.65—1.75 (2H, m), 1.99—2.08 (2H,
m), 2.31 (3H, s), 3.45—4.05 (5H, m), 4.37—4.45 (2H, m), 4.71—4.78 (1H,
m), 6.42 (1H, dt, Jꢁ16.0, 7.0 Hz), 6.73 (1H, d, Jꢁ16.0 Hz), 7.15 (2H, d,
Jꢁ8.5 Hz), 7.50—7.65 (2H, m), 7.70—7.90 (4H, m). IR (KBr) cmꢂ1: 1672,
1623. Anal. Calcd for C26H35N5O·3.1HCl·1.9H2O: C, 53.76; H, 7.27; N,
12.06; Cl, 18.92. Found: C, 53.62; H, 7.56; N, 12.09; Cl, 18.97.
1
34d: H-NMR (CDCl3) d: 1.18 (6H, d, Jꢁ6.5 Hz), 1.46 (9H, s), 1.63—
1.76 (2H, m), 1.83—1.93 (2H, m), 3.21—3.30 (2H, m), 3.65—3.76 (2H, m),
3.91 (2H, d, Jꢁ4.5 Hz), 3.97—4.04 (1H, m), 4.23—4.30 (1H, m), 6.33 (1H,
dt, Jꢁ16.0, 4.5 Hz), 6.53 (1H, d, Jꢁ16.0 Hz), 6.73 (2H, d, Jꢁ9.0 Hz), 6.82
(2H, d, Jꢁ9.0 Hz), 7.38 (1H, t, Jꢁ7.5 Hz), 7.47 (1H, d, Jꢁ7.5 Hz), 7.53 (1H,
d, Jꢁ7.5 Hz), 7.60 (1H, s).
35e: MS m/z: 482 (MꢃH)ꢃ. 1H-NMR (DMSO-d6) d: 1.50—1.75 (2H, m),
1.91—2.02 (2H, m), 2.29 (3H, s), 3.40—3.90 (4H, m), 4.37—4.44 (2H, m),
4.50—4.90 (3H, m), 6.63 (1H, dt, Jꢁ16.0, 6.0 Hz), 6.74 (1H, d, Jꢁ16.0 Hz),
6.97 (2H, d, Jꢁ8.5 Hz), 7.15—7.30 (3H, m), 7.40—7.60 (4H, m), 7.56 (1H,
t, Jꢁ7.5 Hz), 7.66 (1H, d, Jꢁ7.5 Hz), 7.77 (1H, d, Jꢁ7.5 Hz), 7.92 (1H, s).
IR (KBr) cmꢂ1: 1672, 1624. Anal. Calcd for C30H35N5O·3.6HCl·1.7H2O: C,
55.99; H, 6.58; N, 10.88; Cl, 19.83. Found: C, 56.13; H, 6.71; N, 10.67; Cl,
20.09.
1
34e: H-NMR (CDCl3) d: 1.46 (9H, s), 1.65—1.75 (2H, m), 1.83—1.92
(2H, m), 3.22—3.32 (2H, m), 3.64—3.75 (2H, m), 4.11 (2H, d, Jꢁ5.0 Hz),
4.23—4.29 (1H, m), 4.52 (2H, s), 6.32 (1H, dt, Jꢁ16.0, 5.0 Hz), 6.48 (1H, d,
Jꢁ16.0 Hz), 6.71 (2H, d, Jꢁ9.0 Hz), 6.81 (2H, d, Jꢁ9.0 Hz), 7.20—7.60
(9H, m).
N-{4-[1-(t-Butoxycarbonyl)piperidin-4-yloxy]phenyl}-N-[(E)-3-(3-
cyanophenyl)-2-propenyl]acetamide (34f) (Method D) To a solution of
3-((E)-3-{4-[1-(t-butoxycarbonyl)piperidin-4-yloxy]phenylamino}-1-
propenyl)benzonitrile 34a (503 mg, 1.16 mmol) in CH2Cl2 (10 ml) were
added pyridine (0.140 ml, 1.73 mmol) and acetic anhydride (0.130 ml,
1.38 mmol) at 0 °C, and the resulting mixture was stirred at room tempera-
ture for 1 h. H2O was added, and the mixture was extracted with EtOAc. The
organic layer was washed with brine, dried and concentrated. The resulting
residue was chromatographed on a silica gel column (hexane/EtOAcꢁ1/1—
0/1) to give 34f (403 mg, 0.847 mmol, 73%) as pale yellow crystals. 1H-
35f: MS m/z: 434 (MꢃH)ꢃ. 1H-NMR (DMSO-d6) d: 1.69—1.80 (2H, m),
1.78 (3H, s), 1.99—2.09 (2H, m), 2.31 (3H, s), 3.45—3.95 (4H, m), 4.36—
4.44 (2H, m), 4.62—4.78 (1H, m), 6.42—6.60 (2H, m), 7.05 (2H, d,
Jꢁ8.5 Hz), 7.28 (2H, d, Jꢁ8.5 Hz), 7.55 (1H, t, Jꢁ7.5 Hz), 7.65—7.79
(2H, m), 7.95 (1H, s). IR (KBr) cmꢂ1: 1672, 1624. Anal. Calcd for
C25H31N5O2·2.9HCl·2.6H2O: C, 51.23; H, 6.72; N, 11.95; Cl, 17.54. Found:
C, 51.01; H, 6.90; N, 11.87; Cl, 17.78.