M. Ichikawa et al. / Bioorg. Med. Chem. 19 (2011) 5207–5224
5219
(4H, m), 4.22–4.32 (1H, m), 4.39 (1H, d, J = 13.4 Hz), 6.21 (1H, s),
6.82–6.88 (3H, m), 6.98–7.05 (1H, m), 7.15–7.25 (1H, m), 7.41
(1H, dd, J = 10.3, 2.0 Hz). IR(ATR) cmꢁ1 3381, 2951, 1635, 1466,
1392, 1242, 1180, 1036, 754. Anal. Calcd for C33H45ClN2O7: C,
64.22; H, 7.35; N, 4.54. Found: C, 64.16; H, 7.47; N, 4.38.
Calcd for C33H45ClN2O7: C, 64.22; H, 7.35; N, 4.54. Found: C, 64.11;
H, 7.42; N, 4.44.
4.1.1.52. (aR)-(3S)-1-{4-[{4-chloro-2-ethoxy-6-[(S)-hydroxy(2-
methoxyphenyl)methyl]phenyl}(2,2-dimethylpropyl)amino]-4-
oxobutanoyl}piperidine-3-carboxylic acid ((S)-(aR)-22d). Com-
pound (S)-(aR)-22d was prepared from (S)-(aR)-19d in a similar
manner described for (S)-(aR)-21a in 87% yield as colorless amor-
phous. 1H NMR (CDCl3) d 0.93 (9H, s), 1.22–1.31 (1H, m), 1.43–1.49
(3H, m), 1.59–1.84 (2H, m), 1.94–2.66 (7H, m), 2.86–3.52 (3H, m),
3.70 (3H, s), 3.71–3.90 (1H, m), 3.94–4.14 (3H, m), 4.43–4.53 (2H,
m), 6.13 (1H, d, J = 6.1 Hz), 6.64 (1H, d, J = 2.2 Hz), 6.75–6.79 (1H,
m), 6.81–6.88 (1H, m), 7.05–7.12 (1H, m), 7.27–7.34 (1H, m),
7.87–7.81 (1H, m). IR (ATR) cmꢁ1 2951, 1728, 1622, 1466, 1392,
1286, 1241, 1180, 1030, 754. MS (ESI) m/z 589 [(M+H)+, Cl35],
591[(M+H)+, Cl37]. Anal. Calcd for C31H41ClN2O7: C, 63.20; H,
7.01; N, 4.76. Found: C, 62.91; H, 7.20; N, 4.58.
4.1.1.49. (aR)-1-{4-[{4-chloro-2-ethoxy-6-[(S)-hydroxy(2-
methoxyphenyl)methyl]phenyl}(2,2-dimethylpropyl)amino]-4-
oxobutanoyl}piperidine-4-carboxylic acid ((S)-(aR)-21d)
. Com-
pound (S)-(aR)-21d was prepared from (S)-(aR)-18d in a similar
manner described for (S)-(aR)-21a in 80% yield as colorless amor-
phous. 1H NMR (CDCl3) d 0.95 (9H, s), 1.47 (3H, t, J = 7.0 Hz), 1.51–
1.73 (4H, m), 1.80–2.03 (2H, m), 2.09–2.27 (2H, m), 2.49–2.67 (2H,
m), 2.74–2.88 (1H, m), 3.03–3.22 (2H, m), 3.32 (1H, dd, J = 13.5,
7.0 Hz), 3.71 (3H, d, J = 2.2 Hz), 3.80–3.91 (1H, m), 3.96–4.15 (2H,
m), 4.51 (1H, dd, J = 13.5, 9.2 Hz), 6.14 (1H, s), 6.61 (1H, d,
J = 2.2 Hz), 6.76–6.79 (1H, m), 6.82–6.88 (1H, m), 7.05–7.13 (1H,
m), 7.28–7.33 (1H, m), 7.90–7.84 (1H, m). IR (ATR) cmꢁ1 2952,
1736, 1658, 1620, 1466, 1392, 1288, 1242, 1028, 754. MS (ESI)
m/z 571 [(MꢁOH)+, Cl35], 589[(M+H)+, Cl35]. Anal. Calcd for
4.1.1.53. (aS)-(3S)-1-{4-[{4-Chloro-2-ethoxy-6-[(S)-hydroxy(2-
methoxyphenyl)methyl]phenyl}(2,2-dimethylpropyl)amino]-4-
oxobutanoyl}piperidine-3-carboxylic acid ((S)-(aS)-22d). Com-
pound (S)-(aS)-22d was prepared from (S)-(aS)-19d in a similar
manner described for (S)-(aR)-21a in 93% yield as colorless amor-
phous. 1H NMR (CDCl3) d 0.89 (9H, s), 1.35–1.46 (4H, m), 1.59–1.89
(3H, m), 1.98–2.12 (1H, m), 2.14–2.27 (1H, m), 2.29–2.49 (2H, m),
2.71–3.02 (3H, m), 3.09–3.28 (1H, m), 3.44–3.63 (1H, m), 3.83 (3H,
s), 3.96–4.13 (2H, m), 4.30–4.44 (1H, m), 6.21 (1H, s), 6.81–6.90
(3H, m), 6.98–7.08 (1H, m), 7.24–7.16 (1H, m), 7.41 (1H, d,
J = 2.0 Hz). IR (ATR) cmꢁ1 2954, 1724, 1618, 1464, 1392, 1286,
1242, 1111, 1039, 754. MS (ESI) m/z 589 [(M+H)+, Cl35], 591
[(M+H)+, Cl37]. Anal. Calcd for C31H41ClN2O7: C, 63.20; H, 7.01; N,
4.76. Found: C, 63.09; H, 7.16; N, 4.63.
C
31H41ClN2O7ꢀ0.25H2O: C, 62.72; H, 7.05; N, 4.72. Found: C,
62.61; H, 7.08; N, 4.55.
4.1.1.50. (aS)-1-{4-[{4-chloro-2-ethoxy-6-[(S)-hydroxy(2-meth-
oxyphenyl)methyl]phenyl}(2,2-dimethylpropyl)amino]-4-oxob-
utanoyl}piperidine-4-carboxylic acid ((aS)-(S)-21d). Compound
(S)-(aS)-21d was prepared from (S)-(aS)-18d in a similar manner
described for (S)-(aR)-21a in 36% yield as colorless amorphous.
1H NMR (CDCl3) d 0.92 (9H, s), 0.96 (3H, s), 1.27–1.31 (1H, m),
1.40–1.50 (4H, m), 1.72–1.94 (2H, m), 2.15–2.28 (2H, m), 2.30–
2.46 (2H, m), 2.48–2.68 (4H, m), 2.72–2.87 (1H, m), 2.89–3.03
(1H, m), 3.78 (3H, s), 3.84–3.89 (2H, m), 6.20–6.29 (1H, m), 6.32–
6.41 (1H, m), 6.83–6.92 (1H, m), 7.03–7.10 (1H, m), 7.25–7.28
(1H, m), 7.32–7.36 (1H, m), 7.42–7.52 (1H, m), 7.75–7.67 (1H,
m). IR (ATR) cmꢁ1 2951, 1726, 1624, 1466, 1392, 1286, 1242,
1182, 1030, 754. MS (ESI) m/z 589 [(M+H)+, Cl35], 591[(M+H)+,
Cl37]. Anal. Calcd for C31H41ClN2O7ꢀ0.25H2O: C, 62.72; H, 7.05; N,
4.72. Found: C, 62.79; H, 7.15; N, 4.48.
4.1.1.54. N-[4-Chloro-2-(propan-2-yloxy)phenyl]-2,2-dimethyl-
propanamide (10e). To
a stirred solution of 10j (4.01 g,
17.6 mmol) in tetrahydrofuran (200 mL) at 0 °C, 2-propanol
(2.02 ml, 26.4 mmol) and triphenylphosphine (6.92 g, 26.4 mmol)
was added, followed by a drop in diethyl azodicarboxylate (40%
in toluene, 11.5 g, 26.4 mmol). After 2 h, a saturated aqueous solu-
tion of ammonium chloride was added and the mixture was ex-
tracted with AcOEt. The extract was washed with brine, dried
over Na2SO4, and then concentrated in vacuo. The residue was
purified by silica gel column chromatography (n-hexane/
AcOEt = 10:1 as eluent) to give compound 10e (4.40 g, 16.3 mmol,
93%) as a pale yellow oil. 1H NMR (CDCl3) d 1.31 (9H, s), 1.39 (6H, d,
J = 6.1 Hz), 4.52–4.59 (1H, m), 6.86 (1H, d, J = 2.2 Hz), 6.92 (1H, dd,
J = 8.8, 2.2 Hz), 8.13 (1H, s), 8.36 (1H, dd, J = 13.4, 8.8 Hz). IR (ATR)
cmꢁ1 3428, 2976, 1684, 1595, 1508, 1479, 1408, 1246, 1119, 962,
819, 586. MS (ESI) m/z 270 [(M+H)+, Cl35], 272 [(M+H)+, Cl37].
4.1.1.51. (aR) and (aS)-ethyl (3S)-1-{4-[{4-chloro-2-ethoxy-6-
[(S)-hydroxy(2-methoxyphenyl)methyl]phenyl}(2,2-dimethyl-
propyl)amino]-4-oxobutanoyl}piperidine-3-carboxylate ((S)-
(aR)-19d, (S)-(aS )-19d). Compound (S)-(aR)-19d (74%) and (S)-
(aS)-19d (7%) were prepared from (S)-17d in a similar manner
described for (S)-(aR)-18d as colorless amorphous. (S)-(aR)-19d;
1H NMR (CDCl3) d 0.94 and 0.95 (9H, s), 1.22 and 1.26 (3H, t,
J = 7.1 Hz), 1.28–1.82 (2H, m), 1.46 (3H, t, J = 7.0 Hz), 2.00–2.36
(3.5H, m), 2.42–2.44 (2H, m), 2.77–2.87 (0.5H, m), 2.96–3.22 (2H,
m), 3.26–3.33 (2H, m), 3.70 (3H, s), 3.72–3.84 (1H, m), 3.96–4.19
(5H, m), 4.42–4.58 (2H, m), 6.11–6.17 (1H, m), 6.36 (1H, d,
J = 4.9 Hz), 6.60–6.63 (1H, m), 6.76–6.78 (1H, m), 6.83–6.87 (1H,
m), 7.07–7.12 (1H, m), 7.28–7.33 (1H, m), 7.86–7.91 (1H, m). IR
(ATR) cmꢁ1 3330, 2945, 1660, 1626, 1466, 1392, 1288, 1242,
1178, 1113, 1030, 754. MS (ESI) m/z 617 [(M+H)+, Cl35],
619[(M+H)+, Cl37]. Anal. Calcd for C33H45ClN2O7: C, 64.22; H,
7.35; N, 4.54. Found: C, 64.28; H, 7.49; N, 4.35. (S)-(aS)-19d; 1H
NMR (CDCl3) d 0.89 (9H, s), 1.18–1.28 (3H, m), 1.28–1.51 (3H,
m), 1.43 (3H, t, J = 7.1 Hz), 1.60–1.82 (3H, m), 1.97–2.09 (1H, m),
2.13–2.26 (1H, m), 2.27–2.48 (2H, m), 2.64–2.94 (3H, m), 3.15
(1H, dd, J = 13.7, 10.0 Hz), 3.54–3.79 (1H, m), 3.83 (3H, s), 3.84
(3H, s), 3.96–4.20 (4H, m), 4.39 (1H, dd, J = 13.4, 4.2 Hz), 4.47–
4.57 (1H, m), 6.19–6.25 (1H, m), 6.79–6.90 (3H, m), 6.98–7.07
(1H, m), 7.15–7.25 (1H, m), 7.43–7.37 (1H, m). IR(ATR) cmꢁ1
3317, 2935, 1728, 1660, 1626, 1475, 1529, 1219, 1176, 1032,
1003, 760. MS (ESI) m/z 617 [(M+H)+, Cl35], 619[(M+H)+, Cl37]. Anal.
4.1.1.55. N-{4-Chloro-2-[hydroxy(2-methoxyphenyl)methyl]-6-
(propan-2-yloxy)phenyl}-2,2-dimethylpropanamide (13e). Com-
pound 13e was prepared in a similar manner described for 13a in
40% yield as colorless crystal. 1H NMR (CDCl3) d 1.31 (9H, s), 1.34
(6H, dd, J = 23.4, 11.7 Hz), 4.49–4.52 (2H, m), 5.97 (1H, d,
J = 3.4 Hz), 6.78 (1H, s), 6.81 (1H, d, J = 7.3 Hz), 7.01–7.04 (1H, m),
7.23–7.26 (3H, m), 7.60–7.62 (1H, m). IR (ATR) cmꢁ1 3523, 2972,
1670, 1585, 1491, 1319, 1111, 1047, 1014, 831, 754. MS (ESI,
neg) m/z 404 (MꢁH)ꢁ.
4.1.1.56. {5-Chloro-2-[(2,2-dimethylpropyl)amino]-3-(propan-
2-yloxy)phenyl}(2-methoxyphenyl)methanol (14e). Compound
14e was prepared in a similar manner described for 14a in 37%
yield as colorless oil. 1H NMR (CDCl3) d 0.99 (9H, s), 1.35 (6H, dd,
J = 5.5, 2.7 Hz), 2.63 (1H, d, J = 11.0 Hz), 2.76 (1H, d, J = 11.0 Hz),
3.83 (3H, s), 4.48–4.57 (1H, m), 6.33 (1H, s), 6.48 (1H, d,