T. Nemoto et al. / Bioorg. Med. Chem. 19 (2011) 1205–1221
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5.1.17. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-methoxy-
morphinan-6 -yl)methyl]-4-methoxybenzamide (6f)
J = 8.0 Hz), 6.97 (1H, m), 7.24–7.38 (3H, m). MS (FAB) m/z = 461
[M+H]+. HRMS (FAB) Calcd for C28H33N2O4 [M+H]+: 461.2440.
Found: 461.2447.
a
Compound 6f was prepared from compound 5 according to the
procedure used to prepare compound 6a by use of 4-methoxyben-
zoyl chloride instead of phenylacetyl chloride. Yield, 60% (two
5.1.22. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-hydroxymor-
phinan-6a-yl)methyl]-3-hydroxybenzamide hydrochloride
steps from 4). IR (film): 1643 cmÀ1
:
1H NMR (300 MHz, CDCl3) d:
0.04–0.20 (2H, m), 0.43–0.63 (2H, m), 0.98 (1H, m), 1.26 (1H, dt,
J = 12.5, 2.0 Hz), 1.46 (1H, m), 1.53–1.95 (5H, m), 2.07 (1H, dt,
J = 2.0, 12.5 Hz), 2.24 (1H, dt, J = 4.5, 13.0 Hz), 2.37 (1H, dd,
J = 7.0, 13.0 Hz), 2.52–2.70 (3H, m), 3.13 (1H, d, J = 18.0 Hz), 3.72
(1H, m), 3.77 (3H, s), 3.84 (3H, s), 3.88 (1H, dd, J = 6.5, 14.0 Hz),
3.99 (1H, dd, J = 6.5, 14.0 Hz), 6.57 (1H, d, J = 2.5 Hz), 6.69 (1H,
dd, J = 2.5, 8.0 Hz), 6.80 (1H, t, J = 6.5 Hz), 6.94 (2H, dd, J = 2.5,
8.0 Hz), 7.00 (1H, d, J = 8.0 Hz), 7.84 (2H, dd, J = 2.5, 8.0 Hz). MS
(FAB) m/z = 489 [M+H]+. HRMS (FAB) Calcd for C30H37N2O4
[M+H]+: 489.2753. Found: 489.2765.
(KNT-30ÁHCl)
KNT-30ÁHCl was prepared from KNT-30 according to the proce-
dure used to prepare KNT-3ÁHCl. Yield, 70%. Mp 202–208 °C (dec).
Anal. Calcd for C28H32N2O4ÁHClÁH2O: C, 65.30; H, 6.85; N, 5.44.
Found: C, 65.41; H, 6.82; N, 5.30.
5.1.23. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-methoxymor-
phinan-6a-yl)methyl]-2-methoxybenzamide (6h)
Compound 6h was prepared from compound 5 according to the
procedure used to prepare compound 6a by use of 2-methoxyben-
zoyl chloride instead of phenylacetyl chloride. Yield, 88% (two
5.1.18. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-hydroxy-
steps from 4). IR (film): 1652 cmÀ1 1H NMR (300 MHz, CDCl3) d:
.
morphinan-6
KNT-29 was prepared from Compound 6f according to the pro-
cedure used to prepare KNT-3. Yield, 91%. IR (KBr): 1641 cmÀ1 1H
a
-yl)methyl]-4-hydroxybenzamide (KNT-29)
0.06–0.22 (2H, m), 0.46–0.58 (2H, m), 0.90–1.01 (1H, m), 1.24
(1H, dt, J = 12.5, 2.0 Hz), 1.46–1.54 (1H, m), 1.57–1.95 (5H, m),
2.04–2.14 (1H, m), 2.19–2.34 (1H, m), 2.40–2.74 (4H, m), 3.14
(1H, d, J = 18.0 Hz), 3.64 (1H, d, J = 5.5 Hz), 3.78 (3H, s), 3.82 (1H,
dd, J = 6.5, 14.0 Hz), 4.02 (3H, s), 4.08 (1H, dd, J = 6.5, 14.0 Hz),
6.57 (1H, d, J = 2.5 Hz), 6.69 (1H, dd, J = 2.5, 8.0 Hz), 6.98 (1H, d,
J = 8.0 Hz), 7.01 (1H, dd, J = 2.0, 8.0 Hz), 7.08 (1H, dt, J = 2.0,
8.0 Hz), 7.45 (1H, dt, J = 2.0, 8.0 Hz), 8.22 (1H, dd, J = 2.0, 8.0 Hz),
8.40 (1H, t, J = 6.5 Hz). MS (FAB) m/z = 489 [M+H]+. HRMS (FAB)
Calcd for C30H37N2O4 [M+H]+: 489.2753. Found: 489.2753.
.
NMR (300 MHz, CD3OD) d: 0.14–0.28 (2H, m), 0.48–0.68 (2H, m),
0.87–0.99 (1H, m), 1.16–1.23 (1H, m), 1.47–1.67 (3H, m), 1.72–
1.92 (3H, m), 2.12–2.28 (2H, m), 2.45 (1H, dd, J = 7.0, 12.5 Hz),
2.54–2.62 (1H, m), 2.61 (1H, dd, J = 6.0, 12.5 Hz), 2.65 (1H, dd,
J = 5.5, 18.0 Hz), 3.14 (1H, d, J = 18.0 Hz), 3.66 (1H, d, J = 14.5 Hz),
3.71 (1H, d, J = 5.5 Hz), 4.00 (1H, d, J = 14.5 Hz), 6.48 (1H, d,
J = 2.5 Hz), 6.57 (1H, dd, J = 2.5, 8.0 Hz), 6.84 (2H, dd, J = 2.5,
8.0 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.80 (2H, dd, J = 2.5, 8.0 Hz). MS
(FAB) m/z = 461 [M+H]+. HRMS (FAB) Calcd for C28H33N2O4
[M+H]+: 461.2440. Found: 461.2456.
5.1.24. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-hydroxymor-
phinan-6
KNT-31 was prepared from compound 6h according to the pro-
cedure used to prepare KNT-3. Yield, 84%. IR (KBr): 1642 cmÀ1 1H
a-yl)methyl]-2-hydroxybenzamide (KNT-31)
5.1.19. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-hydroxymor-
.
phinan-6
(KNT-29ÁHCl)
a
-yl)methyl]-4-hydroxybenzamide hydrochloride
NMR (300 MHz, CD3OD) d: 0.16–0.30 (2H, m), 0.48–0.70 (2H, m),
0.89–1.01 (1H, m), 1.18–1.26 (1H, m), 1.49–1.72 (3H, m), 1.72–
1.94 (3H, m), 2.18–2.34 (2H, m), 2.57 (1H, dd, J = 7.0, 12.5 Hz),
2.57–2.66 (1H, m), 2.64 (1H, dd, J = 6.0, 12.5 Hz), 2.74 (1H, dd,
J = 5.5, 18.0 Hz), 3.15 (1H, d, J = 18.0 Hz), 3.76 (1H, d, J = 14.5 Hz),
3.77 (1H, d, J = 5.5 Hz), 3.99 (1H, d, J = 14.5 Hz), 6.50 (1H, d,
J = 2.5 Hz), 6.59 (1H, dd, J = 2.5, 8.0 Hz), 6.85 (1H, dd, J = 2.0,
8.0 Hz), 6.88 (1H, dt, J = 2.0, 8.0 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.36
(1H, dt, J = 2.0, 8.0 Hz), 7.89 (1H, dd, J = 2.0, 8.0 Hz). MS (FAB) m/
z = 461 [M+H]+. HRMS (FAB) Calcd for C28H33N2O4 [M+H]+:
461.2440. Found: 461.2436.
KNT-29ÁHCl was prepared from KNT-29 according to the proce-
dure used to prepare KNT-3ÁHCl. Yield, 69%. Mp 215–220 °C (dec).
Anal. Calcd for C28H32N2O4ÁHClÁH2O: C, 65.30; H, 6.85; N, 5.44.
Found: C, 65.07; H, 6.87; N, 5.35.
5.1.20. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-methoxymor-
phinan-6a-yl)methyl]-3-methoxybenzamide (6g)
Compound 6g was prepared from compound 5 according to the
procedure used to prepare compound 6a by use of 3-methoxyben-
zoyl chloride instead of phenylacetyl chloride. Yield, 90% (two
steps from 4). IR (film): 1652 cmÀ1
.
1H NMR (300 MHz, CDCl3) d:
5.1.25. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-hydroxymor-
0.06–0.24 (2H, m), 0.46–0.67 (2H, m), 0.91–1.05 (1H, m), 1.26
(1H, dt, J = 12.5, 2.0 Hz), 1.43–1.53 (1H, m), 1.56–1.97 (5H, m),
2.04–2.14 (1H, m), 2.18–2.33 (1H, m), 2.33–2.43 (1H, m), 2.50–
2.72 (3H, m), 3.13 (1H, d, J = 18.0 Hz), 3.76 (1H, m), 3.77 (3H, s),
3.87 (3H, s), 3.87–4.07 (2H, m), 6.58 (1H, d, J = 2.5 Hz), 6.71 (1H,
dd, J = 2.5, 8.0 Hz), 6.98–7.08 (2H, m), 7.30–7.52 (3H, m), one pro-
ton (NH) was not observed. MS (FAB) m/z = 489 [M+H]+. HRMS
(FAB) Calcd for C30H37N2O4 [M+H]+: 489.2753. Found: 489.2754.
phinan-6a-yl)methyl]-2-hydroxybenzamide hydrochloride
(KNT-31ÁHCl)
KNT-31ÁHCl was prepared from KNT-31 according to the proce-
dure used to prepare KNT-3ÁHCl. Yield, 66%. Mp 198–202 °C (dec).
Anal. Calcd for C28H32N2O4ÁHClÁ1.25H2O: C, 64.73; H, 6.89; N, 5.39.
Found: C, 64.63; H, 6.74; N, 5.31.
5.1.26. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-methoxymor-
phinan-6a-yl)methyl]-3-phenylpropionamide (6i)
5.1.21. N-[(17-Cyclopropylmethyl-6b,14b-epoxy-3-hydroxymor-
Compound 6i was prepared from compound 5 according to the
procedure used to prepare compound 6a by use of hydrocinnamoyl
chloride instead of phenylacetyl chloride. Yield, 46% (two steps
phinan-6
KNT-30 was prepared from compound 6g according to the pro-
cedure used to prepare KNT-3. Yield, 73%. IR (KBr): 1640 cmÀ1 1H
a-yl)methyl]-3-hydroxybenzamide (KNT-30)
.
from 4). IR (film): 1660 cmÀ1 1H NMR (300 MHz, CDCl3) d: 0.06–
.
NMR (300 MHz, CD3OD) d: 0.13–0.30 (2H, m), 0.48–0.66 (2H, m),
0.87–0.99 (1H, m), 1.17–1.27 (1H, m), 1.47–1.69 (3H, m), 1.72–
1.94 (3H, m), 2.11–2.30 (2H, m), 2.44 (1H, dd, J = 7.0, 12.5 Hz),
2.52–2.59 (1H, m), 2.59 (1H, dd, J = 6.0, 12.5 Hz), 2.65 (1H, dd,
J = 5.5, 18.0 Hz), 3.14 (1H, d, J = 18.0 Hz), 3.67 (1H, d, J = 14.5 Hz),
3.70 (1H, d, J = 5.5 Hz), 4.00 (1H, d, J = 14.5 Hz), 6.48 (1H, d,
J = 2.5 Hz), 6.58 (1H, dd, J = 2.5, 8.0 Hz), 6.94–6.99 (1H, d,
0.21 (2H, m), 0.46–0.63 (2H, m), 0.91–1.02 (1H, m), 1.16 (1H, dt,
J = 12.5, 2.0 Hz), 1.33–1.42 (1H, m), 1.42–1.62 (2H, m), 1.63–1.82
(3H, m), 2.08 (1H, dt, J = 2.0, 12.5 Hz), 2.20 (1H, dt, J = 4.5,
12.5 Hz), 2.40 (1H, dd, J = 7.0, 12.5 Hz), 2.52–2.72 (5H, m), 2.90–
3.07 (2H, m), 3.12 (1H, d, J = 18.0 Hz), 3.49 (1H, dd, J = 6.0,
14.0 Hz), 3.72 (1H, d, J = 5.5 Hz), 3.79 (3H, s), 3.86 (1H, dd, J = 6.0,
14.0 Hz), 6.40 (1H, t, J = 6.0 Hz), 6.54 (1H, d, J = 2.5 Hz), 6.70 (1H,