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7.3 equiv) was added. The mixture was stirred at room tempera-
ture for 12 h, concentrated and purified by SiO2 chromatography.
C30H31F3N2O8+2H2O: C, 56.25; H, 5.51; N, 4.37. Found: C, 56.79;
H, 5.93; N, 4.38. HPLC (condition A) tR = 4.80 min (98%).
10.6. General procedure for the amidation of 6-b-naltrexamine
10.6.5. 17-Cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-
with a carboxylic acid
[(4’-bromo)benzamido]morphinan (6)
Compund 6 was synthesized according to the general procedure
described above; 6-b-naltrexamine (70 mg, 0.2 mmol, 1 equiv), p-
bromobenzoic acid (62 mg, 0.31 mmol, 1.5 equiv), BOP (137 mg,
0.31 mmol, 1.5 equiv) and N,N-diisopropylethylamine (0.11 mL,
0.61 mmol, 3 equiv) were combined in dichloromethane (2 mL)
followed by basic hydrolysis with K2CO3 to give the title compound
as a white foam (101 mg, 94%). Rf = 0.02 (CH2Cl2/MeOH, 20/1, v/v);
ESI/MS m/z = 525 (MH+); 1H NMR d 7.71 (d, J = 8.1 Hz, 2H), 7.51 (d,
J = 8.1 Hz, 2H), 6.73 (d, J = 7.8 Hz,, 2H), 6.52 (d, J = 7.8 Hz, 1H), 4.56
(d, J = 6.0 Hz, 1H), 4.16–4.13 (m, 1H), 3.12–1.46 (m, 11H), 0.52 (m,
2H), 0.12 (m, 2H); 13C NMR d 166.1, 143.2, 139.9, 133.4, 132.5,
131.7, 130.5, 129.1, 128.2, 125.4, 124.1, 121.8, 119.4, 118.1, 92.6,
70.2, 62.4, 61.9, 59.3, 47.1, 37.6, 36.8, 36.7, 35.9, 9.3, 3.9; HRMS
calcd for C27H30BrN2O4 525.1389, found 525.1382.
6-b-Naltrexamine (100 mg, 0.29 mmol, 1 equiv), the substituted
benzoic acid (0.58 mmol, 2 equiv) and BOP (258 mg, 0.58 mmol,
2 equiv) were dissolved in CH2Cl2 (3 mL). To this solution, Pr2EtN
(0.15 mL, 0.88 mmol, 3 equiv) was added and the mixture was stir-
red at room temperature for 2 h. The solution was concentrated
and filtered through a short column of SiO2 (eluted with EtOAc)
providing a white material. This product was dissolved in MeOH
(3 mL) and K2CO3 (300 mg, 2.2 mmol, 7.5 equiv) was then added.
The mixture was stirred at room temperature for 3 h and concen-
trated to dryness. The residue was purified by SiO2 chromatogra-
phy (CH2Cl2/MeOH, 20/1, v/v) to provide the target compound.
10.6.1. 17-Cyclopropylmethyl-3, 14b-dihydroxy-4, 5
a-epoxy-6
b-[(40-methyl)benzamido]morphinan (4)
Compound 4 was synthesized according to the general proce-
dure described above; 6-b-naltrexamine (100 mg, 0.29 mmol,
1 equiv), p-toluoyl chloride (0.09 mL, 0.7 mmol, 2.4 equiv) and tri-
ethylamine (0.13 mL, 0.91 mmol, 3.1 equiv) were combined in
dichloromethane followed by basic hydrolysis with K2CO3 to give
the title compound as a white solid (107 mg, 79%). Rf = 0.04
(CHCl3/MeOH, 20/1, v/v); mp = 207.6 °C; ESI/MS m/z = 461 (MH+);
1H NMR (CDCl3/CD3OD, 9/1, v/v) d 7.68 (d, J = 8.1 Hz, 2H), 7.23 (d,
J = 8.1 Hz, 2H), 6.67 (d, J = 8.1 Hz,, 2H), 6.51 (d, J = 8.1 Hz, 1H),
4.40 (d, J = 6.6 Hz, 1H), 4.15–4.05 (m, 1H), 3.09–2.96 (m, 2H),
2.60 (m, 2H), 2.34 (s, 3H), 2.12–1.40 (m, 6H) 0.50 (m, 2H), 0.09
(m, 2H); 13C NMR (CDCl3/CD3OD, 9/1, v/v) d 168.1, 142.8, 142.1,
139.9, 131.0, 130.4, 128.9, 128.1, 127.3, 126.7, 123.7, 118.6, 93.0,
70.4, 62.3, 61.9, 59.0, 49.6, 48.7, 47.3, 22.6, 9.3, 3.9, 3.6; HRMS calcd
for C28H33N2O4 461.2440, found 461.2440.
10.6.6. 17-Cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-
[(40-bromo) benzamido]morphinan-oxalate (6-oxalate salt)
The amide product was converted to its oxalate salt using
1 equiv of oxalic acid dihydrate in methanol. Anal. Calcd for
C27H29BrN2O4+2C2H2O4+H2O: C, 51.46; H, 4.88; N, 3.87. Found: C,
51.66; H, 5.16; N, 3.24. HPLC (condition A) tR = 5.15 min (98%).
10.6.7. 17-Cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-
[(40-iodo) benzamido]morphinan (7)
Compound 7 was synthesized according to the general proce-
dure described above; b-naltrexamine (50 mg, 0.20 mmol,
1 equiv), p-iodobenzoic acid (55 mg, 0.22 mmol, 1.1 equiv), BOP
(97 mg, 0.22 mmol, 1.1 equiv) and N,N-diisopropylethylamine
(0.08 mL, 0.44 mmol, 2.2 equiv) were combined in dichlorometh-
ane (2 mL) followed by basic hydrolysis with K2CO3 to give the title
compound as a white foam (83 mg, 97%). Rf = 0.05 (CH2Cl2/MeOH,
10.6.2. 17-Cyclopropylmethyl-3,14b-dihydroxy-4, 5
a
-epoxy-6 b-
20/1, v/v); ESI/MS m/z = 572.9 (MH+); 1H NMR
d 7.68 (d,
[(40-methyl)benzamido]morphinan-oxalate (4-oxalate salt)
Compound 4 (50 mg, 0.11 mmol, 1 equiv) was converted to its
oxalate salt using 1 equiv of oxalic acid in methanol (3 mL). Anal.
Calcd for C30H34N2O8+3H2O: C, 59.59; H, 6.67; N, 4.63. Found: C,
60.35; H, 6.81; N, 4.59. HPLC (Condition A) tR = 5.14 min (99%).
J = 8.1 Hz, 2H), 7.55 (d, J = 8.1 Hz, 2H), 6.72 (d, J = 8.1 Hz, 2H),
6.51 (d, J = 8.1 Hz, 1H), 4.56 (d, J = 6 Hz, 1H), 4.11–4.08 (m, 1H),
3.1–1.44 (m, 11H), 0.51 (m, 2H), 0.11 (m, 2H); 13C NMR d 166.4,
143.2, 140, 137.8, 137.1, 133.9, 130.5, 129.1, 128.2, 124, 119.4,
118.1, 92.3, 70.2, 62.4, 62.0, 59.2, 47.2, 37.6, 36.8, 36.7, 35.9, 9.3,
3.9; HRMS calcd for C27H30IN2O4 573.1250, found 573.1237.
10.6.3. 17-Cyclopropylmethyl-3,14b-dihydroxy-4, 5a-epoxy-6b-
[(40-trimethylfluoro)benzamido]morphinan (5)
10.6.8. 17-Cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b-
Compound 5 was synthesized according to the general proce-
dure described above; 6-b-naltrexamine (100 mg, 0.29 mmol,
1 equiv), 4-(trifluoromethyl)benzoyl chloride (0.12 mL, 0.73 mmol,
2.5 equiv) and triethylamine (0.12 mL, 0.88 mmol, 3 equiv) were
combined in dichloromethane followed by basic hydrolysis with
K2CO3 to give the title compound as a white solid (117 mg, 78%
yield). Rf = 0.11 (CHCl3/MeOH, 20/1, v/v); mp = 157.5 °C; ESI/MS
m/z = 515 (MH+); 1H NMR d 7.92 (d, J = 8.4 Hz, 2H), 7.63 (d,
J = 8.4 Hz, 2H), 6.67 (d, J = 7.8 Hz,, 2H), 6.53 (d, J = 7.8 Hz, 1H),
4.60 (d, J = 5.4 Hz, 1H), 4.16–4.13 (m, 1H), 3.15–1.44 (m, 11H),
0.54 (m, 2H), 0.13 (m, 2H); 13C NMR d 166.2, 142.6, 139.4, 137.4,
130.5, 128.1, 127.3, 125.4, 125.1, 124.3 121.8, 119.4, 118.1, 92.6,
70.4, 62.3, 61.9, 59.2, 51.3, 50.8, 47.2, 22.6, 9.3, 3.9; HRMS calcd
for C28H30F3N2O4 515.2158, found 515.2137.
[(40-iodo) benzamido]morphinan-oxalate (7-oxalate salt)
The amide product was converted to its oxalate salt using
1 equiv of oxalic acid dihydrate in methanol. Anal. Calcd for
C29H31IN2O8+2H2O: C, 49.87; H, 5.05; N, 4.01. Found: C, 49.44; H,
5.23; N, 5.74. HPLC (condition A) tR = 5.20 min (98%).
10.6.9. 17-Cyclopropylmethyl-3,14b-dihydroxy-4,5
a-epoxy-6b-
[(40-t-butyl) benzamido]morphinan (8)
Compound 8 was synthesized according to the general proce-
dure described above; b-naltrexamine (50 mg, 0.15 mmol,
1 equiv), 4-t-butylbenzoyl chloride (0.14 mL, 0.70 mmol, 4.7 equiv)
and NEt3 (0.07 mL, 0.88 mmol, 5.9 equiv) were combined in dichlo-
romethane (2 mL) followed by basic hydrolysis with K2CO3 to give
the title compound as a white solid (47 mg, 64%). Rf = 0.09 (CH2Cl2/
MeOH, 20/1, v/v); mp = 151.1 °C; ESI/MS m/z = 503 (MH+), 501
(MHꢀ); 1H NMR d 7.75 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H),
6.72 (d, J = 7.8 Hz, 2H), 6.55 (d, J = 7.8 Hz, 1H), 4.53 (d, J = 5.7 Hz,
1H), 4.21–4.18 (m, 1H), 3.14–1.44 (m, 11H), 0.54 (m, 2H), 0.13
(m, 2H); 13C NMR d 167.2, 143.1, 139.5, 137.4, 131.4, 130.6,
127.3, 126.6, 125.5, 124.5, 119.4, 118.0, 93.2, 70.1, 62.4, 62.0,
10.6.4. 17-Cyclopropylmethyl-3,14b-dihydroxy-4, 5a-epoxy-6b-
[(40-trimethylfluoro) benzamido]morphinan-oxalate (5-oxalate
salt)
The amide product was converted to its oxalate salt using
1 equiv of oxalic acid dihydrate in methanol. Anal. Calcd for