A mixture of NTX·HCl (0.15 g, 0.40 mmol) and 1-methyl-1-
phenylhydrazine (50 mL, 0.052 g, 0.42 mmol) was dissolved in
0.1 N HCl (3 mL) using a 15 mL plastic centrifuge tube as the
reaction vessel. After heating in a boiling water bath for 1.5 h, the
mixture was cooled to ambient temperature and then chilled at
4 ◦C for 30 min. After centrifugation (10,000 rpm, 4 ◦C; 5 min),
the su◦pernatant was discarded and the precipitate dried in vacuo
at 45 C to furnish N1¢-Me-NTI·HCl (0.14 g, 73%) as a beige
powder of 99% purity by reversed-phase HPLC. Characteristic
1H NMR signals1 for the free base (CDCl3, 300 MHz): d 7.40 (d,
J = 7.8 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.17 (ddd, J = 1.0 Hz,
J = 6.9 Hz, J = 8.2 Hz, 1H), 7.0 (ddd, J = 1.0 Hz, J = 6.9 Hz, J =
7.8 Hz, 1H), 3.80 (s, 3H). HRMS (ESI) calcd for C27H29N2O3
[M+H]+ 429.2173; found: 429.2162. Procedure B (isolation by
evaporation). As described above, NTX·HCl (0.15 g, 0.40 mmol)
and 1-methyl-1-phenylhydrazine (50 mL, 0.052 g, 0.42 mmol) in
0.1 N HCl (3 mL) were heated in a boiling water bath for 1.5 h,
and then cooled to ambient temperature. The entire reaction
mixture was evaporated to dryness under reduced pressure, and
then dried in vacuo at 45 ◦C to furnish N1¢-Me-NTI·HCl (0.20 g,
97%) as a beige powder of 98% purity by reversed-phase HPLC.
for C26H25ClN2O3 · H2O: C, 66.88; H, 5.82; N, 6.00. Found: C,
67.29; H, 5.54; N, 5.93. Procedure B (aqueous Fischer conditions,
HCl salt): A mixture of NTX·HCl (0.15 g, 0.40 mmol) and 2-
chlorophenylhydrazine·HCl (0.080 g, 0.44 mmol) was dissolved
in water (3.0 mL) using a 15 mL plastic centrifuge tube as
the reaction vessel. After heating in a boiling water bath for
1.5 h, the mixture was cooled to ambient temperature and then
chilled at 4 ◦C for 30 min to◦give a brown precipitate. After
centrifugation (10,000 rpm, 4 C; 5 min), the supernatant was
discarded and the precipitate suspended in ice-cold 0.1 N HCl
(2 mL), vortexed thoroughly, and then centrifuged again. This
process was repeated three times, and the solid was then dried
in vacuo at 45 ◦C to furnish 7¢-Cl-NTI·HCl·0.4 H2O (0.16 g)
as a brown powder of 90% purity by reversed phase HPLC in
an effective 78% molar yield when adjusted for purity. 1H NMR
data obtained for the free base as reported in Procedure A above.
HRMS (ESI) calcd for C26H26ClN2O3 [M+H]+ 449.1626; found:
449.1618. Anal. Calcd for C26H25ClN2O3 · 0.4 H2O: C, 68.46; H,
5.70; N, 6.14, Cl, 7.77. Found: C, 68.43; H, 6.25; N, 6.46, Cl,
7.92.
17-(Cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxymorphi-
nan-6-one, (E)-2-nitrophenylhydrazone hydrochloride (naltrex-
one o-nitrophenylhydrazone·HCl, 9). A mixture of NTX·HCl
(0.15 g, 0.40 mmol) and o-nitrophenylhydrazine (0.065 g,
0.41 mmol, 1.03 equiv) in 0.1 N HCl (3 mL) was refluxed
for 1.5 h, and then cooled to ambient temperature. The bright
orange paste was collected by filtration, and washed with 0.1
N HCl until the filtrate was pale yellow. The solid was dried in
vacuo at 45 ◦C to furnish the monohydrate of the title compound
(0.16 g, 75%) as a yellow powder of 96% purity by reversed-phase
HPLC. 1H NMR (free base, CDCl3, 300 MHz): d 12.74 (s, 1H),
8.11 (dd, J = 1.2 Hz, J = 7.6 Hz, 1H), 7.77 (dd, J = 1.2 Hz,
J = 8.5 Hz, 1H), 7.47 (ddd, J = 1.2 Hz, J = 7.0 Hz, J = 7.6 Hz,
1H), 6.77 (ddd, J = 1.2 Hz, J = 7.0 Hz, J = 8.5 Hz, 1H), 6.69
(d, J = 8.1 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.49 (bs, 1H),
5.36 (s, 1H), 5.13 (bs, 1H), 3.15 (d, J = 6.1 Hz, 1H), 3.03 (d, J =
18.5 Hz, 1H), 2.94 (m, 1H), 2.70 (dd, J = 4.3 Hz, J = 11.9 Hz,
1H), 2.58 (dd, J = 6.1 Hz, J = 18.5 Hz, 1H), 2.46 (m, 1H), 2.39
(d, J = 6.6 Hz, 2H), 2.33 (dd, J = 4.9 Hz, J = 11.9 Hz, 1H),
2.16 (m, 1H), 1.71 (m, 1H), 1.56 (m, 2H), 0.85 (m, 1H), 0.54 (m,
2H), 0.13 (m, 2H). HRMS (ESI) calcd for C26H29N4O5 [M+H]+
17-(Cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-3,14-di-
hydroxy-benzo[b]furano [6,7:2¢,3¢] morphinan hydrochloride (nal-
triben hydrochloride, NTB·HCl, 2). A mixture of NTX·HCl
(1.13 g, 3.00 mmol) and O-phenylhydroxylamine·HCl (0.46 g,
3.16 mmol, 1.05 equiv) in 6.0 N HCl (30 mL) was refluxed for
4 h. The reaction was cooled to ambient temperature, and then
refrigerated at 4 ◦C overnight. The precipitate was collected by
filtration, and washed with ice-cold 6.0 N HCl until the filtrate
◦
was colorless. The solid was dried in vacuo at 45 C to furnish
NTB·HCl (1.26 g, 93%) as a pale brown powder of 98% purity by
reversed-phase HPLC. Characteristic 1H NMR signals2 for the
free base (CDCl3, 300 MHz): d 7.42 (d, J = 8.1 Hz, 1H), 7.37 (d,
J = 7.4 Hz, 1H), 7.25 (ddd, J = 1.3 Hz, J = 7.2 Hz, J = 8.1 Hz,
1H), 7.15 (ddd, J = 0.9 Hz, J = 7.2 Hz, J = 7.4 Hz, 1H). HRMS
(ESI) calcd for C26H26NO4 [M+H]+ 416.1862; found: 416.1869.
17-(Cyclopropylmethyl)-6,7-didehydro-4,5a-epoxy-3,14-di-
hydroxy - 7¢-chloro-indolo[6,7:2¢,3¢] morphinan (7¢-chloronaltri-
ndole, 7¢-Cl-NTI, 5). Procedure A (classical Fischer conditions,
free base). A mixture of NTX·HCl (0.75 g, 2.0 mmol) and 2-
chlorophenylhydrazine·HCl (0.54 g, 3.0 mmol) was dissolved in
MeOH (20 mL) that had been treated with HCl (g) to 10% by
weight. After reflux under nitrogen for 4.5 h, the reaction mixture
was cooled, and solvent removed under reduced pressure. The
residue was dissolved in MeOH, and then partitioned between
EtOAc and saturated Na2CO3. The combined organic extracts
were dried (Na2SO4), filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography
using a gradient of hexane/EtOAc (70/30) containing 2 - 10%
MeOH and 2% triethylamine to give 0.72 g ◦(77%) of 7¢-Cl-NTI
477.2138; found: 477.2154. Anal. Calcd for C26H28ClN4O5
H2O: C, 58.92; H, 5.71; N, 10.57. Found: C, 58.78; H, 5.68;
N, 10.51.
·
Acknowledgements
We thank Dr. Yong-de Lu for preparation of 7¢-Cl-NTI using
classical Fischer conditions. We thank the National Cancer
Institute (P50 CA 103130: Center for Single Photon-Emitting
Cancer Imaging Agents) for support of this research, and for
a postdoctoral fellowship (RAD) through the Career Develop-
ment Core. We also acknowledge resources provided by Harry
S. Truman Memorial Veterans’ Hospital, the University of
Missouri Life Sciences Mission Enhancement Program, and
NSF CHE-95-31247 and NIH 1S10RR11962-01 awards for
NMR instrumentation.
1
monohydrate as a yellow powder (mp 240 C, dec). H NMR
(CDCl3, 300 MHz): d 8.52 (s, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.09
(d, J = 7.5 Hz, 1H), 6.91 (t, J = 7.7 Hz, 1 H), 6.62 (d, J = 8.1 Hz,
1H), 6.54 (d, J = 8.1 Hz, 1H), 5.67 (s, 1H), 5.23 (br. s, 1H), 3.37
(d, J = 6.1 Hz), 3.13 (d, J = 18.5 Hz, 1H), 2.86 (d, J = 15.5 Hz,
1H), 2.81 - 2.73 (m, 2H), 2.63 (d, J = 15.5 Hz, 1H), 2.49 - 2.25
(m, 4H), 1.77 (d, J = 11.8 Hz, 1H) 1.26 (br s, 1 H), 0.89 (m, 1H),
0.57 (d, J = 7.3 Hz, 2H), 0.17 (d, J = 4.6 Hz, 2H). Anal. Calcd
308 | Green Chem., 2010, 12, 304–309
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