Syntheses of 10-oxo, 10α-hydroxy, and 10β-hydroxy derivatives of a potent κ-opioid receptor agonist, TRK-820

Article abstract of DOI:10.1248/cpb.52.664

Syntheses of 10-oxo, 10α-hydroxy, and 10β-hydroxy derivatives of a potent κ-opioid receptor selective agonist, TRK-820, are described. These derivatives were supposed to be potential degradation products in formulation of TRK-820 as a result of autoxidati

Full text of DOI:10.1248/cpb.52.664

664
Chem. Pharm. Bull. 52(6) 664—669 (2004)
Vol. 52, No. 6
a
b
Syntheses of 10-Oxo, 10 -Hydroxy, and 10 -Hydroxy Derivatives of a
k
Potent -Opioid Receptor Agonist, TRK-820
Hiromasa HORIKIRI, Noriyuki HIRANO, Yoichiro TANAKA, Junji OISHI, Hitoshi HATAKEYAMA,
Kuniaki KAWAMURA,* and Hiroshi NAGASE
Pharmaceutical Research Laboratories, Toray Industries, Inc.; 1111 Tebiro, Kamakura, Kanagawa 248–8555, Japan.
Received December 11, 2003; accepted March 6, 2004
Syntheses of 10-oxo, 10a-hydroxy, and 10b-hydroxy derivatives of a potent k-opioid receptor selective ago-
nist, TRK-820, are described. These derivatives were supposed to be potential degradation products in formula-
tion of TRK-820 as a result of autoxidation. 10-Oxo-TRK-820 11 was derived from 10-oxo-4,5-epoxymorphinan
14 in 10 steps in 32% overall yield. Reduction of the 10-oxo group in 4,5-epoxymorphinan with NaBH4 gave 10b-
hydroxy-4,5-epoxymorphinan, exclusively. A stepwise inversion method of the 10b-hydroxy group to produce
10a-hydroxy-4,5-epoxymorphinan was established. By HPLC analyses, 10a-hydroxy-TRK-820 12 was confirmed
to be one of the degradation products in developing formulation of TRK-820.
Key words TRK-820; degradation product; 10-oxo-4,5-epoxymorphinan; 10-oxo-TRK-820; 10a-hydroxy-TRK-820; 10b-hy-
droxy-TRK-820
Three types of opioid receptors (m, d, k) are now well es- might have higher selectivity or affinity to k-opioid receptor
tablished by not only pharmacological studies but also mole- as shown in ketocyclazocine 7 and ethylketocyclazocine 8.
cular biological studies.1—3) Especially, the k-opioid receptor To confirm if those compounds actually exist in the develop-
has been of interest because its activation produces analgesia ing formulation of TRK-820, we intended to synthesize those
with minimum physical dependence and respiratory depres- oxidative degradation products such as 10-oxo 11, 10a-hy-
sion.4) Thus, a highly selective k-opioid agonist may provide droxy 12, and 10b-hydroxy 13 derivatives of TRK-820.
a useful analgesic free from abuse potential and the adverse Herein we wish to report the syntheses of compounds 11, 12,
effects of a m-agonist like morphine.4,5)
and 13, starting from 10-oxo-4,5-epoxymorphinan 14 which
We have already described the design and synthesis of was prepared by a convenient oxidation method of the 10-
(E)-N-[17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy- benzylic position in 4,5-epoxymorphinan derivatives previ-
morphinan-6b-yl]-3-(furan-3-yl)-N-methylprop-2-enamide ously reported by us (Fig. 4).16) From the synthetic point of
monohydrochloride 1, TRK-820 (Fig. 1), and its pharmaco- view, it was presumed to be difficult to transform the steri-
logical activity.6) TRK-820 exhibited high k-opioid agonistic cally hindered 10b-hydroxy group in 4,5-epoxymorphinan
activity, antipruritic actions,7,8) and higher analgesic action
than morphine and a prototype of k-opioid agonist, U-
50488H.6) Now clinical trials of TRK-820 are in progress
(Phase III in Europe and Phase IIb in Japan) as an antipru-
ritic agent for uraemic pruritus.
Recently, decomposition products of morphine 29) and nal-
trexone 310) were newly confirmed to occur in formulated
samples. The degradation products of morphine 2 were iden-
tified to be 10a-hydroxymorphine 4 and 10-oxomorphine 5,
Fig. 1. Structure of TRK-820
and 2-chloro-10a-hydroxynaltrexone 6 was identified as a
degradation product of natrexone 3 (Fig. 2). In a former
work, 10-oxomorphine 5 was also identified as a decomposi-
tion product in crystalline morphine 2.11) TRK-820 has the
same 4,5-epoxymorphinan structure like morphine 2 and nal-
trexone 3, therefore similar type of degradation products
might occur in formulation of TRK-820.
On the other hand, some k-opioid selective ligands like
ketocyclazocine 712) and ethylketocyclazocine 813) have an
oxo group in common on their benzylic positions. Further-
Fig. 2
more, it was described that introduction of an oxo group at
the 10-position of KT-90 9,14) a k-opioid agonist, gave KT-95
1015) which exhibited higher analgesic activity and affinity to
k-opioid receptor than those of KT-90 (Fig. 3).
Hence we were interested in that similar degradation prod-
ucts, confirmed in morphine 2 and naltrexone 3, might occur
in the developing formulation of TRK-820. In addition to the
above assumptions, those oxidative degradation products
Fig. 3
∗ To whom correspondence should be addressed. e-mail: Kuniaki_Kawamura@nts.toray.co.jp
© 2004 Pharmaceutical Society of Japan

June 2004
665
Fig. 4
Reagents and conditions: (a) 3 M HCl, 1,4-dioxane, reflux, 21 h; (b) KI, K2CO3, cy-
clopropylmethyl bromide, dry DMF, room temperature, 3.5 h (79% in 2 steps); (c)
BnNHCH3, PhCO2H, PhH, reflux, 16 h; NaBH3CN, CH3OH, 0 °C to room temperature,
1.5 h (66%); (d) n-PrSH, NaH, dry DMF, 95 °C, 3 h (91%); (e) H2, 10% Pd–C, o-ph-
thalic acid, CH3OH, CHCl3, room temperature, 12.5 h; (f) (E)-3-(3-furyl)acryloyl chlo-
ride, Na2CO3, THF, H2O, room temperature, 1.5 h; (g) 2.5 M NaOH, CH3OH, room tem-
perature, 1 h (81% in 3 steps).
Chart 1
Fig. 5
into the 10a-hydroxy group by inversion reaction. In fact,
Mitsunobu reaction17) was in vain in this system. We also
wish to report the effective stepwise inversion method of the
10b-hydroxy group in 4,5-epoxymorphinan.
Results and Discussion
The target compounds were synthesized by a route shown
in Charts 1, 2, and 5. 10-Oxo-4,5-epoxymorphinan derivative
14 was used as the starting marterial which was synthesized
in accordance with our oxidation method.16) Deprotection of
the Boc and ketal groups of compound 14 under acidic con-
ditions gave diketoamine 15, and the resulting secondary
amino group was alkylated with cyclopropylmethyl bromide
in the presence of potassium iodide and potassium carbonate
to afford diketone 16 in 79% yield (2 steps). Stereoselective
reductive-amination of compound 16 with N-benzylmethyl-
amine by using NaBH3CN was performed in accordance
with the literature18) to give compound 17 in 66% yield after
chromatographic separation. The reaction proceeded regiose-
lectively only on the 6-oxo group due to the steric bulkiness
on the 10-oxo group. The stereochemistry of the 6-position
Reagents and conditions: (a) Ac2O, NaHCO3, H2O, 1,4-dioxane, room temperature,
16.5 h (81%); (b) NaBH4, CH3OH, 0 °C to room temperature, 2.5 h (71%).
Chaer 2
Reagents and conditions: (a) NaBH4, CH3OH, 0 °C to room temperature, 22 h (60%).
Chart 3
1
was elucidated to be 6b configuration by H-NMR spectral
Thus, the 3-hydroxy group of compound 11 was acetylated
and the resulting acetate was treated with NaBH4 in CH3OH
at room temperature to successfully give 10b-hydroxy-TRK-
820 13 exclusively. In this reaction, both the reduction of 10-
oxo group and the deacetylation were taken place (Chart 2).
The stereochemistry of the 10-position on compound 13
was elucidated to be 10b-hydroxy configuration by 1H-NMR
spectral analysis of the 10-proton, which was observed at
dꢀ5.03 (1H, d, Jꢀ5.1 Hz) that was similar to the litera-
tures.10,12)
A similar stereoselectivity of 10-oxo hydride reduction
was observed by reduction of model compound 17 (Chart 3).
Stereochemistry of the resulting compound 21 was analyzed
by NOESY and COSY spectra, and positive NOE signal was
observed between the 8-axial proton and the 10-position pro-
ton. The results and the reported fact19) that NaBH4 reduction
of 10-oxomorphinan derivatives gave 10b-hydroxy com-
pounds allowed the stereochemistry of the 10-position in
compounds 13 and 21 to be identified as 10b-hydroxy con-
figuration.
analysis of the 5-proton, which was observed at dꢀ4.80 with
an axial–axial coupling of 8.1 Hz between the 5- and 6-pro-
tons. Demethylation of compound 17 by using thiolate anion
produced phenol 18 in 91% yield. Phenol 18 was debenzy-
lated by hydrogenolysis and the resulting crude product
which has a secondary amino group and a 3-hydroxy group
was reacted with 2 equivalents of (E)-3-(3-furyl)acryloyl
chloride in the presence of sodium carbonate to produce
amide ester intermediate. This phenol ester portion was hy-
drolyzed by addition of 2.5 M NaOH solution to produce 10-
oxo-TRK-820 11 in 81% yield (3 steps).
With compound 11 in hand, the next step was to synthe-
size 10a-hydroxy compound 12 and its 10b-epimer 13 by
hydride reduction of the 10-oxo group in compound 11.
Treatment of compound 11 with NaBH4 in CH3OH resulted
in complete recovery of the starting material 11. The results
suggest that compound 11 is easily convertible into quinon-
methide form 20 under the hydride reduction conditions (Fig.
5).

666
Vol. 52, No. 6
10-proton, which was observed at dꢀ6.23 (1H, s). No cou-
pling constant (J9—10ꢀ0 Hz) of the 10-proton strongly sug-
gests the 10b-H configuration.10) The 3-O-Boc group and the
10a-acetoxy group were successively hydrolyzed by aqueous
sodium hydroxide, then ammonium hydroxide to finally pro-
duce 10a-hydroxy-TRK-820 12.
Compounds 11, 12, and 13 were measured on HPLC
analyses21) with developing formulation of TRK-820. Reten-
tion time of one decomposition product (relative retention
time 0.8 versus TRK-820 in HPLC analyses) in the develop-
ing formulation of TRK-820 was coincident with that of
compound 12. Its coincidence was subsequently confirmed
by HPLC spiking experiments using compound 12. The re-
sults indicated that compound 12 was actually identified to
be one of the oxidative degradation products in formulated
samples of TRK-820. The degradation pattern of TRK-820
in the developing formulation was considered to be similar to
those of morphine 2 and naltrexone 3.
Reagents and conditions: (a) MsCl, Et3N, dry CH2Cl2, 0 °C, 2 h; (b) NaOAc, AcOH,
0 °C to room temperature, 18 h (71% in 2 steps).
Chart 4
Conclusion
Three types of the 10-position oxidized derivatives of
TRK-820 (10-oxo-TRK-820 11, 10a-hydroxy-TRK-820 12,
and 10b-hydroxy-TRK-820 13) were synthesized from 10-
oxo-4,5-epoxymorphinan 14 which was easily derived from
noroxycodone. The overall yields of the above derivatives
were 32% in 7 steps (10-oxo-TRK-820), 18% in 9 steps
(10b-hydroxy-TRK-820), and 18% in 13 steps (10a-hy-
droxy-TRK-820), respectively. In this study, the stepwise in-
version method of the 10b-hydroxy group in 4,5-epoxymor-
phinan system was established. Compound 12 was confirmed
to be one of the degradation products in the developing for-
mulation of TRK-820 by HPLC analyses. Detailed formula-
tion studies for control of the degradation products and phar-
macological studies of compounds 11, 12, and 13 are now
under way.
Reagents and conditions: (a) (Boc)2O, Na2CO3, n-Bu4NI, H2O, CHCl3, room temper-
ature, 54.5 h (quant.); (b) NaBH4, CH3OH, 0—5 °C, 2 h (quant.); (c) MsCl, Et3N, dry
CH2Cl2, 0 °C to room temperature, 20 h; (d) NaOAc, AcOH, room temperature, 10.5 h
(69% in 2 steps); (e) aq. NaOH, THF, room temperature, 48 h; (f) 28% ammonia solu-
tion, CH3OH, room temperature, 43 h (81% in 2 steps).
Experimental
Chart 5
General Methods All reactions requiring anhydrous conditions were
conducted under atmosphere of dry argon. Syntheses of compounds 11, 12,
13, 24, 25, and 26 were carried out under protection from light. The progress
of reactions and purity of intermediates were monitored on Merck analytical
silica gel TLC plates 60 F254. For column chromatography Merck silica gel
60 (0.063—0.200 mm) was used. Melting points were measured on Yanaco
MP-500D melting point apparatus without correction. 1H-NMR spectra were
measured (TMS internal standard) on Varian Gemini 2000 (300 MHz) or
unityplus (500 MHz) spectrometer. IR spectra were measured on JASCO
FT/IR-410. Electron ionization mass spectra (EI-MS) and high-resolution
electron ionization mass spectra (HR-EI-MS) were measured on JMS-
Then we tried inversion of the 10b-hydroxy group to syn-
thesize the 10a-hydroxy compound by using model com-
pound 22 (Chart 4). Although the inversion did not proceed
under Mitsunobu’s conditions,17) stepwise treatments of com-
pound 22 with methanesulfonyl chloride in the presence of
triethylamine followed by sodium acetate in acetic acid suc-
cessfully gave 10a-acetate 23 in 71% yield (2 steps) exclu-
sively. The stereochemistry of the 10-position in 10a-acetate DX303. Electrospray ionization mass spectra (ESI-MS) and high-resolution
electrospray mass spectra (HR-ESI-MS) were measured on micromass LCT.
23 was also elucidated by NOESY and COSY spectra. Posi-
tive NOE signal was observed between the 16-axial proton
and the 10-position proton.
LC-MS were measured on Waters micromass ZQ.
4,5a-Epoxy-14b-hydroxy-3-methoxymorphinan-6,10-dione (15) To a
stirred solution of compound 14 (74.45 g, 162.0 mmol) in 600 ml of 1,4-
Next, we applied the above stepwise inversion method to
the synthesis of 10a-hydroxy-TRK-820 12 (Chart 5). The 3-
hydroxy group of 10-oxo-TRK-820 11 was protected by the
Boc group20) which is more stable than an acetyl group under
basic conditions. The 10-Oxo group of compound 24 was re-
duced by NaBH4 in CH3OH to give 10b-hydroxy-3-O-Boc
compound 25 in quantitative yield, which was subjected to
the above stepwise inversion sequence to produce 10a-ace-
toxy-3-O-Boc compound 26 in 69% yield (2 steps). The
stereochemistry of the 10-position on compound 26 was elu-
dioxane was added a 3 M aq. HCl solution (400 ml, 1200 mmol), and the
mixture was heated under reflux for 21 h. The solution was concentrated and
then cooled to 0 °C. The mixture was basified by adding a 3.9 M aq. NaOH
solution (300 ml, 1175 mmol) and saturated aq. NaHCO3 solution. The mix-
ture was extracted with CHCl3, and the organic layer was concentrated in
vacuo to give 44.76 g of compound 15 as an amorphous solid.
1H-NMR (300 MHz, CDCl3) d: 1.58—1.73 (2H, m), 1.93—2.00 (1H, m),
2.34 (1H, dt, Jꢀ14.4, 3.0 Hz), 2.50—2.70 (2H, m), 2.78—2.85 (1H, m),
3.06 (1H, dt, Jꢀ14.7, 5.4 Hz), 3.25 (1H, s), 4.02 (3H, s), 4.75 (1H, s), 4.85
(1H, broad s), 6.89 (1H, d, Jꢀ8.4 Hz), 7.47 (1H, d, Jꢀ8.4 Hz). IR (KBr)
cmꢁ1: 3356, 1723, 1681, 1598, 1497, 1281. HR-EI-MS m/z Mꢂ Calcd for
C17H17NO5: 315.1107. Found: 315.1093.
1
cidated to be 10a configuration by H-NMR analysis of the
17-(Cyclopropylmethyl)-4,5a-epoxy-14b-hydroxy-3-methoxymorphi-

June 2004
667
nan-6,10-dione (16) To a stirred suspension of compound 15 (44.50 g, combined organic layer was concentrated in vacuo to give 38.97 g of crude
141 mmol), KI (47.33 g, 285 mmol), and K2CO3 (40.39 g, 292 mmol) in products. To a stirred solution of the crude products in 320 ml of CH3OH
700 ml of dry DMF was added dropwise cyclopropylmethy bromide
(27.5 ml, 283 mmol) at room temperature. After stirring for 3.5 h, water was
was added a 2.5 M aq. NaOH solution (45.0 ml, 112 mmol), and stirring was
continued at room temperature for 1 h. After the reaction was completed, 3 M
added to the suspension and extracted with CHCl3. The organic layer was aq. HCl solution was added dropwise to the solution for neutralization in an
concentrated, and water was added to the residue. The mixture was extracted ice bath, and saturated aq. NaHCO3 solution was added to basify. Then
with EtOAc, and the organic layer was washed with water, dried over CH3OH was removed by concentration, and the resulting residue was ex-
Na2SO4, and concentrated in vacuo to give 44.77 g of crude products. This
was chromatographed on silica gel. Elution with CHCl3/CH3OH (20/1) gave
41.14 g (79%) of compound 16 as an amorphous solid.
tracted with CHCl3. The organic layer was concentrated in vacuo to give
46.36 g of crude products. This was chromatographed on silica gel. Elution
with CHCl3/CH3OH (100/1—50/1) gave 33.22 g of the residue, and this
1H-NMR (300 MHz, CDCl3) d: 0.10—0.16 (1H, m), 0.33—0.38 (1H, m), residue was precipitated by EtOAc/CH3OH (3/1) to give 21.21 g of com-
0.52—0.60 (2H, m), 0.94 (1H, m), 1.63 (1H, dt, Jꢀ13.9, 4.2 Hz), 1.74 (1H,
pound 11. The filtrate was repeatedly purified to give totally 27.08 g (81% in
dt, Jꢀ13.0, 3.0 Hz), 1.93—2.01 (1H, m), 2.18 (1H, dt, Jꢀ12.4, 4.2 Hz), 3 steps) of compound 11 as a pale yellow powder.
2.24—2.38 (2H, m), 2.56—2.72 (2H, m), 2.90 (1H, dd, Jꢀ12.7, 5.7 Hz),
3.06 (1H, dt, Jꢀ14.4, 5.1 Hz), 3.32 (1H, s), 4.01 (3H, s), 4.77 (1H, s), 4.98 0.50—0.60 (2H, m), 0.90—1.00 (1H, m), 1.40—2.00 (3H, m), 2.10—2.30
1H-NMR (300 MHz, CDCl3) d: 0.07—0.20 (1H, m), 0.30—0.40 (1H, m),
(1H, s), 6.86 (1H, d, Jꢀ8.4 Hz), 7.42 (1H, d, Jꢀ8.4 Hz). IR (KBr) cmꢁ1
:
(4H, m), 2.30—2.50 (1H, m), 2.66 (1H, dd, Jꢀ12.9, 6.3 Hz), 2.80—2.90
3447, 1727, 1671, 1594, 1502, 1271. HR-EI-MS m/z Mꢂ Calcd for (1H, m), 3.06 (2H, s), 3.15 (1H, s), 3.23—3.27 (1H, m), 3.70—3.80 (0.7H,
C21H23NO5: 369.1576. Found: 369.1602. m), 4.58—4.64 (2H, m), 4.64—4.80 (0.3H, m), 6.26 (0.7H, d, Jꢀ15.6 Hz),
6b-(N-Benzyl)methylamino-17-(cyclopropylmethyl)-4,5a-epoxy-14b- 6.56—6.63 (1.3H, m), 6.90 (0.3H, d, Jꢀ8.4 Hz), 7.01 (0.7H, d, Jꢀ8.4 Hz),
hydroxy-3-methoxymorphinan-10-one (17) A stirred mixture of com- 7.20—7.45 (3.4H, m), 7.59 (0.3H, d, Jꢀ15.6 Hz), 7.64 (0.3H, s). IR (KBr)
pound 16 (41.11 g, 111.2 mmol), N-benzylmethylamine (29.0 ml, 224.7 cmꢁ1: 3411, 1650, 1616, 1292. HR-EI-MS m/z Mꢂ Calcd for C28H30N2O6:
mmol), and benzoic acid (13.76 g, 112.6 mmol) in 700 ml of benzene was re-
fluxed for 16 h using a Dean–Stark apparatus. After removing benzene, the
mixture was dissolved in 1000 ml of CH3OH. To the stirred mixture was
added NaBH3CN (14.03 g, 223.0 mmol) at 0 °C. After stirring for 10 min,
the temperature was raised to room temperature and the stirring was contin-
ued for 1.5 h. After that, the solution was concentrated and the residue was
490.2104. Found: 490.2084. mp 198 °C (dec.).
(E)-N-[17-(Cyclopropylmethyl)-4,5a-epoxy-3,10b,14b-trihydroxy-
morphinan-6b-yl]-3-(furan-3-yl)-N-methylprop-2-enamide (13) To
stirred solution of compound 11 (2.03 g, 4.13 mmol) in 45 ml of 1,4-dioxane
was added NaHCO3 (3.71 g, 44.1 mmol) in 15 ml of water followed by Ac2O
(2.00 ml, 21.2 mmol) at room temperature. After stirring for 16.5 h, the reac-
a
dissolved in CHCl3 and a saturated aq. NaHCO3 solution. The organic layer tion mixture was extracted with EtOAc, and the organic layer was washed
was separated, and dried over Na2SO4, and concentrated in vacuo to give with water and a saturated aq. NaCl solution, dried over Na2SO4, and con-
83.11 g of crude products. This was chromatographed on silica gel. Elution
centrated in vacuo to give 2.09 g of crude products. This was chro-
with CHCl3/CH3OH (50/1) gave 34.78 g (66%) of compound 17 as an amor- matographed on silica gel. Elution with n-hexane/EtOAc (1/2) gave 1.79 g
phous solid.
(81%) of 3-O-acetate. To a stirred solution of the product (1.78 g,
1H-NMR (300 MHz, CDCl3) d: 0.06—0.12 (1H, m), 0.28—0.33 (1H, m), 3.34 mmol) in 30 ml of CH3OH was added NaBH4 (300.0 mg, 7.93 mmol) at
0.48—0.56 (2H, m), 0.92 (1H, m), 1.32 (1H, dt, Jꢀ13.8, 2.4 Hz), 1.52— room temperature. After stirring for 2.5 h, a saturated aq. NaHCO3 solution
1.71 (3H, m), 1.97—2.23 (3H, m), 2.36 (3H, s), 2.39 (1H, dt, Jꢀ12.7,
5.4 Hz), 2.54—2.67 (2H, m), 2.82 (1H, dd, Jꢀ12.1, 5.1 Hz), 3.20 (1H, s),
was added to the reaction mixture, and the mixture was extracted with
CHCl3. The organic layer was washed with a saturated aq. NaCl solution,
3.66 (1H, d, Jꢀ13.5 Hz), 3.81 (1H, d, Jꢀ13.5 Hz), 3.97 (3H, s), 4.80 (1H, d, and dried over Na2SO4, and concentrated in vacuo to give 1.62 g of crude
Jꢀ8.1 Hz), 6.82 (1H, d, Jꢀ8.4 Hz), 7.17—7.35 (4H, m), 7.35—7.39 (2H, products. This was chromatographed on silica gel. Elution with
m). IR (KBr) cmꢁ1: 3433, 1672, 1618, 1507, 1286. HR-EI-MS m/z Mꢂ CHCl3/CH3OH (30/1—10/1) gave 1.17 g (71%) of compound 13 as an
Calcd for C29H34N2O4: 474.2519. Found: 474.2516.
amorphous solid.
6b-(N-Benzyl)methylamino-17-(cyclopropylmethyl)-4,5a-epoxy-
1H-NMR (300 MHz, CDCl3) d: 0.15—0.20 (2H, m), 0.48—0.57 (2H, m),
0.82—0.95 (1H, m), 1.37—1.47 (3H, m), 1.60—1.75 (1H, m), 2.10—2.30
(2H, m), 2.59—2.66 (1H, m), 2.76—2.89 (2H, m), 2.96—3.04 (1H, m), 3.00
(2H, s), 3.13 (1H, s), 3.15—3.18 (1H, m), 3.65—3.80 (0.7H, m), 4.48 (0.7H,
d, Jꢀ8.1 Hz), 4.49—4.62 (0.6H, m), 5.03 (1H, d, Jꢀ5.1 Hz), 6.33 (0.7H, d,
Jꢀ15.3 Hz), 6.56 (0.3H, d, Jꢀ15.3 Hz), 6.59 (0.3H, d, Jꢀ1.7 Hz), 6.66
(0.7H, d, Jꢀ1.7 Hz), 6.85 (0.3H, d, Jꢀ8.2 Hz), 6.90 (0.3H, d, Jꢀ8.2 Hz),
3,14b-dihydroxymorphinan-10-one (18) To
a stirred suspension of
sodium hydride (1.81 g, 45.2 mmol) in 60 ml of dry DMF was added drop-
wise n-PrSH (4.10 ml, 45.2 mmol) in an ice cooled bath, and the mixture
was stirred for 90 min. To the stirred suspension was added dropwise a solu-
tion of compound 17 (5.25 g, 11.06 mmol) in 65 ml of dry DMF, and the
mixture was heated at 95 °C for 3 h. Water was slowly added to the suspen-
sion and then solid NaCl was added. The mixture was extracted with CHCl3, 6.94 (1.4H, broad s), 7.32 (0.7H, d, Jꢀ1.7 Hz), 7.38 (0.3H, d, Jꢀ1.7 Hz),
and the organic layer was concentrated in vacuo to give 7.18 g of crude prod- 7.39 (0.7H, s), 7.40 (0.7H, d, Jꢀ15.3 Hz), 7.54 (0.3H, d, Jꢀ15.3 Hz), 7.62
ucts. This was chromatographed on silica gel. Elution with CHCl3/CH3OH (0.3H, s). IR (KBr) cmꢁ1: 3391, 1647, 1593. HR-EI-MS m/z Mꢂ Calcd for
(50/1) gave 4.64 g (91%) of compound 18 as an amorphous solid.
C28H32N2O6: 492.2260. Found: 492.2284.
6b-(N-Benzyl)methylamino-17-(cyclopropylmethyl)-4,5a-epoxy-
1H-NMR (300 MHz, CDCl3) d: 0.07—0.12 (1H, m), 0.28—0.33 (1H, m),
0.48—0.56 (2H, m), 0.88—0.94 (1H, m), 1.23—1.32 (1H, m), 1.60—2.00 10b,14b-dihydroxy-3-methoxymorphinan (21) To a stirred solution of
(4H, m), 2.10—2.30 (2H, m), 2.33 (3H, s), 2.30—2.41 (1H, m), 2.45—2.55 compound 17 (231 mg, 0.486 mmol) in 10 ml of CH3OH was added NaBH4
(1H, m), 2.63 (1H, dd, Jꢀ13.0, 6.0 Hz), 2.70—2.86 (1H, dd, Jꢀ12.1,
4.5 Hz), 3.20 (1H, s), 3.45 (1H, d, Jꢀ13.5 Hz), 3.84 (1H, d, Jꢀ13.5 Hz),
4.73 (1H, d, Jꢀ8.4 Hz), 6.82 (1H, d, Jꢀ8.4 Hz), 7.20—7.33 (6H, m). IR
(82.0 mg, 2.16 mmol) at room temperature. After stirring for 23 h, a satu-
rated aq. NaHCO3 solution was added to the reaction mixture, and extracted
with CHCl3. The organic layer was washed with saturated aq. NaCl solution,
(KBr) cmꢁ1: 3422, 1669, 1613, 1292. HR-EI-MS m/z Mꢂ Calcd for and dried over Na2SO4, and concentrated in vacuo to give 224 mg of crude
C28H32N2O4: 460.2362. Found: 460.2336.
products. This was chromatographed on silica gel. Elution with
(E)-N-[17-(Cyclopropylmethyl)-4,5a-epoxy-3,14b-dihydroxy-10-oxo- CHCl3/CH3OH (50/1—20/1) gave 140 mg (60%) of compound 21 as an
morphinan-6b-yl]-3-(furan-3-yl)-N-methylprop-2-enamide (11) To
a
amorphous solid.
solution of compound 18 (31.48 g, 68.35 mmol) in 120 ml of CHCl3 and
500 ml of CH3OH was added o-phthalic acid (11.76 g, 70.78 mmol) and 10%
Pd–C (20.12 g), and the mixture was stirred under a hydrogen atmosphere at
room temperature for 12.5 h. The Pd–C catalyst was then removed by filtra-
tion through hyflo super-cell® and washed with CH3OH. The CH3OH solu-
tion was concentrated in vacuo to give 44.76 g of secondary amine,21) which
was used in the next steps without further purification. To a stirred solution
of the above crude products (42.86 g, 68.35 mmol) in 300 ml of water and
300 ml of THF was added Na2CO3 (24.33 g, 204.7 mmol) followed by (E)-3-
(3-furyl)acryloyl chloride (21.78 g, 139 mmol) at room temperature. After
stirring for 1.5 h, the reaction mixture was quenched with conc. HCl for neu-
tralization in an ice bath, and then a saturated aq. NaHCO3 solution was
added to basify. The resultant mixture was extracted with EtOAc, and the
1H-NMR (500 MHz, CDCl3) d: 0.11—0.19 (2H, m), 0.46—0.55 (2H, m),
0.86—0.94 (1H, m), 1.30 (1H, dt, Jꢀ12.5, 3.5 Hz), 1.40 (1H, dd, Jꢀ13.0,
2.5 Hz), 1.51—1.55 (1H, m), 1.62 (1H, dt, Jꢀ13.5, 3.7 Hz), 1.91—2.00 (1H,
m), 2.27 (1H, dt, Jꢀ12.5, 5.0 Hz), 2.33 (3H, s), 2.54—2.63 (2H, m), 2.77—
2.86 (2H, m), 3.00 (1H, dd, Jꢀ13.2, 6.2 Hz), 3.13 (1H, d, Jꢀ5.3 Hz), 3.71
(1H, d, Jꢀ13.5 Hz), 3.78 (1H, d, Jꢀ13.5 Hz), 3.90 (3H, s), 4.73 (1H, d,
Jꢀ7.0 Hz), 4.96 (1H, d, Jꢀ5.3 Hz), 6.79 (1H, d, Jꢀ8.3 Hz), 6.90 (1H, d,
Jꢀ8.3 Hz), 7.20 (1H, t, Jꢀ7.5 Hz), 7.28 (2H, t, Jꢀ7.5 Hz), 7.36 (2H, d,
Jꢀ7.5 Hz).
10a-Acetoxy-6b-(N-benzyl)methylamino-3-benzyloxy-17-(cyclopropyl-
methyl)-4,5a-epoxy-14b-hydroxymorphinan (23) To a stirred solution
of compound 22 (295 mg, 0.533 mmol) in dry CH2Cl2 was added dropwise
Et3N (0.450 ml, 3.22 mmol) followed by MsCl (0.08 ml, 1.03 mmol) at 0 °C.

668
Vol. 52, No. 6
After stirring for 2 h, to this solution was added dropwise a solution of
NaOAc (612 mg, 7.46 mmol) in 8.0 ml of acetic acid at 0 °C and the temper-
ature was gradually raised to room temperature. After stirring for 18 h, this
solution was poured into saturated aq. NaHCO3 solution to basify and the
mixture was extracted with CHCl3. The organic layer was washed with a sat-
urated aq. NaCl solution, dried over Na2SO4, and concentrated in vacuo to
give 332 mg of crude products. This was chromatographed on silica gel. Elu-
tion with n-hexane/EtOAc (2/1—1/1—0/1) gave 226 mg (71%) of com-
pound 23 as an amorphous solid.
NaCl solution, dried over Na2SO4, and concentrated in vacuo to give 40.77 g
of crude products. This was chromatographed on silica gel. Elution with n-
hexane/EtOAc gave 23.84 g (69% in 2 steps) of compound 26 as an amor-
phous solid.
1H-NMR (300 MHz, CDCl3) d: 0.08—0.21 (2H, m), 0.45—0.60 (2H, m),
0.75—0.95 (1H, m), 1.43 (7H, s), 1.51 (2H, s), 1.30—1.60 (1H, m), 1.60—
1.70 (3H, m), 1.70—1.90 (1H, m), 2.09 (3H, s), 2.20—2.40 (2H, m), 2.40—
2.60 (1H, m), 2.60—2.80 (2H, m), 3.02 (3H, s), 3.14 (1H, s), 3.65—3.80
(0.7H, m), 3.80—4.00 (0.3H, m), 4.75 (0.8H, d, Jꢀ7.8 Hz), 5.08 (0.2H, d,
1H-NMR (500 MHz, CDCl3) d: 0.13—0.16 (2H, m), 0.50—0.55 (2H, m), Jꢀ8.4 Hz), 6.23 (1H, s), 6.53 (1H, d, Jꢀ15.3 Hz), 6.60 (0.3H, s), 6.73 (0.7H,
0.86—0.90 (1H, m), 1.50 (1H, dd, Jꢀ13.0, 2.5 Hz), 1.60—1.64 (2H, m), s), 6.80—6.90 (0.3H, m), 6.90 (0.7H, d, Jꢀ8.4 Hz), 7.01 (0.3H, d,
1.68—1.74 (1H, m), 1.88—2.03 (1H, m), 2.04—2.10 (1H, m), 2.06 (3H, s), Jꢀ8.7 Hz), 7.08 (0.7H, d, Jꢀ8.7 Hz), 7.39 (1H, s), 7.48 (1H, d, Jꢀ15.3 Hz),
2.23 (1H, dt, Jꢀ12.5, 5.3 Hz), 2.34 (3H, s), 2.43 (1H, dd, Jꢀ12.5, 6.9 Hz), 7.62 (1H, s). IR (KBr) cmꢁ1: 3418, 1763, 1739, 1654, 1612, 1277, 1232,
2.64—2.72 (3H, m), 2.94 (1H, s), 3.72 (1H, d, Jꢀ13.8 Hz), 3.81 (1H, d, 1144. HR-ESI-MS m/z [MꢂH]ꢂ Calcd for C35H43N2O9: 635.2969. Found:
Jꢀ13.8 Hz), 4.77 (1H, d, Jꢀ7.9 Hz), 4.82 (1H, broad s), 5.23 (2H, s), 6.17 635.3000.
(1H, s), 6.74 (1H, d, Jꢀ8.3 Hz), 6.82 (1H, d, Jꢀ8.3 Hz), 7.17—7.21 (1H,
m), 7.23—7.31 (3H, m), 7.34 (2H, t, Jꢀ7.3 Hz), 7.38 (2H, d, Jꢀ7.3 Hz), morphinan-6b-yl]-3-(furan-3-yl)-N-methylprop-2-enamide (12) To
7.44 (2H, d, Jꢀ7.3 Hz). stirred solution of compound 26 (23.80 g, 37.49 mmol) in 300 ml of THF
(E)-N-[17-(Cyclopropylmethyl)-4,5a-epoxy-3,10a,14b-trihydroxy-
a
(E)-N-[3-tert-Butoxycarbonyloxy-17-(cyclopropylmethyl)-4,5a-epoxy- was added dropwise a solution of NaOH (3.01 g, 75.25 mmol) in 150 ml of
14b-hydroxy-10-oxomorphinan-6b-yl]-3-(furan-3-yl)-N-methylprop-2- water at room temperature. After stirring for 3 h, 150 ml of water was added
enamide (24) To a stirred solution of compound 11 (26.91 g, 54.85 mmol)
in 500 ml of CHCl3 was added Na2CO3 (36.74 g, 346.6 mmol), 300 ml of
water, (Boc)2O (30.0 ml, 130.5 mmol), and n-Bu4NI (4.92 g, 13.31 mmol)
successively at room temperature. After stirring for 54.5 h, to the reaction
to the mixture and stirring was continued for 45 h for hydrolysis of the ac-
etate portion. The reaction mixture was extracted with EtOAc, washed with
a saturated aq. NaCl solution, and concentrated in vacuo to give 22.77 g of
crude products. To a stirred solution of the crude products (22.77 g,
mixture was added solid NaCl, and the mixture was extracted with CHCl3. 37.49 mmol) in 250 ml of CH3OH was added 70 ml of 28% ammonia solu-
The organic layer was dried over Na2SO4 and concentrated in vacuo to give tion at room temperature. After stirring for 43 h, a white solid was precipi-
71.61 g of crude products. This was chromatographed on silica gel. Elution
with CHCl3/CH3OH (50/1) gave 36.43 g (quant.) of compound 24 as an
amorphous solid.
tated. The resultant solid was filtered and washed with CH3OH, dried under
vacuum conditions to give 13.03 g of compound 12. The above filtrate was
purified repeatedly to give 1.92 g of compound 12. Totally 14.95 g (81% in 2
1H-NMR (300 MHz, CDCl3) d: 0.02—0.10 (1H, m), 0.20—0.30 (1H, m), steps) of compound 12 was obtained as a white powder.
0.40—0.50 (2H, m), 0.70—0.90 (1H, m), 1.34 (7H, s), 1.35—1.45 (1H, m),
1H-NMR (300 MHz, DMSO-d6) d: 0.05—0.26 (2H, m), 0.40—0.60 (2H,
1.43 (2H, s), 1.45—1.70 (3H, m), 2.00—2.30 (2.6H, m), 2.30—2.50 (1.4H, m), 0.85—1.00 (1H, m), 1.15—1.40 (2H, m), 1.40—1.50 (1H, m), 1.75—
m), 2.53 (1H, dd, Jꢀ13.0, 6.0 Hz), 2.90—3.05 (1H, m), 2.93 (2H, s), 3.06 1.85 (1H, m), 1.85—2.00 (1H, m), 2.00—2.25 (2H, m), 2.30—2.40 (1H, m),
(1H, s), 3.21 (1H, s), 3.55—3.70 (0.7H, m), 3.70—3.85 (0.3H, m), 4.73 2.40—2.60 (2H, m), 2.84 (2H, s), 2.92 (1H, s), 3.08 (1H, s), 3.50—3.65
(1.6H, d, Jꢀ7.5 Hz), 5.08 (0.4H, d, Jꢀ7.5 Hz), 6.37 (0.6H, d, Jꢀ15.0 Hz),
(0.7H, m), 4.15—4.25 (0.3H, m), 4.63 (0.7H, d, Jꢀ8.1 Hz), 4.65—4.90
6.45—6.55 (1.4H, m), 7.03—7.10 (1H, m), 7.28—7.45 (3H, m), 7.51 (1H, (1.3H, m), 5.20 (0.4H, d, Jꢀ4.5 Hz), 5.25 (0.6H, d, Jꢀ5.1 Hz), 6.41 (0.6H,
s). IR (KBr) cmꢁ1: 3423, 1764, 1682, 1654, 1611, 1276, 1241, 1143. HR-EI- d, Jꢀ15.3 Hz), 6.65 (0.8H, s), 6.70—6.85 (2H, m), 6.89 (0.4H, d,
MS m/z Mꢂ Calcd for C33H38N2O8: 590.2628. Found: 590.2612.
Jꢀ15.3 Hz), 7.00 (0.2H, s), 7.21 (0.7H, d, Jꢀ15.3 Hz), 7.36 (0.3H, d,
Jꢀ15.3 Hz), 7.67 (0.7H, s), 7.71 (0.3H, s), 7.92 (0.6H, s), 8.02 (0.4H, s),
(E)-N-[3-tert-Butoxycarbonyloxy-17-(cyclopropylmethyl)-4,5a-epoxy-
10b,14b-dihydroxymorphinan-6b-yl]-3-(furan-3-yl)-N-methylprop-2- 9.18 (0.3H, broad s), 9.63 (0.6H, broad s). IR (KBr) cmꢁ1: 3378, 3218,
enamide (25) To a stirred solution of compound 24 (36.31 g, 54.85 mmol)
in 300 ml of CH3OH was added NaBH4 (5.22 g, 137.9 mmol) at 0—5 °C.
After stirring for 2 h, the reaction mixture was concentrated in vacuo. The
1645, 1594, 1504, 1442, 1403, 1318, 1159. HR-EI-MS m/z Mꢂ Calcd for
C28H32N2O6: 492.2260. Found: 492.2279. mp 262 °C (dec.).
residue was dissolved in CHCl3 and water. The organic layer was partitioned References and Notes
and washed with a saturated aq. NaHCO3 solution and saturated aq. NaCl
solution, dried over Na2SO4, and concentrated in vacuo to give 40.08 g of
crude products. The residue was treated with THF to give precipitate of
compound 25 (26.96 g, 82%) and 8.69 g of the residue from the filtrate. This
was chromatographed on silica gel. Elution with CHCl3/CH3OH (50/1—
25/1) gave 5.87 g (18%) of compound 25. Totally 32.83 g (quant.) of com-
pound 25 was obtained as a white powder.
1) Knapp R. J., Malatynska E., Fang L., Li X., Babin E., Nguyen M.,
Santoro G., Varga E. V., Hruby V. J., Roeske W. R., Yamamura H. I.,
Life Sci., 54, 463—469 (1994).
2) Wang J. B., Johnson P. S., Persico A. M., Hawkins A. L., Griffin C. A.,
Uhl G. R., FEBS Lett., 338, 217—222 (1994).
3) Mansson E., Bare L., Yang D., Biochem. Biophys. Res. Commun., 202,
1431—1437 (1994).
1H-NMR (300 MHz, CDCl3) d: 0.15—0.30 (2H, m), 0.50—0.70 (2H, m),
0.90—1.10 (1H, m), 1.43 (7H, s), 1.51 (2H, s), 1.30—1.60 (1H, m), 1.60—
1.80 (3H, m), 2.20—2.50 (3H, m), 2.50—2.80 (2H, m), 2.80—2.90 (1H, m),
3.00 (3H, s), 3.18 (1H, s), 3.50—3.65 (0.3H, m), 3.65—3.80 (0.7H, m), 4.71
(0.7H, d, Jꢀ7.5 Hz), 4.95—5.15 (1.3H, m), 6.40—6.60 (1.4H, m), 6.70
(0.6H, s), 7.00—7.10 (2H, m), 7.40 (1.4H, d, Jꢀ16.2 Hz), 7.47—7.57 (0.6H,
m), 7.60—7.65 (1H, m). IR (KBr) cmꢁ1: 3402, 1761, 1651, 1599, 1278,
1246, 1145. HR-ESI-MS m/z [MꢂH]ꢂ Calcd for C33H41N2O8: 593.2863.
Found: 593.2870. mp 169 °C.
(E )-N-[10a-Acetoxy-3-tert-butoxycarbonyloxy-17-(cyclopropyl-
methyl)-4,5a-epoxy-14b-hydroxymorphinan-6b-yl]-3-(furan-3-yl)-N-
methylprop-2-enamide (26) To a stirred solution of compound 25 (32.08
g, 54.12 mmol) in 500 ml of CH2Cl2 was added dropwise Et3N (70.0 ml,
502 mmol) followed by MsCl (12.60 ml, 162 mmol) at 0 °C, and the temper-
ature was gradually raised to room temperature. After stirring for 20 h, a sat-
urated aq. NaHCO3 solution was added to the solution, and the mixture was
4) Millan M. J., Trends Pharmacol. Sci., 11, 70—76 (1990).
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tsuura H., Tajima C., Endo T., Chem. Pharm. Bull., 46, 366—369
(1998).
7) Togashi Y., Umeuchi H., Okano K., Ando N., Yoshizawa Y., Honda T.,
Kawamura K., Endoh T., Utsumi J., Kamei J., Tanaka T., Nagase H.,
Eur. J. Pharmacol., 435, 259—264 (2002).
8) Umeuchi H., Togashi Y., Honda T., Nakao K., Okano K., Tanaka T.,
Nagase H., Eur. J. Pharmacol., 477, 29—35 (2003).
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92, 485—493 (2003).
10) Meredith W., Nemeth G. A., Boucher R., Carney R., Haas M., Sig-
vardson K., Teleha C. A., Tetrahedron Lett., 44, 7381—7384 (2003).
11) Proksa B., Pharmazie, 39, 687—688 (1984).
12) Michne W. F., Albertson N. F., J. Med. Chem., 15, 1278—1281 (1972).
extracted with CHCl3. The organic layer was washed with a saturated aq. 13) Archer S., Seyed-Mozaffari A., Ward S., Kosterlitz H. W., Paterson S.
NaCl solution, and dried over Na2SO4, and concentrated in vacuo to give
46.13 g of crude products. To a stirred solution of the crude products in
400 ml of CHCl3 was added a solution of NaOAc (16.75 g, 204.1 mmol) in
175 ml of acetic acid at room temperature. After stirring for 10.5 h, this solu-
tion was poured into 28% ammonia solution to basify and the mixture was
extracted with CHCl3. The organic layer was washed with a saturated aq.
J., McKnight A. T., Corbett A. D., J. Med. Chem., 28, 974—976
(1985).
14) Takayanagi I., Goromaru N., Koike K., Konno F., Mori T., Yoshida M.,
Kanematsu K., Gen. Pharmac., 21, 541—546 (1990).
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June 2004
669
16) Horikiri H., Kawamura K., Heterocycles, 63, 865—870 (2004).
17) Mitsunobu O., Synthesis, 1981, 1—28 (1981).
18) Sayre L. M., Portoghese P. S., J. Org. Chem., 45, 3366—3368 (1980).
19) Rapoport H., Masamune S., J. Am. Chem. Soc., 77, 4330—4335
(1955).
4.6 mm; YMC). The HPLC conditions were as follows: mobile phase,
50 mM NaH2PO4 aq. solution/CH3CNꢀ95/5 (V/V) (A) and 50 mM
NaH2PO4 aq. solution/CH3CNꢀ60/40 (V/V) (B); flow rate, 1.0
ml/min; column temperature, 40 °C. The gradient elution profile was 0
to 0% B for 0 to 10 min, 0 to 100% B for 10 to 75 min.
20) Greene T. W., Wuts P. G. M., “Protective Groups in Organic Synthe- 22) The crude products showed no signals for N-benzylic protons of com-
sis,” John Wiley & Sons Ltd., 1999, p. 281.
21) The samples were measured on a Shimadzu LC-10A series (UV at
280 nm) with an analytical column (YMC-Pack AM-303, 250ꢃ
pound 18 in 1H-NMR spectral analysis and molecular ion peak
(m/zꢀ371 [MꢂH]ꢂ) corresponding to the desired secondary amine in
LC-MS analysis.