Synthesis and characterization of thienorphine and its glucuronide conjugate

Article abstract of DOI:10.1081/SCC-200050367

Thienorphine (1) is a very potent oripavine derivative with mixed agonist and antagonist opioid receptor activities. It was prepared with 7α-acetyl-6,14-endoethenotetrahydrothebaine as stated material by Grignard reaction, cyanidation, demethylation, and N-alkylation. The structure of 1 · HCl was elucidated by X-ray analysis. As part of a continuing program to define the metabolism and distribution of thienorphine in animals and man, the putative metabolite, 3-glucuronide, was synthesized.

Full text of DOI:10.1081/SCC-200050367

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Synthesis and Characterization of
Thienorphine and Its Glucuronide Conjugate
Chun‐He Liu a , He Liu a , Xiang‐Yu Han a , Bo Wu a , Bo‐Hua Zhong a &
Ze‐Hui Gong a
a No. 7 Department , Beijing Institute of Pharmacology and Toxicology ,
Beijing, P. R. China
Published online: 20 Aug 2006.
To cite this article: Chun‐He Liu , He Liu , Xiang‐Yu Han , Bo Wu , Bo‐Hua Zhong & Ze‐Hui Gong (2005)
Synthesis and Characterization of Thienorphine and Its Glucuronide Conjugate, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:5, 701-710, DOI: 10.1081/
SCC-200050367
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Synthetic Communicationsw, 35: 701–710, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050367
Synthesis and Characterization of
Thienorphine and Its Glucuronide Conjugate
Chun-He Liu, He Liu, Xiang-Yu Han, Bo Wu,
Bo-Hua Zhong, and Ze-Hui Gong
No. 7 Department, Beijing Institute of Pharmacology and Toxicology,
Beijing, P. R. China
Abstract: Thienorphine (1) is a very potent oripavine derivative with mixed agonist
and antagonist opioid receptor activities. It was prepared with 7a-acetyl-6,14-
endoethenotetrahydrothebaine as stated material by Grignard reaction, cyanidation,
.
demethylation, and N-alkylation. The structure of 1 HCl was elucidated by X-ray
analysis. As part of a continuing program to define the metabolism and distribution
of thienorphine in animals and man, the putative metabolite, 3-glucuronide, was
synthesized.
Keywords: Thienorphine, X-ray analysis, glucuronide conjugate
Opioid analogues still remain important drugs for the relief of severe pain and
morphine is still the drug of choice in such situations.[1–4] One to the high
patient-to-patient variability in response to opioids, complete pain control is
only achieved by increasing the dose, which causes side effects like nausea,
respiratory depression, and mood disturbance. This is further complicated
by development of tolerance to the analgesic effect.[5] The abuse of cocaine
and other stimulant drugs is becoming a significant social and public health
concern in the world. For many years, the search for new centrally acting
opioid derivatives with pain-relieving properties and without undesired side
Received in Poland 15 October 2004
Address correspondence to He Liu, No. 7 Department, Beijing Institute of Pharma-
cology and Toxicology, Beijing 100850, P. R. China. E-mail: del@vijay.com

702
C.-H. Liu et al.
effects, such as addiction, obstipation, etc., has been the goal of a large number
of scientists. Consequently, a wide variety of modifications of the well-known
alkaloids morphine, codeine, and thebaine were described.[6–8]
We have engaged in the synthesis and biological activity study of
oripavine derivative for many years, as a result, N-cyclopropylmethyl-
7a-[1-(R)-1-hydroxy-1-methyl-3-(thien-2-yl)propyl]-6,14-endoethanotetra-
hydronororipavine (thienorphine 1), was found to be a very potent oripavine
derivative with mixed agonist and antagonist opioid receptors activities.
Compound 1 showed very good analgesic activity in the mouse using
the acetic acid writhing model, mouse heat radiant tail-flick assay, and
mouse heat plate test. The potent effect against morphine and heroin of thie-
norphine also was observed, and the effective duration was more 100 hours.
Thus, thienorphine is on preclinic study as an analgesic and abstention drug.
The metabolism of 1 was compared to that of the drugs containing the
hydroxy group,[9–12] glycoconjugate is one of the major metabolites. As
part of a continuing program to define the metabolism and distribution of 1
in animals and man, the putative metabolite, 3-glucuronide was required as
a metabolic standard. This paper both describes the efficient syntheses 3-
glucuronide of metabolite and presents a study of the scope of an inverse
addition technique applied to glucuronidation.
1 was prepared by a modified method as described in the literature.[13–16]
According to Scheme 1, 2 was coupled with Grignard reagent, 2-(thiophen-
2-yl)ethylmagnesium bromide, togive3. This Grignard reaction shows a remark-
ably high degree of stereoselectivity. The R isomer was the almost sole product,
whereas the S isomer was not afforded. A mixture of the intermediate 3 and
cyanogens bromide in dried CH2Cl2 was refluxed to obtain 4. 5 was obtained
by treating 4 with KOH in diethylene glycol at 205–2108C. 1 was prepared by
N-alkylation of 5. The structure of 1 was established by nuclear magnetic
resonance (NMR), mass (MS) spectroscopy, and elemental analysis.
The structure of thienorphine hydrochloride was confirmed by X-ray
.
crystal-structure analysis. The ORTEP view of 1 HCl with atom labeling is
shown in Fig. 1. It consists of a protonated thienorphine cation, one Cl2
anion, and one H2O molecule. The crystal structure of 1 reveals that it
maintains the “T” shape of the morphine structure and contains a C6–C14
enthano bridge.[17,18] The piperidine ring adopts a favored chair conformation
and the cyclopropylmethyl group is located at the equatorial position as
expected. The C7 substituent is a 1-hydroxyl-1-methyl- 3-(thienyl-2-)propyl
group adapting R-configuration.
The hydroxyl group O(4) is included by forming an intramolecular
hydrogen bond with methyl ether oxygen O(3), and the distance between
˚
O(4) and O(3) is 2.675 A with the H O separation 1.989 A, falling into
˚
. . .
[19]
. . .
the normal range of the O O separation for hydrogen bonding,
the
. . .
bond angle is 142.198. The intermolecular hydrogen bonds, O–H O,
. . . . . .
Cl H–O, and Cl H–N were formed by the O atoms of the water

Thienorphine and Its Glucuronide Conjugate
703
Scheme 1. i) 2-(thien-2-yl)ethylmagnesium bromide, anhydrous Et2O. ii) CNBr,
CH2Cl2. iii) KOH, diethylene glycol. iv) Cyclopropylmethyl bromide, NaHCO3, DMF.
molecule, hydroxyl group of aryl ring, protonated N atom of the piperidine
. . .
ring and the Cl2 anion. The O O, Cl N, and Cl O separations are in
. . .
. . .
˚
. . .
. . .
the range of 2.660ꢀ3.193 A with the H O and H Cl separations in the
˚
range of 1.857ꢀ2.372 A, the bond angles are 151.59ꢀ171.248.
Thienorphine-3-glucuronide 9 was synthesized by the additional of the
solid bromo sugar 8 to a concentrated solution of a slight excess of the
lithium salt of 1 in methanol at room temperature and hydrolysis with
lithium hydroxide (Scheme 2).[20–22]
EXPERIMENTAL
General
Solvents were purified by standard procedures. Melting points were deter-
1
mined using a RY-1 apparatus and are uncorrected. H NMR spectra were
recorded on Varian UNITY INOVA 600 MHz and JNM-ECA-400 400 MHz
instrument in the solvent indicated later. Chemical shift values are reported
in parts per million (ppm) relative to that for tetramethylsilane used as an

704
C.-H. Liu et al.
Figure 1. Crystal structure of N-cyclopropylmethyl-7a-[(R)-1-hydroxyl-1-methyl-
3-(thieny-2-)propyl])-6,14-endoethano-6,7,8,9-trahydronororipavine 1.
internal reference standard. Spectral splitting patterns are designated as
follows: s, singlet; br, broad; d, doublet; t, triplet; m, multiplet. Mass
spectra were obtained using API3000 instruments. Elemental analysis was
carried at the CarloErba-1106. Optical rotations were measured on a
Scheme 2. i) NaOH/CH3OH; Ac2O/Pyridine. ii) 30% HBr in AcOH. iii)
.
LiOH H2O/CH3OH.

Thienorphine and Its Glucuronide Conjugate
705
PE-243B instrument. Single-crystal X-ray diffraction measurement was
carried out on a Bruker Smart 1000 CCD diffractometer.
All reactions were monitored by thin layer chromatography (TLC) on
25 ꢀ 75 mm glass sheets precoated with silica gel (GF254) to a thickness of
0.25 mm and viewed at 254 nm UV-light.
7a-[(R)-1-Hydroxy-1-methyl–3-(thien-2-yl)propyl]-6,14-
endoethanotetrahydro- thebaine (3)
To the Grignard reagent prepared from magnesium shavings (7.2 g, 0.3 mol)
and 2-(2-bromoethyl)thiophene (19.1 g, 0.1 mol) in absolute ether (300 mL)
a
solution of 7a-acetyl-6,14-endo-ethenotetrahydrothebaine 2 (19.2 g,
0.05 mol) in absolute benzene (100 mL) and absolute ether (100 mL) was
added dropwise over a period of 1 h. Then the solution was stirred under
gentle reflux for 3 h, allowed to cool to room temperature, and the saturated
aqueous ammonium chloride solution (500 mL) was added. The mixture
was extracted with ether (3 ꢀ 150 mL), the combined organic phase was
washed with brine, dried (Na2SO4), and evaporated to obtain a crude
product. The crude product was purified by crystallization from methanol to
1
give colorless crystal 3 (18.6 g). Yield: 75%. M.p. 183–1858C. H-NMR
(DMSO-d6) (d): 7.29(1H, d, J ¼ 5.0 Hz, ArH), 6.93(1H, m, ArH), 6.85(1H,
m, ArH), 6.73(1H, d, J ¼ 8.2 Hz, ArH), 6.55(1H, d, J ¼ 8.2 Hz, ArH),
4.61(1H, s, OH), 4.39(1H, s, 5b-H), 3.77(3H, s, Ar-OCH3), 3.41(3H, s,
6-OCH3), 2.82–2.94(4H, m), 2.58–2.76(2H, m), 2.10–2.27(4H, m), 1.80–
2.05(4H, m), 1.66–1.76(2H, m, CH2), 1.45–1.55(2H, m, CH2), 1.30(3H, s,
20-CH3), 1.18–1.24(1H, m, CH), 1.07(1H, m, CH), 0.58(1H, m). ESI-MS:
496.1(M þ 1). [a]2D0 ¼ 279.0 (c ¼ 0.50, CH2Cl2). Anal. calc. For
C29H37NO4S (495.68): C 70.30, H 7.47; found: C 70.18, H 7.56.
N-Cyano-7a-[1-(R)-1-hydroxy-1-methyl–3-(thien-2-yl)propyl]-6,14-
endoethano tetrahydronorthebaine (4)
A solution of cyanogens bromide (12.2 g, 0.11 mol) and 3 (13.6 g, 0.027 mol) in
dry methylene chloride (108 mL) was stirred under reflux for 5 h. The solution
was evaporated to dryness. The residue was purified by re-crystallization from
ethanol to give colorless crystal 4 (12.7 g). Yield: 91%. M.p. 171–1738C. ESI-
MS: 507.0(M þ 1). Anal. calc. For C29H34N2O4S (506.66): C 68.77, H 6.72;
found: C 68.81, H 6.72.
7a-[1-(R)-1-Hydroxy-1-methyl–3-(thien-2-yl)propyl]-6,14-
endoethanoetrahydro-nororipavine (5)
A mixture of 4 (12 g, 0.024 mol) and potassium hydroxide (30 g, 0.54 mol) in
diethylene glycol (150 g) was vigorously stirred at 205–2108C under nitrogen

706
C.-H. Liu et al.
gas for 2 h. The mixture was then poured into stirred water (500 mL) contain-
ing crushed ice, adjusted pH to 8–9 with the saturated aqueous ammonium
chloride solution. The precipitated solid was collected and recrystallized
from methanol to give colorless crystal 5 (8.7 g). Yield: 91%. M.p. 268–
2708C. ESI-MS: 468.2(M þ 1). Anal. calc. For C27H33NO4S (467.62): C
69.38, H 7.07; found: C 69.30, H 6.87.
N-Cyclopropylmethyl-7a-[1-(R)-1-hydroxy-1-methyl–3-(thien-2-
yl)propyl]-6,14-endoethanoetrahydronororipavine (1)
A mixture of 5 (7.0g, 0.015 mol), cyclopropylmethyl bromide (4.1g, 0.030 mol),
and dried sodium bicarbonate (4.0g, 0.048 mol) in N,N-dimethylformamide
(200mL) was vigorously stirred at 70–808C under nitrogen gas for 16h. The
mixture was filtered. The filtrate was evaporated to dryness. The residue was
dissolved with CH2Cl2, dried (Na2SO4) and evaporated to obtain a crude
product. The crude product was purified by chromatography on silica gel
column, eluting with a CH2Cl2/MeOH mixture (20:1) to give white solid, then
crystallized from methanol to give colorless crystal 1 (3.8g). Yield: 48%. M.p.
1
170–1728C. IR (KBr): 3406, 3224, 2989, 2926, 1634, and 1609. H-NMR
(CHCl3-d) (d): 8.98(1H, s, Ar-OH), 7.29(1H, d, J ¼ 5.0 Hz, ArH), 6.93(1H, m,
ArH), 6.85(1H, m, ArH), 6.73(1H, d, J ¼ 7.9 Hz, ArH), 6.55(1H, d,
J ¼ 7.9 Hz, ArH), 4.61(1H, s, OH), 4.39(1H, s, 5b-H), 3.41(3H, s, 6-OCH3),
2.85–2.98(4H, m), 2.58–2.76(2H, m), 2.10–2.27(4H, m), 1.80–2.05(4H, m),
1.66–1.76(2H, m, CH2), 1.45–1.55(2H, m, CH2), 1.30(3H, s, 20-CH3), 1.18–
1.24(1H, m, CH), 1.07(1H, m, CH), 0.75(1H, m, Cprop-CH), 0.58(1H, m),
0.44(2H, m, Cprop-CH2), 0.08(2H, m, Cprop-CH2). 13C-NMR (CHCl3-d) (d):
3.48, 3.97, 9.39, 17.7, 23.2, 23.9, 29.8, 31.6, 35.6, 35.9, 43.5, 43.6, 45.7, 47.2,
52.8, 58.3, 59.8, 75.8 (C16, C19), 80.5, 97.4, 116.5, 117.4, 119.5, 122.7,
123.9, 126.7, 128.1, 132.2, 145.5, 146.0. ESI-MS: 522.1(M þ 1).
[a]2D0 ¼ 281.2 (c ¼ 0.50, CH3OH). Anal. calc. For C31H39NO4S (521.64): C
71.37, H 7.53, N 2.68, S 6.15; found: C 71.17, H 7.63, N, 2.46, S 6.01.
.
Hydrochloride 1 HCl:
M.p.
255–2578C.
Anal.
calc.
For
.
C31H39NO4S HCl(558.18): C 66.71, H 7.22, N 2.51; found: C 66.59, H
7.43, N, 2.46.
Methyl (Tri-O-acetyl-a-D-glucopyranosyl bromide)uronate (8)
The compound was prepared by treating D-glucurono-3,6-lactone 6 with a
methanolic solution of sodium hydroxide and acetylation of the resulting
crude product mixture with acetic anhydride and perchloric acid as
described previously. The b anomer 7 was crystallized from 2-propsnol.
M.p. 154–1588C. ESI-MS: 377.0(M þ 1).

Thienorphine and Its Glucuronide Conjugate
707
A solution of 7 (1.5 g, 4 mmol) in 27% hydrobromic acid in acetic acid
(20 mL) was stirred at room temperature for 12 h. The solution allowed to
stand in the refrigerator overnight. The mixture was evaporated to dryness.
The residue was dissolved with chloroform, washed with cold saturated
aqueous sodium bicarbonate and water. After drying the chloroform solution,
the solvent was removed under reduced pressure. The residual syrup was recrys-
1
tallized from ethanol to give yellow crystal 8. Yield: 65%. M.p. 74–768C. H-
NMR (DMSO-d6) (d): 6.94(1H, d, J ¼ 4Hz). 5.42(1H, t, J ¼ 9.4 Hz), 5.28(1H,
t, J ¼ 9.4 Hz), 5.14(1H, dd, J ¼ 4Hz, J ¼ 9.2 Hz), 4.47(1H, d, J ¼ 9.4 Hz),
3.67(3H, s, OCH3), 2.05(3H, s, CH3), 2.02(6H, s, 2CH3). ESI-MS: 397.0(M þ 1).
Thienorphine-3-glucuronide (9)
A solid of 8 (1g, 2.5 mmol) was added into a solution of 1 (1.5g, 2.9 mmol) and
.
LiOH H2O (0.12 g, 2.8 mmol) in MeOH (15 mL). After the addition, the mixture
.
was allowed to stand at room temperature for 2 h. Then a solution of LiOH H2O
(0.36g, 8.4 mmol) was added with stirring for 2 h. The mixture was evaporated to
dryness. The residue was dissolved with CH2Cl2, purified by chromatography on
silica gel column, eluting with a CH2Cl2/MeOH mixture (4 : 1) to give yellow
solid: 9 (720mg, 41%). M.p. 268–2408C. 1H NMR (DMSO-d6) (d): 7.29(1H,
d, J ¼ 5.0 Hz, ArH), 6.93(1H, m, ArH), 6.83–6.88(2H, m, ArH), 6.53(1H, d,
J ¼ 8.1 Hz, ArH), 5.22(1H, br, OH), 5.04(1H, br, OH), 4.93(1H, d, J ¼
6.5 Hz, CH), 4.65(1H, s, OH), 4.39(1H, s, 5b-H), 3.43(3H, s, 6-OCH3),
3.20(3H, m, 3CH), 2.89–2.97(4H, m), 2.73(1H, t, J ¼ 8.9 Hz), 2.60(1H, d,
J ¼ 7 Hz), 2.20–2.27(4H, m), 1.80–2.01(5H, m), 1.70–1.75(2H, m, CH2), 1.54
(2H, d, J ¼ 10Hz, CH2), 1.30(3H, s, 20-CH3), 1.19–1.23(1H, m, CH), 1.07(1H,
m, CH), 0.75(1H, m, Cprop-CH), 0.58(1H, m), 0.44(2H, m, Cprop-CH2),
0.08(2H, m, Cprop-CH2). 13C NMR (CHCl3-d) (d): 3.44, 3.65, 9.29, 18.2,
22.4, 23.4, 24.3, 29.1, 30.8, 35.1, 35.3, 43.0, 43.1, 44.5, 45.8, 52.1, 58.0, 59.0,
71.9, 73.3, 74.7(C16, C19), 76.5, 79.4, 95.4, 101.5, 118.2, 118.9, 123.1, 124.0,
126.8, 130.1, 132.7, 138.6, 145.7, 147.0, 172.9. ESI-MS: 698.4(M þ 1), 522.1.
[a]2D0 ¼ 242.0 (c ¼ 0.5, CH3OH).
.
X-ray Crystal-Structure Analysis of 1 HCl
Crystals suitable for X-ray structure determination were obtained from the
filtrate by slow evaporation of the solvent. The determination of unit cell par-
ameters and data collections was performed with Mo Ka radiation
˚
(l ¼ 0.71073 A) and unit cell dimensions were obtained with least-
squares refinements. The structure was solved by direct methods with
SHELXL-97 program[23] and all data were corrected by using semi-empirical
absorption corrections (SADABS) method. All the other nonhydrogen atoms
were located in successive difference Fourier syntheses. The final refinement
was carried out by full matrix least-squares methods with anisotropic thermal
parameters for nonhydrogen atoms on F2. The hydrogen atoms were added

708
C.-H. Liu et al.
Table 1. Crystallographic data and structure refinement summary for 1
Empirical formula
Molecular weight
Measured temperature
Crystal size (mm3)
Crystal system
C31H42NO5S
576.17
293(2) K
0.47 ꢀ 0.42 ꢀ 0.10
Orthorhombic
P212121
Space group
Unit cell dimensions
˚
a ¼ 10.4168(4) A
˚
b ¼ 13.1207(7) A
˚
c ¼ 21.1964(9) A
3
Volume V (A )
˚
2897.0(2)
4
1.321
Z
Dcalcd (g cm23
)
m (mm21
F (000)
)
0.245
1232
u range (8)
Completeness to u
2.50–27.488
99.5%
h/k/l
213/13, 216/17, 227/27
6594
373
Reflection unique
Parameters refined
Final R indices [I ꢁ 2s(I)]
R1 ¼ 0.0297,
wR2 ¼ 0.0463
0.00
Absolute structure parameter
Goodness of fit
Residual electron densities (e A
0.00033(11)
0.276 and 20.254
23
)
˚
theoretically, and riding on the concerned atoms and refined with fixed thermal
factors. Further details of the structure analyses are given in Table 1.
Crystallographic data for the structure reported in this paper have been
deposited with the Cambridge Crystallographic Data Center as supplementary
publications (CCDC No. 212448). Copies of available materials can be
obtained free of charge on application to the Director, CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: þ44 int. code (þ44)(1223) 336-033;
e-mail: deposit@ccdc.cam.ac.uk).
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