Selective synthesis of both isomers of morphine 6-β-D-glucuronide and their analogs

Article abstract of DOI:10.1016/S0040-4020(00)01080-2

A stereoselective synthesis of both isomers of the pharmaceutically important morphine 6-β-D-glucuronide (M6G) and its analogs was developed. The method is based on the use of ZnBr₂ for the key coupling reaction. It was shown that the α/β stere

Full text of DOI:10.1016/S0040-4020(00)01080-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1083±1092
Selective synthesis of both isomers of morphine 6-b-d-glucuronide
and their analogs
Igor Rukhman, Lev Yudovich, Gennadiy Nisnevich and Arie L. Gutmanp
Department of Chemistry, Technion-Israel Institute of Technology, Haifa 32000, Israel
Received 21 July 2000; revised 23 October 2000; accepted 9 November 2000
AbstractÐA stereoselective synthesis of both isomers of the pharmaceutically important morphine 6-b-d-glucuronide (M6G) and its
analogs was developed. The method is based on the use of ZnBr2 for the key coupling reaction. It was shown that the a/b stereoselectivity
of the reaction can be directed and controlled by the amount of ZnBr2. This paper describes the synthesis, analysis and characterization of the
a-isomer of M6G, useful as a reference marker for testing purity and stability of the morphine 6-b-d-glucuronide (M6G). q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
morphine 6-b-d-glucuronide (M6G) and morphine 3,6-b-
d-diglucuronide (M3,6-diG) (Fig. 1).
Morphine and other opioid analogs1 are used as powerful
analgesics. It has been shown1 that the major pathway for
detoxi®cation of morphine and analogs in the human body is
conjugation with d-glucuronic acid in the liver to produce
several glucuronides: morphine 3-b-d-glucuronide (M3G),
It has been demonstrated,2,3 that much of the analgesic effect
is due not to morphine itself but rather to one of its main
metabolites, morphine 6-b-d-glucuronide. Furthermore, is
has been shown that morphine's other main metabolite,
Figure 1.
Keywords: alkaloids; a/b stereocontrol; glycosidation; orthoesters.
Corresponding author. Fax 1972-4-834-3341; e-mail: chgutman@tx.technion.ac.il
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01080-2

1084
I. Rukhman et al. / Tetrahedron 57 (2001) 1083±1092
Scheme 1.
M3G, antagonizes the analgesic effect of morphine.
This potential pharmaceutical importance of M6G as a
powerful analgesic and replacement to morphine
prompted several researchers to explore ways for its
selective synthesis.
publications7a,16 the presence of the a-isomer was noticed
after glycosylation. However, this a-isomer was never
isolated and characterized.11
In the present paper we report a high-yielding and stereo-
selective synthesis that enables us at will to obtain either
morphine 6-b-d-glucuronide 6 (M6G) or morphine 6-a-d-
glucuronide 7 (M6aG).
All literature-reported methods 4,5,6,7a,b,8,16 of M6G
preparation are highly b stereoselective, but in several
Ê
Table 1. The a/b selectivity (reaction conditions: CH2Cl2, re¯ux 48±72 h, MS 4 A)
Glucuronate ester, 1a±c
3-O-protected morphine, 2a±d
ZnBr2, equiv.
Ratio, a/bb
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2c
2d
2d
0.7
0.8
0.9
1.0
1.1
1.2
1.5
1.7
2.0
2.5
1.0
1.4
1.0
2.0
1.0
1:7a
1:7a
1:5a
1:2a
1:1.5a
2:1a
4:1a
6:1a
8:1a
~8:1a
1:8
1:5
1:6
5:95
1:99
1b
1b
1b
1b
1b
1b
2a
2b
2b
2c
2c
2c
1.0
1.0
1.5
0.8
1.0
1.5
1:2.5
1:9
1:6
1:18
1:7
1:4
1c
1c
1c
2a
2c
2c
1.0
1.0
0.8
1:3
1:10
1:25
a Ratio was determined by 1H NMR spectroscopy.
b Ratio was determined by HPLC.

I. Rukhman et al. / Tetrahedron 57 (2001) 1083±1092
1085
Scheme 2.
2. Results and discussion
two baseline-separated peaks. Thus, the developed HPLC
method permitted the detection of trace amounts of M6aG
in the pharmaceutical grade M6G.
For tentative experiments methyl 2,3,4-tri-O-acetyl-d-
glucopyranosyluronate bromide (1a) and 3-O-acetyl-
morphine (2a) were prepared by known protocols15 and
coupling was tested under various reaction conditions and
with different catalysts.9,10 It was found that with ZnBr2
glycosylation proceeded to completion with minimal
In a previous publication12 we also reported a detailed
1H NMR spectroscopic investigation of M6aG that
has been conducted in order to ascertain the chemical
identity and anomeric con®guration of the glycosidic link-
age. All signals were fully assigned on the basis of two-
dimensional COSY spectra and by comparison with
spectra of reference compounds obtained under identical
conditions.
9
undesired products. Interestingly, use of MgBr2 instead of
ZnBr2 under similar reaction conditions led to formation of
orthoester 5a (40% isolated yield) without any traces of the
glycosides 3a or 4a. Based on these initial results, future
investigation concentrated around ZnBr2 as catalyst
(Scheme 1).
In our synthetic study, we also investigated the dependence
of stereoselectivity on different protecting groups on
morphine as well as on the glucopyranosyl bromide. For
morphine protecting groups, it was found that the use of
methoxycarbonyl17 2b as protecting group afforded best
selectivity in the acetyl 2a, benzoyl 2c, and methoxycarbo-
nyl series (see Table 1). For glucopyranosyl bromide
protecting groups the best results were obtained with the
benzoyl protecting group15 1b. However, changes in
protecting groups on the sugar moiety did not result in a
signi®cant improvement in the a/b stereoselectivity (Table
1). Interestingly, very high stereoselectivity and good yield
(85%) were observed with codeine (Table 1), even when
excess of ZnBr2 was used.
It was found, that the stereochemical outcome of glycosyl-
ation was strongly in¯uenced by the amount of ZnBr2: thus,
use of two and more equivalents of ZnBr2 in the reaction
between 3-O-acetylmorphine 2a and glucopyranosyl bro-
mide 1a afforded a mixture of isomers with an a/b ratio
of 8:1, while use of 0.8 equiv. of ZnBr2 in this reaction led to
the opposite ratio of isomers, a/bˆ1:8. As can be seen in
Table 1, the dependency of stereoselectivity of glycosyl-
ation on the amount of ZnBr2 was observed in all cases
for various acyl-protecting groups both on morphine and
glucopyranosyl bromide.
In the present work the chemical and physical properties of
M6aG were studied and a signi®cant difference in the solu-
bility between the two isomers was detected. Thus, M6aG
was poorly soluble in cold water and only slightly soluble in
warm water. Therefore, when a mixture of isomers 4a/3a
(a/b ratio 8:1) was hydrolyzed and cooled, only pure
M6aG 7 crystallized from the aqueous solution (Scheme
2). M6aG and M6G were analyzed by HPLC and under
conditions described in our previous paper12 it appeared as
Based on results described above, we speculated that two
different pathways take place in this reaction13a: (1) a cata-
lytic amount of ZnBr2 initially forms the dioxolanylium
cation13a that may be stereoselectively opened to the 1,2-
trans-product13b 3a±i and/or may form the orthoester13b
5a±d, which may then transform into desired b-isomer
3a±i after addition of a catalytic amount of ZnBr2;13f,g (2)
the presence of excess of ZnBr2 (Br2 source) together with
Table 2. The in¯uence of the solvent on the orthoester's formation and the stereoselectivity
Glucuronate ester, 1a±c
3-O-protected morphine, 2a±d
ZnBr2, equiv.
Solvent
Ratio
1a
1a
1a
2a
2a
2a
1.7
1.7
1.0
CH2Cl2/EtOAc
CH3CN
CH2Cl2/EtOAc
4a(a)/3a(b)ˆ1:2a
4a(a)/3a(b)ˆ1:1a,b
4a(a)/3a(b)ˆ1:4a,b
1a
1a
1a
2b
2b
2b
1.0
1.0
1.0
CHCl3
CHCl3/EtOAc
THF
4d(a)/3d(b)ˆ1:8b
5b(ortho)/3d(b)ˆ2:1a,b
5b(ortho) onlya,b
1a
2c
1.0
CH2Cl2/EtOAc
5c(ortho)/3f(b)ˆ1:1a,b
a Ratio was determined by 1H NMR spectroscopy.
b Ratio was determined by HPLC.

1086
I. Rukhman et al. / Tetrahedron 57 (2001) 1083±1092
Table 3. The optimized glycosidation procedure (ZnBr2: 0.6 equiv. then 0.3 equiv.)
Glucuronate ester, 1a±c
3-O-protected morphines, 2a±d
Solvent
Ratioa,b
Yieldc
1a
1a
1b
2a
2a
2a
CH2Cl2
CHCl3
CHCl3
only b
only b
only b
80%
82%
76%
1a
1b
2b
2b
CHCl3
CHCl3
only b
only b
85%
75%
1a
1b
2c
2c
CHCl3
CHCl3
only b
only b
72%
74%
a Ratio was determined by 1H NMR spectroscopy.
b Ratio was determined by HPLC.
c Isolated yield.
3-O-protected morphine (amino function) may result in the
formation of the highly reactive b-glucopyranosyl bromide
(in situ anomerization)13d,e that reacts much faster than
a-glucopyranosyl bromide to give a-isomer 4a±i via
ionic intermediates.13c This assumption would explain
well the a-isomer/b-isomer/orthoester selectivity in the
glycosylation.
of 1,2-orthoester 5a±d and that a further amount of ZnBr2
transfers it to the desired b-isomer. To check this, we
carried out the following experiments: coupling between
3-O-methoxycarbonyl morphine (2b) and glucopyranosyl
bromide 1a was performed in chloroform gradually increas-
ing the amount of ZnBr2. It was found that after addition of
0.6 equiv. of ZnBr2 the main reaction product was the
orthoester 5b. Addition of another 0.3 equiv. of ZnBr2 at
this stage, cleanly transferred all orthoester into the desired
b-isomer 3d without traces of a-isomer. Using this pro-
cedure, we prepared other derivatives (Table 3) with differ-
ent protecting groups on morphine and glucopyranosyl
bromide. In all cases very high stereoselectivity (.99%
b-isomer by HPLC) was obtained.
To examine this proposition, solvents like THF or ethyl
acetate, which complex with ZnBr2 were added to the reac-
tion mixture. In the case of 3-O-(methoxycarbonyl)mor-
phine (2b), addition of ethyl acetate led to the partial
formation of 1,2-orthoester 5b with a ®nal 5b/3d ratio of
2:1 without detectable traces of the a-isomer 4d. Use of
THF as reaction solvent led only to formation of orthoester
5b in 87% yield. This product was isolated and character-
ized. For 3-O-benzoyl morphine (2c), addition of ethyl
acetate afforded a 1:1 5c/3f ratio without the presence of
a-isomer 4f (see Scheme 1 and Table 2). For 3-O-acetyl-
morphine (2a) we could not detect the presence of ortho-
ester 5a in the reaction mixture because no separation
between the orthoester 5a and the b-isomer 3a was obtained
by HPLC or other analytical methods, except NMR spectro-
scopy. However, the orthoesters 5a and 5d were prepared by
another procedure (see Experimental part).
We adopted the above procedure also for the preparation of
the protected dihydromorphine 6-b-d-glucuronide (dihy-
droM6G) 9 by reaction between 3-O-(methoxycarbonyl)-
dihydromorphine (8) and 1a (Scheme 3). The desired b-
isomer 9 was isolated in 75% yield.
After alkaline hydrolysis of 3a±h by a modi®cation of a
published procedure7 followed by crystallization, pure
M6G 6 (or in the case of 9, the dihydroM6G 10) was
obtained in good yields. The structures of M6G and
dihydroM6G were con®rmed by NMR and IR measure-
ments, which showed that the spectroscopic data were
consistent with the literature.4±6,14
These results indicated that according to the ®rst reaction
path some minimal amount of ZnBr2 is needed for formation
Scheme 3.

I. Rukhman et al. / Tetrahedron 57 (2001) 1083±1092
Table 4. Physical data of the compounds 3a±i, 5a±d and 9
1087
Producta,e,f
[a]D (c 1, CHCl3)c
Melting pointb (8C)
MS (CI) (m/z) (M111)
3ad
3b
3c
3d
3e
3f
3g
3h
3ig
9
2131.6
284.6
2112.0
2138.9
2108.8
225.6
2114.4
284.2
2132.5
2122.2
296.3
178±179
115±116
188±189
176±177
184±185
201±202
144±147
158±163
115±116
158±159
99±100
645
831
729
660
745
706
791
893
617
662
645
660
706
617
5a
5b
5c
5d
2105.3
234.3
297.4
99±100
103±104
86±88
a All compounds appeared as white to light yellow solids.
b Melting points are uncorrected.
c Recorded at 208C.
d Lit.4b (C32H37O13N£1/2H2O) ‰aŠ 2140 (c 0.5, CHCl3), mp 186±1888C.
26
D
e Satisfactory microanalyses obtained: C ^0.39; H ^0.30; N ^0.23.
f Characteristic IR data were obtained for all compounds: FT-IR (KBr) 2900, 1630±1780, 1450 cm21
.
g Lit.4b (C32H37O13N£2H2O) ‰aŠ 2140 (c 0.5, CHCl3), mp 112±1148C.
26
D
In conclusion, a stereoselective synthesis of both isomers of
M6G was developed. The method is based on use of ZnBr2
and the selectivity of this reaction may be controlled by
amount of ZnBr2 added. The process provided both high
stereoselectivity and good yields. The synthesis avoids
expensive reagents, cleanly produces the desired products
avoiding tedious puri®cation and can be easily scaled up for
M6G preparation in pharmaceutically suf®cient quantities
without losses in stereoselectivity. Synthesis and analysis of
a-M6G makes it possible to verify its content in the phar-
maceutical grade M6G.
3.1. 3-O-Methoxycarbonyl morphine 2b and
dihydromorphine 8: typical procedure
To the solution of pre-dried dihydromorphine (2.88 g,
10 mmol) in water (60 mL) and MeOH (5 mL) the solution
of NaHCO3 (4.20 g, 50 mmol) in water (42 mL) was added
in one portion. The resulting suspension was stirred for 1 h
at ambient temperature and then cooled to 08C. A solution of
methyl chloroformate (1.89 g, 20 mmol) in CH2Cl2 (20 mL)
was added during 30 min and after complete dissolution of
precipitate, the two-phase mixture was heated to room
temperature and stirred for an additional 1 h. Then the layers
were separated and the aqueous layer was washed with
CH2Cl2 (2£30 mL). The combined organics were re-
extracted twice with a solution of citric acid (8.00 g) in
water (100 mL). The aqueous phase was washed with
CH2Cl2, then basi®ed with solid NaHCO3 to pH9 and
extracted with CH2Cl2 (2£50 mL). The organic phase was
washed with water and brine, dried over anhydrous Na2SO4,
®ltered and the solvent was evaporated in vacuo, affording
the title compound 8 (3.42 g, quantitative yield) as a white
powder. FT-IR (Nujol) nmax cm21 3520, 2930, 1750, 1452;
1H NMR (CDCl3) d 6.79, 6.62 (2d, 2H, Jˆ8.4 Hz, Harom),
4.57 (d, 1H, Jˆ5.1 Hz), 4.11 (m, 1H), 3.88 (s, 3H, C-3
OCO2Me), 3.48 (m, 1H), 3.08 (m, 1H), 2.99 (d, 1H,
Jˆ18.7 Hz), 2.51 (dd, 1H, Jˆ4.4, 12.1 Hz), 2.38 (m, 1H),
2.37 (s, 3H, NMe), 2.18 (m, 2H), 1.81 (m, 2H), 1.63 (dd, 1H,
Jˆ3.1, 10.2 Hz), 1.38 (m, 1H), 1.25 (m, 2H); 13C NMR
(CDCl3) d 152.8, 133.6, 131.9, 130.2, 128.4, 92.2, 66.6,
59.7, 56.6, 46.9, 42.8, 42.5, 40.0, 36.6, 28.2, 20.5, 18.2;
MS (CI): m/z 346 (M111); Anal. calcd for C19H23NO5
(345.39): C 66.07; H 6.71; N 4.06. Found: C 66.02; H
6.62; N 4.05.
3. Experimental
CH2Cl2 and CHCl3 were distilled over CaH2 and stored over
Ê
4 A molecular sieves. Anhydrous Et2O from Bio-Lab Ltd.
(Jerusalem, Israel) was used without additional puri®cation.
All 3-O-protected morphines were crystallized and vacuum
dried overnight at 408C. Silica gel 60 (Merck, 230±400
mesh) was used for column chromatography. Silica gel 60
F254 plates (Merck) were used for TLC. All NMR spectra
were recorded on a Bruker AM-400 spectrometer. Melting
points were determined in open capillary tubes with
Electrothermal IA 9300 Digital melting point apparatus.
Chemical-ionization (CI) mass spectrometry was performed
with a Varian Matt-71. Elemental analyses were performed
by the Microanalytical Laboratory of the Institute of
Chemistry (The Hebrew University, Jerusalem). HPLC
was carried out on a Merck±Hitashi Lachrom Series 7000
apparatus with 284 nm UV detector. HPLC analyses were
performed at 258C and a ¯ow rate of 1 mL min21 on the
column LiChrospher 100 RP-18 by using the following
system: A: 0.1% aq. solution of sodium heptanesulfonate
(1000 mL), adjusted to pH5.5 with HOAc (2 mL) and
25% aq. NH3 (2.4 mL): B: MeOH. Gradient: 0 min, 90%
A, 10% B; 5 min, 90% A, 10% B; 10 min, 50% A. 50% B;
15 min, 50% A, 50% B; 25 min, 10% A, 90% B; 45 min,
10% A, 90% B. Optical rotations were measured at 589 nm
with a JACSO DIP-370 polarimeter.
3.1.1. 3-O-(Methoxycarbonyl)morphine (2b). Compound
2b (a white solid) was prepared as described above from
morphine hydrochloride trihydrate in quantitative yield.
 Ã
20
D
a
2193.0 (c 1, CHCl3), mp 118±1198C (dec.) [Lit.17
116±1208C (dec.)]; FT-IR (Nujol) nmax cm21 3500, 2900,
1750, 1448; 1H NMR (CDCl3) d 6.84, 6.62 (2d, 2H,

1088
I. Rukhman et al. / Tetrahedron 57 (2001) 1083±1092
Table 5. 1H NMR data for compounds 3a±i and 9
Product 1H NMR (CDCl3), d, J (Hz)
H-10 (J1 ,2
)
H-20 (J1 ,2 , J2 ,3
)
H-50 (J4 ,5
)
0
H-6 m Others
0
0
0
0
0
0
0
3a
3b
4.88 d (7.2) 5.07 dd (7.2, 7.7) 4.09 d (8.8) 4.28
6.69, 6.52 (2d, 2H, Jˆ8.0, Harom), 5.65 (d, 1H, Jˆ9.5, 8-H), 5.25 (m, 3H, 30-H, 40-H,
7-H), 4.86 (d, 1H, Jˆ6.5), 3.72 (s, 3H, CO2Me), 3.33 (m, 1H), 3.02 (d, 1H, Jˆ18.9),
2.61 (m, 1H), 2.56 (m, 1H), 2.40 (s, 3H, NMe), 2.29±2.39 (m, 2H), 2.28 (s, 3H, C-3
Ac), 2.08 (s, 3H, Ac), 2.03 (s, 6H, 2 Ac), 1.93±2.03 (m, 1H), 1.90 (m, 1H)
7.97, 7.91, 7.87 (3d, 6H, Jˆ7.7, 3 COPh), 7.27±7.52 (m, 9H, 3 COPh), 6.64, 6.50
(2d, 2H, Jˆ8.1, Harom), 5.82 (m, 2H, 30-H, 40-H), 5.72 (d, 1H, Jˆ10.0, 8-H), 5.31 (d,
1H, Jˆ10.0, 7-H), 5.28 (d, 1H, Jˆ5.8), 3.63 (s, 3H, CO2Me), 3.36 (m, 1H), 3.03 (d,
1H, Jˆ18.8), 2.69 (br s, 1H), 2.57 (m, 1H), 2.42 (s, 3H, NMe), 2.28±2.43 (m, 2H),
2.10 (s, 3H, C-3 Ac), 2.02 (m, 1H), 1.87 (m, 1H)
4.96 d (6.4) 5.57 dd (6.4, 6.2) 4.46 d (8.1) 4.49
3c
4.91 d (7.6) 5.10 dd (7.6, 8.0) 4.10 d (9.2) 4.28
4.91 d (7.7) 5.04 dd (7.7, 8.5) 4.08 d (9.5) 4.33
6.68, 6.50 (2d, 2H, Jˆ8.0, Harom), 5.63 (d, 1H, Jˆ10.0, 8-H), 5.28 (m, 3H, 30-H,
40-H, 7-H), 4.87 (d, 1H, Jˆ5.6), 3.69 (s, 3H, CO2Me), 3.32 (m, 1H), 3.02 (d, 1H,
Jˆ18.8), 2.42±2.60 (m, 5H), 2.41 (s, 3H, NMe), 2.27±2.40 (m, 2H), 2.26 (s, 3H,
C-3 Ac), 2.01 (m, 1H), 1.88 (m, 1H), 1.05±1.13 (m, 18H, 3 i-PrCO)
6.77, 6.52 (2d, 2H, Jˆ8.2 Hz, Harom), 5.64 (d, 1H, Jˆ9.7 Hz, 8-H), 5.22±5.29 (m,
3H, 30-H, 40-H, 7-H), 4.93 (d, 1H, Jˆ5.8 Hz), 3.87 (s, 3H, C-3 OCO2CH3), 3.72 (s,
3H, CO2CH3), 3.33 (m, 1H), 3.03 (d, 1H, Jˆ19.7 Hz), 2.62 (s, 1H), 2.56 (m, 1H),
2.40 (s, 3H, NCH3), 2.20±2.38 (m, 2H), 2.10 (s, 3H, Ac), 2.01±2.10 (m, 1H), 2.01
(s, 6H, 2 Ac), 1.89 (d, 1H, Jˆ9.7 Hz)
3d
3e
3f
4.92 d (7.2) 5.11 dd (7.2, 7.5) 4.10 d (9.3) 4.27
4.87 d (7.1) 4.97 dd (7.1, 7.5) 4.02 d (8.7) 4.30
4.95 d (7.5) 5.01 dd (7.5, 8.1) 4.05 d (9.3) 4.31
6.69, 6.51 (2d, 2H, Jˆ7.6 Hz, Harom), 5.64 (d, 1H, Jˆ9.5 Hz, 8-H), 5.27 (m, 3H,
30-H, 40-H, 7-H), 4.87 (d, 1H, Jˆ6.3 Hz), 3.80 (s, 3H, C-3 OCO2CH3), 3.70 (s, 3H,
CO2CH3), 3.32 (m, 1H), 3.02 (d, 1H, Jˆ18.8 Hz), 2.45±2.61 (m, 5H), 2.44 (s, 3H,
NCH3), 2.29±2.43 (m, 2H), 2.26 (m, 1H), 1.99 (m, 1H), 1.87 (d, 1H), 1.04±1.16 (m,
18H, 3£COi-Pr)
8.17 (d, 2H, Jˆ7.6, C-3 Bz), 7.58 (t, 1H, Jˆ7.6, C-3 Bz), 7.48 (t, 2H, Jˆ7.6, C-3
Bz), 6.83, 6.57 (2d, 2H, Jˆ8.5, Harom), 5.72, 5.33 (2d, 2H, Jˆ9.8, 8-H, 7-H), 5.19
(m, 2H, 30-H, 40-H), 4.92 (d, 1H, Jˆ5.7), 3.70 (s, 3H, CO2Me), 3.36 (m, 1H), 3.06
(d, 1H, Jˆ18.9), 2.64 (br s, 1H), 2.60 (m, 1H), 2.42 (s 3H, NMe), 2.30±2.43 (m,
1H), 1.99 (m, 1H), 1.97 (s, 3H, Ac), 1.95 (s, 6H, 2 Ac), 1.87 (d, 1H)
8.17 (d, 2H, Jˆ7.6, C-3 Bz), 7.58 (t, 1H, Jˆ7.1, C-3 Bz), 7.48 (td, 2H, Jˆ7.6, 7.1,
C-3 Bz), 6.84, 6.56 (2d, 2H, Jˆ8.2, Harom), 5.67 (d, 1H, Jˆ9.1, 8-H), 5.25 (m, 3H,
30-H, 40-H, 7-H), 4.92 (d, 1H, Jˆ5.5), 3.68 (s, 3H, CO2Me), 3.34 (m, 1H), 3.06 (d,
1H, Jˆ18.8), 2.63 (br s, 1H), 2.56 (m, 1H), 2.26±2.53 (m, 7H), 2.20 (m, 1H), 2.02
(m, 1H), 1.93 (d, 1H, Jˆ10.8), 1.00±1.07 (m, 12H, 2 i-PrCO), 0.84, 0.80 (2d, 6H,
Jˆ6.7 Hz, i-PrCO)
3g
3h
3I
9
5.00 d (6.2) 5.44 dd (6.2, 6.0) 4.37 d (8.0) 4.49
4.96 d (7.5) 5.07 dd (7.5, 8.8) 4.09 d (9.5) 4.35
4.82 d (7.1) 4.77 dd (7.1, 8.0) 4.04 d (9.3) 4.00
8.10 (d, 2H, Jˆ7.7), 7.86 (d, 4H, Jˆ7.7), 7.75 (d, 2H, Jˆ7.7), 7.19±7.51 (m, 12H),
6.81, 6.56 (2d, 2H, Jˆ8.5, Harom), 5.77 (m, 3H, 30-H, 40-H, 8-H), 5.35 (d, 1H,
Jˆ10.0, 7-H), 5.31 (d, 1H, Jˆ6.0), 3.57 (s, 3H, CO2Me), 3.36 (m, 1H), 3.06 (d, 1H,
Jˆ18.8), 2.68 (br s, 1H), 2.56 (dd, 1H, Jˆ12.0, 3.9), 2.42 (s, 3H, NMe), 2.30±2.41
(m, 2H), 2.02 (td, 1H, Jˆ12.0, 4.6), 1.91 (m, 1H)
6.60, 6.48 (d, 1H, Jˆ8.0, Harom), 5.65 (d, 1H, Jˆ9.9, 8-H), 5.30 (m, 2H, 30-H, 7-H),
5.23 (dd, 1H, Jˆ9.5, 8.8, 40-H), 4.90 (d, 1H, Jˆ5.9), 3.75 (s, 3H, C-3 OMe), 3.73 (s,
3H, CO2Me), 3.31 (q, 1H, Jˆ5.9, 3.1), 3.00 (d, 1H, Jˆ18.8), 2.61 (br s, 1H), 2.53
(dd, 1H), 2.41 (s, 3H, NMe), 2.38 (td, 3H), 2.26 (dd, 1H), 2.13 (s, 6H, 2 Ac), 2.02
(m, 1H), 2.00 (s, 3H, Ac), 1.85 (d, 1H, Jˆ12.3), 1.74 (m, 1H)
6.83, 6.60 (2d, 2H, Jˆ8.0, Harom), 5.17 (m, 2H, 30-H, 40-H), 4.66 (d, 1H, Jˆ4.2),
3.84 (s, 3H, C-3 OCO2Me), 3.70 (s, 3H, CO2Me), 3.07 (m, 1H), 2.95 (d, 1H,
Jˆ18.8), 2.49 (dd, 1H, Jˆ12.2, 4.4), 2.37 (m, 1H), 2.35 (s, 3H, NMe), 2.19 (m, 2H),
2.05 (s, 3H, Ac), 1.97 (s, 3H, Ac), 1.95 (s, 3H, Ac), 1.88 (td, 1H), 1.70 (d, 1H,
Jˆ11.7), 1.55 (m, 1H), 1.44 (m, 2H), 1.24 (m, 1H), 0.95 (m, 1H)
Jˆ8.2 Hz, Harom), 5.78, 5.24 (2d, 2H, Jˆ10.0 Hz, 8-H, 7-H),
4.98 (d, 1H, Jˆ6.4 Hz), 4.18 (m, 1H), 3.90 (s, 3H, C-3
OCO2Me), 3.62 (m, 1H), 3.03 (d, 1H, Jˆ18.9 Hz), 2.66
(m, 1H), 2.55 (dd, 1H, Jˆ11.6, 3.8 Hz), 2.40 (s, 3H,
NMe), 2.34 (m, 2H), 2.12 (m, 2H), 1.90 (m, 1H); 13C
NMR (CDCl3) d 153.5, 144.2, 134.0, 133.0, 132.5, 132.3,
127.7, 92.4, 65.8, 58.8, 55.6, 46.3, 42.9, 42.6, 40.3, 35.1,
20.7; MS (CI): m/z 344 (M111); Anal. calcd for C19H21NO5
(343.37): C 66.46; H 6.16; N 4.08. Found: C 66.82; H 6.52;
N 3.87.
(TLC monitoring). More CH2Cl2 (80 mL) was added and
the suspension was ®ltered through Celite and stirred for
20 min with saturated aqueous solution of NaHCO3
(80 mL). The aqueous phase was separated, washed with
CH2Cl2, the organics were combined, washed with water,
dried over anhydrous Na2SO4, ®ltered and evaporated. The
residue (9.10 g) was passed through a short silica gel
column (CH2Cl2/MeOH, 97:3) to give 6.20 g of the crude
product as slight yellow solid (mixture of a and b isomers
in ratio of 8:1, respectively). The mixture was dissolved in
50 mL of MeOH, 5% aqueous solution of NaOH (35 mL)
was added dropwise and the resulting slight yellow solution
was stirred overnight at room temperature. Then the mixture
3.1.2. Morphine 6-a-d-glucuronide (7). A suspension of
the vacuum pre-dried 3-O-acetylmorphine (2a) (3.27 g,
10 mmol), 1a (5.95 g, 15 mmol) and molecular sieves 4A
(9.00 g) in dry CH2Cl2 (70 mL) was stirred for 30 min at
room temperature. Then ZnBr2 (25 mmol) was added and
the resulting suspension was re¯uxed for 48 h with stirring
Ê
was acidi®ed to pH5 with acetic acid, cooled to 08C and
diluted with EtOH (150 mL). The milky suspension was
stirred for 4 h at 08C, ®ltered and the white powder was
washed with EtOH, recrystallized from hot water and

I. Rukhman et al. / Tetrahedron 57 (2001) 1083±1092
Table 6. 13C NMR data for compounds 3a±i and 9
1089
Product
13C NMR (400 MHz, CDCl3), d
C-10
C-5
Others
3a
3b
118.9
118.9
99.0
98.1
169.9, 169.1, 168.5, 167.2, 149.9, 132.2, 131.5, 131.3, 130.1, 128.7, 121.7, 89.3, 73.2,
72.6, 71.9, 71.1, 69.2, 58.6, 52.7, 46.2, 43.4, 42.9, 40.9, 35.6, 20.8, 20.5, 20.4, 20.3
168.6, 167.8, 165.4, 165.0, 164.8, 151.2, 133.2, 133.05, 133.0, 131.9,131.6, 131.0, 130.3,
129.7, 129.6, 129.4, 128.9, 128.6, 128.2, 128.1, 121.8, 89.4, 72.6, 72.4, 71.7, 71.6, 69.2,
58.7, 58.6, 46.2, 43.4, 42.8, 40.8, 23.3, 20.9, 20.3
3c
3d
3e
3f
118.9
119.0
118.9
119.3
119.0
119.0
98.9
98.0
98.8
97.8
98.4
98.1
175.8, 175.1, 175.0, 168.6, 167.3, 150.0, 132.2, 131.4, 130.2, 128.7, 121.6, 89.6, 73.0,
72.7, 71.5, 70.8, 69.0, 58.6, 52.6, 46.1, 43.6, 43.0, 41.0, 35.6, 33.7, 20.8, 20.6, 18.8, 18.75,
18.7, 18.6
169.8, 169.5, 169.3, 154.5, 150.3, 132.6, 132.1, 131.7, 130.0, 128.7, 121.4, 89.1, 89.0,
72.7, 72.6, 72.2, 72.1, 71.9, 71.0, 69.4, 58.6, 58.5, 55.4, 53.1, 46.1, 43.6, 42.9, 41.0, 40.9,
35.6, 20.8, 20.5, 20.4
175.8, 175.1, 175.0, 168.6, 167.3, 150.0, 132.2, 131.1, 130.2, 128.7, 121.6, 89.6, 73.0,
72.7, 71.5, 70.8, 69.0, 58.5, 52.6, 46.1, 43.6, 42.9, 41.0, 35.6, 33.7, 20.8, 20.6, 18.9, 18.8,
18.7, 18.6
170.0, 169.8, 169.4, 168.3, 164.3, 150.6, 133.0, 132.5, 131.7, 131.6, 130.4, 129.7, 129.4,
128.4, 122.4, 92.0, 77.6, 70.8, 69.5, 69.4, 68.3, 58.6, 52.4, 46.1, 43.9, 43.0, 41.4, 35.7,
21.0, 20.6, 20.5, 20.0.
175.8, 175.2, 175.1, 170.2, 167.3, 152.3, 133.4, 132.4, 131.3, 130.4, 130.3, 129.4, 128.9,
128.5, 121.9, 89.7, 71.5, 70.8, 69.3, 58.6, 52.7, 46.2, 44.0, 43.1, 41.2, 35.8, 33.8, 33.6,
21.0, 18.8, 18.5
167.8, 165.3, 165.0, 164.3, 164.0, 150.2, 133.2, 133.1, 132.8, 132.2, 131.7, 131.6, 130.4,
130.2, 129.75, 129.7, 129.6, 129.2, 129.16, 128.9,128.85, 128.2, 128.1, 128.0, 121.9, 90.1,
72.9, 72.4, 71.6, 71.4, 69.2, 58.7, 52.6, 46.2, 43.8, 43.0, 41.1, 35.5, 20.9
172.1, 170.0, 169.4, 167.4, 149.2, 147.4, 142.1, 130.6, 130.2, 128.8, 127.1, 113.4, 88.1,
72.8, 72.1, 71.9, 71.3, 69.6, 58.9, 56.3, 52.9, 46.5, 43.5, 43.1, 41.1, 36.0, 20.6, 20.5.
169.9, 169.3, 169.2, 167.4, 154.8, 149.4, 132.6, 131.8, 129.8, 121.9, 88.7, 73.5, 72.4, 72.2,
71.4, 69.3, 59.5, 55.5, 52.7, 46.1, 43.0, 42.9, 38.0, 37.2, 29.6, 23.2, 20.6, 20.4, 19.8.
3g
3h
3I
9
118.9
118.9
98.0
98.6
dried under reduced pressure at 1008C to give the title
compound 7 as a white solid (2.80 g, 63% yield). Melting
point of approx. 3108C (dec.), a 286.9 (c 1, DMSO);
Na2SO4, ®ltered and evaporated. The residue (25.5 g) was
chromatographed on a short silica gel column (CH2Cl2/
MeOH, 40:1) to give 19.7 g of the crude product that was
recrystallized from EtOH to afford the desired b isomer 3g
as a light yellow solid (14.2 g, 70%) (Tables 4±6).
 Ã
20
D
FT-IR (KBr) cm21 1600 (COO2), 2400±2800
1
(Z(H)N1Me); H NMR (D2O) d 6.58, 6.50 (2d, 2H, Jˆ
8.1 Hz, Harom), 5.67 (d, 1H, Jˆ9.5 Hz, 8-H), 5.27 (d, 1H,
Jˆ9.5 Hz, 7-H), 5.01 (d, 1H, Jˆ5.7 Hz), 4.93 (d, 1H, Jˆ
2.8 Hz, 10-H), 4.21 (m, 1H), 4.15 (d, 1H, Jˆ9.5 Hz, 50-H),
4.00 (m, 1H), 3.63 (t, 1H, Jˆ9.5 Hz, 30-H), 3.45 (dd, 1H,
Jˆ2.8, 9.5 Hz, 20-H), 3.36 (t, 1H, Jˆ9.5 Hz, 40-H), 3.09 (m,
2H), 2.95 (m, 1H), 2.79 (s, 3H, NMe), 2.77 (m, 2H), 2.17
(m, 1H), 1.96 (d, 1H, Jˆ14.3 Hz); 13C NMR (D2O) d 175.4,
148.4, 140.9,129.8, 127.5, 126.0, 123.1, 119.8, 117.3, 98.4,
90.0, 73.1, 72.5, 72.4, 71.5, 70.7, 59.5, 46.7, 42.3, 40.3,
38.2, 32.8, 20.5; FAB-MS: Calcd for C23H27NO9 m/z
461.1762. Found: [M1] 461.1773, (M111) 462.1749.
Anal. calcd for C23H27NO9£H2O (479.48): C 57.61; H
6.10; N 2.92. Found: C 57.79; H 6.32; N 2.73.
3.2.1. Methyl [30,40-di-O-acetyl-10,20-O-(3-O-acetylmor-
phine-6a-yl)ethylidene-d-gluco-pyranosid]uronate (5a)
and methyl [30,40-di-O-acetyl-10,20-O-(codeine-6a-yl)
ethylidene-d-glucopyranosid]uronate (5d). A solution of
2a or 2b (1.00 g, 3.1 mmol), 1a (1.93 g, 4.6 mmol) and
tetrabutylammonium bromide (0.52 g, 1.5 mmol) in dry
collidine (6 mL) was stirred overnight under nitrogen at
558C. After this time, collidine (<5.5 mL) was removed
under reduced pressure and the residue was dissolved in
CH2Cl2 (25 mL), washed successively with saturated
aqueous solution of NaHCO3, water and brine and dried
over anhydrous Na2SO4. After removing CH2Cl2 in vacuo
the residue was chromatographed on a silica gel column to
give the title compound 5a as a white powder (1.4 g, 71%)
or the title compound 5d as a light yellow solid (1.5 g, 76%)
(Tables 7 and 8).
3.2. Glycosylation of 3-O-protected morphines. Typical
procedure: 3-O-Benzoyl-6-O-(methyl 20,30,40-tri-O-
benzoyl-b-d-glucopyranosyluronate)morphine (3g)
3.2.2. Methyl [30,40-di-O-acetyl-10,20-O-(3-O-(methoxy-
carbonyl)morphine-6a-yl)ethylidene-d-glucopyranosid]-
uronate (5b). A suspension of the vacuum pre-dried 3-O-
(methoxycarbonyl)morphine 2b (3.00 g, 8.8 mmol), 1a
A
suspension of 3-O-benzoylmorphine 2c (10.0 g,
Ê
25.7 mmol), 1c (16.1 g, 33.5 mmol) and 4 A molecular
sieves (25 g) in dry CH2Cl2 (150 mL) was stirred for
30 min at room temperature. Then ZnBr2 (5.8 g,
25.7 mmol) was added and the resulting suspension was
re¯uxed for 60 h with stirring (TLC monitoring). After
disappearance of the starting material, re¯ux was stopped
and more CH2Cl2 (200 mL) was added. The suspension was
®ltered through Celite and stirred for 20 min with 150 mL of
saturated aqueous solution of NaHCO3. The aqueous phase
was separated, washed once with CH2Cl2, the organics were
combined, washed with water, dried over anhydrous
Ê
(5.20 g, 13.1 mmol) and 4 A molecular sieves (8.00 g) in
dry THF (60 mL) was stirred for 30 min at room tempera-
ture. Then ZnBr2 (1.97 g, 8.8 mmol) was added and the
resulting suspension was re¯uxed for 3 h with stirring
(TLC monitoring). CH2Cl2 (100 mL) was added and the
suspension was ®ltered through Celite and stirred for
20 min with saturated aqueous solution of NaHCO3
(60 mL). The aqueous phase was separated, washed once

1090
I. Rukhman et al. / Tetrahedron 57 (2001) 1083±1092
Table 7. 1H NMR data for compounds 5a±d
Product
1H NMR (CDCl3), d, J (Hz)
H-10 (J1 ,2
)
H-20 (J1 ,2 , J2 ,3
)
H-30 (J2 ,3 , J3 ,4
)
H-40 (J3 ,4 , J4 ,5
)
H-50 (J4 ,5
)
0
H-6 m
4.10
Others
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
5a
5.89 d (4.8)
5.88 d (5.0)
5.33 d (3.5)
4.50 dd (4.8, 3.9)
4.51 dd (5.0, 3.0)
4.80 dd (3.5, 5.3)
5.23 t (3.9)
5.13 dd (3.9, 8.3)
5.13 dd (3.5, 7.8)
5.02 dd (6.0, 8.2)
4.26 d (8.3)
4.26 d (7.8)
4.77 d (8.2)
6.70, 6.50 (2d, 2H, Jˆ8.0, Harom),
5.58 (d, 1H, Jˆ9.6, 8-H), 5.29 (d,
1H, Jˆ9.6, 7-H), 4.82 (d, 1H,
Jˆ5.9), 3.74 (s, 3H, CO2Me),
3.33 (m, 1H), 3.02 (d, 1H,
Jˆ18.8), 2.62 (br s, 1H), 2.55
(dd, 1H), 2.40 (s, 3H, NMe),
2.37±2.24 (m, 2H), 2.17 (s, 3H,
C-3, Ac), 2.09, 2.08 (2 s, 6H, 2
Ac), 2.02 (m, 1H), 1.88 (d, 1H,
Jˆ11.0), 1.77 (s, 3H, ortho Me).
6.77, 6.50 (2d, 2H, Jˆ8.0, Harom),
5.58 (d, 1H, Jˆ9.0, 8-H), 5.28 (d,
1H, Jˆ9.0, 7-H), 4.84 (d, 1H,
Jˆ5.5), 3.84 (s, 3H, C-3
5b
5.23 dd (3.0, 3.5)
4.10
OCO2Me), 3.74 (s, 3H, CO2Me),
3.35 (m, 1H), 3.02 (d, 1H,
Jˆ18.8), 2.63 (m, 1H), 2.57 (dd,
1H), 2.40 (s, 3H, NMe), 2.32 (m,
2H), 2.11, 2.10 (2s, 6H, 2 Ac),
2.04 (m, 1H), 1.90 (d, 1H,
Jˆ11.0), 1.75 (s, 3H, ortho Me).
8.22 (d, 2H, Jˆ7.7, C-3 Bz), 7.55
(t, 1H, Jˆ7.7, C-3 Bz), 7.46 (t,
2H, Jˆ7.7, C-3 Bz), 6.80, 6.57
(2d, 2H, Jˆ8.1, Harom), 5.69 (d,
1H, Jˆ10.0, 8-H), 5.31 (d, 1H,
Jˆ10.0, 7-H), 4.96 (d, 1H,
5c
5.54 dd (5.3, 6.0)
4.01
Jˆ5.6), 3.50 (s, 3H, CO2Me),
3.35 (m, 1H), 3.06 (d, 1H,
Jˆ18.9), 2.60 (m, 1H), 2.54 (dd,
1H), 2.41 (s, 3H, NMe), 2.34 (m,
2H), 1.99, 1.98 (2s, 6H, 2 Ac),
1.96 (m, 2H), 1.49 (s, 3H, ortho-
Me).
5d
5.92 d (4.7)
4.52 dd (4.7, 3.3)
5.24 dd (3.3, 3.6)
5.13 dd (3.6, 7.9)
4.27 d (7.9)
4.12
6.59, 6.48 (2d, 2H, Jˆ8.2, Harom),
5.61 (d, 1H, Jˆ9.7, 8-H), 5.29 (d,
1H, Jˆ9.6, 7-H), 4.78 (d, 1H,
Jˆ6.0), 3.80 (s, 3H, C-3 OMe),
3.78 (s, 3H, CO2Me), 3.42 (m,
1H), 3.00 (d, 1H, Jˆ18.6), 2.75
(m, 1H), 2.65 (dd, 1H), 2.45 (s,
3H, NMe), 2.33 (m, 2H), 2.09 (s,
6H, 2 Ac), 2.05 (m, 1H), 1.87 (d,
1H, Jˆ12.3), 1.77 (s, 3H, ortho-
Me).
Table 8. 13C NMR data for compounds 5a±d
Product
13C NMR (400 MHz, CDCl3), d
C-10
Ortho (C-70)
Others
5a
5b
5c
5d
119.0
118.9
119.0
119.2
122.3
169.2, 168.8, 168.7, 168.3, 149.9, 132.2, 131.6, 131.5, 130.7, 129.4, 121.6, 96.4, 91.9, 91.8,
72.9, 68.9, 68.8, 68.3,, 58.7, 52.7, 46.2, 43.6, 43.0, 41.0, 35.5, 21.6, 20.9, 20.7, 20.6
169.1, 168.8, 168.6, 153.4, 149.7, 132.4, 131.7, 130.7, 129.1, 121.2, 96.3, 92.0, 72.7, 68.8,
68.7, 68.6, 68.3, 58.6, 55.3, 52.6, 46.1, 43.5, 42.9, 40.9, 35.4, 21.5, 20.8, 20.6.
169.2, 168.8, 168.7, 168.6, 148.9, 134.0, 133.7, 133.6, 132.4, 130.4, 129.7, 128.4, 122.4, 96.4,
92.5, 69.4, 69.3, 68.3, 68.2, 58.8, 52.5, 46.1, 43.3, 43.0, 41.0, 35.4, 21.7, 20.9, 20.8, 20.5.
168.8, 168.7, 168.4, 167.6, 149.7, 148.3, 132.5, 131.3, 129.4, 127.2, 115.8, 97.3, 92.1, 69.5,
69.4, 68.7, 67.0, 58.6, 56.7, 52.9, 46.4, 43.0, 42.9, 41.5, 36.0, 20.9, 20.8.
122.2
121.7
121.9
with CH2Cl2, the organics were combined, washed with
water, dried over anhydrous Na2SO4, ®ltered and evapo-
rated. The residue (8.00 g) was passed through a short silica
gel column (CH2Cl2/MeOH, 35:1) to give the title
compound 5b (5.00 g, 70%) as a pure white solid by
HPLC and NMR (Tables 4, 7 and 8).
3.2.3. Methyl [30,40-di-O-acetyl-10,20-O-(3-O-benzoyl-
morphine-6a-yl)ethylidene-d-glucopyranosid]uronate
(5c). A suspension of 3-O-benzoylmorphine 2c (1.00 g,
2.57 mmol), 1a (1.35 g, 3.41 mmol) and 4 A molecular
sieves (2.20 g) in dry CH2Cl2 (20 mL) was stirred for
30 min at room temperature, then a solution of ZnBr2
Ê

I. Rukhman et al. / Tetrahedron 57 (2001) 1083±1092
1091
(0.58 g, 2.58 mmol) in EtOAc (2.1 ml) was added dropwise
and the resulting suspension was re¯uxed for 60 h with
stirring (TLC monitoring). More CH2Cl2 (20 mL) was
added, the suspension was ®ltered through Celite and stirred
for 20 min with saturated aqueous solution of NaHCO3
(20 mL). The aqueous phase was separated, washed with
CH2Cl2, the organics were combined, washed with water,
dried over anhydrous Na2SO4, ®ltered and evaporated. The
residue (2.20 g) was chromatographed on a short silica gel
column (CH2Cl2/MeOH, 40:1) to give 1.70 g of the crude
product (1:1 mixture of orthoester 5c and b-isomer 3c by 1H
NMR). The mixture was crystallized from EtOH to give the
pure orthoester 5c (0.68 g, 37.5%) as a white solid (Tables
4, 7 and 8).
8.6 Hz, 20-H), 2.86 (m, 2H), 2.74 (s, 3H, NMe), 2.30 (m,
1H), 2.04 (td, 1H), 1.75 (br d, 1H, Jˆ12.9 Hz), 1.39±1.51
(m, 2H), 1.29 (m, 1H), 0.84 (m, 1H); 13C NMR (DMSO-d6)
d 172.7, 146.0, 138.3, 128.7, 123.6, 118.7, 117.1, 102.1,
86.5, 76.0, 74.8, 74.3, 73.6, 71.8, 59.2, 45.6, 41.7, 41.1,
35.1, 30.6, 22.8, 20.4,19.4; HRMS: Calcd for C23H29NO9
m/z 463.1815. Found: [M1] 463.1813; [M111] 464.1834.
Anal. calcd for C23H29NO9£H2O (481.49): C 57.37; H 6.49;
N 2.91. Found: C 57.30; H 6.65; N 2.58.
3.2.6. Morphine 6-b-d-glucuronide (6). Compound 6 (a
white solid) was prepared as described above from 3a±h in
73±87% yield. a 2198 (c 0.5, H2O), mp 239±2408C
 Ã
20
D
 Ã
20
D
(dec.) [Lit.4a,b for C23H27O9N£2H2O a 2172 (c 0.5,
H2O), mp 254±2568C (dec.)]; HRMS: Calcd for
C23H27NO9 m/z 461.1762. Found: [M1] 461.1763;
[M111] 462.1749. Anal. calcd for C23H27NO9£0.2
EtOH£2H2O (506.70): C 55.47; H 6.40; N 2.77. Found: C
55.81; H 6.40; N 2.75.
3.2.4. Optimized procedure of glycosylation: 3-O-(meth-
oxycarbonyl)-6-O-(methyl 20,30,40-tri-O-acetyl-b-d-gluco-
pyranosyluronate)morphine (3d). A suspension of the 3-O-
(methoxycarbonyl)morphine (2b) (30.0 g, 87.5 mmol), 1a
Ê
(52.0 g, 131.2 mmol) and molecular sieves 4 A (60 g) in
3.2.7. Codeine 6-b-d-glucuronide (12). Compound 12 (a
white solid) was prepared as described above from 3i in
84% yield. a 2224 (c 1, H2O), mp 274±2758C (dec.)
dry CHCl3 (500 mL) was stirred for 30 min at room tempera-
ture, ZnBr2 (11.8 g, 52.5 mmol) was added and the resulting
suspension was re¯uxed for 24 h with stirring and TLC moni-
toring. Then the second portion of ZnBr2 (5.9 g, 26.3 mmol)
was added, and the resulting slightly red-yellow suspension
was re¯uxed for an additional 48 h. CHCl3 was added
(400 mL), the suspension was ®ltered through Celite and
stirred for 20 min with saturated aqueous solution of
NaHCO3 (600 mL). The aqueous phase was separated,
washed with CHCl3, the organics were combined, washed
with water, dried over anhydrous Na2SO4, ®ltered and evapo-
rated. The residue (81 g) was dissolved in EtOAc (700 mL)
and extracted with 1% aqueous HCl (5£300 mL). The
combined aqueous solution was washed twice with EtOAc
and basi®ed up to pH9 with solid NaHCO3 (added in small
portions!). The resulting suspension was extracted with
CH2Cl2 (2£500ml), combined organics were washed with
water and brine and dried over anhydrous Na2SO4. Filtration
and evaporation of solvent afforded 53.0 g of 3d (only b-
isomer by HPLC). After crystallization from EtOH, the title
compound 3d was obtained as white crystals (48.5 g, 85%
yield) (Tables 4±6).
 Ã
20
D
 Ã
20
[Lit.4a,b for C24H29O9N£1/2H2O a 2216 (c 0.5, H2O),
D
mp 276±2788C (dec.)]; FT-IR (KBr) cm21 1600 (COO2),
1
2400±2800 (Z(H)N1Me), 3600; H NMR (D2O) d 6.62,
6.48 (2d, 2H, Jˆ8.2 Hz), 5.50 (d, 1H, Jˆ9.5 Hz, 8-H),
5.22 (d, 1H, Jˆ9.5 Hz, 7-H), 4.95 (d, 1H, Jˆ5.9 Hz), 4.48
(d, 1H, Jˆ7.7 Hz, 10-H), 4.30 (q, 1H, Jˆ2.7, 5.9 Hz), 3.60
(s, 3H, C-3 OMe), 3.50 (d, 1H, Jˆ8.8 Hz, 50-H), 3.32 (m,
2H, 30-H, 40-H), 3.25 (m, 1H), 3.17 (t, 1H, Jˆ7.7 Hz, 20-H),
2.89 (d, 1H, Jˆ19.2 Hz), 2.46 (m, 1H), 2.39 (dd, 1H), 2.15±
2.23 (m, 2H), 2.15 (s, 3H, NMe), 1.87 (td, 1H, Jˆ4.9,
13.1 Hz), 1.65 (d, 1H, Jˆ13.1 Hz); 13C NMR (D2O) d
175.1, 148.9, 140.8, 130.4, 129.3, 129.0, 127.7, 119.3,
113.0, 101.1, 89.2, 75.6, 74.9, 73.0, 72.6, 71.2, 57.3, 56.0,
48.6, 46.0, 45.0, 42.4, 41.0, 37.0, 33.6, 19.8; HRMS: Calcd
for C24H29NO9 m/z 475.1812. Found: [M1] 475.1823;
[M111] 476.1799. Anal. calcd for C24H29NO9£1/2H2O
(484.50): C 59.49; H 6.24; N 2.90. Found: C 59.67; H
6.11; N 3.01.
Acknowledgements
3.2.5. Hydrolysis. Modi®ed procedure: dihydromor-
phine 6-b-d-glucuronide (10). 6.6 g of 9 was dissolved
in MeOH (80 mL) and 5% aqueous solution of NaOH
(15 mL) was added dropwise at room temperature. The
resulted solution was stirred overnight, ®ltered, acidi®ed
with acetic acid to pH5.0, cooled to 08C and the crude
product was precipitated after addition of EtOH (100 mL)
and acetone (400 mL). The precipitate was ®ltered off,
washed twice with EtOH and crystallized from mixture
EtOH/water 5:3. The white solid was ®ltered, washed
twice with a mixture EtOH/water 1:1 and dried for 4 h
We wish to thank Dr Terry Smith of CeNeS Pharma-
ceuticals for useful discussions.
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 Ã
20
D
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