Preparation of benzoate esters of morphine and its derivatives

Article abstract of DOI:10.1007/s00706-012-0803-8

Sustained analgesia is crucial for patients suffering from long-acting pain. Ester derivatives of morphine could enhance the lipophilicity of morphine; consequently its transdermal delivery as well as its duration of action are also increased. Therefore, twenty-one 3-O-, 6-O-, and 14-Obenzoate esters of morphine and their derivatives were synthesized in order to elaborate different synthetic methods suitable for esterification of these widely used compounds. Schotten-Baumann reaction was applied with sodium hydrogen carbonate, triethylamine, or pyridine in methylene chloride or 1,2-dichloroethane as solvents. The presence of 4-dimethylaminopyridine catalyst was also successfully utilized mainly in the case of tertiary alcohols. A novel synthesis of dihydromorphine via diacetyl morphine free of by-products is also presented. Structures of all synthesized compounds were elucidated by ¹H nuclear magnetic resonance (NMR), ¹³CNMR, high-resolution mass spectrometry (HRMS), and electron ionizationmass spectrometry (EI-MS). The log D (pH 7.4) values of the synthesized compounds were determined by a reversed-phase high-performance liquid chromatography (HPLC)-MS-based method, and calculated hydrolysis rate constants are also provided. The synthesized benzoate esters are potential prodrugs of the parent morphine with enhanced lipophilicity, derivatives which can also be used in transdermal drug delivery as prospective long-acting narcotic analgesics.

Full text of DOI:10.1007/s00706-012-0803-8

Monatsh Chem (2012) 143:1431–1440
DOI 10.1007/s00706-012-0803-8
ORIGINAL PAPER
Preparation of benzoate esters of morphine and its derivatives
•
Szabolcs Beni Gergo Toth Bela Noszal
•
•
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Sandor Hosztafi
}
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Received: 23 February 2012 / Accepted: 25 May 2012 / Published online: 26 June 2012
Ó Springer-Verlag 2012
Abstract Sustained analgesia is crucial for patients suf-
fering from long-acting pain. Ester derivatives of morphine
could enhance the lipophilicity of morphine; consequently
its transdermal delivery as well as its duration of action are
also increased. Therefore, twenty-one 3-O-, 6-O-, and 14-O-
benzoate esters of morphine and their derivatives were
synthesized in order to elaborate different synthetic methods
suitable for esterification of these widely used compounds.
Schotten–Baumann reaction was applied with sodium
hydrogen carbonate, triethylamine, or pyridine in methylene
chloride or 1,2-dichloroethane as solvents. The presence of
4-dimethylaminopyridine catalyst was also successfully
utilized mainly in the case of tertiary alcohols. A novel
synthesis of dihydromorphine via diacetyl morphine free of
by-products is also presented. Structures of all synthesized
Introduction
Esterification of pharmacologically active molecules
often leads to prodrugs or more effective derivatives due
to the higher lipophilicity and the better blood–brain
barrier penetration ability of the resulting esters [1].
Morphine and the hydrochloride salt of its 3,6-di-O-
acetyl derivative (heroin) are both effective analgesics,
but also produce undesirable effects such as respiratory
depression, tolerance, and dependence. Although heroin
generally is more potent than morphine when adminis-
tered in vivo, previous clinical studies have found no
advantages of heroin over morphine [2, 3]. Heroin is
enzymatically deacetylated to 6-O-acetylmorphine and
subsequently to morphine by blood esterases in various
tissues of humans, rats, rabbits, and mice [4]. Since both
6-O-acetylmorphine and morphine are pharmacologically
active, the pharmacological effects after heroin adminis-
tration necessarily reflect the combined effects of heroin
and both of its active metabolites. Diacetylmorphine is
assumed to cross the blood–brain barrier rapidly due to
its lipophilicity, resulting in an almost instant effect.
Similar observation was reported in the case of 3,6-di-O-
propionylmorphine. Following subcutaneous administra-
tion of the dipropionyl ester by rat tail-flick method, it
was shown that the 6-O-propionyl derivative is the active
principle responsible for the antinociceptive activity of
3,6-di-O-propionylmorphine [5]. Owen et al. [6] studied
the analgesic activities of various morphine diesters and
found that the esters with increasing alkyl chains dis-
played prolonged duration of action. It is noteworthy that
morphine 3,6-diesters undergo rapid hydrolysis in aque-
ous solution to 6-monoester and the aqueous stability of
these diesters decreases with increasing length of the
alkyl chain.
1
compounds were elucidated by H nuclear magnetic reso-
nance (NMR), 13C NMR, high-resolution mass spectrometry
(HRMS), and electron ionization mass spectrometry (EI-MS).
The log D (pH 7.4) values of the synthesized compounds
were determined by a reversed-phase high-performance
liquid chromatography (HPLC)–MS-based method, and
calculated hydrolysis rate constants are also provided. The
synthesized benzoate esters are potential prodrugs of the
parent morphine with enhanced lipophilicity, derivatives
which can also be used in transdermal drug delivery as
prospective long-acting narcotic analgesics.
Keywords Alkaloids ꢀ Dihydromorphine ꢀ Catalysts ꢀ
NMR spectroscopy ꢀ Lipophilic prodrug
´
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S. Beni (&) ꢀ G. Toth ꢀ B. Noszal ꢀ S. Hosztafi
Department of Pharmaceutical Chemistry,
Semmelweis University, Budapest, Hungary
e-mail: beniszabi@gmail.com; beniszabi@gytk.sote.hu
123

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S. Beni et al.
1432
It was found that the esters of morphine showed gen-
[17]. Our aim was to prepare benzoate esters of morphine
derivatives in order to elaborate various synthetic methods
suitable for benzoylation of hydroxyl groups at positions
C(3), C(6), and C(14).
erally higher lipid and water solubility than morphine and
were also more lipophilic than the parent drug in terms of
octanol-buffer partition coefficients. It is well demonstrated
that transport of morphine through human skin can be
markedly enhanced by the aid of its more lipophilic esters
as prodrugs [7, 8]. Calculated apparent partition coeffi-
cients (log D) [9] of morphine (-0.61), heroin (-0.16),
3-O- (1.91) and 6-O-benzoyl (1.43) monoesters as well as
3,6-dibenzoyl diester (3.95) of the parent compound clearly
demonstrate the effect of esterification on their distribution.
The utilization of the prodrug approach can lead to
reduced first-pass metabolism and also improve oral bio-
availability. Prodrugs are frequently applied in transdermal
drug delivery systems to improve clinical outcome and
patient compliance. Previously it was reported that C(3)
benzoate esters of morphine and various substituted ben-
zoates are more resistant to enzymatic hydrolysis than the
corresponding esters of aliphatic carboxylic acids [10].
This observation was emphasized in our previous publi-
cation, in which the diester 3-O-acetylmorphine-6-sulfate
hydrolyzed during recrystallization from water, yielding
the monoester morphine-6-sulfate [11].
Results and discussion
Benzoates of the phenolic hydroxyl group
Acylation of the phenolic hydroxyl group can be performed
by means of two methods. In the first method (method A in
the ‘‘Experimental’’ section) the reaction of morphine with
benzoyl chloride takes place in the presence of triethyl-
amine using methylene chloride as a solvent. The second
method (method B in the ‘‘Experimental’’ section) utilizes
the Schotten–Baumann reaction; i.e., the morphine deriv-
ative can be reacted with excess benzoyl chloride in the
presence of sodium hydrogen carbonate [10, 18, 19].
Phenolic benzoate esters of morphine, dihydromorphine,
14-hydroxy dihydromorphinone (oxymorphone), naloxone,
and naltrexone (1a, 2a, 3a, 3b, and 3c) were prepared
(Fig. 1). Under Schotten–Baumann conditions the 3,6-
dibenzoates were also detected by means of thin-layer
chromatography (TLC) as by-products from morphine and
dihydromorphine. Oxymorphone, naloxone, and naltrexone
also yielded the by-product. The presence of C(6) enolic
benzoates [20] in the crude products was also detected on
the basis of the NMR spectra. The first method is more
favorable to synthesize C(3) benzoates of morphine
derivatives.
Nicotinoylmorphine esters analogous to our benzoate
derivatives showed prodrug behavior [12]. 3,6-Dinicoti-
noylmorphine ester (Vilan) is commonly used clinically
[13] in patient-controlled analgesia.
The preparation of substituted benzoate esters of 3-hy-
droxymorphinans was described using 2-O-acetylsalicyloyl
chloride and isatoic anhydride for acylation of the phenolic
hydroxyl group of morphine analogs [14]. These prodrugs
possess enhanced bioavailability compared with the parent
compounds, however the receptor binding affinity may be
decreased because of blocking of the phenolic hydroxyl
group.
Preparation of C(6)-benzoates and 3,6-dibenzoates
The reaction of the C(6) hydroxyl group of codeine and
dihydrocodeine resulted in the corresponding benzoates (4a
and 5a) in good yields when the benzoylation reaction was
performed in 1,2-dichloroethane using triethylamine as
acid scavenger. The use of pyridine yielded impure prod-
ucts, and the tedious purification steps significantly
diminished the yields.
It is well documented that thiols, alcohols, and phenols
are frequently protected as their benzoate esters in syn-
thetic organic chemistry [15]. It can be proved that the
benzoate esters are successful prodrugs in therapy [16]. We
have reported earlier the preparation of isocodeine (iso-
morphine) benzoates by means of the Mitsunobu reaction
Fig. 1 The structure of 3-O-
benzoate derivatives
N
N
N
R
16
10
9
OH
14
1
11
4
8
15
2
7
13
12
6
3
5
O
O
O
C H COO
OR
C H COO
6 5
OR
C H COO
O
6
5
6
5
1a
1b
R = H
R = Ac
2a
R = H
3a
R = CH
3
2b R = Ac
3b R = allyl
3c
R = CH C H
3 5
2
123

Benzoate esters of morphine and its derivatives
1433
Fig. 2 The structure of 6-O-
benzoate derivatives
N
N
N
R
O
O
1
RO
OOCC H
O
RO
6
5
OOCC H
R O
OOCC H
6 5
6
5
1
4a
4b
R = CH
R = H
5a
5b
R = CH
R = H
6a R = CH R = Ac
6b
3
3
3
1
R = allyl R = Ac
1
5c R = Ac
6c R = allyl R = H
N
N
N
R
N
OOCC H
OOCC H
6 5
6
5
O
O
C H COO
OOCC H
C H COO
6 5
OOCC H
6
5
6
5
6
5
O
O
CH O
Z
CH O
O
3
3
7a
8
R = CH
3
7b R = allyl
9a
10
Z = O
9b Z = H, OH
Fig. 3 The structure of 3,6-di-O-benzoate derivatives
Fig. 4 The structure of 14-O-benzoate derivatives
We also prepared the C(6) benzoates of 3-O-acetylmor-
phine, 3-O-acetyldihydromorphine, and 3-O-acetylnalorphine
(6a, 5c, and 6b) using the same procedure. These 3-acetyl
6-benzoate esters permitted the preparation of 6-mono-
benzoate esters. The C(3) acetate group can be hydrolyzed
selectively under mild conditions, using hydroxylamine
hydrochloride (6a ? 4b, 5c ? 5b, and 6b ? 6c; Fig. 2)
[21].
from the reaction of 14-hydroxycodeinone and 14-hydroxy-
dihydrocodeinone with excess benzoic anhydride [23].
Reduction of 14-O-benzoylcodeinone with sodium borohy-
dride yielded the C(14) benzoate of 14-hydroxycodeine (9b)
(Fig. 4).
By-product-free synthesis of dihydromorphine
3,6-Dibenzoates were obtained from morphine, dihydro-
morphine, and nalorphine in good yields (7a, 8, and 7b;
Fig. 3), performing the benzoylation reaction with excess
benzoyl chloride and triethylamine. The ‘‘reversed’’ esters
of 3-acetyl 6-benzoate derivatives were also prepared.
Acetylation of 3-O-benzoylmorphine (3-O-benzoyldihydro-
morphine) with acetic anhydride yielded the expected
3-O-benzoyl 6-O-acetyl mixed esters (1b and 2b).
We have also investigated the application of 4-dimeth-
ylaminopyridine (DMAP) as catalyst in the benzoylation
reaction [22]. Both codeine and dihydrocodeine react rap-
idly with benzoyl chloride at room temperature using
DMAP catalyst. The yields are close to quantitative, but the
disadvantage of this method is that isolation of the product
requires purification by column chromatography.
Dihydromorphine (12) was also prepared by a new pro-
cedure. It was observed that the catalytic hydrogenation of
morphine in ethanol or in diluted hydrochloric acid did not
yield pure dihydromorphine. It is well documented that
morphine undergoes rearrangement in the presence of
transition-metal catalysts (Pd, Raney-Ni), yielding several
products besides dihydromorphinone (Scheme 1) [24].
We found that catalytic hydrogenation of diacetyl
morphine (Pd–C, solvent: benzene–methanol) can be per-
formed in almost quantitative yield without detection of
any by-product by TLC and HPLC–MS. Hydrolysis of
diacetyl dihydromorphine (11) resulted in pure 12
(Scheme 2). The hydrolysis was performed by either re-
fluxing 11 in methanol for 10 min with slight excess of
2 M potassium hydroxide, or refluxing 11 in methanol for
5 h with excess saturated sodium carbonate solution.
Preparation of C(14)-benzoates
It is interesting and novel in morphine chemistry that tertiary
alcohols can be benzoylated at room temperature using
DMAP catalyst. Benzoate esters were obtained from
14-hydroxycodeinone and 14-hydroxydihydrocodeinone
(9a and 10). We also prepared the authentic C(14) benzoates
Physicochemical properties of the synthesized
compounds
Reversed-phase HPLC-based log D determination is a
widely used method to measure lipophilicity, in which
123

´
S. Beni et al.
1434
Scheme 1
N
N
Dihydromorphine
+
Pd/C
+
Dihydromorphinone
O
HO
OH
HO
OH
O
Morphine
3-O-Demethyl-dihydrothebainone
Scheme 2
N
N
N
Pd/C
KOH
Ethanol
Benzene/ethanol
OOCCH3 H3COCO
O
O
11
O
H3COCO
HO
OOCCH3
OH
12
Dihydromorphine
> 90%
Diacetylmorphine
Diacetyldihydromorphine
> 90%
partition coefficients can be obtained from time measure-
ments instead of concentration determination [25, 26]. The
retention time is independent of the compound concentra-
tion/amount injected into the chromatographic system, and
it is the main indicator of the true partition process. A
further advantage of this technique is that the measurement
is not affected by impurities/degradation products, espe-
cially in the case of ester compounds, which can easily
undergo hydrolysis in aqueous solution. Therefore, the
log D values of all synthesized ester compounds were
determined by reversed-phase HPLC. Drustrup et al. [7]
determined the log D values of various morphine esters
using reversed-phase chromatography on a C-8 stationary
phase.
Table 1 Determined log D values of the synthesized morphine
benzoates
Compound
tR/min
log k0
log D (pH 7.4)
1a
1b
2a
2b
3a
3b
3c
4a
4b
5a
5b
5c
6a
6b
6c
7a
7b
8
2.57
4.00
2.41
3.95
2.51
6.71
6.16
3.82
2.00
3.89
1.92
3.75
3.83
7.55
3.42
9.99
17.8
9.2
0.41
0.60
0.38
0.59
0.40
0.83
0.79
0.58
0.30
0.59
0.28
0.57
0.58
0.88
0.53
0.99
1.25
0.96
0.75
0.66
0.73
1.32
1.94
1.23
1.92
1.29
2.67
2.55
1.88
0.97
1.90
0.91
1.85
1.88
2.83
1.72
3.22
4.03
3.11
2.44
2.14
2.35
The log D (pH 7.4) values of the synthesized benzoate
esters were determined by a calibration curve using five
morphine derivatives with known log D (pH 7.4) values
ranging from -0.07 to 3.93. The log D values for the
calibration curve were obtained from the literature: mor-
phine (-0.07) [27], codeine (0.22) [27], heroine (0.85)
[27], dipropionylmorphine (1.66) [7], and buprenorphine
(3.93) [27]. The calibration curve was obtained by plotting
log D (pH 7.4) versus log k0 (log D = 0.3097log k0 -
0.0039; R2 = 0.996). The determined log D (pH 7.4) val-
ues are listed in Table 1.
9a
9b
10
5.69
4.60
5.36
The data in Table 1 clearly reflect that the benzoate
esters of morphine are more lipophilic than the propionate
or acetyl esters. The diesters are the most lipophilic com-
pounds; the N-allyl derivative possesses
a
log D
automated reasoning in chemistry) chemical reactivity
model [28, 29]. The estimated second-order rate constants
for neutral hydrolysis are collected in Table 2.
These data show that the benzoate esters of the mor-
phine are more stable than the acetyl derivatives. The
hydrolysis of 6-O and 14-O derivatives is slower than that
of the 3-O derivatives.
(pH 7.4) value of 4.03. In general, the lipophilicity of the
3-O-benzoyl derivatives is higher than the corresponding
6-O-benzoyl derivatives, similar to the acyl compounds
[7].
The hydrolysis rate constants of the synthesized esters
were also calculated using the SPARC (sparc performs
123

Benzoate esters of morphine and its derivatives
1435
and the mass spectrometer was operated in conjunction
with a Jet Stream electrospray ion source in positive ion
mode. Reference masses of m/z = 121.050873 and
922.009798 were used to calibrate the mass axis during
analysis. Mass spectra were processed using Agilent
MassHunter B.02.00 software. Electron ionization mass
spectra were obtained with a VG Trio-2 instrument using
the EI method (70 eV). NMR spectra were recorded on a
VARIAN 600-MHz spectrometer equipped with a z-gra-
dient probehead. Chemical shifts are reported in parts per
million (d) relative to tetramethylsilane (TMS) as internal
standard; coupling constants (J) are given in Hz.
Table 2 Calculated logarithmic values of the second-order hydro-
lysis rate constants for neutral hydrolysis of selected esters (dm3/
mol s)
Compound
Phenolate
Alcohol
Heroin
1b
-9.11 (acetyl)
-10.97 (benzoyl)
-9.11 (acetyl)
-10.97 (benzoyl)
–
-12.77 (acetyl)
-12.77 (acetyl)
-14.02 (benzoyl)
-14.42 (benzoyl)
-14.83 (benzoyl)
6a
7a
9a
Conclusions
The reversed-phase HPLC-based log D (pH 7.4) deter-
mination was investigated by an Agilent 1260 Infinity LC
system in conjunction with an Agilent 6460 triple-quad-
rupole mass spectrometer. For the log D determination, an
Agilent Zorbax SB-C18 column was used. The mobile
phase consisted of acetonitrile:methanol:water 3:1:6. The
pH of the eluent was adjusted to pH 7.4 with ammonium
acetate.
Benzoylation of hydroxyl group in morphine derivatives at
C-3, C-6, and C-14 position was elaborated using different
synthetic procedures. Benzoylation of the C-3 phenolic
hydroxyl group was performed by means of Schotten–
Baumann reaction. C-6 acylation can be achieved with
benzoyl chloride and triethylamine or pyridine catalyst in
1,2-dichloroethane solvent. The benzoylation of the tertiary
C-14 hydroxyl group was performed by the aid of
4-dimethylaminopyridine catalyst at room temperature.
We synthesized 16 new compounds, and their structures
were elucidated by 1H NMR, 13C NMR, HRMS, and
EI-MS. These compounds are potential prodrugs of mor-
phine, as shown by their lipophilicity determined using
reversed-phase liquid chromatography method. It can be
hypothesized that these physicochemical properties will
correspond to better blood–brain barrier penetration ability
as well as long-acting narcotic effect.
General procedures for preparation of morphine
3-benzoates
Method A
Morphine base (2.85 g, 10 mmol) and 6 cm3 triethylamine
were dissolved in 70 cm3 dry dichloromethane at 0–5 °C.
A solution of 1.4 cm3 benzoyl chloride (12 mmol) in
10 cm3 dichloromethane was added dropwise with stirring.
The reaction mixture was stirred at room temperature
for 16 h and was washed with 10 % sodium carbonate
and then with brine. The organic phase was separated and
dried over sodium sulfate. The solution was evaporated,
and the crude product was crystallized from the appropriate
solvent.
We also elaborated a novel procedure for preparation of
dihydromorphine in which the formation of by-products
was eliminated.
Experimental
Method B
Benzoyl chloride (1.2 cm3, 10 mmol) was added in three
portions to a solution of morphine hydrochloride or base
(2 mmol) and 5 g sodium hydrogen carbonate in 50 cm3 of
water. The reaction mixture was stirred at 60 °C for 5 h.
The product was extracted with chloroform. The extract
was washed with brine and dried over sodium sulfate. The
solvent was evaporated, and the residue was crystallized or
purified by means of column chromatography.
All reagents and solvents were purchased from Sigma-
Aldrich and were used as received. Melting points were
measured with a Bu¨chi apparatus in open capillary tubes.
The purity of the synthesized compounds was checked by
TLC on Kieselgel 60 F254 (Merck-5719) plates using the
following eluents: benzene:methanol 8:2 [A], chloro-
form:methanol 9:1 [B], chloroform:acetone:diethylamine
5:4:1 [C]. The spots were visualized by ultraviolet (UV)
light or with the Dragendorff reagents. Each system was
applied to check the purity of the esters. For column chro-
matography, Kieselgel 60 (particle size 0.063–0.2 mm) was
employed with eluent system chloroform:methanol 9:l.
High-resolution accurate masses were determined with
an Agilent 6230 time-of-flight mass spectrometer. Samples
were introduced by the Agilent 1260 Infinity LC system,
General procedures for synthesis of C(6)-benzoates
and 3,6-dibenzoates
3-Acetylmorphine (3.0 g, 10 mmol) and 5.2 cm3 triethyl-
amine were dissolved in 50 cm3 of dried 1,2-dichloroethane.
The solution was stirred and cooled (0–5 °C), and 6.1 cm3
benzoyl chloride (52 mmol) was added dropwise. Stirring
123

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S. Beni et al.
1436
was continued for 30 min at room temperature, then the
mixture was stirred and boiled for 4 h. Then the solution was
evaporated, and the residue was dissolved in chloroform. It
was washed with cold 10 % sodium carbonate, water, and
brine. The organic phase was separated and dried. After
evaporation, the crude product was purified by means of
column chromatography.
evaporated. The crude product was a single spot on TLC
analysis. It was recrystallized from ethanol.
In the second step, 11 was hydrolyzed. A solution of
4.7 g 11 (12.66 mmol) in 75 cm3 ethanol was treated with
25 cm3 concentrated sodium carbonate solution. The
reaction mixture was stirred and refluxed for 4 h. TLC
indicated full conversion. The pH of the solution was
adjusted to 10 by addition of 5 % sodium hydroxide, then
ethanol was evaporated in vacuo. Dihydromorphine
hydrate was precipitated from the alkaline solution by
adjusting the pH to 8 with hydrochloric acid, then the
resulted solution was filtered.
The deacetylation of 3-O-acetyl 6-O-benzoyl derivatives
6a and 5c to the corresponding 6-O-benzoyl derivatives 4b
and 5b was carried out as follows: To 15 cm3 ethanolic
solution of 3-O-acetyl 6-O-benzoyl derivatives (1 mmol),
saturated aqueous solution of 150 mg NH2OHꢀHCl
(2 mmol) was added with stirring. The reaction mixture
was stirred at 50 °C for 2 h. The hydrochloride salt of
6-O-benzoylmorphine was crystallized from the solution.
Ethanol was removed by a rotary evaporator, and the
residue was dissolved in water. The salt was converted to
the base by treatment with saturated sodium carbonate
solution (pH 9). The product was isolated by chloroform
extraction.
7,8-Didehydro-4,5-epoxy-17-methyl-(5a,6a)-morphinan-
3,6-diol 3-benzoate (1a)
Yields: 77 % (method A), 68 % (method B); m.p.:
114–116 °C (ethanol) [Ref. [30] 145 °C (aq. ethanol)].
7,8-Didehydro-4,5-epoxy-17-methyl-(5a,6a)-morphinan-
3,6-diol 3-benzoate 6-acetate (1b, C26H25NO5)
1
Yield: 94 %; m.p.: 145 °C (p. ether); H NMR (600 MHz,
For the preparation of 3,6-dibenzoates a similar proce-
dure as described for the C(6)-benzoates was used: 2.85 g
morphine (10 mmol) and 10.5 cm3 triethylamine were
dissolved in 70 cm3 of dried 1,2-dichloroethane. The
solution was stirred and cooled (0–5 °C), and 12 cm3
benzoyl chloride (104 mmol) was added dropwise. Stirring
was continued for 30 min at room temperature, then the
mixture was stirred and boiled for 4 h. The work-up was
the same as mentioned above.
CDCl3): d = 1.94 (d, J = 12.7 Hz, H-15), 1.98 (s, Ac,
3H), 2.06 (td, J = 12.5, 4.9 Hz, H-15), 2.35 (dd, J = 18.8,
5.8 Hz, H-10), 2.40 (td, J = 12.5, 3.5 Hz, H-16), 2.46 (s,
NCH3), 2.62 (dd, J = 12.5, 4.6 Hz, H-16), 2.77 (s, H-14),
3.09 (d, J = 18.8 Hz, H-10), 3.39 (dd, J = 5.6, 3.1 Hz,
H-9), 5.13–5.15 (m, H-5 and H-6), 5.46 (d, J = 10.0 Hz,
H-8), 5.66 (d, J = 10.0 Hz, H-7), 6.64 (d, J = 8.1 Hz,
H-1), 6.89 (d, J = 8.1 Hz, H-2), 7.49 (t, J = 7.8 Hz,
benzoyl H-meta), 7.62 (t, J = 7.7 Hz, benzoyl H-para),
8.20 (d, J = 7.9 Hz, benzoyl H-ortho) ppm; 13C NMR
(151 MHz, CDCl3): d = 20.5 (CH2), 21.2 (CH3), 32.1
(CH2), 36.9 (CH2), 40.2 (NCH3), 43.2 (C), 46.2 (CH), 60.1
(CH), 64.9 (CH), 90.2 (CH), 119.9 (CH), 122.5 (CH),
126.1 (C), 128.3 (2 CH), 129.2 (C), 129.5 (2 CH), 130.2
(CH), 130.8 (C), 133.3 (CH), 134.3 (CH), 136.8 (C), 146.3
(C), 166.2 (C), 170.4 (C) ppm; HRMS: m/z calcd. for
[M ? H]? ([C26H26NO5]?) 432.1805, found 432.1801;
EI-MS: m/z (%) = 431 (M?, 30), 372 (22).
Utilizing 4-dimethylaminopyridine (DMAP) catalyst
Codeine (0.90 g, 3.0 mmol) and 0.4 g 4-dimethylamino-
pyridine (3.2 mmol) were dissolved in 20 cm3 dry
dichloromethane, 0.35 cm3 benzoyl chloride (3.1 mmol)
was added dropwise whilst cooling with ice, and then the
reaction mixture was stirred for 3 h at room temperature.
The solution was poured into water, and the organic phase
was separated. The latter was washed with water and
brine and dried over sodium sulfate. The solvent was
removed in vacuum, and the residue was subjected to
column chromatography. Pure fractions were crystallized
from ethanol.
4,5-Epoxy-17-methyl-(5a,6a)-morphinan-3,6-diol 3-benzo-
ate (2a, C24H25NO4)
Yields: 70 % (method A), 63 % (method B); m.p.:
106–108 °C (p. ether); 1H NMR (600 MHz, CDCl3):
d = 1.37 (m, H-8), 1.40 (m, H-7), 1.79 (dd, J = 13.4,
2.9 Hz, H-15), 1.88 (m, H-7), 2.27 (td, J = 13.2, 4.7 Hz,
H-15), 2.59 (td, J = 12.6, 4.1 Hz, H-16), 2.72 (m, H-14),
2.78 (s, NCH3), 2.90 (dd, J = 19.4, 5.6 Hz, H-10), 3.11 (d,
J = 19.4 Hz, H-10), 3.29 (dd, J = 12.5, 4.3 Hz, H-16),
3.81 (dd, J = 5.5, 2.6 Hz, H-9), 4.18 (m, H-6), 4.63 (d,
J = 5.5 Hz, H-5), 6.77 (d, J = 8.2 Hz, H-1), 6.97 (d,
J = 8.2 Hz, H-2), 7.50 (t, J = 7.8 Hz, benzoyl H-meta),
7.64 (t, J = 7.7 Hz, benzoyl H-para), 8.20 (d, J = 7.9 Hz,
By-product-free synthesis of dihydromorphine (12)
In the first step, diacetyldihydromorphine (11) was syn-
thesized by the following method: 3.8 g diacetylmorphine
(10.2 mmol) was dissolved in a mixture of 60 cm3 ethanol
and 20 cm3 benzene. The solution was shaken with
hydrogen and 1.5 g Pd–C (5 %) until absorption ceased.
The catalyst was filtered off, and the filtrate was
123

Benzoate esters of morphine and its derivatives
1437
benzoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 18.3 (CH2), 21.9 (CH2), 27.6 (CH2), 34.4 (CH), 39.7
(CH2), 40.0 (C), 41.3 (NCH3), 47.4 (CH), 60.5 (CH), 66.4
(CH), 91.8 (CH), 122.6 (C), 118.9 (CH), 119.8 (CH), 128.5
(2 CH), 129.9 (2 CH), 130.4 (CH), 134.4 (C), 130.7 (C),
139.5 (C), 146.5 (C), 164.6 (C) ppm; HRMS: m/z calcd. for
[M ? H]? ([C24H26NO4]?) 392.1856, found 392.1852;
EI-MS: m/z (%) = 391 (M?, 3), 286 (3).
3-Benzoyloxy-4,5-epoxy-14-hydroxy-17-(2-propenyl)mor-
phinan-6-one (3b, C26H25NO5)
1
Yield: 60 %; m.p.: 199–200 °C (ethyl acetate); H NMR
(600 MHz, CDCl3): d = 1.66 (td, J = 13.9, 3.6 Hz, H-8),
1.67 (m, H-15), 1.90 (ddd, J = 13.5, 4.8, 2.9 Hz, H-8),
2.20 (td, J = 12.2, 3.7 Hz, H-16), 2.33 (dt, J = 14.6,
3.1 Hz, H-7), 2.43 (td, J = 12.7, 5.2 Hz, H-15), 2.64–2.65
(m, H-16 and H-10), 3.03 (td, J = 15.0, 5.1 Hz, H-7), 3.07
(d, J = 5.8 Hz, H-9), 3.17 (d, J = 18.9 Hz, H-10), 3.20
(m, 2H of allyl), 4.71 (s, H-9), 5.21 (d, J = 10.2 Hz, 1H of
allyl), 5.25 (d, J = 17.2 Hz, 1H of allyl), 5.84 (m, 1H of
allyl), 6.75 (d, J = 8.2 Hz, H-1), 6.97 (d, J = 8.2 Hz,
H-2), 7.49 (t, J = 7.8 Hz, benzoyl H-meta), 7.62 (t,
J = 7.7 Hz, benzoyl H-para), 8.22 (d, J = 7.9 Hz, ben-
zoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 23.1 (CH2), 30.5 (CH2), 31.1 (CH2), 36.2 (CH2),
43.4 (CH2), 50.8 (C), 57.8 (CH2), 62.2 (CH), 70.3 (CH),
90.7 (CH), 119.7 (CH), 121.1 (CH), 124.0 (CH2), 127.9
(CH), 128.5 (2 CH), 128.9 (C), 129.5 (C), 130.5 (2 CH),
131.2 (C), 132.7 (C), 134.1 (2 CH), 148 (C), 164.1 (C),
206.2 (C) ppm; HRMS: m/z calcd. for [M ? H]?
([C26H26NO5]?) 432.1805, found 432.1800; EI-MS:
m/z (%) = 431 (M?, 18).
4,5-Epoxy-17-methyl-(5a,6a)-morphinan-3,6-diol
3-benzoate 6-acetate (2b, C26H27NO5)
Yield: 85 %; m.p.: 145–147 °C (ether); 1H NMR (600
MHz, CDCl3): d = 1.17 (m, H-8), 1.46 (m, H-8), 1.50 (m,
H-7), 1.72 (m, H-7), 1.81 (dd, J = 12.6, 2.9 Hz, H-15),
1.85 (s, Ac, 3H), 1.97 (td, J = 12.6, 4.8 Hz, H-15), 2.34
(td, J = 12.5, 3.5 Hz, H-16), 2.38 (m, H-14), 2.48 (s,
NCH3), 2.53 (d, J = 18.8, 5.6 Hz, H-10), 2.66 (dd,
J = 12.3, 3.5 Hz, H-16), 3.09 (d, J = 18.8 Hz, H-10),
3.23 (br s, H-9), 4.70 (d, J = 5.8 Hz, H-5), 5.30 (td,
J = 5.7, 2.7 Hz, H-6), 6.73 (d, J = 8.1 Hz, H-1), 6.98 (d,
J = 8.1 Hz, H-2), 7.50 (t, J = 7.8 Hz, benzoyl H-meta),
7.62 (t, J = 7.7 Hz, benzoyl H-para), 8.17 (d, J = 7.9 Hz,
benzoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 21.1 (CH2), 21.4 (CH3), 24.3 (CH2), 27.3 (CH2), 31.6
(CH2), 38.1 (CH2), 40.2 (NCH3), 42.9 (C), 46.0 (CH), 59.5
(CH), 65.6 (CH), 91.4 (CH), 119.4 (CH), 123.3 (CH),
125.8 (C), 128.5 (2 CH), 129.4 (C), 129.7 (2 CH), 131.0
(C), 133.4 (CH), 137.4 (C), 146.5 (C), 166.3 (C), 170.3
(C) ppm; HRMS: m/z calcd. for [M ? H]? ([C26H28
NO5]?) 434.1962, found 434.1956; EI-MS: m/z (%) = 433
(M?, 40) 374 (12).
3-Benzoyloxy-17-cyclopropylmethyl-4,5-epoxy-14-
hydroxymorphinan-6-one (3c)
Yield: 73 %; m.p.: 175–177 °C (ether) (Ref. [31] 174–
177 °C).
7,8-Didehydro-4,5-epoxy-3-methoxy-17-methyl-(5a,6a)-
morphinane-6-ol benzoate (4a)
Yields: 81 % (NEt3), 83 % (DMAP); m.p.: 130–132 °C (p.
1
ether) (Ref. [32] 130–132 °C); H and 13C NMR spectra
3-Benzoyloxy-4,5-epoxy-14-hydroxy-17-methylmorphinan-
6-one (3a, C24H23NO5)
were found to be identical to those described in Ref. [32];
HRMS: m/z calcd. for [M ? H]? ([C25H26NO4]?)
404.1856, found 404.1859; EI-MS: m/z (%) = 403 (M?,
48), 262 (28).
1
Yield: 61 %; m.p.: 207–209 °C (hexane); H NMR (600
MHz, CDCl3): d = 1.74 (dd, J = 12.8, 2.6 Hz, H-15), 1.79
(td, J = 14.5, 3.8 Hz, H-8), 2.27 (td, J = 12.3, 3.6 Hz,
H-16), 2.34 (dt, J = 14.8, 3.0 Hz, H-7), 2.35 (s, NCH3),
2.59 (dd, J = 12.2, 4.4 Hz, H-16), 2.64 (dd, J = 18.8,
5.4 Hz, H-10), 2.65 (td, J = 14.9, 5.3 Hz, H-7), 2.75 (td,
J = 12.6, 5.2 Hz, H-15), 3.03 (ddd, J = 14.6, 4.9, 2.9 Hz,
H-8), 3.35 (d, J = 18.8 Hz, H-10), 4.44 (d, J = 5.3 Hz,
H-9), 4.81 (s, H-5), 6.80 (d, J = 8.2 Hz, H-1), 7.02 (d,
J = 8.2 Hz, H-2), 7.50 (t, J = 7.8 Hz, benzoyl H-meta),
7.62 (t, J = 7.7 Hz, benzoyl H-para), 8.23 (d, J = 7.9 Hz,
benzoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 23.2 (CH2), 27.0 (CH2), 30.6 (CH2), 35.7 (CH2), 42.9
(NCH3), 45.5 (CH2), 50.9 (C), 58.3 (CH), 83.1 (C), 90.6
(CH), 120.0 (CH), 123.7 (CH), 128.7 (C), 129.5 (C), 129.8
(2 CH), 130.7 (2 CH), 131.3 (C), 133.7 (CH), 138.2 (C),
148.5 (C), 165.5 (C), 206.0 (C) ppm; HRMS: m/z calcd. for
[M ? H]? ([C24H24NO5]?) 406.1654, found 406.1650;
EI-MS: m/z (%) = 405 (M?, 39), 320 (12).
7,8-Didehydro-4,5-epoxy-17-methyl-(5a,6a)-morphinan-
3,6-diol 6-benzoate (4b, C24H23NO4)
Yield: 81 %; m.p.: 270–272 °C (ether); 1H NMR
(600 MHz, CDCl3): d = 1.87 (d, J = 12.5 Hz, H-15),
2.09 (t, J = 12.1 Hz, H-15), 2.34 (dd, J = 18.5, 5.3 Hz,
H-10), 2.39 (t, J = 12.5 Hz, H-16), 2.45 (s, NCH3), 2.61
(d, J = 10.6 Hz, H-16), 2.81 (s, H-14), 3.03 (d,
J = 18.5 Hz, H-10), 3.39 (s, H-9), 5.25 (d, J = 6.8 Hz,
H-5), 5.41 (m, H-6), 5.50 (dt, J = 10.0, 2.5 Hz, H-8), 5.76
(d, J = 10.0 Hz, H-7), 6.53 (d, J = 8.1 Hz, H-1), 6.65 (d,
J = 8.1 Hz, H-2), 7.47 (t, J = 7.8 Hz, benzoyl H-meta),
7.59 (t, J = 7.5 Hz, benzoyl H-para), 8.10 (d, J = 7.9 Hz,
benzoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 22.2 (CH2), 33.9 (CH2), 39.3 (CH2), 40.5 (NCH3),
42.3 (C), 44.3 (CH), 53.2 (CH), 66.3 (CH), 88.7 (CH),
120.2 (CH), 122.3 (CH), 125.7 (C), 126.4 (CH), 128.3 (2
123

´
S. Beni et al.
1438
CH), 129.9 (2 CH), 130.1 (CH), 130.5 (C), 131.1 (C), 133.5
(CH), 138.2 (C), 147.1 (C), 166.1 (C) ppm; HRMS:
m/z calcd. for [M ? H]? ([C24H24NO4]?) 390.1700, found
390.1698; EI-MS: m/z (%) = 389 (M?, 52), 268 (33).
H-7 and H-15), 2.05 (s, Ac, 3H), 2.22 (td, J = 12.2,
3.6 Hz, H-16), 2.35 (m, H-14), 2.40 (s, NCH3), 2.45 (dd,
J = 18.6, 5.5 Hz, H-10), 2.58 (dd, J = 12.2, 4.3 Hz,
H-16), 3.07 (d, J = 18.6 Hz, H-10), 3.16 (m, H-9), 4.70
(d, J = 6.0 Hz, H-5), 5.53 (m, H-6), 6.57 (d, J = 8.1 Hz,
H-2), 6.63 (d, J = 8.1 Hz, H-1), 7.28 (t, J = 7.8 Hz,
benzoyl H-meta), 7.43 (t, J = 7.9 Hz, benzoyl H-para),
7.48 (d, J = 7.5 Hz, benzoyl H-ortho) ppm; 13C NMR
(151 MHz, CDCl3): d = 18.6 (CH2), 20.5 (CH2), 21.6
(CH2), 26.4 (CH2), 34.3 (CH2), 39.5 (CH2), 41.1 (NCH3),
41.5 (CH), 47.7 (C), 61.0 (CH), 67.9 (CH), 87.4 (CH),
119.0 (CH), 123.0 (CH), 127.3 (C), 128.0 (2 CH), 129.7 (2
CH), 130.4 (C), 131.2 (C), 133.1 (CH), 136.7 (C), 149.6
(C), 165.1 (C), 171.1 (C) ppm; HRMS: m/z calcd. for
[M ? H]? ([C26H28NO5]?) 434.1962, found 434.1957;
EI-MS: m/z (%) = 433 (M?, 5), 391 (8).
4,5-Epoxy-3-methoxy-17-methyl-(5a,6a)-morphinane-6-ol
benzoate (5a, C25H27NO4)
Yields: 72 % (NEt3), 76 % (DMAP); m.p.: 163 °C (ether);
1H NMR (600 MHz, CDCl3): d = 1.35 (m, H-8), 1.57 (m,
H-8), 1.70 (t, J = 13.5 Hz, H-7), 1.88 (d, J = 12.5 Hz,
H-15), 1.98 (d, J = 14.9 Hz, H-7), 2.47 (t, J = 12.4 Hz,
H-15), 2.74 (t, J = 12.3 Hz, H-16), 2.88 (s, NCH3), 3.06
(m, H-14), 3.09 (dd, J = 18.9, 5.1 Hz, H-10), 3.20 (d,
J = 18.9 Hz, H-10), 3.29 (d, J = 12.3 Hz, H-16), 3.31 (s,
OCH3), 3.89 (br s, H-9), 4.79 (d, J = 6.2 Hz, H-5), 5.68
(m, H-6), 6.60 (d, J = 8.2 Hz, H-1), 6.76 (d, J = 8.2 Hz,
H-2), 7.26 (t, J = 7.7 Hz, benzoyl H-meta), 7.34 (t,
J = 7.8 Hz, benzoyl H-para), 7.46 (d, J = 7.4 Hz, ben-
zoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 20.5 (CH2), 21.8 (CH2), 28.2 (CH2), 37.6 (CH2),
43.1 (NCH3), 44.0 (CH), 44.3 (C), 48.3 (CH), 56.4 (OCH3),
60.6 (CH), 69.7 (CH), 89.4 (CH), 116.3 (CH), 120.3 (CH),
127.9 (C), 128.1 (2 CH), 129.3 (2 CH), 131.3 (C), 133.4
(C), 134.1 (CH), 140.4 (C), 147.3 (C), 166.8 (C) ppm;
HRMS: m/z calcd. for [M ? H]? ([C25H28NO4]?)
406.2013, found 406.2020; EI-MS: m/z (%) = 405 (M?,
35), 300 (15).
7,8-Didehydro-4,5-epoxy-17-methyl-(5a,6a)-morphinan-
3,6-diol 3-acetate 6-benzoate (6a, C26H25NO5)
Yield: 74 %; m.p.: 115–117 °C (ether); 1H NMR
(600 MHz, CDCl3): d = 1.98 (s, Ac, 3H), 2.00 (d,
J = 12.6 Hz, H-15), 2.35 (td, J = 12.9, 4.7 Hz, H-15),
2.60 (td, J = 12.6, 4.1 Hz, H-16), 2.66 (s, NCH3), 3.04 (dd,
J = 12.8, 3.7 Hz, H-16), 3.13 (d, J = 19.1 Hz, H-10), 3.18
(m, H-14), 3.62 (dd, J = 19.0, 6.0 Hz, H-10), 3.83 (m,
H-9), 5.31 (d, J = 7.1 Hz, H-5), 5.42 (s, H-6), 5.51 (d,
J = 10.0 Hz, H-8), 5.82 (d, J = 10.0 Hz, H-7), 6.66 (d,
J = 8.1 Hz, H-1), 6.81 (d, J = 8.1 Hz, H-2), 7.45 (t,
J = 7.7 Hz, benzoyl H-meta), 7.57 (t, J = 7.7 Hz, benzoyl
H-para), 8.09 (d, J = 7.8 Hz, benzoyl H-ortho) ppm; 13C
NMR (151 MHz, CDCl3): d = 20.5 (CH2), 20.9 (CH3),
32.1 (CH2), 37.3 (CH2), 40.4 (NCH3), 43.2 (C), 46.4 (CH),
60.1 (CH), 61.3 (CH), 90.2 (CH), 119.7 (CH), 121.3 (CH),
126.0 (C), 128.6 (CH), 128.9 (2 CH), 129.2 (C), 129.9 (2
CH), 131.2 (C), 132.3 (CH), 133.3 (CH), 136.1 (C), 145.2
(C), 165.8 (C), 170.5 (C) ppm; HRMS: m/z calcd. for
[M ? H]? ([C26H26NO5]?) 432.1805, found 432.1798;
EI-MS: m/z (%) = 431 (M?, 3).
4,5-Epoxy-17-methyl-(5a,6a)-morphinan-3,6-diol
6-benzoate (5b, C24H25NO4)
1
Yield: 66 %; m.p.: 253–255 °C (ethyl acetate); H NMR
(600 MHz, CDCl3): d = 1.30 (m, H-8), 1.42 (m, H-8), 1.52
(m, H-7), 1.67 (d, J = 12.5 Hz, H-15), 1.88–1.90 (m, H-7
and H-15), 2.25 (td, J = 12.2, 3.6 Hz, H-16), 2.30 (m,
H-14), 2.39 (s, NCH3), 2.46 (dd, J = 18.6, 5.5 Hz, H-10),
2.56 (dd, J = 12.2, 4.3 Hz, H-16), 3.04 (d, J = 18.6 Hz,
H-10), 3.14 (m, H-9), 4.69 (d, J = 6.0 Hz, H-5), 5.52 (m,
H-6), 6.57 (d, J = 8.1 Hz, H-2), 6.63 (d, J = 8.1 Hz, H-1),
7.28 (t, J = 7.8 Hz, benzoyl H-meta), 7.43 (t, J = 7.9 Hz,
benzoyl H-para), 7.48 (d, J = 7.5 Hz, benzoyl H-ortho)
ppm; 13C NMR (151 MHz, CDCl3): d = 20.4 (CH2), 21.5
(CH2), 28.0 (CH2), 37.8 (CH2), 43.2 (NCH3), 43.6 (CH),
44.1 (C), 48.5 (CH), 60.9 (CH), 70.0 (CH), 88.8 (CH),
118.2 (CH), 120.2 (CH), 126.7 (C), 128.2 (2 CH), 130.3
(C), 131.0 (2 CH), 132.5 (C), 134.1 (CH), 139.4 (C), 146.3
(C), 166.8 (C) ppm; HRMS: m/z calcd. for [M ? H]?
([C24H26NO4]?) 392.1856, found 392.1853; EI-MS:
m/z (%) = 391 (M?, 27).
7,8-Didehydro-4,5-epoxy-17-(2-propenyl)-(5a,6a)-
morphinan-3,6-diol 3-acetate 6-benzoate
(6b, C28H27NO5)
Yield: 62 %; m.p.: 97–99 °C (p. ether); 1H NMR (600
MHz, CDCl3): d = 1.87 (s, Ac, 3H), 1.99 (d, J = 12.6 Hz,
H-15), 2.31 (td, J = 12.7, 4.7 Hz, H-15), 2.52 (td,
J = 12.6, 3.5 Hz, H-16), 2.55 (td, J = 19.0, 5.9 Hz,
H-10), 3.08 (d, J = 18.9 Hz, H-10), 3.10–3.13 (m, H-14
and H-16), 3.43 (m, 1H of allyl), 3.53 (m, 1H of allyl), 3.93
(dd, J = 5.8, 3.1 Hz, H-9), 5.30 (m, H-5 and 1H of allyl),
5.34 (d, J = 16.2 Hz, 1H of allyl), 5.42 (m, H-6), 5.51 (d,
J = 10.0 Hz, H-8), 5.80 (d, J = 10.0 Hz, H-7), 6.03 (m,
1H of allyl), 6.63 (d, J = 8.1 Hz, H-1), 6.81 (d,
J = 8.1 Hz, H-2), 7.44 (t, J = 7.7 Hz, benzoyl H-meta),
7.57 (t, J = 7.6 Hz, benzoyl H-para), 8.07 (d, J = 7.8 Hz,
4,5-Epoxy-17-methyl-(5a,6a)-morphinan-3,6-diol
3-acetate 6-benzoate (5c, C26H27NO5)
Yield: 56 %; m.p.: 120–122 °C (p.ether); 1H NMR
(600 MHz, CDCl3): d = 1.35 (m, H-8), 1.40 (m, H-8),
1.55 (m, H-7), 1.64 (d, J = 12.5 Hz, H-15), 1.90–1.80 (m,
123

Benzoate esters of morphine and its derivatives
1439
benzoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 20.3 (CH2), 21.8 (CH3), 33.7 (CH2), 38.9 (CH), 42.7
(C), 44.9 (CH2), 56.2 (CH2), 56.5 (CH), 57.6 (CH2), 68.0
(CH), 88.4 (CH), 117.1 (CH2), 117.5 (CH), 119.7 (CH),
122.6 (C), 128.4 (CH), 128.7 (2 CH), 129.4 (CH), 130.2 (2
CH), 132.3 (C), 132.7 (C), 133.3 (C), 135.5 (CH), 145.2
(C), 166.5 (C), 171.2 (C) ppm; HRMS: m/z calcd. for
[M ? H]? ([C28H28NO5]?) 458.1962, found 458.1959;
EI-MS: m/z (%) = 457 (M?, 32), 415 (60).
7.81 (d, J = 7.9 Hz, 3-O-benzoyl H-ortho), 7.97 (d,
J = 8.0 Hz, 6-O-benzoyl H-ortho) ppm; 13C NMR
(151 MHz, CDCl3): d = 21.5 (CH2), 37.3 (CH2), 41.8
(CH2), 43.5 (CH2), 45.8 (CH2), 56.3 (CH), 57.2 (CH2),
67.1 (CH), 87.7 (CH), 119.8 (CH2), 120.0 (CH), 123.5
(CH), 128.0 (2 CH), 128.2 (CH), 128.3 (2 CH), 128.4 (C),
129.9 (CH), 130.0 (C), 130.2 (C), 130.3 (2 CH), 130.7 (2
CH), 132.1 (C), 133.0 (CH), 133.3 (CH), 133.4 (CH), 133.6
(C), 149.7 (C), 164.0 (C), 165.4 (C) ppm; HRMS:
m/z calcd. for [M ? H]? ([C33H30NO5]?) 520.2118, found
520.2115; EI-MS: m/z (%) = 519 (M?, 45).
7,8-Didehydro-4,5-epoxy-17-(2-propenyl)-(5a,6a)-
morphinan-3,6-diol 6-benzoate (6c, C26H25NO4)
Yield: 47 %; m.p.: 174–176 °C (p. ether); 1H NMR
(600 MHz, CDCl3): d = 1.82 (d, J = 12.6 Hz, H-15),
2.06 (td, J = 12.6, 4.5 Hz, H-15), 2.30 (dd, J = 18.6,
5.5 Hz, H-10), 2.34 (td, J = 12.6, 3.1 Hz, H-16), 2.69 (dd,
J = 12.2, 4.5 Hz, H-16), 2.80 (t, J = 2.9 Hz, H-14), 2.96
(d, J = 18.6 Hz, H-10), 3.20 (m, 2H of allyl), 3.50 (dd,
J = 5.5, 2.9 Hz, H-9), 5.16 (d, J = 10.1 Hz, 1H of allyl),
5.22 (d, J = 6.0 Hz, H-5), 5.23 (d, J = 16.2 Hz, 1H of
allyl), 5.39 (dd, J = 6.0, 2.4 Hz, H-6), 5.48 (d,
J = 10.0 Hz, H-8), 5.75 (d, J = 10.0 Hz, H-7), 5.88 (m,
1H of allyl), 6.52 (d, J = 8.0 Hz, H-1), 6.65 (d,
J = 8.0 Hz, H-2), 7.46 (t, J = 7.7 Hz, benzoyl H-meta),
7.58 (t, J = 7.5 Hz, benzoyl H-para), 8.09 (d, J = 7.8 Hz,
benzoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 21.0 (CH2), 35.1 (CH2), 40.5 (CH), 43.5 (C), 56.3
(CH), 56.5 (CH2), 44.8 (CH2), 58.2 (CH2), 68.7 (CH), 88.5
(C), 116.4 (CH), 117.7 (CH2), 119.7 (CH), 126.3 (C), 128.1
(CH), 128.5 (2 CH), 129.6 (2 CH), 129.9 (CH), 130.2 (C),
133.2 (CH), 135.5 (CH), 137.8 (C), 145.1 (C), 166.0
(C) ppm; HRMS: m/z calcd. for [M ? H]? ([C26H26
NO4]?) 416.1856, found 416.1845; EI-MS: m/z (%) = 415
(M?, 45), 394 (26).
4,5-Epoxy-17-methyl-(5a,6a)-morphinan-3,6-diol
3,6-dibenzoate (8, C31H29NO5)
Yield: 71 %; m.p.: 219–221 °C (ethanol); 1H NMR
(600 MHz, CDCl3): d = 1.31 (m, H-8), 1.51 (m, H-8),
1.60 (m, H-7), 1.83 (d, J = 12.3 Hz, H-15), 1.89 (m, H-7),
1.93 (td, J = 12.2, 4.9 Hz, H-15), 2.31 (td, J = 12.3,
3.6 Hz, H-16), 2.35 (m, H-14), 2.45 (s, NCH3), 2.53 (dd,
J = 18.6, 5.6 Hz, H-10), 2.58 (dd, J = 12.3, 4.3 Hz,
H-16), 3.13 (d, J = 18.6 Hz, H-10), 3.18 (dd, J = 4.7,
2.4 Hz, H-9), 4.79 (d, J = 6.0 Hz, H-5), 5.58 (m, H-6),
6.78 (d, J = 8.2 Hz, H-1), 6.85 (d, J = 8.2 Hz, H-2), 7.30
(t, J = 7.8 Hz, 6-O-benzoyl H-meta), 7.37 (t, J = 7.7 Hz,
3-O-benzoyl H-meta), 7.51 (t, J = 7.5 Hz, 6-O-benzoyl
H-para), 7.52 (d, J = 7.9 Hz, 6-O-benzoyl H-ortho), 7.54
(t, J = 7.5 Hz, 3-O-benzoyl H-para), 7.79 (d, J = 7.9 Hz,
3-O-benzoyl H-ortho) ppm; 13C NMR (151 MHz, CDCl3):
d = 19.5 (CH2), 20.7 (CH2), 26.6 (CH2), 36.8 (CH2), 42.1
(NCH3), 42.6 (CH), 43.2 (C), 47.3 (CH2), 59.9 (CH), 68.5
(CH), 88.3 (CH), 119.1 (CH), 122.2 (CH), 128.1 (2 CH),
128.3 (C), 128.48 (2 CH), 129.3 (C), 130.0 (2 CH), 130.2
(C), 130.4 (2 CH), 131.2 (C), 132.1 (C), 133.0 (C), 133.5
(C), 149.7 (C), 164.1 (C), 165.5 (C) ppm; HRMS:
m/z calcd. for [M ? H]? ([C31H30NO5]?) 496.2124, found
496.2129; EI-MS: m/z (%) = 495 (M?, 45), 390 (8).
7,8-Didehydro-4,5-epoxy-17-methyl-(5a,6a)-morphinan-
3,6-diol 3,6-dibenzoate (7a)
14-Benzoyloxy-7,8-didehydro-4,5-epoxy-3-methoxy-17-
methylmorphinan-6-one (9a, C25H23NO5)
Yield: 66 %; m.p.: 188–190 °C (ethanol) (Ref. [15]
190 °C).
Yield: 66 %; m.p.: 246–248 °C (ethanol); 1H NMR
(600 MHz, CDCl3): d = 1.81 (dd, J = 12.6, 2.2 Hz,
H-15), 2.36 (td, J = 12.2, 3.7 Hz, H-16), 2.37 (s, NCH3),
2.53 (dd, J = 18.7, 5.5 Hz, H-10), 2.56 (dd, J = 12.0,
4.9 Hz, H-10), 2.65 (td, J = 12.4, 5.3 Hz, H-15), 3.34 (d,
J = 18.6 Hz, H-10), 3.85 (s, OCH3), 4.23 (d, J = 5.4 Hz,
H-9), 4.87 (s, H-5), 6.17 (d, J = 10.0 Hz, H-7), 6.65 (d,
J = 8.2 Hz, H-1), 6.72 (d, J = 8.2 Hz, H-2), 7.23 (d,
J = 10.0 Hz, H-8), 7.45 (t, J = 7.7 Hz, benzoyl H-meta),
7,8-Didehydro-4,5-epoxy-17-(2-propenyl)-(5a,6a)-morphi-
nan-3,6-diol 3,6-dibenzoate (7b, C33H29NO5)
Yield: 85 %; m.p.: 150–152 °C (ether); 1H NMR (600
MHz, CDCl3): d = 2.11 (d, J = 12.2 Hz, H-15), 2.70 (br s,
H-15), 2.81 (t, J = 12.4 Hz, H-16), 2.82 (dd, J = 18.6,
5.6 Hz, H-10), 3.16 (br s, H-10), 3.33 (d, J = 9.5 Hz,
H-16), 3.64 (m, 1H of allyl), 3.71 (s, H-14), 3.76 (m, 1H of
allyl), 4.12 (br s, H-9), 5.37 (d, J = 7.0 Hz, H-5), 5.46 (m,
H-6), 5.50 (d, J = 10.1 Hz, H-8), 5.91 (d, J = 10.1 Hz,
H-8), 5.52–5.55 (m, 2H of allyl), 6.33 (m, 1H of allyl), 6.74
(d, J = 8.1 Hz, H-1), 7.01 (d, J = 8.1 Hz, H-2), 7.27
(t, J = 7.8 Hz, 6-O-benzoyl H-meta), 7.31 (t, J = 7.8 Hz,
3-O-benzoyl H-meta), 7.46 (t, J = 7.6 Hz, 6-O-benzoyl
H-para), 7.53 (t, J = 7.5 Hz, 3-O-benzoyl H-para),
7.58 (t, J = 7.7 Hz,
H benzoyl H-para), 7.99 (d,
J = 7.9 Hz, benzoyl H-ortho) ppm; 13C NMR (151 MHz,
CDCl3): d = 22.5 (CH2), 32.0 (CH2), 42.8 (NCH3), 45.6
(CH2), 48.5 (C), 56.5 (OCH3), 58.4 (CH), 79.5 (C), 87.3
(CH), 113.2 (CH), 119.5 (CH), 128.0 (C), 128.3 (2 CH),
129.7 (2 CH), 130.8 (C), 131.8 (C), 132.8 (CH), 138.0
123

´
S. Beni et al.
1440
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(CH), 142.5 (C), 145.6 (C), 193.5 (C) ppm; HRMS: m/z
calcd. for [M ? H]? ([C25H24NO5]?) 418.1654, found
418.1649; EI-MS: m/z (%) = 417 (M?, 20), 312 (100).
5. Whitehouse LW, Paul CJ, Gottschling KH, Lodge BA, By AW
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14-Benzoyloxy-7,8-didehydro-4,5-epoxy-3-methoxy-17-
methyl-(5a,6a)-morphinan-6-ol (9b, C25H25NO5)
Yield: 78 %; m.p.: 220–222 °C (chloroform–p. ether); H
1
NMR (600 MHz, CDCl3): d = 1.87 (dd, J = 12.6, 2.1 Hz,
H-15), 2.33 (s, NCH3), 2.46 (td, J = 12.3, 3.5 Hz, H-16),
2.48 (dd, J = 18.6, 5.5 Hz, H-10), 2.56 (dd, J = 12.1,
4.9 Hz, H-16), 2.68 (td, J = 12.5, 5.2 Hz, H-10), 3.29 (d,
J = 18.8 Hz, H-10), 3.86 (s, OCH3), 4.30 (d, J = 5.9 Hz,
H-9), 4.53 (m, H-6), 5.03 (d, J = 6.7 Hz, H-5), 5.83 (dt,
J = 10.0, 1.5 Hz, H-7), 6.00 (dd, J = 10.0, 2.9 Hz, H-7),
6.61 (d, J = 8.1 Hz, H-1), 6.69 (d, J = 8.1 Hz, H-2), 7.45
(t, J = 7.7 Hz, benzoyl H-meta), 7.56 (t, J = 7.6 Hz,
benzoyl H-para), 7.99 (d, J = 7.9 Hz, benzoyl H-ortho)
ppm; 13C NMR (151 MHz, CDCl3): d = 22.5 (CH2), 31.6
(CH2), 42.8 (NCH3), 45.3 (CH2), 47.0 (C), 56.3 (OCH3),
58.2 (CH), 65.3 (CH), 78.3 (C), 89.1 (CH), 113.2 (CH),
119.3 (CH), 126.7 (C), 128.3 (2 CH), 128.9 (CH), 129.7 (2
CH), 130.6 (C), 131.5 (C), 132.8 (C), 136.5 (CH), 142.5
(C), 145.2 (C), 165.2 (C) ppm; HRMS: m/z calcd. for
[M ? H]? ([C25H26NO5]?) 420.1805, found 420.1798;
EI-MS: m/z (%) = 419 (M?, 10), 315 (63).
´
´
´
11. Varadi A, Gergely A, Beni Sz, Jankovics P, Noszal B, Hosztafi S
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13. Davies A, Zeppetella G, Andersen S, Damkier A, Vejlgoard T,
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14-Benzoyloxy-4,5-epoxy-3-methoxy-17-methylmorphinan-
6-one (10)
}
20. Hosztafi S, Kohegyi I, Simon C, Furst S (1993) Arzneim-Forsch/
¨
Drug Res 43:1200
Yield: 67 %; m.p.: 266–269 °C (chloroform-ethanol) (Ref.
[23] 275–276 °C).
21. Wright CI (1941) J Pharmacol Exp Ther 71:164
22. Berry DJ, Digiovanna CV, Metrick SS, Murugan R (2001)
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4,5-Epoxy-17-methyl-(5a,6a)-morphinan-3,6-diol 3,6-
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23. Freund M, Speyer E (1916) J Prakt Chem 94:135
24. Weiss U, Weiner N (1949) J Org Chem 14:194
´
25. Valko K (2004) J Chrom A 1037:299
Yield: 90 %; m.p.: 165–167 °C (ethanol) (Ref. [33]
167 °C).
26. Kerns EH, Di L, Petusky S, Kleintop T, Huryn D, McConnel O,
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Yield: 99 %; m.p.: 158–159 °C (ethanol) (Ref. [34]
1
155–157 °C); H and 13C NMR spectra were found to be
identical to the ones described in Ref. [11]; HRMS: m/z
calcd. for [M ? H]? ([C17H22NO3]?) 288.1594, found
288.1592.
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123