Racemization of (S)-(+)-10,11-dimethoxyaporphine and (S)-(+)-aporphine: efficient preparations of (R)-(-)-apomorphine and (R)-(-)-aporphine via a recycle process of resolution

Article abstract of DOI:10.1016/j.tetasy.2006.08.005

Efficient preparations of (R)-(-)-apomorphine (R)-1 and (R)-(-)-aporphine (R)-2 based on a recycle process of resolution are described. In this recycle process of resolution, (RS)-(±)-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-(±)-aporphine 2 were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of (R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.

Full text of DOI:10.1016/j.tetasy.2006.08.005

Tetrahedron: Asymmetry 17 (2006) 2210–2215
Racemization of (S)-(+)-10,11-dimethoxyaporphine and
(S)-(+)-aporphine: efficient preparations of (R)-(ꢀ)-apomorphine
and (R)-(ꢀ)-aporphine via a recycle process of resolution
Xiao-Xin Shi,* Feng Ni, Hai-Xia Shang, Ming-Le Yan and Jun-Quan Su
Department of Pharmaceutical Engineering, School of Pharmacy, East China University of Science and Technology, PO Box 363,
130 Mei-Long Road, Shanghai 200237, PR China
Received 8 June 2006; accepted 7 August 2006
Abstract—Efficient preparations of (R)-(ꢀ)-apomorphine (R)-1 and (R)-(ꢀ)-aporphine (R)-2 based on a recycle process of resolution are
described. In this recycle process of resolution, (RS)-( )-10,11-dimethoxyaporphine 3 as the precursor of 1, and (RS)-( )-aporphine 2
were successfully resolved into both enantiomers with (+)-dibenzoyltartaric acid (DBTA). The desired (R)-3 and (R)-2 were obtained and
then, respectively, transformed to compound (R)-1, the hydrochloride salt of (R)-1, diacetate compound 4 and the hydrochloride salt of
(R)-2; while the undesired (S)-3 and (S)-2 were racemized to obtain a racemate, which was suitable for further resolution. A method for
the racemization of the undesired (S)-3 and (S)-2 was extensively studied, in order to obtain high-yielding racemization conditions. A
plausible mechanism for the racemization of (S)-3 and (S)-2 was also proposed.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
unwanted isomer is carried in a separate step. The resolu-
tion and racemization can thus be repeated for multiple
cycles in order to obtain an as high as possible yield of
the desired isomer, the whole procedure is quite simple
and easy to operate. Herein, we report our preparations
of (R)-(ꢀ)-apomorphine (R)-1 and its analogue (R)-(ꢀ)-
aporphine (R)-2 via a recycle process of resolution.
The importance of chiral compounds is widely recognized.
In general, there are two typical ways to obtain chiral
compounds. One is asymmetric synthesis, while the other
is chiral resolution. Despite the revolutionary advances in
asymmetric synthesis over the last few decades, resolution
as a ‘low-tech’ method is still the most important approach
to chiral compounds especially in large scale preparations
or industrial syntheses, as it is often the most economical
and convenient method. However, only a maximum theo-
retical yield of 50% can be achieved during resolution, dis-
carding of the other half (i.e., the unwanted isomer) is
economically and environmentally unacceptable. For this
reason, some strategies such as recycling resolution (recycle
process of resolution),1–9 dynamic kinetic resolution
(DKR),10–12 etc.13,14 have recently been developed and
can usually be used to overcome this disadvantage. These
strategies seem attractive, because the undesired isomer
can be recycled, meaning a theoretical yield of 100% can
still be obtained. For the strategy of recycling resolution
(recycle process of resolution), the resolution is performed
first to separate two isomers, and then racemization of the
(R)-(ꢀ)-Apomorphine and its non-oxygenated analogue
(R)-(ꢀ)-aporphine are of pharmaceutical value,15–22 and
therefore have attracted much interest from synthetic
chemists. Although the total syntheses of (RS)-( )-apo-
morphine (RS)-1 and (RS)-( )-aporphine (RS)-2 have
been well documented,23–31 preparations of (R)-(ꢀ)-apo-
morphine and (R)-(ꢀ)-aporphine are rare.32–37 Recently
we have become interested in developing an effective meth-
od to obtain enough quantity of (R)-(ꢀ)-apomorphine and
(R)-(ꢀ)-aporphine in order to test their physiological roles,
so a strategy based on recycling resolution was chosen to
be used for this purpose.
2. Results and discussion
It is obviously not reasonable to directly resolve (RS)-1
considering the fact that apomorphine is unstable and
*
Corresponding author. E-mail: xxshi@ecust.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.08.005

X.-X. Shi et al. / Tetrahedron: Asymmetry 17 (2006) 2210–2215
2211
rapidly turns dark green on exposure to light and air, the
better way is to resolve the stable (RS)-( )-10,11-dimethoxy-
aporphine (RS)-3 first to gain (R)-(ꢀ)-10,11-dimethoxy-
aporphine (R)-3, and then transform it into (R)-1 after
ether cleavage (Scheme 1, X = OCH3). Compound (RS)-2
is very stable, and can therefore be directly resolved into
(R)-2 and (S)-2 (Scheme 1, X = H).
with (+)-di-p-toluoyl tartaric acid as has been reported by
Cannon et al.,37 (+)-DBTA is cheaper and gave a better
yield here.
While 43% of the desired (R)-3 was obtained from the res-
olution of the (RS)-3 with (+)-DBTA, 40% of undesired
(S)-3 was also obtained. Since (S)-(ꢀ)-apomorphine (S)-1
does not possess significant biological activity, compound
(S)-3 as a precursor of (S)-1 could be discarded. We
attempted to find a method to convert this unwanted
compound (S)-3 into the useful (R)-3. This conversion was
achieved by transforming (S)-3 into (RS)-3 and then into
(R)-3. Compound (S)-3 was thus recycled just by repeating
this racemization and resolution procedure. Herein, the
racemization of (S)-3 was extensively studied, and many
conditions were tried, which are summarized in Table 1.
As can be seen in Table 1, (S)-3 can be efficiently racemized
into (RS)-3 with a strong base such as potassium hydr-
oxide, sodium methoxide, sodium ethoxide, and potassium
tert-butoxide in DMSO at a temperature higher than
120 ꢁC (Table 1, entries 1, 2, 4, 8, 10, and 12). It is difficult
to understand why sodium hydroxide was not a suitable
base for the racemization, when 10 equiv of sodium
hydroxide was used, only a slight amount of racemization
occurred even when heating at 140 ꢁC for 2 h (entry 6).
The solvent effect is dramatic here, DMSO is the only
favorable solvent. Other solvents such as DMF, methanol,
ethanol, etc. could not be used here. Temperature had a
notable impact on the racemization, the temperature
should not be kept below 120 ꢁC (entries 3, 9, and 11).
Resolution
a
N
N
H
H
X
X
b
Racemization
X
X
X = H
X = OCH3 (RS)-3
(RS)-2
X = H
X = OCH3 (S)-3
(S)-2
a
Resolution
N
N
c
H
H
RO
RO
X
X = OCH3
X
X = H
X = OCH3 (R)-3
(R)-2
R = H
R = Ac
(R)-1
(R)-4
d
Scheme 1. Reagents and conditions: (a) 1 equiv (+)-DBTA in EtOAc:
i-PrOH (3:2); (b) 2–3 equiv KOH in DMSO at 120 ꢁC for 2 h; (c) reflux
in HBr–AcOH (6 h); (d) large excess of pyridine and Ac2O at rt.
We also attempted the racemization of (S)-2 in order to
convert the unwanted (S)-2 into the useful (R)-2. We found
that the racemization of (S)-2 could also be carried out (en-
tries 16–18). The favorable solvent was DMSO, with the
temperature kept at 120–140 ꢁC. Suitable bases were potas-
sium hydroxide, sodium ethoxide, and potassium ethoxide.
Surprisingly, the strong base sodium hydroxide also failed
here to racemize (S)-2 into (RS)-2 (entry 15) as it did for
(S)-3 (entry 6), which implies something we have not yet
known for a possible mechanism of racemization.
We found that the total syntheses reported by Neumeyer
et al.28 starting from the Reissert’s compound were much
more convenient than others. As a result Neumeyer
et al.’s procedure28 was followed in our laboratory in order
to obtain (RS)-2 and (RS)-3.
With racemic compounds (RS)-2 and (RS)-3 in hand, we
attempted to resolve them with natural (+)-tartaric acid
to obtain (R)-2 and (R)-3 according to Saari et al.’s
report,38 but unfortunately the salts of 2 and 3 with (+)-
tartaric acid precipitated very slowly in several solvents
tried, and the yields were low. We then turned our attention
to several other chiral acids for resolving (RS)-2 and (RS)-
3. The chiral acids we examined included (ꢀ)-malic acid,
(ꢀ)-acetyl malic acid, (+)-10-camphorsulfonic acid, (+)-
diacetyl tartaric acid, (+)-di-p-toluoyl tartaric acid, and
(+)-dibenzoyl tartaric acid. Finally, we found that both
(RS)-2 and (RS)-3 can be efficiently resolved with (+)-di-
benzoyl tartaric acid (DBTA). The salts of 2 and 3 with
(+)-DBTA precipitated quite fast in the mixed solvent of
ethyl acetate and isopropanol. By adjusting the ratio of
ethyl acetate and isopropanol to 3:2, the highest yields
(43% for 2 and 42% for 3, respectively) of resolution could
be reached. There is another advantage when using (+)-
DBTA as a resolving agent, it can be recovered from aque-
ous solution by extraction with ethyl acetate after neutral-
ization with hydrochloric acid. (RS)-2 can also be resolved
It should be pointed out that there is no need to always use
enantiomerically pure (S)-3 and (S)-2 for the racemization
experiment, the optically enriched compounds from the
mother liquid of the resolution can also be directly used
for the method, (R)-3 and (R)-2 can also be racemized into
(RS)-3 and (RS)-2 under the same conditions.
Davis et al. reported an example of racemization of (R)-3 in
1980,39 when they wanted to prepare (S)-(+)-apomorphine
from (R)-(ꢀ)-apomorphine. Davis et al.’s method of race-
mization included two steps: palladium-catalyzed dehydro-
genation and reduction of an enamine with sodium
cyanoborohydride. Obviously, our method outlined herein
is more inexpensive and more convenient than Davis
et al.’s report.
A plausible mechanism of the racemization is now pro-
posed. As described in Scheme 2, the proton at the stereo-
genic center of (S)-3 or (S)-2 is weakly acidic, it could be
removed by a strong base affording a pyramidal carbanion

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X.-X. Shi et al. / Tetrahedron: Asymmetry 17 (2006) 2210–2215
Table 1. Racemization of (S)-(+)-3 and (S)-(+)-2
Entry
Compound
Base (equiv)
Solvent
Temperature (ꢁC)
Time (h)
PRa (%)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-3
(S)-2
(S)-2
(S)-2
(S)-2
(S)-2
KOH (5)
KOH (2)
KOH (2)
DMSO
DMSO
DMSO
DMSO
DMF
DMSO
DMF
DMSO
EtOH
DMSO
MeOH
DMSO
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
120
120
100
140
120
140
120
120
80c
2
2
2
5
4
2
4
2
10
2
12
2
5
2
2
2
2
2
100
100
65
100
10
6
3
100
24
100
15
94
95
97
80
78
85
84
89
96
88
92
90
90
95
92
96
89
88
KOH (0.5)
KOH (10)
NaOH (10)
NaOH (10)
EtONa (2)
EtONa (10)
MeONa (2)
MeONa (10)
t-BuOK (2)
t-BuOK (2)
LiOH (5)
120
70c
120
120
140
140
120
120
120
100
25
0
NaOH (5)
KOH (3)
EtONa (3)
EtOK (3)
5
100
100
100
a Percentage of racemization.
b Isolated yield of compound 3 or 2.
c Refluxing.
mized into (RS)-3 (or 2). It is notable that a rapid Waldern
type inversion between A-I and A-II needs relatively high
energy to overcome the interconversion barrier, because
torsional strain of both pyramidal carbanions plays a sig-
nificant role. This is why a complete racemization of (S)-
3 (or 2) needs a temperature higher than 120 ꢁC as shown
in Table 1. We also propose that potassium hydroxide first
reacts with DMSO to form a more reactive anion species
(potassium methylsulfinyl methide)43–46 which then reacts
with 3 (or 2) to form the intermediate anion A-I, thus the
dramatic solvent effect can be understood.
O
N
H
N
S
S
X
X
X
H+
2 or 3
A-I
X
X = H or OCH3
O
S
X
.
.
Pyramidal
Inversion
Another mechanism for the racemization of (S)-3 or (S)-2
is also possible. The removal of the proton at the stereo-
genic center of (S)-3 or (S)-2 by a strong base affords a pla-
nar carbanion (A-III)47 in which an unshared electron pair
occupies a conjugate p orbital leading to delocalization of
the electron pair and thus stabilizing the carbanion. Pro-
tonation of the planar carbanion (A-III) would definitely
produce a racemic compound [(RS)-3 or (RS)-2] due to
equal probabilities of access of the proton on both faces
of the plane.
X
H+ ROM
A-III
Planar Anion
O
S
O
N
R
N
H
S
X
X
X
H+
Actually, the shape (planar or pyramidal) of a carbanion
probably depends upon the counterion. For example, a
potassium cation tends to furnish a planar benzylic carban-
ion (A-III), while a lithium cation tends to furnish a pyra-
midal carbanion (A-I or A-II).47 Whenever a pyramidal or
planar carbanion was involved in the mechanism, racemi-
zation would consequently occur. A carefully designed
experiment would support our proposed mechanism, when
the mixture of (S)-2 and 2 equiv of potassium hydroxide
was stirred for 2 h at 120 ꢁC in the deuterated solvent
(DMSO-d6), 1H NMR analysis of the isolated product
showed that a deuterium atom was incorporated at the ste-
reogenic center of (RS)-2, which means that a carbanion
formed during the racemization.
A-II
X
Scheme 2.
A-I in which an unshared electron pair occupies a down-
ward sp3 hybrid orbital,40,41 and the configuration of the
stereogenic center is retained. Carbanion A-I will automat-
ically change into the other pyramidal carbanion A-II via a
Waldern type inversion42 upon heating, an unshared
electron pair will occupy an upward sp3 hybrid orbital in
A-II, and the configuration of the stereogenic center will
be inverted. The above pathway should be reversible, which
means that both (S)-3 (or 2) and (R)-3 (or 2) can be race-

X.-X. Shi et al. / Tetrahedron: Asymmetry 17 (2006) 2210–2215
2213
20
Finally, by refluxing with an excess of hydrobromic acid in-
stead of hydroiodic acid in acetic acid, the dimethyl ether
bonds of (R)-3 were cleaved to furnish the title compound
(R)-1 in a good yield. Free apomorphine is quite unstable,
hence it was transformed into the crystalline apomorphine
hydrochloride (R)-1-HCl which can be stored in a refriger-
ator for more than 6 months. It can also be transformed
into the stable compound (R)-(ꢀ)-10,11-diacetoxyapor-
phine 4 which is converted in vivo to free apomorphine.
This diester derivative of (R)-(ꢀ)-apomorphine serves as
a prodrug of apomorphine and exhibits an extended half-
life.48
(3.55 g) with a specific rotation value of ½aꢁD ¼ þ10:1 (c 1,
methanol). The salt was dissolved in water (20 ml), the pH
of the aqueous solution was then adjusted to 9 by addition
of potassium carbonate, and the aqueous solution was
extracted twice with ethyl acetate (25 ml · 2). Combined
extracts were dried over anhydrous sodium sulfate, and
then evaporated to dryness to afford (R)-(ꢀ)-10,11-dimeth-
20
oxyaporphine (1.60 g, 5.42 mmol) in 42% yield, ½aꢁD
¼
ꢀ172:3 (c 1.4, methanol).
The mother liquid from the above resolution was concen-
trated to dryness, and dissolved in water (50 ml). The aque-
ous solution was made alkaline (pH = 9) by the addition of
potassium carbonate, and extracted twice with ethyl ace-
tate (25 ml · 2). The combined extracts were evaporated
to dryness to give a residue. Ethanol (20 ml) and concen-
trated hydrochloric acid (1 ml, 12 mmol) were then added.
The solution was heated at reflux for 1 h, and then evapo-
rated to dryness under a vacuum to give a viscous oil which
was recrystallized in acetone to yield white crystals of (S)-
(+)-10,11-dimethoxyaporphine hydrochloride. The white
crystals were dissolved in water (20 ml) to form a clear
aqueous solution which was made alkaline (pH = 9) with
potassium carbonate and twice extracted with ethyl acetate
(20 ml · 2). The combined extracts were washed with brine
(10 ml) and dried over anhydrous sodium sulfate. Removal
3. Conclusion
In conclusion, a recycling resolution method for the prep-
arations of (R)-(ꢀ)-apomorphine and (R)-(ꢀ)-aporphine
has been described. Racemization of (S)-(+)-10,11-dimeth-
oxyaporphine and (S)-(+)-apomorphine was extensively
studied, and the best conditions found. A possible mecha-
nism for the racemization has also been proposed.
4. Experimental
4.1. General methods
of the solvent afford (S)-(+)-10,11-dimethoxyaporphine
20
(1.53 g, 5.18 mmol) in 40% yield, ½aꢁD ¼ þ172:1 (c 1.5,
Melting points are uncorrected. 1H NMR spectra were
acquired on a Bruker AM-500 instrument. Chemical shifts
were given on the delta scale as parts per million (ppm)
with tetramethylsilane (TMS) as the internal standard. IR
spectra were recorded on Nicolet Magna IR-550. Mass
spectra were recorded on HP5989A. Column chromatogra-
phy was performed on silica gel. Optical rotations of chiral
compounds were measured on WZZ-1S automatic polar-
imeter at room temperature. All solvents were purified by
standard procedures. All chemicals were analytically pure.
Racemic compounds (RS)-2 and (RS)-3 were prepared
according to a known procedure.28 (+)-Dibenzoyl tartaric
acid (DBTA) was obtained from Aldrich company or made
in our laboratory.49
methanol).
4.3. Typical procedure for the racemization of (S)-(+)-10,11-
dimethoxyaporphine (S)-3
A solution of (S)-(+)-10,11-dimethoxyaporphine (2.00 g,
6.77 mmol) in DMSO (20 ml) was transferred into a round
bottom flask with a stirrer bar under N2. Powdered potas-
sium hydroxide (0.76 g, 13.55 mmol) was added, and then
the mixture was heated to around 120 ꢁC. Stirring was con-
tinued at 120 ꢁC for 2 h. After the mixture was cooled to
room temperature, it was diluted with water (80 ml). The
diluted aqueous solution was extracted twice with toluene
(40 ml · 2), the combined extracts were washed succes-
sively with water (30 ml) and brine (10 ml). After drying
with anhydrous sodium sulfate, the solvent was removed
by a rotavapor. The residue was chromatographed through
a short column of silica gel to give racemic 10,11-dimeth-
4.2. Resolution of (RS)-10,11-dimethoxyaporphine (RS)-3
A
solution of (+)-dibenzoyl tartaric acid (4.61 g,
1
12.86 mmol) in ethyl acetate (45 ml) was transferred into
a three-necked flask with a magnetic stirrer bar. Then a
solution of racemic 10,11-dimethoxyaporphine (3.80 g,
12.86 mmol) in ethyl acetate (15 ml) was added dropwise
within 5 min at room temperature, and white crystals
formed in 15 min. The mixture was heated at reflux, after
which isopropanol (40 ml) was added, and the mixture
turned clear. Refluxing was continued for 1 h, and then
the mixture was allowed to cool to room temperature
and then to 0 ꢁC in an ice bath, causing white needles to
precipitate. Filtration separated the white needles from
the mother liquid which was used to recover (S)-(+)-
10,11-dimethoxyaporphine at the later stage. The white
needles (4.20 g) were recrystallized in the mixed solvent of
ethyl acetate (35 ml) and isopropanol (25 ml) to produce
(R)-(ꢀ)-10,11-dimethoxyaporphinium (+)-dibenzoyl tartrate
oxyaporphine (1.90 g, 6.43 mmol) in 95% yield. H NMR
showed that the product here was identical to the sample
from the total synthesis and thus can be used for further
resolution.
4.4. Preparation of (R)-(ꢀ)-apomorphine hydrochloride
1–HCl
(R)-(ꢀ)-10,11-Dimethoxyaporphine (1.21 g, 4.10 mmol)
was dissolved in acetic acid (20 ml), an aqueous solution
of HBr (20 ml, 48% w/v) was added. The mixture was
heated at reflux for 6 h while stirring under N2. Then the
reaction solution was concentrated to dryness under vac-
uum, the residue was dissolved in water (20 ml). The aque-
ous solution was made alkaline (pH = 8) with NaHCO3,
and extracted twice with ethyl acetate (20 ml · 2). The

2214
X.-X. Shi et al. / Tetrahedron: Asymmetry 17 (2006) 2210–2215
combined extracts were washed with brine (10 ml) and
dried over anhydrous sodium sulfate. Removal of the
solvent gave a bluish oily residue, which was immediately
dissolved in ethanol (20 ml). Concentrated hydrochloric acid
(0.7 ml, 8.4 mmol) and activated carbon (0.5 g) were added,
and the solution heated at reflux for 1 h under N2. The
solution was filtered to remove activated carbon and evap-
orated to dryness under vacuum. Dry acetone (15 ml) was
added, and the mixture stirred vigorously for half an hour,
then left to stand overnight in a refrigerator. The off-white
solid was collected by filtration and washed with ethyl
slowly to room temperature. White needles precipitated,
and the mixture was left to stand overnight. The crystals
were separated from the mother liquid by suction. A white
solid (5.70 g) was obtained and recrystallized in a mixed
solvent of ethyl acetate (45 ml) and isopropanol (32 ml)
to produce (R)-(ꢀ)-aporphinium (+)-dibenzoyl tartrate
20
(5.00 g) with a specific rotation of ½aꢁD ¼ þ26:1 (c 0.5,
methanol). The salt was dissolved in water (30 ml), the
pH of the aqueous solution adjusted to 10 by adding a
powdered potassium carbonate. After double extraction
of the aqueous solution with ethyl acetate (30 ml · 2), the
extracts were combined and dried over anhydrous sodium
acetate. (R)-(ꢀ)-Apomorphine hydrochloride (1.01 g,
20
3.32 mmol) was thus obtained in 81% yield, ½aꢁD ¼ ꢀ48:1
25
sulfate. Removal of the solvent gave (R)-(ꢀ)-aporphine
20
(c 1.0, water) {lit.50 ½aꢁD ¼ ꢀ48:0 (c 1.2, water)}. 1H
(1.96 g, 8.33 mmol) in 43% yield, ½aꢁD ¼ ꢀ151:6 (c 0.6,
1
NMR (CD3OD):
d
8.43 (d, J = 7.9 Hz, 1H), 7.36
methanol). H NMR (CDCl3): d 7.72 (d, J = 7.7 Hz, 1H),
(t, J = 7.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.74
(d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 4.26 (d,
J = 12.1 Hz, 1H), 3.79 (dd, J = 5.2, 11.8 Hz, 1H), 3.49
(dt, J = 3.5, 12.8 Hz, 1H), 3.32–3.43 (m, 2H), 3.19 (s,
3H), 3.10 (dd, J = 3.4, 17.5 Hz, 1H), 2.77 (t, J = 13.7 Hz,
1H). MS(EI) m/z (% relative intensity) 267 (M+, 63),
266(100), 248(11), 224(22), 206(8), 178(5), 152(6), 131(14).
7.57 (d, J = 7.6 Hz, 1H), 7.32(dd, J = 7.1, 7.3 Hz, 1H),
7.21–7.27 (m, 3H), 7.08 (d, J = 7.5 Hz, 1H), 3.15–3.26
(m, 3H), 3.08 (dd, J = 5.8, 11.4 Hz, 1H), 2.66–2.79 (m,
1H), 2.57 (s, 3H), 2.51–2.58 (m, 1H). MS(EI) m/z (% rela-
tive intensity) 235 (M++1, 31), 234 (M+, 100), 219(8),
203(3), 192(32), 178(3), 165(6), 44(6). IR(neat) 3050,
2900, 2750, 2700, 1475, 1440, 745, 700 cmꢀ1
.
4.5. Preparation of diacetate of (R)-(ꢀ)-apomorphine 4
The mother liquid from the above resolution was concen-
trated to dryness. Water (50 ml) was added, and the pH
of the aqueous solution adjusted to 10 by adding powdered
potassium carbonate. Two extractions of the alkaline aque-
ous solution with ethyl acetate (50 ml · 2) and evaporation
of the solvent gave a residue which was dissolved in a
mixed solvent of ethyl acetate (60 ml) and isopropanol
(40 ml). (ꢀ)-Dibenzoyl tartaric acid (3.93 g, 10.97 mmol)
was then added, and the mixture was heated at reflux for
2 h. The mixture was allowed to cool to room temperature
and to stand overnight. A white solid (5.51 g) was obtained
by suction and recrystallized in the mixed solvent of ethyl
acetate (45 ml) and isopropanol (32 ml) to produce
(R)-(ꢀ)-Apomorphine hydrochloride (0.91 g, 3.00 mmol),
acetic anhydride (6 ml), and pyridine (1 ml) were mixed
in a dry round bottom flask with a magnetic stirrer bar.
When the mixture was stirred at room temperature for
3 h, the reaction was complete as monitored by TLC.
The reaction mixture was then diluted with ethyl acetate
(60 ml), and a solution of potassium carbonate (7.60 g,
0.055 mol) in water (60 ml) was added while stirring. The
organic phase was separated, washed successively with
water (20 ml) and brine (10 ml), and then dried over anhy-
drous sodium sulfate. Removal of the solvent gave a pale
yellow crude oil which was chromatographed through a
short column of silica gel to afford (R)-(ꢀ)-10,11-diacet-
(S)-(+)-aporphinium (ꢀ)-dibenzoyl tartrate (4.8 g) with a
20
specific rotation of ½aꢁD ¼ ꢀ26:0 (c 0.5, methanol). After
oxyaporphine 4 (0.95 g, 2.71 mmol) in 90% yield, mp
the neutralization and extraction per the above procedure
as described for (R)-(ꢀ)-aporphinium, (ꢀ)-dibenzoyl
20
127–128 ꢁC (lit.50 127–128 ꢁC), ½aꢁD ¼ ꢀ137:1 (c 0.3, meth-
20
anol) and ½aꢁD ¼ ꢀ89:0 (c 0.5, 0.1 M HCl) {lit.50
tartrate gave (S)-(+)-aporphine (1.91 g, 8.12 mmol) in
24
20
½aꢁD ¼ ꢀ88 (c 1.12, 0.1 M HCl)}. 1H NMR (CDCl3): d
42% yield, ½aꢁD ¼ þ152:0 (c 0.6, methanol).
7.75 (d, J = 7.8 Hz, 1H), 7.16–7.24 (m, 2H), 7.10 (d,
J = 7.7 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 3.12–3.23 (m,
3H), 3.04 (dd, J = 5.9, 11.6 Hz, 1H), 2.75 (dd, J = 3.1,
16.3 Hz, 1H), 2.50–2.61 (m, 2H), 2.55 (s, 3H), 2.31 (s,
3H), 2.27 (s, 3H). MS(EI) m/z (% relative intensity) 351
(M+, 77), 308(68), 266(100), 248(5), 224(10), 206(8),
165(5), 43(8).
4.7. Racemization of (S)-(+)-aporphine (S)-2
(S)-(+)-Aporphine (1.91 g, 8.12 mmol) was dissolved in
DMSO (20 ml). Powdered potassium hydroxide (1.37 g,
24.41 mmol) was added, and then heated to around
120 ꢁC. Stirring was continued at 120 ꢁC under an atmo-
sphere of N2 for 2 h. After work-up per the procedure as
described for (S)-(+)-10,11-dimethoxyaporphine, racemic
aporphine (1.83 g, 7.78 mmol) was obtained in 96% yield.
1H NMR showed that it was identical with the sample from
the total synthesis and could thus be used for further
resolution.
4.6. Resolution of (RS)-aporphine (RS)-2
A
solution of (+)-dibenzoyl tartaric acid (6.91 g,
19.29 mmol) in ethyl acetate (75 ml) was transferred into
a three-necked flask, which was equipped with a condenser
and a mechanical stirrer. Racemic aporphine (4.54 g,
19.29 mmol) was then quickly added at room temperature,
which caused white crystals to form in 15 min. The mixture
was then heated at reflux while stirring. After isopropanol
(50 ml) was added, refluxing was continued for 1.5 h, caus-
ing the mixture to gradually became a clear solution.
Refluxing was stopped, and the mixture allowed to cool
4.8. Preparation of (R)-(ꢀ)-aporphine hydrochloride 2–HCl
(R)-(ꢀ)-Aporphine (1.47 g, 6.25 mmol) was dissolved in
ethanol (20 ml). Concentrated hydrochloric acid (1.0 ml,
12.0 mmol) was then added, and then the solution heated
at reflux for 1 h under an atmosphere of N2. Evaporation

X.-X. Shi et al. / Tetrahedron: Asymmetry 17 (2006) 2210–2215
2215
20. Thomas, J. A. Jpn. J. Pharmacol. 2002, 89, 101.
of the solvent gave a pale yellow oily residue, which was
triturated with ethyl acetate to give (R)-(ꢀ)-aporphine
hydrochloride (1.49 g, 5.48 mmol) as a white solid in 88%
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20
20
yield, ½aꢁD ꢀ 106:6 (c 0.3, methanol) {lit.37 ½aꢁD ¼ ꢀ109:4
(c 0.0019, methanol)}. 1H NMR (CD3OD): d 7.82 (d,
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We thank the Chinese National Natural Science Founda-
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Development Foundation (The Dawn Program: No.
03SG27) for the financial support of this work.
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