Synthesis of (R)-(-)-2-fluoronorapomorphine - A precursor for the synthesis of (R)-(-)-2-fluoro-N-[11C]propylnorapomorphine for evaluation as a dopamine D2 agonist ligand for PET investigations

Article abstract of DOI:10.1002/ejoc.200500295

2-Fluoronorapomorphine, the PET labelling precursor to 2-fluoro-N-[ ¹¹C]propylnorapomorphine, was prepared in 13 steps from codeine in a total yield of 10 %. Codeine was converted in four steps into N-benzylnorcodeine which was oxidised by usin

Full text of DOI:10.1002/ejoc.200500295

FULL PAPER
Synthesis of (R)-(–)-2-Fluoronorapomorphine − A Precursor for the Synthesis
of (R)-(–)-2-Fluoro-N-[11C]propylnorapomorphine for Evaluation as a
Dopamine D2 Agonist Ligand for PET Investigations
Kåre Søndergaard,[a–c] Jesper Langgaard Kristensen,[a] Nic Gillings,[c] and
Mikael Begtrup*[a]
Keywords: Dopamine D2 receptor / 2-Fluoro-N-propylnorapomorphine / PET radioligand / Palladium-catalysed amin-
ation / Balz–Schiemann reaction
2-Fluoronorapomorphine, the PET labelling precursor to 2-
fluoro-N-[11C]propylnorapomorphine, was prepared in 13
steps from codeine in a total yield of 10%. Codeine was con-
verted in four steps into N-benzylnorcodeine which was oxi-
dised by using the Swern protocol. Subsequent acid-cata-
lysed rearrangement afforded N-benzylnormorphothebaine
which was selectively triflylated at the 2-position and piva-
loylated at the 11-position. The triflate underwent palladium-
catalysed amination with benzophenone imine. Amination
conditions required sequential base addition to give substan-
tial conversion of the triflate to the corresponding N-substi-
tuted benzophenone imine. After acidic hydrolysis the re-
sulting aniline was transformed into the 2-fluoro compound
via the Balz–Schiemann reaction. Hydrogenolysis of the N-
benzyl group followed by deprotection of the catechol moiety
using BBr3 provided 2-fluoronorapomorphine.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
dopamine D2 agonists [11C]apomorphine[10] and N-[11C]
propylnorapomorphine.[11–13] The latter provides the best
striatum/cerebellum ratio so far (i.e. region-of-interest to
reference region ratio) of 2.8 in baboon.
It is known that substituents in the 2-position of apo-
morphines can modulate dopaminergic D2 activity and se-
lectivity.[14,15] In particular, the 2-fluoro-N-propylnorapo-
Introduction
Ever since postmortem studies revealed a deficiency in
striatal dopamine in patients with Parkinson’s Disease,[1]
the dopaminergic system has been the subject of intense
research. In particular, the dopamine D2 receptor has
emerged as an important mediator in the central nervous
system for various processes such as motor function and
reward.[2]
Positron emission tomography (PET) is a non-invasive
technique that enables monitoring of, for example, the do-
pamine D2 receptor in the living brain.[3–8] The dopamine
high
D2 receptor exists in two states – a functional state (D2
)
and a non-functional state (D2low). Agonists preferentially
bind to the functional state (i.e. the high affinity state)
whereas antagonists bind equally well to both states.[9] For
this reason agonists may be more sensitive to competition
effects from the endogenous agonist dopamine for imaging
changes in synaptic dopamine concentration. Radioligands
that previously have been used in PET studies to measure
synaptic changes in dopamine concentration include the
[a] The Danish University of Pharmaceutical Sciences, Institute for
Medicinal Chemistry,
Universitetsparken 2, 2100 Copenhagen, Denmark
Fax: +45-35-30-60-40
E-mail: mb@dfuni.dk
[b] University Hospital Rigshospitalet, Neurobiology Research
Unit,
Blegdamsvej 9, 2100 Copenhagen, Denmark
[c] University Hospital Rigshospitalet, PET and Cyclotron Unit,
Blegdamsvej 9, 2100 Copenhagen, Denmark
Scheme 1. The archetypical dopamine D2 receptor agonist (R)-(–)-
apomorphine and two derivatives, NPA and 2F-NPA.
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DOI: 10.1002/ejoc.200500295
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Synthesis of (R)-(–)-2-Fluoronorapomorphine
FULL PAPER
morphine (2F-NPA, Scheme 1) is 66-fold more potent than amination reaction on triflate 4. Compound 4 could come
the parent N-propylnorapomorphine (NPA, Ki 0.012 nM from dihydroxy compound 5 which is available from either
vs. 0.80 nM). Also the D1/D2 selectivity increased from 425 N-benzylnorcodeinone (6) or N-benzylnorthebaine via
to 57700 when changing the 2-substituent from hydrogen acid-catalysed rearrangement. We preferred to design our
to fluorine.[16–18] In view of this, we set out to prepare 2- synthetic route from the former since thebaine is both ex-
fluoronorapomorphine − a precursor for the preparation of pensive and toxic. α,β-Unsaturated ketone 6 is derived from
2-fluoro-N-[11C]propylnorapomorphine.
N-benzylnorcodeine (7) – a compound available in 4 steps
from codeine (8).
The synthesis commenced by converting codeine (8,
Scheme 3) by a known synthetic sequence into N-benzyl-
norcodeine (7).[20] Thus, codeine was O-acetylated followed
by N-carbamoylation/N-demethylation by the use of α-chlo-
roethyl chloroformate (ACE-Cl).[21] The resultant carba-
Results and Discussion
Introduction of the positron-emitting radionuclide car-
bon-11 into apomorphines is usually accomplished by re-
acting their corresponding norapomorphines with an elec-
trophile such as [11C]methyl iodide or [11C]propanoyl chlo-
ride. This transformation is only viable in a late stage of the
synthetic sequence due to the very short half-life of carbon-
11 (20.4 min). Therefore, previously reported syntheses of
2F-NPA by Neumeyer et al.[17] and Berenyi et al.[19] are not
amenable to PET chemistry since introduction of the N-
propyl group is performed in the early stages of the synthe-
sis. Thus a new synthetic strategy had to be developed to
provide 2-fluoronorapomorphine as a precursor for carbon-
11 labelling.
The target 2-fluoro compound 1 (Scheme 2) appropri-
ately protected at the catechol moiety and at the nitrogen
as in 2, would allow chemical transformations to be carried
out in the 2-position. The introduction of fluorine via di-
azotisation of a 2-aminoapomorphine has been reported
previously by Ramsby et al.[14] The 2-fluoro compound 2
could therefore be derived from masked aniline 3 which in
turn could be generated by the use of a palladium-catalysed Scheme 3. Four-step sequence towards 7.
Scheme 2. Retrosynthetic analysis.
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K. Søndergaard, J. L. Kristensen, N. Gillings, M. Begtrup
FULL PAPER
mate was cleaved in refluxing methanol with concomitant an N-demethylation on the aporphine skeleton. Such a
methanolysis of the acetyl ester to give 9. The secondary transformation was performed recently utilising a non-clas-
amine 9 was then selectively N-alkylated with benzyl bro- sical modified Polonovski reaction where glaucine was con-
mide in the presence of K2CO3 in DMF thus providing 7 verted to norglaucine.[26] However, this approach failed on
which contains a convenient N-protecting group removable our aporphine template.
at a late stage in the synthesis.[20]
The crucial step for introducing the masked aniline in the
Oxidation of 7 (Scheme 4) to ketone 6 was accomplished 2-position from triflate 4a turned out to be difficult. Many
by the Swern protocol [DMSO, (COCl)2]. Attempts to oxi- experiments were performed with benzophenone imine as
dise 7 by other methods such as TEMPO/re-oxidants[22,23] the ammonia equivalent.[27] Numerous amination reactions
[24]
or activated MnO2
failed. Skeletal rearrangement was were attempted including well-established protocols
achieved by treating 6 with methanesulfonic acid[25] to give using Pd(OAc)2/BINAP/Cs2CO3,[27] Pd2(dba)3/Xantphos/
rise to the dihydroxy compound 5 which was selectively tri- Cs2CO3
[28,29]
and Pd(dba)2/dppf/tBuONa.[30] All failed to
flated at the 2-position with 5-chloro-2-[bis(trifluoromethyl- provide acceptable yields of the desired aniline 3a. Some
sulfonyl)amino]pyridine. Acylation at the 11-hydroxy group conversion was achieved when using Pd2(dba)3/X-Phos/
with pivaloyl chloride was performed in the same pot. This Cs2CO3.[31] Catalyst loading, solvent and temperature were
gave a 43% overall yield of 4a from 7. A more obvious also varied. Many amination reactions require only a slight
route would be to oxidise codeine directly and perform the excess of base but in our case it was beneficial to add se-
outlined synthesis on the codeine scaffold. However, pro- veral equivalents of Cs2CO3. When starting with five equiv-
duction of the labelling norapomorphine precursor requires alents of Cs2CO3 the reaction slowed down considerably
after 75 minutes of reflux in toluene. Addition of another
five equivalents of base caused the reaction to run to com-
pletion within an additional 90 minutes. This feature may
be attributed to the “base effect” hypothesis which suggests
that liquid-solid interphase deprotonation of the palladi-
um(ii)-amine complex is the rate-determining step.[32] It was
found that using 1.2 equiv. benzophenone imine, 0.04 equiv.
Pd2(dba)3, 0.16 equiv. X-Phos and 5 + 5 equiv. Cs2CO3 in
refluxing toluene provided full conversion of triflate 4a into
imine 3a. Treating imine 3a with 1 m hydrochloric acid gave
aniline 3b in 66% yield over two steps from 4a (Scheme 5).
The aniline 3b was converted into the corresponding dia-
zonium hexafluorophosphate by treatment with tert-butyl
nitrite[33] and hexafluorophosphoric acid followed by heat-
ing in an ionic liquid[34] gave the fluoro-arene 2a (Scheme 6)
which was subsequently hydrogenolysed to provide second-
ary amine 2b. The Balz–Schiemann reaction gave rise to
some reduction of the diazonium salt to the parent 2-H
Scheme 4. Synthesis of triflate 4a.
Scheme 5. The palladium-catalysed amination of triflate 4a.
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Synthesis of (R)-(–)-2-Fluoronorapomorphine
FULL PAPER
were packed with silica gel 60 (230–400 mesh) as the stationary
phase. TLC plates (Merck 60, F254) were visualised by dipping into
a solution containing ninhydrin (0.6 g), acetic acid (1.5 mL) and
water (13.3 mL) in nBuOH (300 mL) and heating until coloured
spots appeared. 1H NMR, gCOSY, gHSQC gHMBC and 19F
compound. Attempts to avoid this by using freshly pre-
pared tert-butyl nitrite[35] or by exclusion of moisture failed.
Treatment of 2b with BBr3 furnished the labelling precursor
1 as the hydrobromic salt in a yield of 43% from 3b.
NMR were performed on
a Varian Mercury-plus 300 MHz
(IDPFG). 13C NMR was performed on a Varian Gemini 300 MHz.
Optical rotations are given in 10–1 deg cm2 g–1. Mass spectra were
recorded on a JMS-HX/HX110A tandem mass spectrometer. Melt-
ing points are uncorrected.
(R)-(–)-N-Benzyl-10-methoxy-11-pivaloyloxy-2-(trifluoromethylsul-
fonyloxy)noraporphine (4a): A solution of oxalyl chloride (3.2 mL,
36.5 mmol, 1.3 equiv.) in dry CH2Cl2 (40 mL) was cooled to –
78 °C. To this was added dropwise a solution of DMSO (5.2 mL,
73.1 mmol, 2.6 equiv.) in dry CH2Cl2 (10 mL). The mixture was
kept at –78 °C for 15 min before adding a solution of N-benzylnor-
codeine (7) (10.54 g, 28.1 mmol, 1.0 equiv.) in dry CH2Cl2 (20 mL)
followed by stirring at –78 °C for 1 h before adding Net3 (20 mL,
141 mmol, 5 equiv.). The mixture was allowed to reach room tem-
perature and transferred to a separating funnel and washed with
1 m NaOH and with saturated aqueous NaHCO3. The organic
phase was dried (MgSO4), filtered and concentrated in vacuo to
give crude N-benzylnorcodeinone (6) (10.66 g) as a yellow solid
which was sufficiently pure for further reaction. Rf = 0.24 (2%
MeOH in CHCl3). M.p. 62–65 °C. [α]2D5.1 = –246.5 (c = 0.14,
Scheme 6. Introduction of fluorine via the Balz–Schiemann reac-
tion and concomitant deprotection.
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 7.40–7.20 (m, 5 H, N–
CH2–C6H5), 6.67 [d, J(1,2) = 8.2 Hz, 1 H, H-1/H-2], 6.64 (d, 1 H,
H-1/H-2), 6.58 [dd, J(7,14) = 2.0, J(7,8) = 10.2 Hz, 1 H, H-7], 6.05
In summary we have devised a route to a labelling pre- [dd, J(8,14) = 2.9 Hz, 1 H, H-8], 4.69 (s, 1 H, H5), 3.84 (s, 3 H,
-OCH3), 3.76 (d, Jgem = 13.4 Hz, 1 H, N–CH2–C6H5), 3.69 (d, 1
H, N–CH2–C6H5), 3.44 [dd, J(9,14) = 3.1, J(9,10a) = 5.2 Hz, 1 H,
H-9], 3.24 [dd, J(14,10a) = 5.1 Hz, 1 H, H-14,], 3.14 [d, J(10b,10a)
= 18.4 Hz, 1 H, H-10b,], 2.65 [ddd, J(16a,15a) = 1.6, J(16a,15b) =
4.8, J(16a,16b) = 12.1 Hz, 1 H, H-16a,], 2.35 [td, J(16b,15) = 3.7,
J(16b,15) = 8.3 Hz, 1 H, H-16b], 2.33 (dd, 1 H, H-10a), 2.06 [td,
J(15b,15a) = 12.2 Hz, 1 H, H-15b], 1.83 (ddd, 1 H, H-15a). 13C
NMR (75 MHz, CDCl3): δ = 195.1 (C=O), 150.0, 145.3, 142.9,
139.2, 132.8, 129.8, 129.1, 128.8, 127.6, 126.6 (Ar), 120.4, 115.0 (C7
+ C8), 88.7 (C5), 59.7 (N–CH2–Ph), 57.2 (-OCH3), 57.1 (C9), 45.4
cursor for the most potent D2 receptor agonist yet known.
The key step of the synthesis is a palladium-catalysed amin-
ation of an apomorphine derivative. Utilising a modified
Balz–Schiemann reaction the fluorine was introduced at the
2-position and subsequent deprotection gave the labelling
precursor 1.
This procedure has the potential for installation of a vari-
ety of other functionalities at the 2-position either by a
Sandmeyer reaction on aniline 3b or by palladium-catalysed
cross coupling of the triflate 4a. This opens up further pos- (C16), 44.1 (C13), 42.0 (C14), 34.5 (C15), 21.8 (C10). The crude
N-benzylnorcodeinone (6) was dissolved in neat CH3SO3H (50 mL)
and heated to 95 °C under a flow of nitrogen for 1 h. The resultant
syrup was transferred to a continuous extraction apparatus and
basified with NaOH (34 g in 200 mL water) at 0 °C. The pH was
then adjusted to ca. 8 by addition of solid NaHCO3. Continuous
extraction with Et2O for 16 h gave a solution which was concen-
trated to give crude N-benzylnormorphothebaine (5) (10.93 g), Rf
= 0.38 [MeOH/CHCl3 (1:9)]. H NMR (300 MHz, [D6]acetone): δ
= 7.90 [d, J(1,3) = 2.2 Hz, 1 H, H-1], 7.46–7.20 (m, 5 H,
=NCH2C6H5), 6.82 [d, J(8,9) = 8.1 Hz, 1 H, H-8/H-9], 6.76 (d, 1
sibilities to fine-tune ligand-receptor interactions of PET
tracers and optimisation of in vivo properties such as lipo-
philicity/hydrophilicity. In addition, this synthesis gives ac-
cess to 2-substituted apomorphines with different N-substit-
uents, which are known to influence the pharmacological
profile of apomorphine significantly.[36]
The precursor 1 can readily be converted into either [11C]
2F-NPA by a known radiochemical sequence.[12] Addition-
ally [11C]2F-APO and 2-fluoro-N-[11C]ethylnorapomor-
1
phine can be prepared by labelling with the corresponding H, H-8/H-9), 6.53 (d, 1 H, H-3), 4.33 (d, Jgem = 13.8 Hz, 1 H,
[11C]alkyl iodides.[10,37] The labelling and the PET imaging
=NCH2C6H5), 3.85 (s, 3 H, Ar–OCH3), 3.33–3.20 (m, 4 H), 3.02–
2.82 (m, 2 H), 2.66–2.43 (m, 2 H), 2.36–2.23 (m, 1 H). 13C NMR
results will be published elsewhere.
(75 MHz, [D6]acetone): δ = 155.7, 147.0, 144.1, 140.0, 134.5, 133.8,
130.5, 129.2, 128.6, 127.1, 126.9, 121.0, 118.8, 114.3, 113.8, 110.2
(Ar), 60.7 (C6a), 58.9 (=NCH2C6H5), 56.1 (Ar–OCH3), 49.4 (C5),
35.8 (C7). 29.8 (C4). The crude phenol 5 (10.93 g) was taken up as
Experimental Section
General: Solvents were distilled under anhydrous conditions. All
reagents were used without further purification unless specified.
Evaporation was performed on a rotary evaporator with the tem-
perature kept below 40 °C. Glassware used for moisture sensitive
reactions were flame-dried under reduced pressure and cooled to
room temperature under a stream of nitrogen prior to use. Columns
a slurry in CH2Cl2 (100 mL). To this was added with stirring Net3
(20 mL, 141 mmol, 5 equiv.) and 2-(5-chloropyridyl)trifluorosul-
fonimide (12.1 g, 30.9 mmol, 1.1 equiv.). The mixture was stirred
for 1.5 h before adding freshly distilled pivaloyl chloride (5.2 mL,
42.2 mmol, 1.5 equiv.) and DMAP (172 mg, 1.41 mmol,
0.05 equiv.). The mixture was left stirring until the singlet at δ =
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K. Søndergaard, J. L. Kristensen, N. Gillings, M. Begtrup
FULL PAPER
3.90 ppm disappeared in the NMR spectrum[38] and then washed
once with saturated aqueous NaHCO3. The organic phase was
dried (MgSO4), filtered and concentrated in vacuo. The crude ma-
terial was purified by column chromatography to give the title com-
pound 4a (7.17 g, 43% over four steps) as a bright yellow fluffy
fied with solid NaHCO3 followed by extraction with EtOAc. Dry-
ing of the organic phase (MgSO4), filtration and concentration in
vacuo gave the pure aniline 3b (1.57 g, 66% over two steps) as a
light brown fluffy solid. M.p. 101–103 °C. [α]2D5 = –131.0 (c = 0.10,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 7.47–7.23 (m, 6 H,
=NCH2C6H5 + H-1), 7.11 [d, J(8,9) = 8.2 Hz, 1 H, H-8/H-9], 6.84
solid. Rf = 0.20 [EtOAc/pet. ether (1:4)]. M.p. 74–76 °C. [α]2D5
=
1
–187.5 (c = 0.13, CHCl3). H NMR (300 MHz, CDCl3): δ = 7.80 (d, 1 H, H-8/H-9), 6.41 [d, J(3,1) = 1.6 Hz, 1 H, H-3,], 4.34 (d, Jgem
(br. S, 1 H, H-1), 7.41–7.18 (m, 5 H, =NCH2C6H5), 7.11 [d, J(8,9) = 13.7 Hz, 1 H, =NCH2C6H5), 3.83 (s, 3 H, Ar–OCH3), 3.52 (br.
= 8.2 Hz, 1 H, H-8/H-9], 6.96 [br. D, J(3,1) = 2.2 Hz, 1 H, H-3], s, 2 H, Ar–NH2), 3.42 [br. d, J(6a,7a) = 12.4 Hz, 1 H, H-6a], 3.34
6.87 (d, 1 H, H-8/H-9), 4.32 (d, Jgem = 13.7 Hz, 1 H, =NCH2C6H5), (d, 1 H, =NCH2C6H5), 3.21 [dd, J(7b,6a) = 3.5, J(7b,7a) = 13.8 Hz,
3.81 (s, 3 H, Ar–OCH3), 3.47 [br. D, J(6a,7a) = 12.3 Hz, 1 H, H-
6a], 3.35 (d, 1 H, =NCH2C6H5), 3.23 [dd, J(7b,6a) = 3.8, J(7b,7a)
1 H, H-7b], 3.08–2.90 (m, 2 H, H-4a + H-5a), 2.70–2.52 (m, 2 H,
H4b + H7a), 2.45–2.32 (m, 1 H, H-5b), 1.43 [s, 9 H, Ar–OC-
= 12.3 Hz, 1 H, H-7b], 3.13–2.97 (m, 2 H, H-4a + H-5a), 2.67 [d, OC(CH3)3]. 13C NMR (75 MHz, CDCl3): δ = 176.1 [Ar–OC-
J(4b,4a) = 18.8 Hz, 1 H, H-4b], 2.65 (t, 1 H, H-7a), 2.46–2.30 (m, 1 OC(CH3)3], 151.1, 144.5, 139.5, 137.7, 134.9, 132.1, 130.3, 129.4,
H, H-5b), 1.38 [s, 9 H, Ar–OCOC(CH3)3]. 13C NMR (75 MHz,
129.0, 128.7, 127.4, 126.9, 125.8, 114.8, 113.9, 111.1 (Ar), 60.2
CDCl3): δ = 176.4 [Ar–OCOC(CH3)3], 151.2, 148.1, 138.9, 138.0, (C6a), 59.2 (=NCH2C6H5), 56.6 (Ar–OCH3), 49.2 (C5), 39.4 [Ar–
137.0, 136.5, 133.8, 130.0, 129.3, 128.8, 127.6, 127.3, 126.0, 120.5,
OCOC(CH3)3], 35.7 (C7), 29.7 (C4), 27.7 [Ar–OCOC(CH3)3].
119.1 [q, CF3, J(C,F) = 321 Hz], 118.9, 112.4 (Ar), 60.3 (C6a), 59.1
C29H32N2O3 (456.58): calcd. C 76.29, H 7.06, N 6.14; found C
(=NCH2C6H5), 56.6 (Ar–OCH3), 48.6 (C5), 39.6 [Ar–OCOC(CH3) 76.03, H 7.28, N 5.98.
3], 34.7 (C7), 29.9 (C4), 27.6 [Ar–OCOC(CH3)3]. 19F NMR
(282 MHz, CDCl3): δ = –73.7. MS (EI): m/z = 589 [M]·+.
C30H30F3NO6S (589.62): calcd. C 61.11, H 5.13, N 2.38; found C
61.20, H 5.35, N 2.26.
(R)-(–)-2-Fluoronorapomorphine Hydrobromide (1): Aniline 3b
(111 mg, 0.243 mmol, 1.0 equiv.) was dissolved in CH3CN (2 mL)
and the solution was cooled to 0 °C under nitrogen before adding
60% aqueous HPF6 (84 μL, 0.559 mmol, 2.3 equiv.). The mixture
(R)-(–)-2-Amino-N-benzyl-10-methoxy-11-pivaloyloxynoraporphine was stirred at 0 °C for 15 min then at room temperature for 15 min
(3b): Under anhydrous conditions triflate 4a (3.08 g, 5.22 mmol,
1.0 equiv.), benzophenone imine (1.05 mL, 6.27 mmol, 1.2 equiv.)
and finely ground Cs2CO3 (8.51 g, 26.1 mmol, 5 equiv.) were mixed
in dry toluene (20 mL) followed by the addition of X-Phos (398 mg,
before cooling to 0 °C. Freshly prepared tBuONO[35] (43 μL,
0.365 mmol, 1.5 equiv.) was added and the mixture was stirred for
2 hours before it was concentrated to dryness. The crude diazonium
salt was dissolved in [emim][BF4] (see Scheme 6) (1.5 mL) and
0.836 mmol, 0.16 equiv.) and Pd2(dba)3·CHCl3 (216 mg, heated to 90 °C under nitrogen for 1 h. After cooling to room tem-
0.209 mmol, 0.04 equiv.). The mixture was heated to 110 °C under
nitrogen. After 75 min an additional charge of finely ground
perature the solution was transferred to a separating funnel and
NEt3 (2 mL) was added. The mixture was extracted with EtOAc
Cs2CO3 (8.51 g, 26.1 mmol, 5 equiv.) was added. After another and the organic phase was decanted. The extraction was continued
90 min the mixture was allowed to cool to room temperature and
then filtered. The filter cake was washed several times with EtOAc.
The combined organic phase was washed with saturated aqueous
NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The
crude product was purified by column chromatography to give a
viscous yellow oil which after washing with pentane (to remove co-
eluting benzophenone imine) provided the desired imine 3a (2.60 g)
as a yellow foam. Rf = 0.39 [EtOAc/pet. ether (1:2)]. M.p. 78–81 °C.
1H NMR (300 MHz, CDCl3): δ = 7.90–7.20 (m, 15 H, Ar), 7.15
until no more product was observed in the organic phase as judged
by TLC [Rf = 0.44, EtOAc/pet. ether (4:6, 10 mL) + 1 drop of
NEt3]. The combined organic phase was washed with saturated
aqueous NaHCO3, dried (MgSO4), filtered and concentrated to
give crude 2-fluoroaporphine 2a (120 mg). This was dissolved in
AcOH (1.5 mL) followed by the addition of 10% Pd/C (50 mg) and
exposed to H2 (1 atm, balloon). The mixture was stirred vigorously
for 19 hours after which the hydrogenolysis was complete as judged
by TLC (Rf = 0.56, 5% NH4OH and 10% MeOH in EtOAc). The
(br. s, 1 H, H-1), 7.10 [d, J(8,9) = 8.2 Hz, 1 H, H-8/H-9], 6.82 (d, mixture was worked up by dilution with MeOH (3 mL) followed
1 H, H-8/H-9), 6.50 (br. s, 1 H, H-3), 4.34 (d, Jgem = 13.5 Hz, 1 H, by filtration through a pad of celite. After concentration in vacuo
=NCH2C6H5). 3.81 (s, 3 H, Ar–OCH3), 3.42 [br. d, J(6a,7a) =
13.5 Hz, 1 H, H-6a], 3.36 (d, 1 H, =NCH2C6H5), 3.13 [dd, J(7b,6a)
the resultant syrup was separated between EtOAc and saturated
aqueous NaHCO3. The water phase was extracted with EtOAc and
= 3.3, J(7b,7a) = 13.7 Hz, 1 H, H-7b], 3.03 [dd, J(5a,4a) = 4.9, the combined organic phase was dried (MgSO4), filtered and con-
J(5a,5b) = 10.9 Hz, 1 H, H-5a], 2.90 [dt, J(4a,4b) = 16.6 Hz, 1 H,
H-4a,], 2.61 (t, 1 H, H-7a), 2.50 (d, 1 H, H-4b), 2.36 (t, 1 H, H-
5b), 1.42 [s, 9 H, Ar–OCOC(CH3)3]. 13C NMR (75 MHz, CDCl3):
selected data (from the region of aliphatic group signals): δ = 60.4
(C6a), 59.4 (=NCH2C6H5), 56.6 (Ar–OCH3), 49.2 (C5), 39.5 (Ar–
centrated to give an oily residue which was purified by column
chromatography [MeOH/CHCl3 (1:9) + 1% NEt3] to give second-
ary amine 2b (49 mg) containing 7% (based on 1H NMR) of
R-(–)-10-methoxy-11-pivaloyloxynoraporphine (resulting from re-
duction of the diazonium salt) which could not be separated by
OCOC(CH3)3], 35.2 (C7), 29.7 (C4), 27.7 [Ar–OCOC(CH3)3]. MS chromatography. 1H NMR (300 MHz, CDCl3): δ = 7.62 [br. d,
(EI): m/z = 620 [M]·+. C42H40N2O3 (620.78): calcd. C 81.26, H 6.49,
N 4.51; found C 81.00, H 6.20, N 4.22. Imine 3a (2.60 g) was dis-
solved in THF (70 mL) followed by addition of 1 m aqueous HCl
J(1,F) = 10.6 Hz, 1 H, H-1], 7.08 [d, J(8,9) = 7.6 Hz, 1 H, H-8/H-
9], 6.85 (d, 1 H, H-8/H-9), 6.78 [br. d, J(3,F) = 8.9 Hz, 1 H, H-3],
3.92 [br. d, J(6a,7a) = 13.3 Hz, 1 H, H-6a], 3.81 (s, 3 H, Ar–OCH3),
(2 mL). The mixture was stirred at room temperature for 90 min 3.42–3.28 (m, 1 H, H-5a), 3.12–2.98 (m, 2 H), 2.86 [dd, J(7b,6a) =
before adding another load of 1 m aqueous HCl (12 mL). After
stirring for an additional 50 min full conversion was achieved as
judged by TLC (Rf = 0.14 in EtOAc/pet. ether (1:2, 10 mL) + 1
drop of NEt3). The reaction mixture was partitioned between
EtOAc and 1 m HCl. The aqueous phase was washed several times
with EtOAc until no more benzophenone imine was detected in the
organic phase as judged by TLC. The aqueous phase was then basi-
4.6, J(7b,7a) = 13.9 Hz, 1 H, H-7b], 2.80–2.57 (m, 3 H), 1.40 [s, 9
H, Ar–OCOC(CH3)3]. 13C NMR (75 MHz, CDCl3): δ = 176.3 [Ar–
OCOC(CH3)3], 161.5 [C–F, J (C,F) = 242 Hz], 151.7, 138.1, 136.1,
135.9, 132.4, 129.5, 127.9, 125.8, 115.0 [J(C,F) = 21 Hz], 113.3
[J(C,F) = 23 Hz], 111.8 (Ar), 56.5 (Ar–OCH3), 53.6 (C6a), 43.1
(C5), 39.4 [Ar–OCOC(CH3)3], 37.2 (C7), 29.8 (C4), 27.6 [Ar–OC-
OC(CH3)3]. 19F NMR (282 MHz, CDCl3): δ = –117.3. m/z: 370 [M
4432
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4428–4433

Synthesis of (R)-(–)-2-Fluoronorapomorphine
FULL PAPER
+ 1]+ calcd. for (C22H24FNO3 + H+) 370. The methyl aryl ether 2b
(49 mg) was dissolved in CH2Cl2 (2 mL) and a 1.0 m solution of
BBr3 in CH2Cl2 (2.7 mL, 2.65 mmol, 20 equiv.) was added. The
mixture was stirred for 1.5 h under nitrogen and then concentrated.
The resultant brown solid was dissolved in MeOH (10 mL) and
refluxed for 40 min and then concentrated in vacuo. The solid was
redissolved in MeOH (10 mL) and activated carbon (50 mg) was
added. The mixture was heated to reflux and quickly filtered
through a pad of celite. After concentration to dryness the remain-
ing solid was washed several times with CHCl3 providing the title
compound 1 (37 mg, 43% over 4 steps) as an off-white solid. The
product was contaminated with 7% norapomorphine hydrobro-
mide as judged by the H1-protons at 8.37 (contaminant) and 8.16
(title compound) in 1H NMR spectroscopy. M.p. (decomp.) at
230 °C. [α]2D5 = –38.2 (c = 0.15, MeOH). 1H NMR (300 MHz,
CD3OD): δ = 8.16 [dd, J(1,3) = 2.1, J(1,F) = 11.4 Hz, 1 H, H-1],
6.86 [dd, J(3,F) = 8.7 Hz, 1 H, H-3], 6.75 [d, J(8,9) = 7.9 Hz, 1 H,
H-8/H-9], 6.64 (d, 1 H, H-8/H-9), 4.31 [dd, J(6a,7b) = 3.1, J(6a,7a)
= 13.8 Hz, 1 H, H-6a], 3.78–3.64 (m, 1 H, H-5a), 3.45–3.22 (m, 2
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Received: April 27, 2005
Published Online: September 7, 2005
Eur. J. Org. Chem. 2005, 4428–4433
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4433