Synthesis of 2-fluoro-11-hydroxy-N-propylnoraporphine: A potential dopamine D2 agonist

Article abstract of DOI:10.1021/ol051010d

(Chemical Equation Presented) 2-Fluoro-11-hydroxy-N-propylnoraporphine 4 (2-F-11 -OH-NPa) was synthesized from thebaine in 13 steps with an overall yield of 1.35%. The key steps included the Pd-catalyzed 3-dehydroxylation of 14-hydroxymorphine, S_N2 substitution of Ts^- by F ^-, and CH₃SO₂OH-promoted rearrangement of the substituted morphinandiene. The dopamine binding affinity of this compound was also investigated on rat brain membranes, and as expected, this compound displayed high affinity and selectivity at the D₂ receptor.

Full text of DOI:10.1021/ol051010d

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3239-3242
Synthesis of
2-Fluoro-11-hydroxy-N-propylnoraporphine:
A Potential Dopamine D2 Agonist
Ao Zhang, Csaba Csutoras,† Rushi Zong, and John L Neumeyer*
Medicinal Chemistry Laboratory, Alcohol and Drug Abuse Research Center, McLean
Hospital, HarVard Medical School, 115 Mill Street, Belmont, Massachusetts 02478
neumeyer@mclean.harVard.edu
Received May 3, 2005
ABSTRACT
2-Fluoro-11-hydroxy-N-propylnoraporphine 4 (2-F-11-OH-NPa) was synthesized from thebaine in 13 steps with an overall yield of 1.35%. The
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key steps included the Pd-catalyzed 3-dehydroxylation of 14-hydroxymorphine, SN2 substitution of Ts by F , and CH3SO2OH-promoted
rearrangement of the substituted morphinandiene. The dopamine binding affinity of this compound was also investigated on rat brain membranes,
and as expected, this compound displayed high affinity and selectivity at the D2 receptor.
R-(-)-apomorphine (1a, R-(-)-APO) (Figure 1), a well-
known dopamine (DA) agonist, has clinical utility in the
treatment of Parkinson’s disease and erectile dysfunction.1b,c
A major limitation of its clinical use is its poor oral
bioavailability. In the last three decades, a number of
aporphine analogues have been synthesized and evaluated
at DA receptors in an effort to increase the oral activity and
extend the duration of action. Most of these structure and
activity relationship (SAR) studies were focused on the
functional optimizations at three positions: N-6, C-10, and
C-2. As a result, the N-propyl analogue 1b (R-(-)-NPA)
was found to be more potent than R-(-)-APO (1a).2 In
addition, it was found that the C-2 position can tolerate a
variety of functional substituents without significant effect
on the affinity and selectivity at dopamine D2 receptor.1 For
example, introducing a hydroxyl group at C-2 resulted in
compound 2a which displayed potent DA agonist activity
although the binding affinity was slightly lower than NPA
(1b).3a-c It was noteworthy that 2-fluoroapomorphine (2c)
and its N-propyl analogue (2b), with a more electronegative
fluoro substituent at the C-2, showed remarkably high affinity
and selectivity at the dopamine D2 receptor. Compound 2b
is among the most potent and selective D2 agonist synthesized
so far with IC50 of 0.07 nM at D2 and 1.3 µM at D1 receptors,
(3) (a) Neumeyer, J. L.; Reischig, D.; Arana, G. W.; Campbell, A.;
Baldessarini, R. J.; Kula, N. S.; Watling, K. J. Med. Chem. 1983, 26, 516.
(b) Neumeyer, J. L.; Arana, G. W.; Law, S. J.; Lamont, J. S.; Kula, N. S.;
Baldessarini, R. J. J. Med. Chem. 1981, 24, 1440. (c) Neumeyer, J. L.;
Arana, G. W.; Ram, V. J.; Kula, N. S.; Baldessarini, R. J. J. Med. Chem.
1982, 25, 990. (d) Gao, Y.; Baldessarini, R. J.; Kula, N. S.; Neumeyer, J.
L. J. Med. Chem. 1990, 33, 1800. (e) Berenyi, S.; Csutoras, Cs.; Makleit,
S.; Auth, F.; Laszlovszky, I.; Kiss, B.; Karpati, E.; Low, M. Med. Chem.
Res. 1997, 509. (f) Auth, F.; Laszlovszky, I.; Kiss, B.; Karpati, E.; Berenyi,
S.; Csutoras, Cs.; Makleit, S.; Low, M. Differential effects of 2-(ethylthio)-
apomorphine enantiomers on striatal dopamine oVerflow in ViVo Neuro-
chemistry; Teelken, A.; Korf, J., Eds.; Plenum Press: New York, 1997; p
215. (g) Ramsby, S.; Neumeyer, J. L.; Grigoriadis, D.; Seeman, P. J. Med.
Chem. 1989, 32, 1198. (h) Neumeyer, J. L.; Gao, Y.; Kula, N. S.;
Baldessarini, R. J. J. Med. Chem. 1990, 33, 3122. (i) Csutoras, Cs.; Zhang,
A.; Zhang, K.; Kula, N. S.; Baldessarini, R. J.; Neumeyer, J. L. Bioorg.
Med. Chem. 2004, 3553.
† Current Address: Department of Chemistry, Eszterha´zy Ka´roly Uni-
versity, 4 Lea´nyka Street, Eger, Hungary, H-3300.
(1) (a) Nomenclature used in this series is as follows: NPA ) N-n-
propylnorapomorphine which has a catechol moiety; NPa ) N-n-propyl-
noraporphine which has a monohydroxyphenyl moiety. (b) Tyne, H. L.;
Parson, J.; Sinott, A.; Fox, S. H.; Steiger, M. J. J. Neurol. 2004, 251, 1370.
(c) Neumeyer, J. L.; Baldessarini, R. J.; Booth, R. J. In Burger’s Medicinal
Chemistry and Drug DiscoVery, 6th ed.; Abraham, D. J., Ed.; John Wiley
& Sons: New York, 2003; p 711.
(2) Menon, M. K.; Clark, W. G.; Neumeyer, J. L. Eur. J. Pharm. 1978,
52, 1.
10.1021/ol051010d CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/18/2005

Figure 1. Structures of potent aporphine analogues.1a
respectively.3h Another noteworthy finding was that the 10-
hydroxyl group was not a requirement for high dopamine
D2 receptor activity and can be replaced or eliminated. For
example, the 10-dehydroxylated analogue 3 (11-OH-NPa)
displayed even higher affinity and selectivity for D2 (Ki )
28 nM) than apomorphine 1a.3i Further investigation of 3
indicated that, when administered orally, it retained high
pharmacological potency and displayed longer duration of
action.3i
On the basis of these findings, especially upon integration
of the information from compound 2b and 3, it was very
apparent to us that a combination of the introduction of a
fluoro group at C-2 position and the elimination of the 10-
hydroxyl group will generate compounds with high DA
receptor affinity and better pharmacological properties. Thus,
we describe in this report the synthesis of R-(-)-2-fluoro-
11-hydroxy-N-propylnoraporphine (4, 2-F-11-OH-NPa) (Fig-
ure 1).
The key approach to the synthesis of compound 4 was
the introduction of a fluoro substituent at the C-2 of the
aporphine skeleton. There were two possible approaches to
achieve this objective: paths a and b as described in Figure
2. Both paths included the rearrangement of thebaine or its
analogues to yield the aporphine skeleton as the key step.
In path a, the 2-F substitution was introduced after the
rearrangement of the diene ring system through the key
intermediate 2a and 2b, while in path b the fluorine atom
was introduced before the rearrangement of the diene ring
system through the intermediate 5 and 6.
To evaluate which path was more effective and convenient,
we first attempted path a (Scheme 1). The synthesis was
initiated from thebaine, which was first N-demethylated
followed by realkylation to yield N-propylnorthebaine 7.2
Upon CH3SO3H-catalyzed rearrangement, diene 7 was
converted to aporphine 8 which followed a slightly modified
procedure to yield 2-aminocarbonyldimethylmethoxy-10,11-
methylenedioxy-N-propylnoraporphine 10, as described in
our earlier reports.3g,h Compound 10 was then subjected to
a Smiles rearrangement followed by a Schiemann reaction
to yield the 2-F-NPA 2b in low yield (25-50%).3g,h
As proposed in path a (Figure 2), elimination of the 10-
hydroxyl group in compound 2b by selective triflation of
the 10-hydroxyl group or by selective formation of tetrazolo
ether 12, followed by palladium-catalyzed reduction, would
produce the expected 2-fluoro-11-hydroxy-N-propylnorapor-
phine 4 (Scheme 1). However, triflation3i of the catechol 2b
(PhNTf2/Et3N or Tf2O/Py) only gave a mixture, and no
monotriflate 12 could be isolated after column chromatog-
raphy. Similarly, selective formation3 of the tetrazolo ether
of the 10-hydroxyl moiety by treating 2b with 1-phenyl-5-
Cl-tetrazole and K2CO3 was not successful. In consideration
of the difficulty in selective elimination of the 10-hydroxyl
group and the low yield in the Smiles rearrangement
described above, we decided to attempt the synthesis of 4
via path b.
Parallel to our early work, Berenyi4-8 reported an alterna-
tive procedure to prepare 2-fluoroapomorphine 2c. In this
procedure, the 2-fluoro function was introduced after forma-
Figure 2. Possible approaches to 11-hydroxy-2-fluoro-N-propylnoraporphine 4.
3240
Org. Lett., Vol. 7, No. 15, 2005

Scheme 1a
Scheme 2a
a Reagents and conditions: (a) m-CPBA; (b) BBr3 (1 M), -78
°C to rt; (c) Li-Selectride, THF; (d) Tf2NPh, Et3N; (e) Pd(OAc)2,
HCOOH, DMF; (f) TsCl, Py; (g) Bu4NF, CH3CN; (h) PBr3, CHCl3,
0-60 °C, (i) NaOBut, EtOH, 90 °C; (j) DEAD, benzene, reflux;
(k) Py‚HCl; (l) Prl, K2CO3, EtOH, reflux.
a Reagents and conditions: (a) DEAD, benzene, reflux; (b)
Py‚HCl, EtOH, rt; (c) Prl, K2CO3, EtOH, reflux; (d) CH3SO2OH;
(e) HOAc, HBr (48%), reflux; (f) CH2Br2, NaOH, DMSO; (g)
BrC(CH3)2CONH2, K2CO3; (h) NaH, HMPA, rt to 100 °C; (i) 5 N
HCl, reflux; (j) NaNO2, HPF6 (60%), 0 °C; (k) BCl3 (1 M), rt; (l)
PhNTf2, Et3N or 5-Cl-1-Ph-tetrazole, K2CO3, DMF; (m) Pd(OAc)2,
HCOOH, DMF, or Pd(OH)2, H2.
treating 16 with tBu4NF. Treatment of 17 with PBr3 followed
by NaOBut gave diene 18 in 56% overall yield. N-Demethyl-
ation3c,4 of 18 using DEAD and Py‚HCl followed by
treatment with PrI and K2CO3 yielded 6-F-3,6-didemethoxy-
N-propylnorthebaine 5 in 50% combined yield.
tion of the apomorphine carbon skeleton avoiding the Smiles
rearrangement and resulted in a better overall yield. Thus,
we decided to develop a similar procedure to prepare our
target molecule 4.
The synthesis was initiated from thebaine, which was
converted to 14-OH-morphine 13 using the reported proce-
dures (Scheme 2).8-12 Selective triflation of the 3-hydroxyl
group followed by palladium-catalyzed reduction furnished
3-demethoxy-14-hydroxymorphine 15 in 64% yield.3i,13 To-
sylation14,15 of the 6-hydroxyl group gave 16 in 80% yield,
which was further converted to 6R-F-14-OH-3-deoxymor-
phine 17 in 70% yield by an SN2 substitution8 with F-, upon
The next step was the acid-catalyzed rearrangement of the
diene 5 to yield the target aporphine 4. Using CH3SO3H at
room temperature or 90 °C, a procedure reported by Berenyi
et al. on the catecholic precursor,8 did not yield any
significant product 4, except a more polar complex which
was isolated by chromatography and identified as the dimer
19 (Scheme 3). This was in agreement with Berenyi’s result.8
Scheme 3a
(4) Neumeyer, J. L.; Law, S. J.; Meldrum, B.; Anlezark, G.; Watling,
K. J. J. Med. Chem. 1981, 24, 898.
(5) (a) Ram, V. J.; Neumeyer, J. L. J. Org. Chem. 1982, 47, 4372. (b)
Derrick, I.; Neilan, C. L.; Andes, J.; Husbands, S. M.; Woods, J. H.; Traynor,
J. R.; Lewis, J. W. J. Med. Chem. 2000, 44, 3348.
(6) Berenyi, S.; Makleit, S.; Rantal, F. Acta Chim. Hung. 1985, 120,
201.
(7) Simon, Cs.; Hosztafi, S.; Makleit, S.; Berenyi, S. Synth. Commun.
1991, 21, 2309.
(8) (a) Berenyi, S.; Hosztafi, S.; Makleit, S. J. Chem. Soc., Perkin Trans.
1. 1992, 2693. (b) Berenyi, S.; Czirjak, M.; Makleit, S. J. Chem. Soc., Perkin
Trans. 1 1993, 2137.
a Reagents and conditions: (a) CH3SO3H, 0 °C.
(9) Hauser, F. M.; Chen, T.; Carroll, F. I. J. Med. Chem. 1974, 17, 1117.
(10) Rice, K. C. J. Med. Chem. 1977, 20, 164.
(11) Iijima, I.; Minamikawa, J.; Jacobson, A. E.; Brossi, A.; Rice, K. C.
J. Med. Chem. 1978, 21, 398.
(12) Sargent, L. J.; Schwartzman, L. H.; Small, L. F. J. Org. Chem. 1958,
23, 1247.
(13) Weiss, U.; Daum, S. J. J. Med. Chem. 1965, 8 (1), 123.
(14) Hedberg, M. H.; Johansson, A. M.; Nordvall, G.; Yliniemela, A.;
Li, H. B.; Martin, A. R.; Hjorth, S.; Unelius, L.; Sundell, S.; Hacksell, U.
J. Med. Chem. 1995, 38, 647.
After several attempts with this reaction, we found that
compound 416 could be obtained in up to 20% isolated yield
when the rearrangement was conducted at 0 °C.
The in vitro affinity of compound 4 for dopamine (DA)
D1 and D2 receptors was determined by radioligand competi-
tion assays, using membrane preparations from DA-rich
corpus striatum (caudatoputamen) tissue from rat forebrain,
following a similar procedure reported previously.3i As
(15) Makleit, S.; Radics, L.; Bognar, R.; Mile, T. Acta Chim. Hung. 1972,
74, 111.
Org. Lett., Vol. 7, No. 15, 2005
3241

expected, this compound displayed good affinity and selec-
tivity at dopamine D2 receptor with Ki of 39 and 800 nM at
D2 and D1 receptors, respectively, which was comparable to
our previously evaluated compound 3 (Ki: 28.5 nM for D2,
700 nM for D1). Further pharmacological studies with
compounds 3 and 4 are in progress.
catalyzed 3-dehydroxylation of 13 through the triflate precur-
sor 14, SN2 substitution of the tosylate 16 by Bu4NF, and
CH3SO2OH-promoted rearrangement of the diene 5. As
expected, this compound displayed good affinity and selec-
tivity at the D2 receptor.
t
Thus, 2-fluoro-11-hydroxy-N-propylnoraporphine 4 (2-F-
11-OH-NPa) was synthesized from thebaine in 13 steps with
an overall yield of 1.35%. The key steps included the Pd-
Acknowledgment. We thank the Branfman Family
Foundation for financial support, Dr. Ross J. Baldessarini
and Mrs. Nora S. Kula for the in vitro binding assay, and
Mallinckrodt, Inc., for its generous donation of thebaine.
(16) The free base 2-F-11-OH-NPa 4 was converted to its HCl salt: mp
1
>250 °C dec; MS m/z (rel intensity) 297 (M+, 70); H NMR (base, CD3-
OD) δ 0.96 (t, 3H), 1.61 (m, 2H), 2.50 (m, 3H), 2.73 (m, 1Hm), 2.91 (m,
1H), 3.14 (m, 3H), 3.34 (m, 1H), 6.74 (d, J8,9 ) 8 Hz, 1H), 6.77 (dd, 1H),
6.87 (d, J9,10 ) 8 Hz, 1H), 7.08 (t, 1H), 7.8 (dd, 1H); 13C NMR (base,
CDCl3) δ 12.0, 19.4, 29.4, 35.0, 48.8, 56.3, 59.2, 112.3 (d, J ) 24 Hz),
113.4 (d, J ) 21 Hz), 115.5, 120.7, 128.4, 130.9, 133.3, 133.4, 135.4, 138.7,
152.7, 161.2 (d, J ) 240 Hz); MS m/z (rel intensity) 297 (M+, 70). Anal.
(C19H20FNO‚HCl) Calcd: C, 68.36; H, 6.34; N, 4.20. Found: C, 68.31; H,
6.38; N, 4.15.
Supporting Information Available: Full experimental
details for all transformations and the analytical characteriza-
tion of all new compounds described. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL051010D
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Org. Lett., Vol. 7, No. 15, 2005