Convenient methods for the synthesis of d4, d2 and d6 isotopomers of 4-(4-fluorobenzyl)piperidine

Article abstract of DOI:10.1002/jlcr.936

Pure 4-(4-fluoro-[2,3,5,6-²H₄]benzyl)piperidine was prepared via the Grignard reaction of 4-fluoro-[2,3,5,6-²H ₄]bromobenzene and pyridine-4-aldehyde followed by consecutive deoxygenation and heteroatomic ring saturation in the presence of palladium on carbon catalyst. An improved method for the catalytic H/D exchange in benzylic positions of 4-(4-fluorobenzyl)piperidine and its d₄ derivative has also been described. Copyright

Full text of DOI:10.1002/jlcr.936

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 421–427.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.936
Research Article
Convenient methods for the synthesis of d4, d2 and d6
isotopomers of 4-(4-fluorobenzyl)piperidine
1
la Agai , Ga
k1, Be
´
´
bor Tarka
´ ´
nyi2, La
´
szlo
´
Vida1 and
´
´
Agnes Proszenya
´
Ferenc Faigl1,*
1 Department and Research Group of Organic Chemical Technology, Budapest
University of Technology and Economics and Hungarian Academy of Science, H-1512
Budapest, Hungary
2 Gedeon Richter Ltd., H-1475 Budapest, Gyomro+i u´t 19-21, Hungary
¨
Summary
Pure 4-(4-fluoro-[2,3,5,6-2H4]benzyl)piperidine was prepared via the Grignard
reaction of 4-fluoro-[2,3,5,6-2H4]bromobenzene and pyridine-4-aldehyde followed by
consecutive deoxygenation and heteroatomic ring saturation in the presence of
palladium on carbon catalyst. An improved method for the catalytic H/D exchange in
benzylic positions of 4-(4-fluorobenzyl)piperidine and its d4 derivative has also been
described. Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: deuterium-labelled compounds; Grignard reaction; catalytic hydrogena-
tion; palladium on carbon; benzylpiperidines
Introduction
The efficacy of NR2B selective NMDA receptor antagonists in neuroprotec-
tion, anti-hyperalgesic and anti-Parkinson animal models have attracted
significant recent interest.1,2 Typical antagonists contain basic nitrogen which,
in most cases, is contained within a 1,4-diaralkylpiperidine ring, such as in
(1R,2S)-3-[4-benzylpiperidin-1-yl)-1-(4-hydroxyphenyl)-2-methyl-1-propanol
(Ro 25,6981)3 or in 6-[2-[4-(4-fluorobenzyl)-piperidyl]-ethanesulfinyl]-3H-
benzoxazol-2-one (CI-1041, besonprodil, Scheme 1).4
Stable isotopically labelled derivatives of these compounds are necessary for
pharmacological research.5,6 The substituted benzylpiperine moiety is an
essential part of the above-mentioned NMDA receptor antagonists in many
*Correspondence to: F. Faigl, Department and Research Group of Organic Chemical Technology,
Budapest University of Technology and Economics and Hungarian Academy of Science, H-1512 Budapest,
Hungary. E-mail: ffaigl@mail.bme.hu
Contract/grant sponsor: Gedeon Richter Ltd.
Copyright # 2005 John Wiley & Sons, Ltd.
Received 8 December 2003
Revised 4 February 2005
Accepted 7 February 2005

´
A. PROSZENYAK ET AL.
´
422
HO
N
OH
O
O
O
S
N
H3C
F
N
Ro 25,6981
CI-1041
Scheme 1. Examples of biologically active benzylpiperidine derivatives
cases, therefore, development of efficient methods for the preparation of
deuterium-labelled 4-benzylpiperidine derivatives would be of significant
practical importance. Sajiki et al.7 have reported a process for the H/D
exchange at the benzylic positions of alkylbenzenes and diphenylmethane
using a palladium on carbon catalyst at room temperature.7 Recently,
Franklin et al.8 have published the synthesis of a d1–d8 isotopomeric mixture
of an N-alkylated 4-(4-fluorobenzyl)piperidine derivative.8 Such mixtures can
create trouble during the evaluation of pharmaceutical investigations.
Synthesis of isotopomerically pure deuterium-labelled benzylpipieridines
would be a solution of these problems. In order to identify such a method,
systematic investigations of the synthesis of deuterium-labelled derivatives of
4-(4-fluorobenzyl)piperidine have been carried out in our laboratory.
Results and discussion
In the first attempt, the application of Sajiki’s catalytic method7 has been
attempted for the H/D exchange of the benzylic hydrogens in 4-(4-
fluorobenzyl)piperidine. According to the GC-MS analysis, 93.4% of the
starting material remained unchanged following prolonged reaction times
whilst 6.6% of the starting material was found to have lost fluorine.
In a second attempt, 4-(4-fluorobenzyl)pyridine ð1Þ was dissolved in a
methanolic hydrogen chloride solution and the solution treated with
deuterium gas in the presence of a palladium on carbon catalyst. These
reaction conditions were identical to those developed for the piperidine
synthesis in our laboratory.9,10 After consumption of the calculated amount of
deuterium gas, the product, 4-(4-fluorobenzyl)piperidine ð2Þ, was found to
contain no deuterium. When the same experiments were repeated in
deuterated alcohol in the presence of deuterium chloride, a mixture of d7-2–
d11-2 isotopomers of the product were obtained in high yield (Scheme 2). On
the basis of the GC-MS and 1H-NMR investigations, it can be stated that the
hydrogen atoms in the benzylic position have been completely exchanged and
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 421–427

CONVENIENT METHODS FOR THE
423
F
F
F
2H
2H
2H
2H
2H
2H
2H
2H
i
2H
2H
+ .... +
2H
2H
2H
2H
2H
2H
2H
2H
N
N
H.HCl
N
H.HCl
1
d7-2
d11-2
Scheme 2. Synthesis of the d7–d11 isotopomers of 4-(4-fluorobenzyl)piperidine
2
2
2
(2, i: H2, Pd/C, C2H3O2H, H2O, HCl)
some of the original hydrogens from pyridine were also exchanged (d9-2–d11-2
isotopomers). In other words, the deuterated protic solvent acts as the
deuterium source for these reactions rather than the direct introduction of
deuterium occuring from deuterium gas. It is in accordance with the literature
data on the competitive H/D exchange of the acidic hydrogens from the protic
solvents on the surface of palladium catalyst.11
Preparation of 4-(4-fluorophenyl-[2H2]methyl)piperidine (d2-2) and 4-(4-
fluoro-[2,3,5,6-2H4]phenyl-[2H2]methyl)piperidine (d6-2)
The saturated heterocyclic ring of 4-(4-fluorobenzyl)piperidine remained intact
when treated with deuterium gas in deuterated alcoholic solution of deuterium
chloride in the presence of a palladium on carbon catalyst at 608C9,10 whilst,
under the same conditions, the H/D exchange reaction was almost complete
for the benzylic position. Thus d2-2 was synthetised in 90% isotopomeric
purity calculated on the basis of the benzylic hydrogens (Scheme 3).
Deuterium incorporation in benzylic position could be increased close to
95% when the exchange reaction was repeated in fresh deuterated solvent
when starting from the 80% d2-2 isotopomer-containing product. In the same
way, 4-(4-fluoro-[2,3,5,6-2H4]benzylpiperidine (d4-2) could also be deuterated
in the benzylic position and thus d6-2 was prepared in 90% isotopomeric and
chemical purity. It has to be mentioned that prolonged reaction time and
elevated temperature (higher that 608C, 6 h) resulted in contamination of d2-2
and d6-2 with 5–7% of the defluorinated derivatives (calculated from the GC-
MS data). Purification of these crude products was carried out by repeated
recrystallization of the hydrochloride salts followed by distillation of the
liberated base in vacuum (the free base is air sensitive).
Preparation of 4-(4-fluoro-[2,3,5,6-2H4]benzyl)piperidine (d4-2 isotopomer)
Synthesis of the titled compound was accomplished using our newly
developed synthesis of substituted benzylpiperidines.9,10 The starting material
Copyright # 2005 John Wiley & Sons, Ltd.
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A. PROSZENYAK ET AL.
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424
X
X
X
X
X
X
F
X
X
F
X
X
X
X
X
X
F
X
F
X
X
X
F
X
X
Y
Y
H
H
HO
iii
iv
i
ii
Br
X
N
H
N
N
H.HCl
4 X=H
d5-4 X=2H
3 X=H
d4-3 X=2H
5 X=H
d4-5 X=2H
2X=H
d4-2 X=2H
d2-2 X=H, Y=2H
d6-2 X=2H, Y=2H
Scheme 3. Preparation of the d4-, d2-2 and d6-2 isotopomers (i: Br2, FeCl3,
2
CH2Cl2; ii: Mg, THF then pyridine-4-aldehyde; iii: H2, Pd/C CH3OH; iv: H2,
2
Pd/C, C2H3O2H, HCl)
2H
2H
2H
2H
2H
2H
2H
F
F
F
2H
2H
2H
2H
2H
2H
2H
2H
d6-2
d4-2.HCl
4
N
H.HCl
N
H
Scheme 4.
1-bromo-4-fluoro-[2,3,5,6-2H4]benzene (d4-3) could be obtained from 1-
bromo-4-fluorobenzene with AlCl3-catalyzed H–D exchange,12 or by bromi-
nation of the commercially available [2,3,4,5,6-2H5]fluorobenzene (d5-4). We
used a modified version of the second, simpler method for gaining access to the
pure 1-bromo-4-fluoro-[2,3,5,6-2H4]benzene (d4-3) in good yield (Scheme 4).
4-Fluoro-[2,3,5,6-2H4]phenyl-hydroxymethyl)pyridine (d4-5) was obtained
from d4-3 and pyridine-4-aldehyde by Grignard reaction. Deoxygenation
and heteroaromatic ring saturation was accomplished using our method10
yielding the hydrochloric acid salt of 4-(4-fluoro-[2,3,5,6-2H4]benzyl)piperidine
(d4-2.HCl) in more than 98% chemical and isotopomeric purities (Scheme 3).
The abundance of deuterobromobenzene derivatives to be found in the
literature,13–17 makes our method for preparation of 4-(4-fluoro-[2,3,5,6-2H4]
benzyl)piperidine (d4-2) one which can be generally applied to the synthesis of a
wide range of deuterium-labelled benzylpiperidine derivatives.
Experimental
Materials and methods
All commercial starting materials were purchased from Aldrich and
Merck-Schuchardt and were used without further purification. Anhydrous
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CONVENIENT METHODS FOR THE
425
terahydrofuran was obtained by distillation from sodium wire after the
characteristic blue colour of in situ-generated sodium diphenylketyl had been
found to persist. All Grignard-reactions were carried out under dry argon
atmosphere.
1H-NMR spectra were recorded in hexadeuteriodimethylsufoxide or
deuteriochloroform solution at 300 and 500 MHz (Varian Innova Spectro-
meters). Chemical shifts refer to tetramethylsilane ðd ¼ 0 ppmÞ, coupling
constants are given in Hz. Melting point were determined using Buchi
¨
capillary melting point apparatus. IR spectra were recorded as KBr pellets
with a Perkin-Elmer Spectrum 1000 FT-IR spectrophotometer. GC-MS
analyses were recorded on a Finnigan Mat/Automass II GC/MS. Gas
chromatography was performed using a DB-5 capillary column (30 m ꢀ
0.25 mm ID, 0.25 mm film). The temperature program: 458C (hold 3 min)
heating to 3008C at 108C/min, hold 15 min.
4-(4-Fluoro-[a,a-2H2]benzyl)piperidine (d2-2)
4-(4-Fluorobenzyl)piperidine (2, 0.022 mol, 0.42 g) was dissolved in a
mixture of [2H4]-methanol (5 ml) and deuterium chloride solution
(0.005 mol/ml D2O, 0.49 ml). Catalyst (10% Pd/C, 0.20 g) was added and
the solution was stirred with deuterium gas under 3 bar pressure at 608C
for 6 h. At 258C the catalyst was filtered and the solution was concentrated
in vacuo. The residue was recrystallized 3 times from ethanol (5.5 ml)/ diethyl
ether (130 ml) mixture then treated with a 5% aqueous sodium hydroxide
solution (2.5 ml) in the presence of dichloromethane (10 ml). The aqueous
phase was extracted with dichloromethane (3 ꢀ 5 ml), the organic
solutions combined and washed with brine (5 ml), dried over sodium
sulfate and concentrated in vacuo. Final purification was carried out by
distillation of the residue oil (0.24 g) in vacuo to yield 4-(4-fluoro-
[a,a-2H2]benzyl)piperidine (d2-2), deuterium content in benzylic position:
1
90%. H-NMR (300 MHz, CDCl3): d 1.10–1.19 (m, 2H), 1.57–1.62 (m, 3H),
2.52 (t, J ¼ 11:4, 2.2H (0.2H, residue of the benzylic hydrogens)), 3.04
(d, J ¼ 12:0, 2H), 6.91–6.98 (m, 2H), 7.05–7.09 (m, 2H). Ms (M/Z): 42, 55, 56,
69, 84, 195.
4-(4-Fluoro-[a,a,2,3,5,6-2H6]benzyl)piperidine (d6-2)
This compound was prepared from d4-2.HCl using the above-described
method. Deuterium content of the product was 590% calculated on the
1
basis of the six labelled positions. H-NMR (300 MHz, CDCl3): d 1.10–1.19
(m, 2H), 1.57–1.62 (m, 3H), 2.52 (t, J ¼ 11:4, 2.2H (0.2H residue of the
benzylic hydrogens)), 3.04 (d, J ¼ 12:0, 2H). GC-MS (M/Z): 42, 55, 56, 69,
84, 199.
Copyright # 2005 John Wiley & Sons, Ltd.
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A. PROSZENYAK ET AL.
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1-Bromo-4-fluoro-[2,3,5,6-2H4]benzene (d4-3)
Bromine (34.84 g, 0.218 mol) in dichloromethane (40 ml) was added dropwise
at 188C to a solution (40 ml) of [2,3,4,5,6-2H5]fluorobenzene (d5-4, 20 g,
0.2 mol) and 0.6 g FeCl3 over a 60 min period. The mixture was stirred for a
further 30 min after which chilled water (60 ml) was added. The organic layer
was separated and washed with water (2 ꢀ 60 ml), aqueous sodium bisulfite
(2 g in 40 ml) and again with water (40 ml), dried over anhydrous sodium
sulfate and evaporated to dryness. The crude product was purified by
atmospheric distillation to yield compound d4-3, 29.87 g (83.4%); colorless oil,
b.p. 150–1528C; GC-MS: M/Z 40, 52, 72, 76, 78, 99, 178, 180.
(4-Fluoro-[2,3,5,6-2H4]phenyl)pyridin-4-ylmethanol (d4-5)
A solution of pyridine-4-aldehyde (0.161 mol, 17.19 g) in tetrahydrofuran
(50 ml) was added to the Grignard-reagent prepared from d4-3 (0.167 mol,
29.87 g) and magnesium turnings (0.164 mol, 3.93 g) in tetrahydrofuran
(200 ml) at 208C. After 10 h stirring, saturated ammonium chloride solution
(65 ml) and brine (60 ml) were poured into the reaction mixture, the phases
were separated and the tetrahydrofuran solution was dried and concentrated
in vacuo. The crude product was recrystallized from toluene (80 ml) to give a
1
white solid (d4-5); m.p. 132–1348C; H-NMR (300 MHz, CDCl3): d 5.75 (d,
J ¼ 2:7, 1H), 6.19 (d, J ¼ 2:7, 1H), 7.36–7.47 (m, 2H), 8.47–8.52 (m, 2H); IR
(KBr pellets, cmꢁ1) nmax 1604, 1420, 1192, 1052, 792, 648.
4-(4-Fluoro-[2,3,5,6-2H4]benzyl)piperidine hydrochloride (d4-2.HCl)
A mixture of 10% Pd/C catalyst (5 g), c. HCl (5 ml) and methanol solution
(100 ml) of d4-5 (10.35 g, 0.05 mol) was hydrogenated at atmospheric pressure
at ambident temperature until equivalent amount of hydrogen gas was
consumed. The reaction mixture was warmed up to 60–658C and, after the
consumption of further three equivalents of hydrogen gas, allowed to cool and
the catalyst was filtered and the solution concentrated in vacuo. Treatment of
the residue with diethyl ether (50 ml) gave compound d4-2.HCl in pure form;
m.p. 162–1648C; 1H-NMR (300 MHz, CDCl3): d 1.31–1.49 (m, 2H), 1.62–1.86
(m, 3H), 2.52 (d, J ¼ 7:1, 2H), 2.70–2.84 (m, 2H), 3.14–3.24 (m, 2H), 9.14
(br. s, 2H); IR (KBr pellets, cmꢁ1) nmax 2920, 1576, 1428, 1312, 1204, 1120.
GC-MS of the base d4-2: M/Z 56, 84, 98, 113, 197.
Conclusion
Convenient and generally applicable methods have been developed for the
preparation of d2, d4 and d6 isotopomers of 4-(4-fluorobenzyl)piperidines. On
the basis of the experimental results, we concluded that the use of both a
deuterated acid and alcohol-type solvent are essential in these protocols as
Copyright # 2005 John Wiley & Sons, Ltd.
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CONVENIENT METHODS FOR THE
427
these components are the primer source of deuterium in the H/D exchange
reaction.
Acknowledgements
The authors are indebted to Gedeon Richter Ltd. for the financial support.
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