Influence of [2H]-labelled acetic acid as solvent in the synthesis of [2H]-labelled perhexiline

Article abstract of DOI:10.1002/jlcr.1696

Preparation of deuterium-labelled perhexiline from an unsaturated analogue was performed via reduction with deuterium gas and PtO₂ in acetic acid. Low incorporation was observed when using acetic acid as solvent (most abundant mass peak was M_D0⁺ ), but when changing the solvent to deuterium-labelled acetic acid, e.g. acetic acid-OD or acetic acid-d₄, a higher incorporation was observed (most abundant mass peak was M_D8⁺). Using hydrogen gas instead of deuterium gas withdeuterium-labelled acetic acid, high levels of deuterium incorporation were observed (most abundant mass peak was M_D5⁺). An attempt to reduce a precursor with a fully deuterated pyridine to obtain perhexiline with a higher content of deuterium failed. Copyright

Full text of DOI:10.1002/jlcr.1696

Research Article
Received 14 August 2009,
Revised 14 October 2009,
Accepted 18 October 2009
Published online 25 November 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1696
Influence of [2H]-labelled acetic acid as
solvent in the synthesis of [2H]-labelled
perhexiline
Ã
Søren Christian Schou
Preparation of deuterium-labelled perhexiline from an unsaturated analogue was performed via reduction with deuterium
gas and PtO2 in acetic acid. Low incorporation was observed when using acetic acid as solvent (most abundant mass peak
was M1D0), but when changing the solvent to deuterium-labelled acetic acid, e.g. acetic acid-OD or acetic acid-d4, a higher
incorporation was observed (most abundant mass peak was M1D8). Using hydrogen gas instead of deuterium gas with
deuterium-labelled acetic acid, high levels of deuterium incorporation were observed (most abundant mass peak was M1D5).
An attempt to reduce a precursor with a fully deuterated pyridine to obtain perhexiline with a higher content of deuterium
failed.
Keywords: perhexiline; deuterium; platinum oxide; labelled acetic acid
An alternative route to suitable precursors for deuterated
perhexiline is shown in Scheme 2, where the intermediate 6 is
isolated before dehydration.
Dehydration was carried out by refluxing compound 6 in
conc. HCl for 1 h, affording the two dehydration products 4 and
7 in 44 and 37% yield, respectively.
Following the same procedure as described above (Scheme 1)
starting from 2-picoline-d7, the deuterated perhexiline precursor 8
(Figure 2) was prepared, but in an unexpected low yield of 20%.
When preparing compound 8, two byproducts, the 6-butyl pyridine
derivatives 9 and 10, were observed and could be isolated as a
Introduction
Racemic perhexiline (1) is used as a prophylactic agent for the
treatment of angina and is thought to act by inhibiting
mitochondrial carnitine palmitoytransferase-1. This shifts myocar-
dial metabolism from fatty acid to glucose utilization that results
in increased ATP production with the same O2 consumption and
consequently increases myocardial efficiency. Perhexiline is
indicated to reduce the frequency of moderate to severe attacks
of angina pectoris due to coronary artery disease in patients that
have not responded to other conventional therapy or for patients
where such therapy may be contraindicated. Its clinical use has
been limited by its narrow therapeutic window and high inter
and intraindividual pharmacokinetic variability (Figure 1).
In an attempt to make deuterated perhexiline to be used as
internal standard for GC-MS analysis, direct H/D exchange
protocols using (PPh3)3RuCl2 or (CO)6Ru2Cl4 as described in the
literature were used.1 Unfortunately, the outcome of these
reactions was a low incorporation of deuterium into the
molecule, affording a product which was useless as an internal
standard. Thus, we decided to prepare deuterated perhexiline
via catalytic reduction with deuterium gas of a suitable
unsaturated precursor.
N
H
Figure 1. The structure of (7)-perhexiline.
O
N
N
1. n-BuLi
+
+
Results and discussion
2. SOCl
N
The unsaturated analogue of perhexiline, 2-(2,2-dicyclohexyl-vinyl)-
pyridine 4, to be used as starting material for the catalytic reduction
with deuterium gas, was synthesised in a one pot reaction in 59%
yield. 2-Picoline (2) was deprotonated with n-BuLi at À781C, and
subsequently dicyclohexyl-methanone (3) was added at À201C
to the prepared lithium species. After 10 min, the reaction
mixture was cooled to À781C, and SOCl2 was added to facilitate
the dehydration during warm-up. Two unsaturated perhexiline
precursors 4 (59%) and 5 (34%) were isolated (Scheme 1).
2
3
4
5
Scheme 1. Preparation of perhexiline precursors.
LEO Pharma, Medicinal Chemistry Research, Industriparken 55, DK-2750
Ballerup, Denmark
*Correspondence to: Søren Christian Schou, LEO Pharma, Medicinal Chemistry
Research, 55 Industriparken, DK-2750 Ballerup, Denmark.
E-mail: soeren.schou@leo-pharma.com
J. Label Compd. Radiopharm 2010, 53 31–35
Copyright r 2009 John Wiley & Sons, Ltd.

S. C. Schou
O
N
N
N
1. n-BuLi
OH
HCl
+
+
2. NH Cl
reflux, 1h
N
2
3
7
6
4
Scheme 2. Alternative route to suitable precursors.
mixtureinanamountcorrespondingto 37%yield. Thesebyproducts
(unlabelled) were not observed in the synthesis of compound 4.
The formation of 9 and 10 occurred by reaction of the butyl
anion from n-BuLi with the pyridine ring. Such addition products
have been observed before.2,3
Compound 4 and the deuterium-labelled compound 8 were
selected as precursors for the catalytic reduction experiments.
For the reduction of the pyridine moiety to the corresponding
piperidine, a method recently reported by Birman et al.4 was used,
using PtO2 in acetic acid at ambient pressure and temperature.
A straightforward reduction of compound 4 with deuterium
gas should label perhexiline with 7 deuterium atoms (Scheme 3).
An analysis of the reaction mixture using LC-MS showed that the
most abundant mass was not M1D7 but MD11, demonstrating that
the precursor had been reduced mainly with hydrogen
(protium) and not deuterium. The source of protium had to
be the acetic acid. Experiments using different variants of
deuterium-labelled and non-labelled acetic acid as solvents
should identify the protium source.
D
N
D
N
D
N
D
D
D
D
D
D
D
D
D
D
D
8
9
10
Figure 2. The structure of 8, 9 and 10.
H,D
The crude reaction mixtures were filtered through a syringe
filter before GC-MS analysis. The volatility of a compound
changes with the degree of deuteration5 which causes the mass
spectra to change slightly across the GC-peak. To get a precise
D,H
D,H
H,D
H,D
D2 or H2
PtO2
N
H,D
N
H
determination of the degree of deuteration, the mass, M1D1, MD12
,
Acetic acid-dx
etc., were extracted from the chromatogram using the software
Xcalibur (ver. 2.07 provided by Thermo), and thereby a ‘corrected’
mass spectrum, based on the area from the ion count, could be
obtained. The ‘corrected’ mass spectra are shown in Table 1.
For experiments carried out under a deuterium atmosphere,
using acetic acid-OD or acetic acid-d4 as solvent gave the
highest incorporation level of deuterium (M1D7 was dominant
peak). Using acetic-d3 acid low incorporation of deuterium was
observed and the most dominant peak was M1D1. Using acetic
acid, a higher M1D1 peak was observed (85 versus 26 in
perhexiline), but still with M1D0 as the most dominant peak.
rt, 20h
H,D
x = 0, 1, 3, 4
4
1
Scheme 3. General reduction setup.
Table 1. Corrected mass spectra from the different experiments
Peak intensities found in the GC-MS
Solvent
Gas MD10 M1D1 MD12 MD13 MD14 M1D5 M1D6 M1D7 MD18 MD19 MD110 M1D11 M1D12 M1D13 M1D14
Acetic acid
Acetic
acid-OD
D2
D2
100
1
85
1
47
2
15
3
5
8
1
19
—
53
—
90
—
100
—
68
—
33
—
6
—
4
—
—
—
—
Acetic-d3 acid D2
Acetic acid-d4 D2
93 100
38
3
3
41
32
3
1
76
—
5
—
94
— —
10 100
—
68
—
38
—
100
—
—
85
—
6
—
49
—
2
—
15
—
—
—
3
—
—
—
2
—
—
—
—
—
—
2
100
9
1
25
18
Acetic acid
Acetic
acid-OD
H2
H2
—
100
—
78
16
Acetic-d3 acid H2
100
6
20
15
4
3
—
92
—
—
81
—
51
—
24
—
7
—
3
—
—
—
—
—
—
—
—
Acetic acid-d4 H2
29
71
100
Perhexiline
www.jlcr.org
100
26
—
—
—
—
—
—
—
—
—
—
—
—
—
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 31–35

S. C. Schou
When performing the reduction under a hydrogen atmosphere, To investigate a potential H/D exchange in the final product
a high degree of incorporation was seen in the experiments using formed by the reduction, a set of experiments was performed
acetic acid-OD or acetic acid-d4 (M1D5 was dominant peak). Using using the same conditions as used for the reduction (Scheme 4).
acetic-d3 acid or acetic acid as solvents, no incorporation of
These experiments showed that no H/D exchange took place
deuterium was observed. This showed that the exchangeable in the product perhexiline under the standard conditions given
acidic protons were involved in the reduction. The catalyst in Scheme 4 (Table 2).
promotes the exchange of the exchangeable acidic deuterium
To obtain high levels of deuterium incorporation, reductions
with the hydrogen gas affording deuterium gas. Such effects have should be performed in OD-solvents.
been reported before, not with deuterium-labelled acetic acid but
with deuterated ammonium formate in deuterated methanol6 or
D2O.7–10 Derdau6 has reported the preparation of labelled
piperidines, piperazines and tetrahydroquinolines using Pd/C and
deuterated ammonium formate in deuterated methanol, and Sajiki
etal.9 showedthatD2 canbegenerated insitu bystirring D2O under
a H2 atmosphere with Pd/C as catalyst for the exchange reaction.
An equilibrium mixture of acetic acid (-OD) and H2-gas in our
experiments would have an approximate molar ratio D/H = 93/7
(500 mL acetic acid-OD = 8.3 mmol D and 7 mL H2-gas = 0.6 mmol H).
The outcome of the reduction with such a mixture would result in
labelled perhexiline with a predicted highest molar ion at M1D6. A fast
reduction with H2-gas, before any substantial exchange of H and D
has taken place, would result in no or little deuterium incorporation.
The highest peak was observed at M1D5, which shows that reduction
takes place with a fully (or nearly) equilibrated H/D-mixture.
Esaki and co-workers11 have reported a direct deuterium
transfer from D2O to the product when performing H/D
exchange reactions in alkyl-substituted benzene derivatives in
a Pd/C–H2–D2O system.
To investigate whether a direct deuterium/hydrogen ex-
change takes place between acetic acid-OD and the aromatic
precursor 4 prior to reduction, remaining starting material from
the reduction was analysed. MS-Analysis showed the same mass
peak as for non-reacted precursor, with 269 as the dominant
peak. Thus, no direct deuterium transfer from acetic acid-OD to
the precursor occurred.
In an attempt to make perhexiline with a higher content of
deuterium, 8 was used as the precursor. Surprisingly, neither D2
nor H2 could reduce compound 8 to the corresponding piperidine
using the same conditions as used for the reduction of 4.
Conclusion
In conclusion, the deuterium found in the product comes from
reduction of the double bonds. No subsequent H/D exchange
reaction was observed. The highest level of deuterium incorpora-
tion was observed when acetic acid-OD and deuterium gas was
used. Using acetic acid (-OH) lower levels of incorporation was
observed, proving that the exchangeable proton is taking part in
the reduction. No direct deuterium transfer from OD-labelled
acetic acid was observed. Due to the fast equilibrium 2CH3COOD
1H2"2CH3COOH1D2, catalysed by PtO2, reduction of the
unsaturated perhexiline precursor 4 will give perhexiline labelled
with deuterium at a level that reflects the amount of deuterium in
the total proton/hydrogen-gas pool.
Experimental
General
All reactions were performed in a stainless steel manifold purchased
from RC Tritec, Teufen, Switzerland. D2 (99.8 atom % D) was
purchased from Isotec, H2 (99.996%) was purchased from
˚
Sigma-Aldrich. THF was dried over molecular sieves (4 A). All other
solvents and reagents were used as received, purchased from
Sigma-Aldrich.
1H and 13C NMR spectra were obtained in CDCl3 on a Bruker
AV600 spectrometer with a 5 mm TCI-Cryoprobe or a Bruker
DRX500 spectrometer with a 5 mm PAPPI-probe. Chemical shifts
are reported in ppm with tetramethylsilane (TMS, d = 0.00) as
internal reference. All air and moisture sensitive reactions were
carried out in oven-dried (1201C) glassware under an inert
atmosphere of argon. Column chromatography was performed
using silica gel 60 (Merck) (70–230 mesh).
D2
Standard procedure for reduction
PtO2
N
No reaction
H
Acetic acid-dx
rt, 20h
PtO2 (8 mol%) was weighed into a 4 mL round bottom reaction
flask containing a Teflon-coated stir bar (3 Â 10 mm). The
substrate (0.037 mmol), dissolved in dry solvent (500 mL), was
added. The reaction mixture was frozen in liquid N2 and
evacuated (below 3.5 Â 10À3 mbar), thawed and then stirred
x = 0, 1, 3, 4
1
Scheme 4. Setup to investigate a potential H/D exchange.
Table 2. Corrected mass spectra from the experiments investigating a possible H/D exchange reaction
Peak intensities found in GC-MS
Solvent
M1D0
M1D1
M1D2
M1D3
M1D4
M1D5
M1D6
M1D7
Acetic acid
Acetic acid-OD
Acetic-d3 acid
100
100
100
25
28
35
4
5
6
1
1
1
—
—
—
—
—
—
—
—
—
—
—
—
Acetic acid-d4
100
100
31
26
5
1
—
—
—
—
—
—
—
—
Perhexiline
—
—
J. Label Compd. Radiopharm 2010, 53 31–35
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

S. C. Schou
under D2- or H2-atmosphere (1340–722 mbar) for 20 h at rt. The
1H NMR (600 MHz, CDCl3)d8.44 (d, J = 4.8, 1H), 7.60 (t, J = 7.7,
reaction mixture was filtered through a syringe filter (Whatman, 1H), 7.15 (d, J = 7.8, 1H), 7.14–7.10 (m, 1H), 6.32 (s, 1H), 2.97–2.84
0.45 mm) and concentrated in vacuo affording a colourless film. (m, 2H), 1.83 (d, J = 12.6, 2H), 1.73 (dd, J = 28.4, 13.0, 6H), 1.61
(t, J = 11.7, 2H), 1.52 (t, J = 11.8, 2H), 1.36–1.02 (m, 8H), 0.96
2-(2,2-Dicyclohexyl-vinyl)-pyridine (4)
(q, J = 12.2, 2H).
13C NMR (151 MHz, CDCl3)d161.95, 147.82, 136.75, 124.52,
120.96, 77.81, 46.16, 39.15, 27.98, 27.94, 27.32, 27.18,
26.78.
2-(2-Cyclohexyl-2-cyclohexylidene-ethyl)-pyridine (5). Preparation A:
2-Methyl-pyridine (5 mmol, 465 mg, 494 mL) was dissolved in dry
THF (15 mL) in a dry flask charged with argon. The solution was
cooled to À781C and n-BuLi (1.6 M in hexanes, 5 mmol,
3.125 mL) was added dropwise. The clear, colourless solution
turned red/orange and became milky during the addition. The
reaction mixture was allowed to warm-up to À201C and
dicyclohexyl-methanone (5 mmol, 971 mg, 985 mL, dissolved in
dry THF (5 mL)) was added dropwise. The colourless solution
was stirred at À201C for 10 min and cooled to À781C. SOCl2
(7.5 mmol, 892 mg, 544 mL) was dissolved in dry THF (5 mL) and
added dropwise affording a yellow reaction mixture. The
reaction mixture was stirred for an additional 5 min at À781C
and then allowed to warm-up to rt. During warm-up the yellow
solution turned beige and milky. The reaction mixture was
stirred at rt for 30 min and then poured into a separation funnel
containing sat. Na2CO3 (30 mL), EtOAc (30 mL) was added and
the phases were separated. The aqueous phase was extracted
with EtOAc (3 Â 30 mL) and the combined organic phases were
dried (MgSO4), filtered and concentrated in vacuo affording
1.43 g of pale yellow oil. The oil was purified by silica gel
chromatography using a gradient of heptane:ethyl acetate
[100:0-83:17] affording compound 4 as a colourless oil in 59%
yield (793 mg, 2.94 mmol) and compound 5 as colourless oil in
34% yield (460 mg, 1.70 mmol).
2-(2,2-Dicyclohexyl-vinyl)-pyridine (4)
2-(2-Cyclohex-1-enyl-2-cyclohexyl-ethyl)-pyridine (7). Preparation
B: 1,1-Dicyclohexyl-2-pyridin-2-yl-ethanol (6) was dissolved in
conc. HCl (50 mL) and heated to reflux for 1 h. The reaction
mixture was allowed to cool to rt, and pH was adjusted to 10
using sat. Na2CO3. The basified reaction mixture was extracted
with EtOAc (4 Â 50 mL). The combined organic phases were
dried (Na2SO4), filtered and concentrated in vacuo affording
798 mg crude product as colourless oil. The oil was purified by
silica gel chromatography using a gradient of heptane:ethyl
acetate [100:0-83:17] affording compound 4 as colourless oil in
44% yield (353 mg, 1.31 mmol) and compound 7 as colourless oil
in 37% yield (302 mg, 1.12 mmol).
Compound 7: 1H NMR (500 MHz, CDCl3)d8.50–8.45 (m, 1H),
7.50 (td, J = 7.6, 1.8, 1H), 7.02 (dd, J = 7.5, 4.8, 2H), 5.10 (s, 1H),
3.08 (dd, J = 13.2, 4.6, 1H), 2.62 (dd, J = 13.2, 11.2, 1H), 2.18–2.08
(m, 1H), 2.00–1.89 (m, 2H), 1.88–1.80 (m, 1H), 1.79–1.72 (m, 1H),
1.72–1.58 (m, 5H), 1.54–1.28 (m, 5H), 1.26–1.07 (m, 3H), 1.05–0.93
(m, 1H), 0.91–0.78 (m, 1H).
13C NMR (126 MHz, CDCl3)d162.19, 148.88, 137.53, 135.45,
123.87, 123.61, 120.43, 54.43, 40.09, 39.48, 31.73, 31.33, 26.73,
26.69, 26.66, 25.78, 25.23, 22.97, 22.73.
1
Compound 4: H NMR (500 MHz, CDCl3)d8.57 (dd, J = 4.8, 0.8,
1H), 7.59 (td, J = 7.7, 1.9, 1H), 7.14 (d, J = 7.9, 1H), 7.05 (ddd,
J = 7.5, 4.9, 0.9, 1H), 6.31 (s, 1H), 3.07 (tt, J = 11.7, 3.4, 1H), 2.09
(dd, J = 13.8, 5.7, 1H), 1.76 (ddd, J = 16.2, 14.8, 8.7, 8H), 1.66–1.52
(m, 2H), 1.51–1.13 (m, 10H).
2-(2,2-Dicyclohexyl-vinyl)-pyridine-d5 (8)
2-Methyl-pyridine-d7 (2.5 mmol, 250 mg) was dissolved in dry
THF (10 mL) in a dry flask charged with argon. The solution was
cooled to À781C and n-BuLi (1.6 M in hexanes, 2.5 mmol,
1.55 mL) was added dropwise. The clear, colourless solution
turned red/orange and became milky during addition. The
reaction mixture was allowed to warm-up to À201C and then
dicyclohexyl-methanone ((2.5 mmol, 486 mg, 492 mL) in dry THF
(2 mL)) was added dropwise. The colourless solution was stirred
at À201C for 10 min and cooled to À781C. SOCl2 (3.75 mmol,
446 mg, 272 mL) in dry THF (2 mL) was added dropwise affording
a yellow reaction mixture. The reaction mixture was stirred for
an additional 5 min at À781C and allowed to warm-up to rt.
During warm-up, the yellow solution became beige and milky.
13C NMR (126 MHz, CDCl3)d158.00, 149.23, 135.67, 123.64,
123.02, 120.40, 40.81, 40.08, 35.13, 30.70, 27.16, 26.31, 26.26, 26.15.
Compound 5: 1H NMR (600 MHz, CDCl3)d8.53–8.48 (m, 1H), 7.54
(td, J = 7.7, 1.9, 1H), 7.13 (d, J = 7.9, 1H), 7.05 (dd, J = 6.8, 5.2, 1H),
3.63 (s, 2H), 2.62 (ddd, J = 11.5, 7.5, 3.4, 1H), 2.32 (t, J = 5.4, 2H),
2.13–2.06 (m, 2H), 1.66 (dd, J = 10.1, 2.5, 2H), 1.61–1.54 (m, 5H),
1.48 (dd, J = 7.5, 4.0, 2H), 1.37 (d, J = 10.7, 2H), 1.29–1.16 (m, 5H).
13C NMR (151 MHz, CDCl3)d162.24, 148.96, 136.13, 135.96,
130.67, 121.92, 120.54, 40.92, 36.84, 31.78, 31.72, 30.21, 28.71,
28.14, 27.09, 26.75, 26.08.
1,1-Dicyclohexyl-2-pyridin-2-yl-ethanol (6)
2-Methyl-pyridine (3 mmol, 279 mg) was dissolved in dry THF The reaction mixture was stirred at rt for 30 min, poured into a
(10 mL) in a dry flask charged with argon. The solution was cooled separation funnel containing sat. Na2CO3 (20 mL), diluted with
to À781C and then n-BuLi (3 mmol, 1.9 mL) was added dropwise. EtOAc (20 mL), and the phases were separated. The aqueous
The colourless clear solution turned red/orange during the phase was extracted with EtOAc (3 Â 20 mL) and the combined
addition of n-BuLi. The reaction mixture was allowed to warm- organic phases were dried (MgSO4), filtered and concentrated in
up to À201C and dicyclohexyl-methanone (3 mmol, 583 mg, in dry vacuo affording 963 mg of light brown oil. The oil was purified
THF (4 mL)) was added. The coloured reaction mixture turned by silica gel chromatography using a gradient of heptane:ethyl
colourless during the addition. The reaction mixture was stirred at acetate [100:0-83:17] affording compound 8 as colourless oil in
À201C for 10 min and the reaction was quenched with sat. NH4Cl 20% yield (140 mg, 0.51 mmol).
(20 mL). The phases were separated and the aqueous phase
1H NMR (600MHz, CDCl3)d3.06 (tt, J = 11.9, 3.3, 1H), 2.10 (ddd,
extracted with EtOAc (3 Â 20 mL). The combined organic phases J = 11.2, 8.2, 3.2, 1H), 1.83–1.71 (m, 6H), 1.71–1.63 (m, 2H), 1.59
were dried (MgSO4), filtered and concentrated in vacuo affording (dd, J = 13.3, 1.6, 2H), 1.42 (qd, J = 12.3, 3.1, 2H), 1.37–1.14 (m, 8H).
the desired product as colourless oil in quantitative yield (862 mg,
3 mmol) and Used without further purification.
13C NMR (151 MHz, CDCl3)d157.90 (d, J = 29.5), 148.87 (dd,
J = 52.5, 25.4), 135.32 (dd, J = 46.7, 22.1), 123.30 (dd, J = 49.1,
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 31–35

S. C. Schou
24.4), 122.61, 119.95 (dd, J = 46.9, 22.4), 40.75, 40.03, 35.11, 30.60
(d, J = 17.1), 27.14, 26.29, 26.23, 26.13.
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Acknowledgement
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I am grateful to my colleague, Gunnar Grue-Sørensen, Depart-
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discussions and invaluable assistance and support, Lars Dencker
Nielsen and Maj-Britt Sund, Department of New Products, for the
GC-MS analysis and the Department of Spectroscopy and
Physical Chemistry at LEO Pharma for obtaining high resolution
NMR-spectra.
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