Synthesis of deuterium-labelled drugs by hydrogen-deuterium (H-D) exchange using heterogeneous catalysis

Article abstract of DOI:10.1002/jlcr.1848

Multi-deuterium incorporations into drugs, such as theophylline, caffeine, valpromide, phenytoin, and trimethoprim, were post-synthetically achieved by Pd/C-, Pt/C-, or/and Rh/C-catalyzed hydrogen-deuterium exchange reactions under neutral conditions usin

Full text of DOI:10.1002/jlcr.1848

Research Article
Received 18 September 2010,
Revised 27 October 2010,
Accepted 28 October 2010
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1848
Synthesis of deuterium-labelled drugs by
hydrogen–deuterium (H–D) exchange using
heterogeneous catalysis
Nkaelang Modutlwa, Tomohiro Maegawa,z Yasunari Monguchi,y and
Ã
Hironao Sajiki
Multi-deuterium incorporations into drugs, such as theophylline, caffeine, valpromide, phenytoin, and trimethoprim, were
post-synthetically achieved by Pd/C-, Pt/C-, or/and Rh/C-catalyzed hydrogen–deuterium exchange reactions under neutral
conditions using deuterium oxide as the deuterium source in the presence of hydrogen gas. The present study offers facile
and convenient methods for the preparation of highly deuterated medicines, which are expected to be used as long-lasting
medicines as well as internal standards for metabolic studies and for the quantitative analyses of the parent drugs.
Keywords: multiple deuteration; hydrogen–deuterium exchange; heavy-hydrogen drug; palladium on carbon; platinum on carbon;
rhodium on carbon; deuterium oxide
method, which produces deuterated compounds more rapidly
and cost effectively. Although a number of post-synthetic H–D
Introduction
The pharmaceutical industry has been investigating on deuterium
substitution, since Elison et al. demonstrated the inhibition of the
enzymatic oxidation of morphine by deuterating the N-methyl
hydrogens.1 The deuteration of drugs is expected to extend the
duration of the biological activity and increase the stability based
on the isotope effect; the carbon–deuterium (C–D) bonds
withstand chemical or enzymatic cleavage relative to the
carbon–hydrogen (C–H) bonds.2–5 The improvement of the
therapeutic activities of clinical medicines by the H–D displace-
ments have been reported: (1) amphetamines were more readily
transported into the brain and persistent in the deuterated form
and the activity was maintained longer6; (2) halogenated
anesthetics, such as selvoflane, when deuterated, were no longer
oxidized to the toxic forms within the body7; and (3) deuterium-
labelled long-chain fatty acids and fluoro-D-phenylalanine were
resistant to breakdown by their target microorganisms.8 More
recently, deuterium-substituted clinical medicines, such as
paroxetine (antidepressant),9 atazanavir (HIV drug),10 and venla-
faxine (antidepressant),11 were synthesized as long-lasting drug
candidates by the pharmaceutical industry. Furthermore, much
attention has been drawn to the use of deuterium-labelled drugs
as tracers for the investigation of human drug metabolism12 or as
surrogates for quantitative analysis using gas or liquid chromato-
graphy combined with mass spectrometry (GC-MS or LC-MS).13–15
Two contrasting strategies are used for the synthesis of
deuterium-labelled compounds. The first strategy is the total-
synthetic approach using commercially available deuterium-
labelled precursors as the starting materials, although it involves
long synthetic routes and requires expensive deuterium-labelled
starting materials. The second strategy is based on the
post-synthetic hydrogen–deuterium (H–D) exchange reaction
exchange reactions have been reported in the literature
using metal catalysts, most of them require harsh conditions,
such as strong bases or acids,16 expensive reagents, such as
D2 gas,17 and special pressure, base and/or acid resistant
equipment.18 Furthermore, these methods in general achieved
a low degree of deuterium efficiency.19 Hence, the develop-
ment of efficient H–D exchange reactions is a challenging subject.
We have recently developed palladium on carbon (Pd/C)-
hydrogen gas (H2)-deuterium oxide (D2O) system that led to the
efficient introduction of deuterium atoms into a variety of
compounds, including bioactive molecules, such as sulfametha-
zine (antibacterial), nalidixic acid (antibacterial), antipirine (analge-
sic), and allopurinol (antiurolithic).20 Platinum on carbon (Pt/C) was
found to be an effective catalyst to introduce deuterium atoms on
aromatic nuclei rather than the alkyl chain compared to Pd/C.21
Ibuprofen (analgesic) was fully deuterated using 5% Pt/C–H2–D2O
followed by 10% Pd/C–H2–D2O systems.22 Lately, the simulta-
neous use of Pd/C and Pt/C achieved the efficient deuteration of
phentermine, which was a key intermediate for the synthesis of
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4
Daigaku-nishi, Gifu 501-1196, Japan
Ã
Correspondence to: Hironao Sajiki, Laboratory of Organic Chemistry, Gifu
Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
E-mail: sajiki@gifu-pu.ac.jp
yCorrespondence to: Yasunari Monguchi, Laboratory of Organic Chemistry, Gifu
Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
E-mail: monguchi@gifu-pu.ac.jp
zCurrent address: Graduate School of Pharmaceutical Sciences, Osaka University,
Suita 565-9871, Japan.
J. Label Compd. Radiopharm 2010, 53 686–692
Copyright r 2010 John Wiley & Sons, Ltd.

N. Modutlwa et al.
the deuterium-labelled mephentermine (antihypotensive) and was 86.0 mg (97%). Isotopic distribution (EIMS): 2% d2, 18% d3,
oxethazaine (local anesthetic).23
64% d4, 14% d5, 2% d6 1H NMR (DMSO-d6, 1,4-dimethoxybenzene
In this paper we describe the post-synthetic H–D exchange as an internal standard) d 8.01 (s, 0.05H), 3.40–3.38 (s, 0.24H),
2
reactions of xanthines, valpromide, phenytoin, and trimetho- 3.20–3.19 (s, 2.71H). H NMR (DMSO) d 8.03 (br s) 3.39 (br s).
prim using heterogeneous Pd/C, Pt/C or/and Rh/C catalysts.
[2H]Caffeine (Scheme 1)
First step. Method A: A mixture of caffeine (97.0 mg, 0.5 mmol),
10% Pd/C (29.1 mg, 30 wt%), and D2O (3 mL) was stirred at 1601C
for 48 h. Yield was 82.5 mg (85%).
Experimental section
General
Second step. Method A: A mixture of deuterated caffeine
(49.0 mg, 0.25 mmol, obtained from the first step in Scheme 1),
10% Pd/C (9.8 mg, 20 wt%), and D2O (1.5 mL) was stirred at 1601C.
Yield was 44.0 mg (90%). Isotopic distribution (EIMS): 4% d4, 12% d5,
25% d6, 38% d7, 16% d8, 4% d9, and 1% d10. 1H NMR (D2O, DSS as
an internal standard) d 7.88 (s, 0.02), 3.90–3.87 (s, 0.55H), 3.30–3.25
The 1H and 2H NMR spectra were recorded using a JEOL AL-400 or
1
2
EX-400 spectrometer (400 MHz for H NMR; 61MHz for H NMR).
The chemical shifts (d) are expressed in parts per million referenced
to tetramethylsilane (0.00 ppm for CDCl3/1H NMR), 3-(trimethylsi-
lyl)propanesulfonic acid sodium salt (DSS) (0.00 ppm for D2O/1H
NMR and for H2O/2H NMR), or solvent peaks (7.26ppm for CHCl3/2H
NMR; 2.49 ppm for DMSO-d6/1H NMR and for DMSO/2H NMR). The
deuterium content was determined using internal standards (1,4-
dimethoxybenzene, p-anisic acid, or DSS). The EI and FAB mass
spectra were taken by a JEOL JMS-SX 102A spectrometer.
Deuterium isotopic distributions were determined by the compar-
ison of peak heights of mass spectra between labelled product and
unlabelled substrate according to the Bergman’s methods.24 The
analytical thin-layer chromatography was carried out on pre-coated
Silica Gel 60 F254 plates (Merck, Art 5715) and visualized with UV
light or stain (bromocresol green reagent for valpromide). The 10%
Pd/C and 5% Pt/C were purchased from the Aldrich Chemical Co.,
and the 10% Rh/C was obtained from the N.E. Chemcat Co.
Deuterium oxide (99.9% isotopic purity) was purchased from
Cambridge Isotope Laboratories, Inc., or Division of Spectra Gases,
Inc. All other reagents were obtained from commercial sources and
used without further purification. Sealed tubes (60 mL) were
obtained from Taiatsu Techno Corporation.
2
(s, 2.55H). H NMR (H2O) d 7.75 (br s), 3.72 (br s), 3.27 (br s).
[2H]Valpromide (Scheme 2)
First step: Method A: A mixture of valpromide (72.0 mg,
0.5 mmol), 10% Pd/C (14.4 mg, 20 wt%), and D2O (4 mL) was
stirred at 1601C. Yield was 72.0 mg (100%). Chloroform was used
for workup in place of methanol.
Second step: Method A: A mixture of deuterated valpromide
(50.0 mg, 0.35mmol, obtained from first step), 10% Rh/C (21.6 mg,
30 wt%), and D2O (4mL) was stirred at 1601C for 48h. Yield was
47.0 mg (94%). Chloroform was used for workup in place of
methanol. Isotopic distribution (FAB1 MS): 7% d12, 10% d13, 28%
1
d14, and 56% d15. H NMR (CDCl3, 1,4-dimethoxybenzene as an
internal standard) d. 2.13–2.10 (m, 0.009H), 1.59–1.54 (m, 0.32H),
2
1.43–1.26 (m, 1.03H), 0.93–0.86 (m, 0.92H). H NMR (CHCl3) d 2.09
(br s), 1.52 (br s), 1.34–1.23 (br t), 0.84 (br s).
[2H]Phenytoin (Table 4, Entry 4)
Method A: A mixture of phenytoin (126 mg, 0.5 mmol), 5% Pt/C
(25.2 mg, 20 wt%), 10% Pd/C (25.2 mg, 20 wt%), and D2O (5 mL)
was stirred at 1801C. Yield 99.0 mg (79%). Acetone was used for
workup in place of methanol. Isotopic distribution (EIMS): 5% d8,
23% d9, 58% d10, and 14% d11. 1H NMR (DMSO-d6, 1,4-
General procedure for the H–D exchange reaction
Method A: A sealed tube was charged with a substrate
(0.15–1.0 mmol), catalyst (10–30 wt% of the substrate), and D2O
(1–5mL). The air inside the tube was exchanged with hydrogen
(60 mL, approximately 2.6 mmol) by five vacuum-hydrogen gas
cycles. The sealed tube was placed in an oil bath heated at
110–1801C, and stirred for 24 h. After cooling to room temperature,
the reaction mixture was diluted with methanol (5 mL), and then
filtered through a membrane filter (Millipore Millex-LG, 0.45 mm) to
remove the catalyst. The collected catalyst was washed with
methanol (2 ꢀ 5 mL), and the filtrate was concentrated in vacuo.
Method B: A 15-mL test tube was charged with a substrate
(0.15–0.50 mmol), catalyst (10–20wt% of the substrate), and D2O
(1–5 mL). After the test tube was sealed with a septum, the air
inside was exchanged with hydrogen (15 mL, approximately
0.66 mmol) by five vacuum-hydrogen cycles. The mixture was
stirred at 50–901C for 24 h using a Chemistation personal organic
synthesizer (EYELA, Tokyo). After cooling to room temperature, the
reaction mixture was diluted with methanol (5 mL), and then
filtered through a membrane filter (Millipore Millex-LG, 0.45 mm) to
dimethoxybenzene as an internal standard)
2
(m, 0.44H). H NMR (DMSO) d 7.37–7.26 (br d).
d 7.51–7.34
[2H]Trimethoprim (Table 5, Entry 4)
Method A. A mixture of trimethoprim (145mg, 0.5 mmol), 10%
Pd/C (29.0 mg, 20wt%), 5% Pt/C (29.0 mg, 20wt%), and D2O
(3mL) was stirred at 1801C for 34h. Yield 145 mg (100%). Acetone
was used for workup in place of methanol. Isotopic distribution
(EIMS): 3% d3, 12% d4, 32% d5, 29% d6, 15% d7, 6% d8, 2% d9, and
1% d10. 1H NMR (DMSO-d6, p-anisic acid as an internal standard) d
7.51 (s, 0.03H), 6.61 (s, 0.17H), 3.72 (s, 3.54H), 3.61 (s, 2.04H), 3.54
2
(s, 0.26H). H NMR (DMSO) d 6.83 (br s), 3.97 (br s).
Results and discussion
remove the catalyst. The collected catalyst was washed with Deuteration of xanthines (theophylline and caffeine)
methanol (2 ꢀ 5mL) and the filtrate was concentrated in vacuo.
The structurally related xanthine alkaloids, such as caffeine
and theophylline, are widely used in medical care.25 Caffeine
is used as a psychoactive drug, while theophylline is used as
Method A. A mixture of theophylline (90.0 mg, 0.5 mmol), 10% Pd/ a bronchodilator.25 The International Sports Authorities regu-
C (18.0mg, 20 wt%), and D2O (1.5mL) was stirred at 1601C. Yield late the presence of the xanthines in biological samples,
[2H]Theophylline (Table 1, Entry 1)
J. Label Compd. Radiopharm 2010, 53 686–692
Copyright r 2010 John Wiley & Sons, Ltd.
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N. Modutlwa et al.
e.g., caffeine and theophylline are prohibited in racing horses.26 Entry 1).27 The low deuterium incorporation into the N1-methyl
Labelled xanthines are used as internal standards to analyze the group would be attributed to the steric hindrance caused
quantity of these xanthines in the body fluids of the horses by the neighboring two keto groups at the 2 and 6-positions.
using isotope dilution-mass spectrometry coupled with gas or The lowering of the temperature to 1401C maintained the high
liquid chromatography in anti-doping and forensic labora- deuterium contents (Entry 3), although they dropped at the
tories.26 The deuterium-labelled theophylline ([2H6]theophylline) N3-methyl group by either increasing or further decreasing the
was conventionally synthesized via methylation of either temperature (180 or 901C; Entries 2 and 4). Other activated
7-benzylguanine with CD3I or 6-aminouracil with (CD3O)2SO2, carbon-supported transition metal catalysts, such as 10%
while the methylation of theophiline using CD3I afforded Rh/C, 10% Ru/C, 10% Au/C, and 5% Pt/C, were found to be far
the corresponding N7-deuterium-methylated [2H3]caffeine.26 less active for the H–D exchange reaction on the N3-methyl
Although the synthetic methods were reliable, expensive group (Entries 5–8). However, the use of Pt/C led to the
deuterium-labelled methylating reagents were necessary.
completely selective deuterium incorporation at the 8-position
When theophylline (0.5 mmol) was stirred with 10% Pd/C (Entry 8).28
(20 wt%: 20% of theophylline weight) in D2O (1.5 mL) under an
The H–D exchange reaction of caffeine (0.5 mmol) was
H2 atmosphere at 1601C, satisfactory and selective deuterium investigated using the 10% Pd/C (20 wt%)–D2O (1.5 mL)–H2
incorporation was achieved on the methyl group at the system that afforded the best deuterium efficiency in the case of
N3-position and the 8-position of the purine nucleus (Table 1, theophylline (Table 2). When the reaction was carried out at
Table 1. H–D exchange reaction of theophylline
1
D3C
O
N
O
Catalyst (20 wt %)
H2
H
N
H
N
N
N
8
D
N
D2O (1.5 mL), 24 h
N
O
O
N
CD3
3
0.5 mmol
Temp (1C)
Entry
Catalyst
D content (%)a
N3 (CD3)
Yield (%)
N1 (CD3)
8 (D)
1
2
3
4
5
6
7
8
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Rh/C
10% Ru/C
10% Au/C
5% Pt/C
160
180
140
90
160
160
160
160
10
0
4
4
1
13
8
0
92
63
96
21
54
15
11
0
95
96
98
98
98
96
98
96
94
89
94
88
97
92
92
88
1
aDetermined by H NMR.
Table 2. Pd/C-catalyzed H–D exchange reaction of caffeine
7
CD3
O
1
O
10% Pd/C (20 wt %)
D3C
N
N
H2
N
N
N
8
D
N
N
D2O (1.5 mL), 24 h
O
O
N
CD3
3
0.5 mmol
Entry
Temp (1C)
D content (%)a
N3 (CD3)
Yield (%)
N1 (CD3)
N7 (CD3)
8 (D)
1
2
3
90
160
180
0
19
22
23
90
82
0
57
51
96
96
96
98
98
98
1
aDetermined by H NMR.
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 686–692

N. Modutlwa et al.
901C, the H–D exchange reaction took place with a 96% first deuteration improved the deuterium efficiency at the
deuterium efficiency at the 8-position, but the methyl groups at N7-position to 82% (Scheme 1).
the N1-, N3-, and N7-positions were hardly deuterated (Entry 1).
As the temperature was raised, the deuterium efficiency of the Deuteration of anticonvulsants (valpromide and phenytoin)
N3-methyl group significantly increased (Entries 1–3), and the
Anticonvulsants, such as valpromide and phenytoin, are used to
treat epilepsy and to provide relief from non-seizure neurolo-
quantitative deuterium incorporation at the N3-methyl was
achieved at 1801C with a medium deuterium efficiency at the
N7-methyl group (Entry 3). For the reaction using increased
amounts of 10% Pd/C (30 wt%) and D2O (3 mL) at 1601C for 48 h,
a 77% deuterium efficiency was obtained even at the N7-methyl
group with high D contents kept at the N3- and 8-positions
(Scheme 1). The resulting deuterated caffeine was again stirred
in D2O (1.5 mL) under an H2 atmosphere at 1601C for 24 h
in the presence of 10% Pd/C (20 wt%) (Scheme 1). Although
the deuterium atoms were not sufficiently introduced into the
N1-methyl group (15%), reuse of the substrate after the
gical and psychiatric disorders, such as migraines, neuropathy
pain, and mood disorders.29,
30
Deuterium-labelled phenytoin
has been used as a tracer in a bioavailability study using GC-MS
to evaluate the clearance values by analyzing its concentration
in plasma.31 Pharmacokinetic studies of phenytoin are important
because of its narrow therapeutic concentration range, hence
small changes in the bioavailability can cause medical accidents.
Valpromide has a very short half-life (less than 1 h), and a high
clearance value.32 The exchange of the valpromide hydrogens
with deuterium could therefore be expected to increase the
half-life and lower the clearance value due to the isotope effect.
Fully deuterated phenytoin, [2H10]phenytoin, was synthesized by
the modified Bucherer–Bergs reaction of [2H10]benzophenone,33
which was prepared from [2H6]benzene and [2H5]benzoyl
chloride,34 while no synthesis of the deuterated valpromide
has been reported in the literature.
The H–D exchange reaction of valpromide using the Pd/
C–H2–D2O combination did not proceed well at room tempera-
ture (approximately 251C) and 1101C (Table 3, Entries 1 and 2),
while an increase in the temperature to 1601C remarkably
enhanced the deuterium efficiency to ca. 50% on all carbon
atoms (Entry 3). The use of 10% Rh/C (30% of the substrate
weight)35 in place of 10% Pd/C lowered the deuterium
incorporation (Entry 4), but it was improved to more than 55%
on all carbon atoms by the reuse of the moderately deuterated
valpromide obtained in Entry 4 for the H–D exchange reaction
(Entry 5) or the extension of the reaction time from 24 to 48 h
(Entry 6).
77
O
N
17
D3C
O
N
CD3
10% Pd/C (30 wt %)
H2
N
N
N
N
N
98
D
N
D2O (3 mL)
160 °C, 48 h
85%
O
O
CD3
97
0.5 mmol
H2
82
O
18
D3C
CD3
10% Pd/C (20 wt %)
N
N
98
D
N
D2O (1.5 mL)
160 °C, 24 h
90%
O
N
CD3
97
Scheme 1. Stepwise deuteration of caffeine. Deuterium efficiencies are indicated
in italics.
Table 3. The H–D exchange reaction of valpromide
CD3
D2C CD2
Catalyst, H2
O
O
CD
4
H2N
H2N
D2O (4 mL)
D2C CD2
24 h
3
2
0.5 mmol
CD3
1
Entry
Catalyst
Temp (1C)
D content (%)a
Yield (%)
1 (CD3)
2 (CD2) 3 (CD2)
4 (CD)
1
2
3
4
5b
6c
10% Pd/C (20 wt%)
10% Pd/C (20 wt%)
10% Pd/C (20 wt%)
10% Rh/C (30 wt%)
10% Rh/C (30 wt%)
10% Rh/C (30 wt%)
rt
110
160
160
160
160
3
6
52
24
55
67
4
3
48
23
55
66
6
8
48
12
61
71
9
10
52
33
72
82
97
92
100
97
96
80
1
aDetermined by H NMR.
bThe product of Entry 4 was used as the starting material.
c48 h.
J. Label Compd. Radiopharm 2010, 53 686–692
Copyright r 2010 John Wiley & Sons, Ltd.
www.jlcr.org

N. Modutlwa et al.
Based on these results, over an 80% deuterium efficiency of deuterium efficiencies were obtained depending on the
valpromide was finally achieved by the successive H–D temperature (Table 4, Entries 1–3). We also reported the
exchange reactions at 1601C using 10% Pd/C (20 wt%) for 24 h synergistic effect of Pd/C and Pt/C on the simultaneous
and then using 10% Rh/C (30 wt%) for 48 h (Scheme 2). use for the H–D exchange reaction of various arenes to
We have already reported that 5% Pt/C more effectively increase the deuterium incorporation even at the sterically
36
catalyzed the H–D exchange on the aromatic nuclei rather hindered positions.23,
The combined use of 5% Pt/C and
than 10% Pd/C in D2O under an H2 atmosphere.36 When Pt/C 10% Pd/C at 1801C led to the expected quantitative deuteration
was used as the catalyst for the H–D exchange reaction of of phenytoin.
phenytoin, which bears two benzene rings, low-to-moderate
Deuteration of trimethoprim
CD3
Trimethoprim is a diaminopyrimidine derivative with a high
1) 10% Pd/C (20 wt %), H2
potency and specificity as a bacterial dihydrofolate reductase
D2C CD2
D2O (4 mL), 160 °C, 24 h
(DHFR) inhibitor.37 Trimethoprim is effective for the treatment of
acute infections of the urinary and respiratory tracts.38–41 The
deuterated analogs of trimethoprim ([2H2]trimethoprim,
[2H3]terimethoprim, and [2H6]trimethoprim) have been used to
study the binding of trimethoprim with DHFR by high resolution
X-ray and NMR spectroscopy.42 Trimethoprim-d2 was prepared
by the introduction of deuterium atoms on the benzene ring
O
O
100%
CD
91
H2N
H2N
2) 10% Rh/C (30 wt %), H2
D2O (4 mL), 160 °C, 48 h
94%
D2C CD
2 83
CD3
84
0.5 mmol
85
Scheme 2. Stepwise deuteration of valpromide. Deuterium efficiencies are
indicated in italics.
Table 4. The H–D exchange reaction of phenytoin
O
O
NH
NH
HN
O
Catalyst (20 wt %), H2
HN
O
D2O (5 mL), 24 h
D
D
0.5 mmol
Entry
Catalyst
10% Pt/C
5% Pt/C
5% Pt/C
5% Pt/C110% Pd/C
Temp (1C)
D content (%)a
Yield (%)
1
2
3
4
rt
160
180
180
11
50
70
96
100
100
100
79
1
aDetermined by H NMR.
Table 5. The H–D exchange reaction of trimethoprim
4
D
3
CD3
1
D2
C
10% Pd/C (A wt %)
5% Pt/C (B wt %)
H2
NH2
N
NH2
N
O
O
O
N
N
2
H2N
D2O, 24 h
H2N
O CD3
D
D
4
O
O
5
CD3
0.5 mmol
Catalyst loading
3
Entry
D2O (mL)
Temp (1C)
D content (%)a
Yield (%)
A
B
1
2
3
4
5
1
2
3
4b
10
10
20
20
10
20
20
20
1
2
3
3
rt
160
180
180
33
41
71
87
35
7
11
32
15
13
19
41
39
28
38
92
49
94
95
97
100
100
86
100
1
aDetermined by H NMR.
bReaction time was 34 h.
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Copyright r 2010 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2010, 53 686–692

N. Modutlwa et al.
of trimethoprim by the H–D exchange reaction in heated
1 M DCl,39 while multi-step syntheses through deuterated
3,4,5-trimethoxybenzaldehyde were adopted for the preparation
of [2H3]trimethoprim and [2H6]trimethoprim.43, 44
[6] M. Wenzel, J. Label. Compd. Radiopharm. 1989, 27,
1143–1155.
[7] M. T. Baker, W. C. Jr Ronnenberg, J. A. Ruzicka,
C. K. Chiang, J. H. Tinker, Drug Metab. Dispos. 1993, 21,
1170–1171.
When 10% Pd/C and 5% Pt/C (each 10% of substrate weight)
were simultaneously used for the deuteration of trimethoprim
(0.5 mmol) at room temperature with D2O (1 mL) and hydrogen
gas, the deuterium atoms were poorly incorporated (Table 5,
Entry 1). The deuterium efficiency on the pyrimidine nucleus
was improved to 94% by raising the temperature to 1601C and
the amounts of D2O and 5% Pt/C to 2 mL and 20 wt%,
respectively (Entry 2). The ease of the H–D exchange of the
pyrimidine hydrogen would be rationally explained by the
directing effect of the adjacent ring nitrogen atom; the active
palladium metal could be readily located near the C–H bond of
the pyrimidine ring by the coordination with the lone pair of the
neighboring ring nitrogen.20 Further increase in the D2O and
10% Pd/C quantity to 3 mL and 20 wt%, respectively, led to a
significant deuterium incorporation at the benzylic position
(Entry 3). Two hydrogen atoms on the benzene rings were
finally replaced with deuterium atoms with a high efficiency
(92%) by the extension of the reaction time to 34 h, although
the extent of deuteration on the methoxy group was only
slightly improved (Entry 4). The low deuterium incorporation of
the methoxy group was identical to that of the alkyl groups of
the alkoxyarenes previously reported by us.45 The deuterated
trimethoprim might be valuable to investigate the binding
with DHFR because the location of its deuterium atoms is
different from that of the previously reported deuterated
trimethoprims.
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Conclusion
We have successfully deuterated xanthines, valpromide, pheny-
toin, and trimethoprim using the heterogeneous Pd/C-, Pt/C-,
or/and Rh/C-catalyzed H–D exchange reactions in the presence
of D2O and H2. One of the most distinctive features of these
methods is their simplicity; no multi-step reaction was required
to access the deuterium-labelled drugs. The protocol for the
H–D exchange reactions could be practical for the preparation
of deuterated analogs with improved biological activities over
the parent drugs, as well as providing standard materials for
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Acknowledgement
We sincerely thank the N.E. Chemcat Corporation for the kind
gifts of the catalysts.
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