Research Article
Received 21 March 2009,
Revised 3 July 2009,
Accepted 6 July 2009
Published online 11 August 2009 in Wiley Interscience
Synthesis of deuterium labelled diclofenac
with improved isotopic enrichment
Ã
Keying Wu,a Lei Tian,a Hongye Li,a Jian Li,a and Liqin Chenb
A five-step synthesis of deuterium-labelled diclofenac starting from 2-phenyl[2H5] acetic acid is described. The synthesis
prevents deuterium from scrambling during the reaction. It offers the labelled compound with over 99% isotopic
enrichment. It also provides a possible alternative route for the synthesis of deuterium-labelled 40-hydroxydiclofenac,
which is the principal human metabolite of diclofenac.
Keywords: deuterium label; diclofenac; improved isotopic enrichment
heating an ethanol solution of (5) with 1.0 M NaOH under gentle
reflux under argon. The overall yield for the new synthesis was a
satisfactory 19%.
Introduction
The synthesis of deuterium-labelled diclofenac1 starting from
[2H5]-bromobenzene was described in the previous publica-
tions.2–5 1H-NMR analysis revealed that during the cyclization
reaction there was some scrambling of deuterium into the other
aryl ring2,3 (average of about one deuterium per molecule). Mass
spectrometry indicated a complicated distribution of mass ions.
It is desirable to synthesize an internal standard with improved
isotopic enrichment (preferably as a single isotopomer).
1H-NMR analysis of compound (6) revealed that the com-
pound has over 99% deuterium enrichment. Mass spectrometry
indicated the following distribution of mass ions: 298 (M14),
97.6%; 297 (M13), 2.4%; 296 (M12), 295 (M11) and 294 (M10),
0%. The compound provided an excellent internal standard in
LC-MS-MS studies.
Experimental
Results and discussion
All reagents were obtained from Sigma-Aldrich and CDN
Isotope. Mass spectra were recorded using a Quattro micro
API mass spectrometer. 1H-NMR spectra were recorded on a
Bruker 300 MHz instrument. Chemical purities were determined
by an Agilent 1200 HPLC with a XDB-C18 column, 5 mm,
4.6 ꢀ 150 mm.
Although Friedel–Crafts reaction under mild condition will not
result in significant loss or scrambling of deuterium label, the
unusual high temperature (150–1551C) cyclization in the
previous synthesis of deuterated diclofenac2 and 40-hydroxy
diclofenc3 was apparently the main factor that was responsible
for the scrambling of deuterium.
2-(2-Iodophenyl[2H4])acetic acid (3)
The new synthesis of 2-(2-(2,6-dichlorophenylamino)phenyl
[2H4])acetic acid (6, deuterium labeled diclofenac) is shown in
Scheme 1. In our synthesis, we chose a new route to avoid the
Friedel–Crafts reaction used in the previous paper.2,3 The
experiments were conducted similarly to the procedure
described for synthesis of 40-hydroxy diclofenac.3 The key of
the synthesis is a two-step iodination of phenyl acetic acid-d5 to
form isotopically pure 2-(2-Iodophenyl[2H4])acetic acid (3),
avoiding the high temperature Friedel–Crafts reaction used in
previous synthesis. Small amounts of isomers were formed and
separated by chromatography after formation of amide. To
further prevent the loss of deuterium, trifluoroacetic acid-d was
used as a solvent, providing a deuterium environment for the
reaction. Compound (3) was obtained with isotopic enrichment
of 99.4%. Standard conversion of 2-iodophenylacetic acid-d4 (3)
to N,N-dimethylamide (4)6 via the acid chloride was followed by
Ullmann coupling of (4) and 2,6-dichloroaniline using activated
copper powder with no deterioration of isotopic purity. The final
hydrolysis step required very carefully controlled conditions to
avoid cyclization of the product and this was achieved by
To a solution of phenylacetic acid-d5 (5.0 g, 35 mmol) in
trifluoroacetic acid-d (60 mL) in an aluminum wrapped flask,
was added Tl(OCOCF3)3 (38.5 g, 71 mmol). A yellow solution was
formed instantaneously. The resulting reaction mixture was
stirred at RT overnight and then treated with a solution of KI
(13.5 g, 81 mmol) in water (100 mL). A dark blue-purple solution
formed. After stirring for 15 min, Na2S2O5 was added until the
solution was mustard yellow (about 8.4 g of Na2S2O5 was used).
The reaction mixture was then cooled in an ice bath and basified
aCollege of Material Science and Technology, Nanjing University of Aeronautics
and Astronautics, Nanjing, Jiangsu Province, People’s Republic of China
bHi-Tech Research Institute and State Key Laboratory of Materials-Oriented
Chemical Engineering, Nanjing University of Technology, China
*Correspondence to: Liqin Chen, Hi-Tech Research Institute and State Key
Laboratory of Materials-Oriented Chemical Engineering, Nanjing University of
Technology, Nanjing 210009, Jiangsu, People’s Republic of China.
E-mail: liqin_chen@hotmail.com
J. Label Compd. Radiopharm 2009, 52 535–537
Copyright r 2009 John Wiley & Sons, Ltd.