Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 590–592.
Published online in Wiley InterScience
JLCR
Short Research Article
Use of simple stable labelled intermediates to produce
complex isotopically labelled internal standardsy
PAUL ALLEN, MIKE HICKEY, LEE KINGSTON*, ANDREW MATHER and DAVID J. WILKINSON
AstraZeneca R & D Charnwood, Bakewell Rd, Loughborough, Leicester LE11 5RH, UK
Received 31 August 2006; Revised 22 January 2007; Accepted 31 January 2007
Keywords: stable isotopically labelled compounds; common fragment synthesis; carbon-13
Introduction
anion. Sulphonation followed by quenching with N-
chlorosuccinimide afforded the sulphonyl chloride,
which, using standard amide coupling with a range of
amines, gave, the target sulphonamides.
Only the simplest [13C]SIL aromatic building blocks
are available and significant synthetic effort is required
to elaborate these further to provide more useful
intermediates as shown in Scheme 2.
Similarly, [2H8]toluene and [2H8]piperazine have
been successfully utilized to provide several SIL
compounds although care has to be taken to avoid
isotopic exchange1 as shown in Scheme 3.
Stable isotopically labelled (SIL) compounds are of
great value in the discovery process as they can confer
greater sensitivity and robustness during the develop-
ment of bioanalytical methods. Once thought of as a
model for radioactive syntheses, SIL compounds are
becoming increasingly important in their own right
and, although structurally similar, can create many
different synthetic challenges. Targets containing
chlorine or sulphur atoms may require up to seven
additional mass units to create sufficient mass differ-
ential from the parent. This can be difficult to achieve
from the limited range of synthetic precursors available
which offer little scope for the introduction of multiple
isotopic labels. Consequently, compounds often have to
be assembled from several different isotopic precursors
or a common fragment to deliver the mass difference
required.
Synthesis with multiple isotopes
Due to constraints of the compound it is sometimes not
possible to use a single isotope source and it is
necessary to use multiple isotopes. An example of
which is shown in Scheme 4. The nature of the
heterocyclic ring affords little opportunity for the
introduction of the extra mass units required. However,
Results and discussion
by incorporating
a nitrogen-15 isotope into ethyl
Common fragment synthesis
[
15N]aminotrifluorocrotonate and subsequent ring clo-
sure gives the thiazalone intermediate. Reaction of
[2H5]epichlorohydrin and [15N]ammonia affords the
labelled amino alcohol that is coupled to the thiazalone
to afford the target compound with a total of seven
mass units greater than the parent.
Where a chemical series is being explored, the identi-
fication and synthesis of an SIL common fragment can
be particularly effective. The 2,3-dichlorobenzenesul-
phonyl chloride (Scheme 1) moiety was just such an
example.
Another example of this strategy is described
in Scheme 5. It was necessary to produce several SIL
compounds in a short period of time in order to select a
best candidate from the series.
Trial reactions were initially undertaken to identify
conditions that maximized the formation of the desired
The hydantoin fragment was common to the
compounds that were under investigation. [13C3]Chlor-
oacetone was prepared from [13C3]acetone with the
monohalogenated product being obtained in good
yield.2 Alkylation followed by microwave-induced ring
*Correspondence to: Lee Kingston, AstraZeneca, Medicinal Chemistry,
Bakewell Road, Loughborough, Leicester LE11 5RH, UK.
E-mail: Lee.Kingston@astrazeneca.com
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.
Allen, Paul
