Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 504.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1226
Short Research Article
1
3
The synthesis of [ C ]N-(3,4-dichlorophenyl)-2,2-
6
y
dimethylpropanamide
KENNETH W. M. LAWRIE*
GlaxoSmithKline, Isotope Chemistry, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 17 August 2006; Revised 14 December 2006; Accepted 15 December 2006
Keywords: carbon-13; diazotization; chlorination
Introduction
The second set is significantly superior to the ‘classic’
method. The yield is higher (75–90% compared to
40–60%), a purer product results and commercially
Stable labelled isotopomers of compounds in drug
development are routinely used as internal standards
available Cu(II)Cl
which for good results needs to be freshly prepared.
The nitro group is readily reduced by SnCl in ethanol
2
can be used as opposed to Cu(I)Cl,
1
3
in LC/MS/MS assays. [
6
C ] N-(3,4-dichlorophenyl)-
2
,2-dimethylpropanamide 1 was required as an inter-
2
mediate in the synthesis of such an isotopomer of
a compound under development at GSK.
at reflux in quantitative yield. The title compound is
formed by reaction with trimethylacetyl chloride in a
two phase reaction (TBME/5M NaOH) in 93% yield.
Results and discussion
1
3
Protection of [
C
6
]aniline as acetanilide moderates its
Conclusions
reactivity and gives good control of regioselectivity of
1
3
nitration. Nitration of [
c. H SO and NaNO gives 4-nitro [
3% yield. The 2-nitro isomer is not detected. Con-
trastingly use of the ‘classic’ HNO /H SO nitration
C
6
]acetanilide with a mixture
A short, high yielding (overall 35–45%) and regiospe-
13
1
3
6
cific synthesis of [ C ] N-(3,4-dichlorophenyl)-2,2-
2
4
3
C
6
]acetanilide in
1
9
dimethylpropanamide 1 has been developed starting
1
3
from the readily available [
6
C ]aniline. The non-
3
2
4
mixture gives around 20% of the 2-nitro isomer. The
protecting group is readily removed by hydrolysis with
aqueous diazotization protocol has been shown to be
superior to traditional methods for the chlorination of
13
1
3
NaOH, and the 4-nitro[
C
6
]aniline chlorinated cleanly
6
[ C ]2-chloro-4-nitroaniline.
and in high yield by reaction with NCS in acetonitrile at
2
reflux. Two sets of conditions were investigated for the
REFERENCES
diazotization/chlorination sequence; (i) ‘classic’ condi-
tions; diazonium salt formation in aqueous HCl with
NaNO2 and decomposition with freshly prepared
Cu(I)Cl and (ii) non-aqueous diazotization with isoamyl
1. Rosevear J, Wilshire JFK. Aust J Chem 1985; 38:
723.
2. Nickson TE, Roche-Dalson CA. Synthesis 1985; 7:
nitrite in acetonitrile and chlorination with Cu(II)Cl
2
.
669.
*
Correspondence to: Kenneth W. M. Lawrie, GlaxoSmithKline, Isotope
Chemistry, Medicines Research Centre, Gunnels Wood Road, Steve-
nage SG1 2NY, UK. E-mail: ken.w.lawrie@gsk.com
Proceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
y
1
6–20 July 2006.
Copyright # 2007 John Wiley & Sons, Ltd.