Syntheses of isotopically labelled xanthines

Full text of DOI:10.1002/jlcr.1229

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 509–510.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1229
Short Research Article
Syntheses of Isotopically Labelled Xanthinesy
KARL M. CABLE*
Isotope Chemistry, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 3 July 2006; Revised 13 December 2006; Accepted 14 December 2006
Keywords: carbon-14; cyanation; palladium; xanthine; zinc cyanide
Introduction
Results and discussion
Pegylated xanthine 1 is a potent inhibitor of endothelial
cell adhesion molecule (ECAM) expression and was
under development for the treatment of inflammatory
disorders. Stable isotope labelled versions of 1 and the
carboxylic acid metabolite 2 were required as internal
standards for LC/MS assay of biological matrix. A
carbon-14 labelled version of 1 at 50–60 mCi/mmol
was required for ADME studies. Acid 2 can be prepared
by the condensation of 4-formyl cinnamic acid with
diaminouracil 6. The resulting imine undergoes an
oxidative cyclization on treatment with iodine.1 Since
Stable isotope labelled compounds
For stable isotope labelled versions the chosen strategy
employed [13C6]-1,4-dibromobenzene 3, one of the
few commercially available 1,4-disubstituted [13C6]
benzene derivatives. Labelled acid 2 was obtained in
52% overall yield from
[
13C6]-1,4-dibromobenzene
(Scheme 1). Sequential functionalization of the two
brominated positions in 3 generated labelled 4-formyl
cinnamate ester 5. This linear synthesis involved the
preparation of [13C6]acid metabolite 2 en route to
labelled 1. A portion of 2 was converted into pegylated
unlabelled diaminouracil
6 was readily available,
labelling of the cinnamate moiety in 2 was investigated.
[
13C6]xanthine 1 in 62% overall yield.
ethyl acrylate
Pd(OAc)2, P(OTol)3
NEt3, reflux
1.n-BuLi, THF, -78˚
2.DMF
Br
Br
CO2Et
*
*
*
67%
89%
Br
OHC
OHC
4
3
5
O
N
Cy
NH2
NH2
1.6, THF
N
13C6
2. I2, THF, reflux
88%
=
*
O
Cy 6
O
N
O
H
2M NaOH
H
N
CO2R
CO2Et
THF, reflux
N
N
N
*
*
N
N
N
O
100%
O
1 R = (CH2CH2O)9CH3
2 R = H
7
Scheme 1
*Correspondence to: Karl M. Cable, Isotope Chemistry, GlaxoSmith-
Kline, Gunnels Wood Road, Stevenage SG1 2NY, UK.
E-mail: karl.m.cable@gsk.com
y
Proceedings 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.

510 K. M. CABLE
*
Zn(CN)2, Pd2(dba)3.CHCl3
HCl gas
EtOH, 20˚
CO2Et
CO2Et
CO2Et
P(o-tolyl)3, NMP,80˚
EtO
*
87% over two
NC
.HCl
87%
*
Br
steps from K14CN
8
9
10
NH
Cy
O
O
NH2
N
dioxane, AcOH
reflux, 78%
NH2
N
Cy
6
O
N
O
H
N
H
N
CO2H
CO2Et
2M NaOH, THF, reflux
94%
N
N
*
*
N
N
N
O
O
2
7
=
14C
*
81%
CDI, DMF, 140˚
O
O
O
N
Me(OCH2CH2)9OH
'MPEG-9'
O
O(CH2CH2O)9CH3
H
N
H
N
N
N
*
*
MeCN, K2CO3
reflux, 71%
N
N
N
N
O
O
N
11
1
Scheme 2
REFERENCES
Carbon-14 labelled compounds
1. Perumattam J. Synth Commun 1989; 19: 3367.
2. Daly JW, Padgett W, Shamim MT, Butts-Lamb P,
Waters J. J Med Chem 1985; 28: 487.
Literature methods for the preparation of 8-aryl
xanthines from diaminouracils often require two or
more steps to construct the xanthine ring system.2,3 It
was envisaged that xanthine 1 could be constructed
more efficiently using a single step process reported for
the synthesis of benzimidazoles.4 Carbon-14 labelled 1
was prepared in 32% overall yield from potassium
3. Peet NP, Lentz NL, Dudley MW, Ogden AL, McCarty
DR, Racke MM. J Med Chem 1993; 36: 4015.
4. De Selms RC. J Org Chem 1962; 27: 2165.
5. Tschaen DM, Abramson L, Cai D, Desmond R,
Dolling U-H, Frey L, Karady S, Shi Y-J, Verhoeven TR.
J Org Chem 1995; 60: 4324.
[
14C]cyanide (Scheme 2).5 Reaction of diaminouracil 6
with imino ether 10 gave [14C]xanthine ester 7 directly.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 509–510
DOI: 10.1002.jlcr