Synthesis of isotopically labelled ZD4054

Full text of DOI:10.1002/jlcr.1177

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 431–432.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1177
Short Research Article
Synthesis of isotopically labelled ZD4054y
JULIE A. BERGIN, HELEN BOOTH, RYAN A. BRAGG, NICK BUSHBY, JOHN R. HARDING*, ANGELA JORDAN
and CLARE D. KING
Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Received 1 August 2006; Revised 6 November 2006; Accepted 20 November 2006
Keywords: isotopic labelling; carbon-14; deuterium; endothelin receptor antagonist
Introduction
ZD4054 1a. This was synthesized in one stage at low
specific activity by cyclization of hydrazide 2 using neat
triethyl [14C]orthoformate (Scheme 1). The product was
obtained in 10% radiochemical yield (based on triethyl
AstraZeneca ZD4054 (3-methoxy-5-methyl-2-({2-[4-
(1,3,4-oxadiazol-2-yl)-phenyl]-pyridyl}-sulphonamido)-
pyrazine) is a specific endothelin A (ETA) receptor
antagonist which is being developed for the treatment
of prostate cancer. This paper describes the synthesis
of the isotopically labelled forms of ZD4054 that were
required to support the development DMPK pro-
gramme.
[
14C]orthoformate) at a specific activity of 15.1 mCi/
mmol with a radiochemical purity >98%.
[pyridyl-2,6-14C]ZD4054 1b
Detailed drug metabolism and distribution studies
were carried our using [pyridyl-2,6-14C]ZD4054 1b.
This was synthesized in three stages from 3-amino-2-
chloro[2,6-14C]pyridine (Scheme 2). 3-Amino-2-chloro-
[2,6-14C]pyridine was converted to 2-chloro[2,6-14C]-
pyridine-3-sulphonyl chloride and this was then
[oxadiazol-5-14C]ZD4054 1a
Early exploratory drug metabolism and distribution
studies were carried out using [oxadiazol-5-14C]
N
N
H14C (OEt)3
H
N
O
S
N
N
O
S
N
NH
H2N
NH
N
O
O
14C
O
O
O
O
N
N
2
1a
Scheme 1
*Correspondence to: John R. Harding, Isotope Chemistry, AstraZeneca,
Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
E-mail: john.harding@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.

432 J. A. BERGIN ET AL.
C
C
N
C
N
C
Cl
O
N
O
S
N
5
C
C
3
HOAc, HCl, NaNO
N
N
O
S
N
O
O
N
2
N
C
O
NH
N
O
C
NaH, toluene
Pd(OAc) ,TPPTS, Et N
CuCl, SO Cl
2
3
2
2
O
O
Cl
Cl
p-xylene, EtOH then NH OH
4
NH
2
SO Cl
2
N
1b
[
C]-4
Scheme 2
Br
B(OH)
B(OH)
H
H
H
H
H
H
H
H
H
4
NaMnO , NaOH
MeOH, H SO
Mg, toluene, THF
Pd(PPh ) , KF ,
B(OMe)
3
H
H
H
MeOH, H O
2
O
O
[2H]-6
[2H]-7
H
H
N
H
H
N
H
N
H
O
H
H
O
H
O
O
H
S
O
H
S
NH NH .H 0
MeOH
O
H
S
N
N
HC(OEt)
N
NH
NH
H N
NH
O
O
O
N
O
O
O
H
O
N
N
N
N
N
[2 H]-2
1c
Scheme 3
reacted with urethane 3 to give the sulphonamide [14C]-
4. Pd(0) catalysed Suzuki coupling with boronic acid 5
followed by in situ hydrolysis of the protected product
gave [pyridyl-2,6-14C]ZD4054 1b. The product was
obtained in 37% overall radiochemical yield at a
specific activity of 50.8 mCi/mmol with a radiochemi-
cal purity >98%.
boronic acid [2H]-6. Oxidation of the methyl group and
esterfication of the resulting carboxylic acid gave the
boronic acid [2H]-7. Pd(0) coupling with sulphonamide
4 followed by treatment with hydrazine monohydrate
gave hydrazide [2H]-2. Cyclization with triethyl ortho-
formate gave [phenyl-2,3,5,6-2H4]ZD4054 1c. The
product was obtained in 11% overall yield at an
incorporation of 498 at %.
[phenyl-2,3,5,6-2H4]ZD4054 1c
[phenyl-2,3,5,6-2H4]ZD4054 1c was prepared as an
internal standard for use in an LC-MS-MS assay for the
quantification of the drug in biological matrices. 1c was
synthesized in six stages from 4-bromo-2,3,5,6-[2H4]
toluene (Scheme 3). 4-Bromo-2,3,5,6-[2H4]toluene was
converted via a Grignard reaction to the corresponding
Conclusions
The chemical routes developed to synthesize ZD4054
have been successfully adapted to introduce separate
labels into the three directly linked 1,3,4-oxadiazolyl,
pyridyl and phenyl rings for different DMPK applications.
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 431–432
DOI: 10.1002.jlcr