Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 634–635.
Published online in Wiley InterScience
JLCR
Short Research Article
13
2
Synthesis of C- and H-labelled AZD4619: a selective PPARa
agonisty
¨
KARIN WIKLUND* and GORAN N. NILSSON
¨
¨
AstraZeneca R&D Molndal, Medicinal Chemistry, SE-431 83 Molndal, Sweden
Received 8 January 2007; Accepted 14 May 2007
Keywords: deuterium; carbon-13; internal standard; PPARa
Introduction
to correct dyslipidemia in IRS and hyperglycemia
of type II diabetes that will reduce cardiovascular
morbidity and mortality. To support our research
PPARa (peroxisome proliferator-activated receptor al-
pha) is a member in the nuclear receptor superfamily
and is a regulator of genes in lipid and fatty acid
metabolism. A disorder in these genes can cause IRS
(insulin resistance syndrome) with dyslipidemia
and type II diabetes. Our approach to the PPARa is
program,
a
stable isotope-labelled compound
(AZD4619) was needed for quantitative mass bio-
analytical studies.
Results and discussion
Commercially available p-cresole-d8 was protected with
methyl iodide to give (1) which was reacted with N-
bromosuccinimide in carbon tetrachloride under
photoirradiation.1 The resulting (2) was directly treated
with K13CN in the presence of 18-crown-6 in acetoni-
trile2 giving the desired 13C-labelled precursor (3).
NaOD was carefully made from Na and D2O and used
for the hydrolysis of nitrile (3) to acid (4). Deprotection
to (5) was performed using microwave heating with
deuterium bromide.Esterification of the carboxylic acid
(5) with benzyl chloride to (6) was done with micro-
waves, followed by reduction to the alcohol (7) with
lithium aluminum deuteride. The complex was
quenched with deuterium oxide and deuterium chlor-
ide. A new protection of the phenol was performed
using benzyl chloride to give (8), whereupon (8) was
treated with mesyl chloride to give mesylate (9), which
was reacted with thioacetic acid in presence of cesium
carbonate to give thioester (10).(10) was deprotected
with sodium methanethiolate in methanol and DMF to
give the free thiol, which was alkylated with alkyl
chloride (11) to give (12). Deprotection to the phenol
(13) was done with boron trifluoride diethyl etherate
and dimethyl sulfide in DCM. The ester hydrolysis to
reach AZD4619 was done with LiOD carefully made
from Li and D2O.
O
O
O
S
OH
O
S
O
D
D
D
D
13C
D
D
D
D
AZD4619
OH
¨
*Correspondence to: Karin Wiklund, AstraZeneca R&D Molndal,
¨
Medicinal Chemistry, SE-431 83 Molndal, Sweden.
E-mail: karin.wiklund@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.
Wiklund, Karin
