Synthesis of isotopically labelled AZD3409 and its metabolites

Full text of DOI:10.1002/jlcr.1175

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 426–427.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1175
Short Research Article
Synthesis of isotopically labelled AZD3409 and its metabolitesy
JULIE A. BERGIN, RYAN A. BRAGG*, NICK BUSHBY, JOHN R. HARDING, ANGELA JORDAN, DAVID A. KILLICK and
CLAIRE L. SILCOCK
Isotope Chemistry, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 15 August 2006; Revised 7 November 2006; Accepted 20 November 2006
Keywords: isotopic labelling; carbon-14; carbon-13; farnesyltransferase inhibitor
Introduction
Results and discussion
AZD3409 is a peptidomimetic farnesyltransferase in-
hibitor (FTI), intended for the treatment of pancreatic,
colon and lung cancers. AZD3409 is a double pro-drug;
the parent form being rapidly broken down to thiol-
ester (AZ11761313) and thiol-acid (AZ11761441)
metabolites. This paper describes the synthesis
of labelled forms of AZD3409, AZ11761313 and
AZ11761441 that were required to support the devel-
opment DMPK programme.
[
14C]AZD3409 was prepared as the malate salt from
methyl-2-bromo-5-nitro[U-14C]benzoate as shown in
Scheme 1. The labelled starting material was coupled
to 4-fluorostyrene via a Heck reaction. Concomitant
reduction of the nitro group and the alkene gave the
aniline, which was coupled to the proline acetal via
reductive amination. Subsequent ester hydrolysis gave
the acid, which was coupled with methionine isopropyl
ester to give the key Met Amide intermediate.
Scheme 1
Selective deprotection of the trityl group gave the
thiol, which was coupled with pyridine-3-carboxylic
acid to give the thioester. Finally, the tert-butoxycarbo-
nyl (BOC) protecting group was removed, and the
product was converted to the malate salt to afford
*Correspondence to: R. A. Bragg, Isotope Chemistry, AstraZeneca,
Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
E-mail: ryan.bragg@astrazeneca.com
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
[
14C]AZD3409, which had a radiochemical purity >98%
Copyright # 2007 John Wiley & Sons, Ltd.

SYNTHESIS OF ISOTOPICALLY LABELLED AZD3409 AND ITS METABOLITES 427
Scheme 2
Scheme 3
and a specific activity of 28 mCi/mmol. The overall
radiochemical yield was 9.7%.
was converted to [13C5,15N]AZD3409 following the
synthetic sequence detailed above.
The Met Amide intermediate also served as the
Stable labelled AZ11761313 and AZ11761441 were
prepared from [13C5,15N]Met Amide in a similar fashion
to that described above.
starting point for the preparation of
[
14C]AZ11-
761313, formed by removal of the BOC and trityl
protecting groups with dilute acid (Scheme 2). Similarly,
14C]AZ11761441 was prepared from [14C]AZD3409 via
[
concomitant hydrolysis of both ester and thioester
groups.
Conclusion
Stable labelled AZD3409 was prepared in six stages
from [13C5,15N]Methionine to provide internal stan-
dards for use in mass spectrometry assays (Scheme 3).
The chemical route to AZD3409 has been successfully
adapted to provide access to both radiolabelled and
stable labelled forms of AZD3409, AZ11761313 and
AZ11761441, which were required to support the
development Drug Metabolism and Pharmokinetics
(DMPK) programme.
[
13C5,15N]Methionine was converted to its isopropyl
ester and coupled to the substituted benzoic acid to
afford the key [13C5,15N]Met Amide intermediate. This
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 426–427
DOI: 10.1002.jlcr