Synthesis of two isotopically labeled 5-HT1B antagonists

Full text of DOI:10.1002/jlcr.1164

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 412–413.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1164
Short Research Article
Synthesis of two isotopically labeled 5-HT1B antagonistsy
CHARLES S. ELMORE*, JAMES E. HALL, XIAOMEI YE and J. RICHARD HEYS
CNS Chemistry, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, Wilmington Del 19850-5437, USA
Received 16 August 2006; Revised 8 November 2006; Accepted 18 November 2006
Keywords: 5-HT1B; N-heterocyclic Iridium complex; tritiation
Introduction
reduction of chromenone to the chromanone and M+4
from further reduction to the chromanol. Since these
impurities would consume a considerable amount of
tritium gas in a non-productive manner, we decided to
investigate alternate catalysts. Attempted exchange
with two other catalysts and Crabtree’s catalyst gave
results similar to those obtained with 5.
Serotonin (5-HT) is a neurotransmitter, and dysfunc-
tions of its transmission have been implicated in a large
number of disease states including migraines, anxiety,
depression, and obesity.1 5-HT1B antagonists have
been suggested as potential treatments for depression
and anxiety and have been shown to be effective in
animal models of these disease states.2 During devel-
opment of 5-HT1B antagonists, C-14 labeled AR-
A000002 and tritium labeled M-549865 were required
and their syntheses will be discussed herein.
Reaction of M-549865 with N-iodosuccinimide in
neat TFA gave iodide 1 and tritiodehalogenation of 1
(2.3 mg of 5% Pd/C, 1.6 mg of 1 and 950 mCi of 3H2)
proceeded cleanly to afford 24 mCi of [3H]M-549865 in
79% radiochemical purity. Purification gave 17 mCi in
99% radiochemical purity with a specific activity of
21 Ci/mmol (Scheme 2). 3H NMR confirmed the site of
labeling.
Results and discussion
The synthesis of [14C]AR-A000002 has been pre-
viously reported by[14C]cyanation of 1-iodo-4-morpho-
linebenzene.4 We used a similar route (depicted in
Scheme 3) to give the HBr salt of [14C]AR-A000002 in
29% radiochemical yield.
M-549865 was required in tritium labeled form for use
in internal studies with a specific activity >20 Ci/mmol.
Exchange methodology using several catalysts was
probed using deuterium gas (500 mbar) in CH2Cl2
(Scheme 1).3 Complex product mixtures were obtained
from these exchange reactions, and the products and
isotopic incorporation of the products varied consider-
ably with catalyst. With catalyst 5, two peaks were
observed in addition to M-549865 by the LC/MS; those
peaks’ retention time and mass spectra were consistent
with cis and trans 2 which could have arisen by
reduction of the p-diamino ring to the corresponding
diaminocyclohexane. Furthermore, investigation of the
peak due to M-549865 showed a mixture of com-
pounds with m/Z of parent, parent +2 and parent +4.
We hypothesized that the M+2 compound resulted from
REFERENCES
1. Maes M, Meltzer HY. In Psychopharmacology: The
Fourth Generation of Progress, Bloom FE, Kepfer DJ
(eds). Raven Press: New York, 1995; 933.
2. Blier P, de Montigny C. Trends Pharmaceut Sci 1994;
15: 220.
3. For examples of T-H exchange reactions see
Garman RN, Hickey MJ, Kingston LP, McAuley B,
Jones JR, Lockley WJS, Mather AN, Wilkinson DJ.
J Label Compd Radiopharm 2005; 48: 75 and
references therein.
*Correspondence to: Charles S. Elmore, CNS Chemistry, AstraZeneca
Pharmaceuticals LP, 1800 Concord Pike, Wilmington Del 19850-5437,
USA. E-mail: chad.elmore@astrazeneca.com
yProceedings of the Ninth International Symposium on the Synthesis
and Application of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
4. Werner T, Berg S, Johansson R. J Label Compd
Radiopharm 2004; 47: 175.
Copyright # 2007 John Wiley & Sons, Ltd.

SYNTHESIS OF TWO ISOTOPICALLY LABELED 5-HT1B ANTAGONISTS 413
O
F
COD
Dn (Hn)
N
D(H)
NH
N
N
H
Ir
N
O
PPh3
N
N
O
+
N
(H)D
O
O
N
N
F
5
O
Cis-and trans-2
H
N
O
Catalyst,CH2Cl2, D2(H2)
O
H
O
Dn (Hn)
F
N
N
O
Dn (Hn)
20h, rt
N
F
N
O
O
N
N
O
O
N
N
O
Scheme 1
3H
O
O
I
O
O
F
F
H
H
N
3
N
1. H2, Pd-C
N
N
O
N
N
O
2. semi-prep HPLC
N
N
N
N
O
O
[3H]M-549865
X=H,M549865
X=I;1
NIS/TFA
Scheme 2
O
1.
CH 3
N
N
N
N
O
N
X
3. Prep-HPLC
DMF
2.
*
H
N
N
CH 3
N
4. iP OH, HOAc
r
N
HBr
O
O
44%
NH2
[14C]AR-A000002
X=Br
X= 14CO 2H
1. tBuLi
2. 14CO2
72%
N
N
*denotes C-14 labeled carbon
93% over two steps
Scheme 3
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 412–413
DOI: 10.1002.jlcr