Cu(I)Br-mediated preparation of 14C-labeled 3-pyridine-acetate derivatives and synthesis of a novel 14C-labeled PDE-IV inhibitor

Article abstract of DOI:10.1002/jlcr.1289

An efficient protocol for the synthesis of ¹⁴C-labeled 3-pyridineacetate (1) and its N-oxide ([¹⁴C]2) is described. Oxidation of this pyridine ([¹⁴C]1) to its N-oxide ([ ¹⁴C]2) proceeded in high yield using H₂O₂ with MeReO₃ as a catalyst. The reaction employs readily available diethyl [2-¹⁴C]malonate. This method has proven to be general in preparation of other pyridineacetate derivatives and their N-oxides which have been typically difficult to prepare by other means. Our development of the Cu(I)Br-coupling methodology as well as application to the synthesis of a ¹⁴C-labeled phosphodiesterase-IV (PDE-IV) inhibitor, [ ¹⁴C]3, are also reported. Copyright

Full text of DOI:10.1002/jlcr.1289

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 277–280.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1289
Short Research Article
14
Cu(I)Br-mediated preparation of C-labeled 3-pyridine-
acetate derivatives and synthesis of a novel
14C-labeled PDE-IV inhibitory
JONATHAN Z. HO* and MATTHEW P. BRAUN
Department of Drug Metabolism, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 19 January 2007; Revised 26 January 2007; Accepted 29 January 2007
Abstract: An efficient protocol for the synthesis of 14C-labeled 3-pyridineacetate ð1Þ and its N-oxide ([14C]2)
is described. Oxidation of this pyridine ([14C]1) to its N-oxide ([14C]2) proceeded in high yield using H2O2
with MeReO3 as a catalyst. The reaction employs readily available diethyl [2-14C]malonate. This method has
proven to be general in preparation of other pyridineacetate derivatives and their N-oxides which have been typically
difficult to prepare by other means. Our development of the Cu(I)Br-coupling methodology as well as application
to the synthesis of a 14C-labeled phosphodiesterase-IV (PDE-IV) inhibitor, [14C]3, are also reported. Copyright #
2007 John Wiley & Sons, Ltd.
F
F
O
O
N
O
N
N
O
O
O
O
OEt
EtO
OEt
14C]1
OEt
*
*
*
*
N
S
[
14C]2
[
F3C
F3C
OH
[
O
* denotes 14C label
14C]3
Keywords: carbon-14 isotope labeling; Cu(I)Br-mediated reactions; 3-pyridineacetate
Introduction
multiple sclerosis5 and Crohn’s disease.6 Surveying the
literature we were somewhat surprised by the lack of
convenient protocols for the efficient and expedient
synthesis of the 14C-labeled ethyl 3-pyridineacetate
intermediate. We report a convenient, straightforward
Cu(I)Br-mediated method that affords 14C-labeled
3-pyridineacetate derivatives in good yields.
At first sight pyridineacetates appear as unexciting
chemical entities, but in fact they have been used in a
wide spectrum of interesting and diverse chemical
reactions that integrate the pyridine ring into many
pharmaceuticals.1 The 3-pyridine group and its deri-
vative play an important role in many biological active
compounds for the treatment of asthma,2 chronic
obstructive pulmonary disease,3 rheumatoid arthritis,4
Results and discussion
Our interest in ethyl 14C-labeled 3-pyridineacetate as
well as other 14C-labeled pyridineacetate esters stem
from a series of on-going PDE-IV research projects.
Critical to their use for us was their synthesis in
reasonable quantities (1–100 mCi) from readily com-
mercially available 14C-labeled starting materials.
*Correspondence to: Jonathan Z. Ho, Department of Drug Metabolism,
Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA.
E-mail: jonathan ho@merck.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.

278 J. Z. HO AND M. P. BRAUN
N
N
Pd(OAc)2
P(Nap)3
P(Nap)3
rt, 16 h
O
O
Br
+
O
B(OH)2
OEt
OEt
NOT Formed
Suzuki Reaction, Scheme 1a
O
Pd(PPh3)4
N
N
THF
O
Zn
+
O
Br
4%
I
Negishi Reaction, Scheme 1b
N
Et4NCl DMF cat. amt. H2SO4
N
O
+
EtO
Sn (Bu)3
Water- Acetone
16%
PdCl2(PPh3)2
OEt
I
Stille Reaction, Scheme 1c
Scheme 1
Space considerations here do not permit a lengthy
discussion on all our failed attempts. Nevertheless, the
application of seemingly straightforward procedures
proved problematic. For example, (a) Suzuki coupling
between 3-pyridineboronic acid (or esters) and bro-
moacetate was fruitless (Scheme 1a)7a; (b) Negishi
coupling employing palladium catalysts between
3-iodopyridine and organozinc reagents derived from
ethyl 2-bromoacetate failed (Scheme 1b)7b; and (c)
Stille reaction between 3-iodopyridine and a stannyla-
cetylene afforded desired product, but the yield was
very disappointing, merely 16% (Scheme 1c).7c The
failure of these procedures forced us to search for an
alternative protocol. In 1975, Bruggink and McKillop8
reported a Cu(I)Br-mediated procedure for the coupling
of ethyl acetoacetate and an aryl iodide.
mixture of ethyl malonate potassium salt, 3-iodopyr-
idine, Cu(I)Br, MgCl2 and EtOH at 1008C for 4 h
afforded the desired ethyl 3-pyridineacetate in 88%
yield. It is important to choose ethyl malonate potas-
sium salt as the starting material since this will
undergo in situ deccaboxylation to form the acetate.
The role of MgCl2 is to facilitate the decarboxylation;
without it, longer reaction time would be needed and
the yield of the desired product would be lower. When
diethyl malonate is used, the product is diethyl
3-pyridinemalonate.9 With a reliable procedure in place
we probed the versatility of the procedure applying it to
a
range of iodopyridines to afford corresponding
pyridineacetates (Scheme 2). This study confirmed that
this method is robust because it works for both
electron-rich and poor iodopyridines.
It is interesting to note that although the Bruggink
and McKillop methodology was reported over 30 years
ago its utilization, as judged by citations, by the
synthetic chemistry community has been largely non-
existent, a fact that may be attributed to the lack of
understanding of its reaction mechanism compared to
its counterpart of Pd-catalyzed reactions. We consid-
ered the Bruggink and McKillop process to have a
number of merits, such as, the catalyst, Cu(I)Br, is
cheap and readily available, the protocol is straightfor-
ward and uncomplicated with no requirement for the
use of expensive ligands, and the reaction process
appears to be versatile with the capacity to afford
multigram quantities of products. This is in contrast to
the procedures outlined in Scheme 1. For the purpose
of further chemical manipulation it was important to us
that the product is an acetate, not a malonate, or an
acetoacete. With this in mind we attempted the
synthesis of 1 (Scheme 2) using a procedure similar to
that reported by Bruggink and McKillop. Stirring a
With this positive result in hand we conducted our
‘hot’ reactions (Scheme 3). By hydrolysis with 1 equiv.
of KOH, diethyl [2-14C]malonate was converted to ethyl
[
14C]malonate, potassium salt, and a crystalline com-
pound. Utilizing our modified protocol mentioned
above, ethyl 2-(pyridine-3-yl)[2-14C]acetate ([14C]1)
was obtained. Oxidation of [14C]1 to its N-oxide [14C]2
was carried out using H2O2 with MeReO3 (MTO) as a
catalyst.10
In an effort to develop new therapeutic agents for the
treatment of asthma, Merck has been engaged in the
study of phosphodiesterase-IV (PDE-IV) inhibitors.
PDE-IV is a high-affinity c-AMP-selective isozyme and
is found in all cell types that have been implicated in
asthma pathogenesis.11 Candidate 3 was identified as a
potent, selective PDE-IV inhibitor12 and a 14C-labeled
tracer was needed for drug metabolism studies. Thanks
to the effort of Merck process research, a 13-step
synthesis of 3 was developed, and the compound 4 is an
advanced intermediate from the 9th step of that very
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 277–280
DOI: 10.1002.jlcr

PREPARATION OF 14C-LABELED 3-PYRIDINEACETATE DERIVATIVES 279
O
O
O
HO
O
Br
HO
O
O
O
Cu(I)Br
81%
+
O
DMF
O
O
N
N
Cu(I)Br
EtOH, reflux
O
MgCl2
+
+
O
O
K
88%
I
Et
O
1
O
O
Cu(I)Br
MgCl2
N
O
N
O
O
K
EtOH, reflux
82%
OEt
I
O
O
Cu(I)Br
MgCl2
N
O
N
+
+
+
O
O
K
EtOH, reflux
71%
OEt
OEt
I
N
O
O
N
N
O
Cu(I)Br
MgCl2
68%
O
O
K
K
EtOH, reflux
F
F
I
N
O
O
O
Cu(I)Br
MgCl2
79%
O
O
EtOH, reflux
MeO
OEt
MeO
I
Scheme 2
O
N
N
Cu(I)Br
MeReO3
30% aqueous H2O2
N
MgCl2
O
O
O
O
O
KOH
I
O
O
O
O
O
K
EtOH
EtOH, reflux
12 h, 91%
OEt
*
OEt
*
*
*
[
14C]-2
[
14C]-1
F2HC
F2HC
F2HC
O
O
O
O
1) Conc. HCl
O
O
MeOH, 60 oC
[
14C]-5
2) LiOH, water
r.t., 2 h
3) PhCl 135 oC 8 h
LiHMDS, THF
N
N
N
N
DMPU, -78 oC 20 h
OTs
N
*
O
S
S
O
F3C
F3C
F3C
F3C
*
S
F3C
F3C
O
OEt
67%
40%
for 3 steps
OMOM
OMOM
OH
[
14C]-3
* denotes 14C label
[
14C]-5
4
Scheme 3
procedure.13 Alkylation of compound 4 with [14C]2 gave
14C]5 in 67% (Scheme 3). The MOM protection group
Conclusion
[
We have developed an efficient Cu(I)Br-mediated pro-
tocol for the synthesis of 14C-labeled 3-pyridineacetate
ð1Þ. We have also demonstrated that this procedure is
general for the preparation of both electron-rich and
was removed with concentrated HCl, the ethyl ester
was hydrolyzed utilizing aqueous LiOH, and the
resulting acid was decaboxylated at 1358C to afford
the final tracer [14C]3. The overall yield for this one-pot,
three-step reaction was 40%.
poor pyridineacetate derivatives. Using
[
14C]1, the
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 277–280
DOI: 10.1002.jlcr

280 J. Z. HO AND M. P. BRAUN
synthesis of a novel PDE-IV tracer of [14C]3 has been
Synlett 1992; 6: 502–504; (d) Hartiwig H. J Org
Chem 2002; 67: 541–549.
accomplished.
8. Bruggink A, McKillop A. Tetrahedron 1975; 31(20):
2607–2616.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 277–280
DOI: 10.1002.jlcr