Carbon-14 labelling of 3-cyanoquinolines

Full text of DOI:10.1002/jlcr.1284

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 578–579.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1284
Short Research Article
Carbon-14 labelling of 3-cyanoquinolinesy
JOHN D. OLSZEWSKI1,*, DAN M. BERGER2 and MICHAEL K. MAY1
1 Chemical Development}Radiosynthesis, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA
2 Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 10965, USA
Received 20 June 2006; Revised 2 January 2007; Accepted 20 January 2007
Keywords: carbon-14; cyanoquinoline; cyano-[14C]-acetic acid; Buchwald; amidine; enaminone
Introduction
The synthesis of [14C]MKI-833 is an example of this
approach (Figure 1).
Wyeth has recently reported the synthesis of 4-anilino-
3-quinolinecarbonitrile analogues, including several
compounds with amines at C7, that have been found
to be inhibitors of MEK1.1,2 The Radiosynthesis Group
Our strategy differs from prior work3 and was
developed as a result of experiences in preparing ring
labelled 14C-cyanoquinoline compounds that were
prone to decomposition. We decided to move the label
outside the ring preparing a core structure useful for
other analogues. [14C]MKI-833 was envisioned to arise
from a [14C]cyanoquinoline, derived from an amidine
and cyano-[14C]acetic acid, aniline substitution at C4
and Buchwald coupling at C7.
and Discovery Chemistry have developed
a novel
labelling approach to the 3-cyanoquinoline core struc-
ture that allows the flexibility to provide analogues.
Cl
S
N
Results and discussion
N
HN
5
8
4
Preparation of amidine 2 used literature procedures
with minor modifications.4,5 Synthesis of tert-butyl
cyano-[14C]acetate 3 was accomplished from bromoa-
cetic acid and [14C]KCN6 followed by esterification.7
The amidine 2 was stirred with excess tert-butyl cyano-
*CN
O
N
3
6
7
2
N
1
N
[
14C]-acetate in IPA at RT to give enaminone 4 which
was filtered off. The enaminone 4 was cyclized to a
Figure 1
[
14C]MKI-833.
cyanoquinoline in a one-pot procedure and followed by
O
O
O
N
O
*
NC
O
O
O
O
O
O
N
OH
3
6 steps
27%
*
72%
BnO
N
H
BnO
N
HO
1
4
O
O
2
Scheme 1
*Correspondence to: John D. Olszewski, Wyeth Research, Chemical
Development}Radiosynthesis, 401 N. Middletown Road, Pearl River,
New York 10965, USA. E-mail: olszewj@wyeth.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.

CARBON-14 LABELLING OF 3-CYANOQUINOLINES 579
O
Cl
*
O
O
CN
O
1. triflic acid
DBU
N
1. TFA, thioanisole
2. Tf2O, pyridine
2.
*
3. oxalyl chloride
58%
BnO
N
H
BnO
N
70%
5
4
O
Cl
O
S
N
Cl
N
*
O
CN
N
4-(1-pyrrolidinyl)piperidine,
K3PO4, Pd2(dba)3,
H2N
7
[
14C]-MKI-833
TfO
pyridine hydrochloride
66%
2-(di-tert-butylphosphino)biphenyl
6
Prep-HPLC
29%
more material in filtrate
Scheme 2
chlorination to 5. At this point, the 4-chloro-3-cyano-
14C]quinoline 5 could be converted into a variety of
2. Boschelli DH. Curr Topics Med Chem 2002; 2:
1051–1063 and references therein.
[
compounds by removal of the protecting groups and
replacement of the chlorine. For [14C]MKI-833, the
benzyl group was removed followed by protection to
give triflate 6. Replacement of the chlorine with aniline
7 gave the penultimate compound. Preparation of
3. Carr RM, Sutherland DR. J Label Compd Radio-
pharm 1994; 34(10): 961–971.
4. Thurston DE, Varanasi SM, Langley DR, Jones GB.
Synthesis 1990; 1: 81–84.
5. Wang T, Lui AS, Cloudsdale IS. Org Lett 1999; 1(11):
1835–1837.
[
14C]MKI-833 was accomplished via Buchwald cou-
pling with 4-(1-pyrrolidinyl)piperidine. The optimized
reaction conditions provided the product in modest
yield. Typical Buchwald coupling solvents8 could not
be used due to solubility issues. Literature precedent
conditions9 and a reaction time of 20 h afforded higher
yields of a cleaner product that was purified by HPLC
and then used for ADME studies (Schemes 1 and 2).
6. Koltai E, Zolyomi G, Komaromy P, Banfi D, Szuts T,
Takacs K. J Label Compd Radiopharm 1981; 18(8):
1107–1113.
7. Shelkov R, Nahmany M, Melman A. J Org Chem
2002; 67(25): 8975–8982.
8. Wolfe JP, Tomori H, Sadighi JP, Yin J, Buchwald SL.
J Org Chem 2000; 65(4): 1158–1174 and references
therein.
9. Wu Y-J, Boissard CG, Greco C, Gribkoff VK,
Harden DG, He H, L’Heureux A, Kang SH, Kinney CG,
Knox RJ, Natale J, Newton AE, Lehtinen-Oboma S,
Sinz MW, Sivarao DV, Starrett Jr. JE, Sun L-Q,
Tertyshnikova S, Thompson MW, Weaver D, Wong HS,
Zhang L, Dworetzky SI. J Med Chem 2003; 46(15):
3197–3200.
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 578–579
DOI: 10.1002.jlcr