Research Article
Received 8 October 2010,
Revised 9 March 2011,
Accepted 10 March 2011
Published online 26 April 2011 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.1887
A modified approach to C-14-labeled
2-(3,4-difluorophenoxy)-5-fluoronicotinic
acid and other halogen-substituted analogsy
Ã
Yinsheng Zhang,a Zhigang Jian,b and Wayne T. Stollea
A modified approach to a carbon-14-labeled pyridine ring system was developed based on the electrocyclic ring-closure of
1,4,4-trisubstituted butadiene. The new method was applied to prepare 2-(3,4-difluorophenoxy)-5-fluoro-[2-14C] nicotinic
acid and other halogen-substituted analogs. The targeted compound was isolated with a radiochemical purity of 498%
and a specific activity of 53 mCi/mmol from four radiochemical steps, starting from ethyl [1-14C] cyanoacetate in an overall
radiochemical yield of 39%.
Keywords: carbon-14; nicotinic acid; pyridine ring formation; aryl ether formation
analysis and electrospray ionization (ESI). 1H and 13C NMR
spectra were recorded on a Varian Gemini 400 MHz instrument.
Introduction
2-(3,4-Difluorophenoxy)-5-fluoronicotinic acid (1, Figure 1) is a
key intermediate for preparing some drug candidates. A C-14-
labeled compound 1 was required in the synthesis of a
radioactive isotope-labeled drug candidate in order to support
absorption, distribution, metabolism and elimination studies of
the drug. According to our preliminary metabolic studies, the
carbon-14 labeling in the circled area was most likely meta-
bolically stable. Therefore, we focused on preparation of the
C-14-labeled compound 1 at either the carbonyl group or
pyridine ring (Figure 1).
Prior to our involvement, Pfizer process chemists have synthe-
sized the compound 1 in four steps as shown in Scheme 1.1
A commercially available compound 2 was first treated with H2SO4/
EtOH to form the ethyl ester 3 in 85% yield. The selective de-
chlorination of the dichloro-substituted ester 3 with Lindlar’s
reagent afforded the desired mono-chloride 4 in 65% yield after
crystallization from isopropyl alcohol.1,2 The product 4 was then
coupled with 3,4-difluorophenol 5 in the presence of a base to
afford the ether 6 in 72% yield. Finally, the ester 6 was hydrolyzed
by NaOH in toluene to furnish the target 1 in 89% yield. The original
synthetic route is not useful for introducing a C-14 into the desired
position. Therefore, we have explored several new synthetic
approaches to C-14-labeled compound 1 or 4. In this paper we
wish to report a modified approach to labeled pyridine ring
synthesis based on the electrocyclic ring-closure of 1,4,4-trisub-
stituted butadiene. We also discuss its application for preparing
2-(3,4-difluorophenoxy)-5-fluoro-[14C] nicotinic acid and other halo-
gen-substituted analogs.
Chemical purity of all labeled compounds was determined by
HPLC and LC-MS. Purifications were done by flash column
chromatography on Biotage Flash 40 system. Quantitation of
radioactivity of C-14-labeled compounds was performed using a
Packard 2200CA liquid scintillation analyzer, with Scintiverse BD
cocktail used throughout. Commercial reagents and solvents
were purchased from Aldrich and used as-received unless
otherwise noted. [14C] ethyl cyanoacetate (250 mCi, 53 mCi/
mmol) was purchased from American Radiolabeled Chemicals,
Inc. The intermediate 4 and unlabeled compound 1 were
provided by Chemical R&D, Sandwich Lab, Pfizer Inc.
(Z)-3-dimethylamino-2-fluoroacrylaldehyde (18)
To a solution of sodium fluoroacetate (10.0 g, 100 mmol) in dry
DMF (80 ml) was added oxalyl chloride (28.0 g) at such a rate
that the reaction temperature was kept below 101C. The mixture
was stirred for 30 min at 01C, and then for another 30 min at
601C. After the reaction mixture was cooled down to 01C,
triethylamine (27.6 ml) was added slowly while the reaction
temperature was kept below 101C. The resulting mixture was
stirred on an ice bath for 30 min and at 50–551C for another
30 min. After cooling down to room temperature, the reaction
aRadiochemical Synthesis Group, Research API, Groton Lab. Pfizer Global R&D,
Eastern Point Rd, Groton, CT 06340, USA
bIsotope Labs, Department of Drug Metabolism and Pharmacokinetics, Novartis
Pharmaceutical Corp., East Hanover, NJ 07936, USA
Experimental
*Correspondence to: Yinsheng Zhang, Radiochemical Synthesis Group, Research
API, Groton Lab. Pfizer Global R&D, Eastern Point Rd, Groton, CT 06340, USA.
E-mail: yinsheng.zhang@pfizer.com
General: All reactions were carried out under an atmosphere of
nitrogen unless otherwise stated. LC-MS data were obtained on
a Water Micromass LCZ mass spectrometer with flow injection
yPresented at the 24th International isotope Society (US northeast chapter)
Symposium, 2008.
J. Label Compd. Radiopharm 2011, 54 382–386
Copyright r 2011 John Wiley & Sons, Ltd.