Novel synthetic approach to fluoro- and amido-disubstituted 3-hydroxypyridin-4-ones

Article abstract of DOI:10.1016/j.jfluchem.2015.02.005

Starting from fluoropyridines as a building block, with chelating functional groups being introduced, several fluoro- and amido-disubstituted 3-hydroxypyridin-4-ones have been synthesized with the intention of improving the pharmaceutical profile of 3-hydroxypyridin-4-ones.

Full text of DOI:10.1016/j.jfluchem.2015.02.005

Journal of Fluorine Chemistry 173 (2015) 29–34
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short Communication
Novel synthetic approach to fluoro- and amido-disubstituted
3-hydroxypyridin-4-ones
a,
b
Yongmin Ma *, Robert C. Hider
a
School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, 548 Binwen Road, Binjiang District, Hangzhou, Zhejiang 310053, PR China
Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NH, UK
b
A R T I C L E I N F O
A B S T R A C T
Article history:
Starting from fluoropyridines as a building block, with chelating functional groups being introduced,
several fluoro- and amido-disubstituted 3-hydroxypyridin-4-ones have been synthesized with the
intention of improving the pharmaceutical profile of 3-hydroxypyridin-4-ones.
ß 2015 Published by Elsevier B.V.
Received 10 January 2015
Received in revised form 10 February 2015
Accepted 16 February 2015
Available online 23 February 2015
Keywords:
3
-Hydroxypyridin-4-one
Iron chelator
Fluoropyridine
Metalation
Carboxylation
Protection
1
. Introduction
-Hydroxypyridin-4-ones (HPOs) are currently one of the main
fluorine plays an increasingly important role in the design of
pharmaceuticals.
Many synthetic methods to introduce a fluorine atom directly
into the pyridine-4-one ring have been attempted but all have
failed [13]. Schlosser’s group has reported that fluoropyridines can
be readily and site selectively metalated by using different lithium
3
candidates for the development of orally active iron chelators [1].
They are also one of the two general classes of molecules having
been reported to possess potential for the treatment of neurode-
generative diseases [2]. Dimethyl-3-hydroxypyridin-4-one (defer-
iprone) has been used clinically as an orally active iron chelator for
treating transfusion-induced iron overload for over a period of
reagents. Subsequent reaction with
a suitable electrophile
achieves the target product [14,15]. This approach subverts our
conventional approach and has directed us to redesign synthetic
pathways of fluorinated 3-hydroxypyridin-4-ones. It is possible to
obtain the target products by starting with a fluorine-containing
precursor and then introducing chelating functional groups. As an
introduction of an electron-withdrawing group on the pyridinone
2
0 years [3]. It has been reported to be effective and safe in the
reversal of oxidative stress in the neurodegenerative disorders
such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and
Friedreich’s ataxia (FA) [4–6]. The efficacy of deferiprone is limited
by extensive metabolism in the liver and therefore a relatively high
dose is required to maintain iron overloaded patients in negative
iron balance [7]. In addition, deferiprone is not particularly
efficient at crossing the blood–brain barrier [8].
An introduction of fluorine into an organic molecule can
significantly improve the chemical and biological properties, such
as its metabolic stability, bioavailability, selective reactivity and
receptor binding interactions [9]. In fact, the role of fluorine in
drug design has been frequently reviewed [10–12]. It is clear that
a
ring can decrease pK value of the 3-pyridinone oxygen atom and
correspondingly result enhanced metal stability constant [16,17],
we would like to report fluorinated HPOs in this present paper
which contain another functional group, the amido group, in order
3
+
to enhance the pFe value and possibly also the metabolic stability
of the ligands [16,18].
2. Results and discussion
The novel synthetic route to 2-fluoro-5-amido substituted
3
-hydroxypyridin-4-one is summarized in Scheme 1. It starts
*
Corresponding author. Tel.: +86 0571 8663 3046.
from the commercially available 2-fluoropyridine (1). Due to the
E-mail address: yongmin.ma@zcmu.edu.cn (Y. Ma).
strong inductive effect of fluorine atom at C2, the starting material
http://dx.doi.org/10.1016/j.jfluchem.2015.02.005
022-1139/ß 2015 Published by Elsevier B.V.
0

3
0
Y. Ma, R.C. Hider / Journal of Fluorine Chemistry 173 (2015) 29–34
Scheme 1. Synthesis of 2-fluoro-5-amido substituted 3-hydroxypyridin-4-one. (a) (1) LDA, THF, ꢀ75 8C, 2 h, (2) B(OMe)
MeI/acetone, reflux overnight, 95%; (c) (1) LTMP, THF, ꢀ75 8C, 20 h; (2) B(OMe) , ꢀ75 8C, 2 h, (3) CH CO H, 0 8C, 1 h, 87%; (d) K
LTMP, THF, ꢀ75 8C, 20 h; (2) dry ice, thaw to r.t., 87%; (f) DCC/NHS/MeNH , r.t., overnight, 67%; (g) BBr , 0 8C to r.t., overnight, 70%.
3
, ꢀ75 8C, 2 h, (3) CH
3 3 2 3
CO H, 0 8C, 1 h, 92%; (b) K CO /
CO /MeI/acetone, reflux overnight, 40%; (e) (1)
3
3
3
2
3
2
3
undergoes lithiation at the ortho-position (C3) by lithium
diisopripylamide (LDA). The lithiated fluoropyridine was trapped
with trimethylborate, followed by in situ reaction with peracetic
acid to afford 2-fluoro-3-hydroxypyridine (2). The hydroxy group
of compound 2 needs to be protected before lithiation and a
simple methyl group was introduced by reacting compound 2
with methyl iodide in the presence of potassium carbonate. When
we attempted to lithiate compound 3 using LDA, no product was
isolated. This may be due to the relatively weaker inductive effect
of methoxy group at ortho-position (C3) as compared to that of the
fluorine atom. Therefore, a stronger metalation reagent lithium
The synthesis of 2-amido-5-fluoro substituted 3-hydroxypyr-
idin-4-one is outlined in Scheme 2. Although 3-fluoropyridine is
commercial available, the lithiation of 3-fluoropyridine derivatives
readily occurs at C2 due to the neighboring fluorine effect. To avoid
this, 2-chloro-3-fluoropyridine (9) was selected as a building block,
where C2 is blocked by chlorine. A similar procedure as that
outlined in Scheme 1 led to the formation of 2-chloro-3-fluoro-4-
hydroxypyridine (10). Subsequent to the conversion of the
hydroxyl function to the methoxy group, another hydroxyl group
was introduced at C5, adjacent to the 4-methoxy group. To obtain
compound 14, the 5-hydroxy group of compound 12 required
protection. The resulting compound 13 was lithiated at C6 and
trapped with dry ice. The carboxy group of compound 14 is readily
converted to amido group by activation with DCC/NHS followed by
amine coupling. To remove the 6-chloro group of compound 15,
hydrogenation in the presence of Pd/C was adopted to afford 16 in
quantitative yield. This procedure does not influence the methoxy
2
,2,6,6-tetramethylpiperidide (LTMP) was investigated. The
resulting lithiated intermediate was again trapped with tri-
methylborate and oxidized by peracetic acid to afford 2-fluoro-4-
hydroxy-3-methoxypyridine (4). Compound 4 can react with MeI/
2 3
K CO to afford two isomers due to its two resonance forms. To
minimize the formation of the N-methyl isomer, polar solvents
such as methanol were avoided as they favor polar products.
When compound 5 was lithiated with LTMP, the lithiation only
occurs at C5, due to neighboring group assistance. The resulting
lithiating intermediate was trapped with dry ice to afford 5-
carboxy-3,4-dimethoxy-2-fluoropyridine (6). The carboxyl group
of compound 6 was activated with dicyclohexylcarbodiimide
3
groups which were readily removed by BBr to obtain the target
product 17.
In comparison with the 1-nonsubstituted HPOs, an introduction
of alkyl group at N1 can dramatically influence its physiochemical
a
properties such as pK s and iron affinity constants [18]. To
introduce an additional alkyl group at N1 of the 2-amido-5-fluoro
0
(
DCC)/N-hydroxy succinimide (NHS), followed by coupling with
substituted HPOs, compound 16 was reacted with ethyl iodide in
methylamine to afford compound 7. The methyl protecting group
was then readily removed using BBr to form the corresponding
3
acetone overnight to afford 1-ethyl substituted compound 18
(Scheme 3). The phenomenon may be explained by a mechanism
which involves the production of an intermediate 1-alkyl
target iron chelator 8.
Scheme 2. Synthesis of 2-amido-5-fluoro substituted 3-hydroxypyridin-4-one. (a) (1) LDA, THF, ꢀ75 8C, 2 h, (2) B(OMe)
MeI/acetone, reflux overnight, 52%; (c) (1) LTMP, THF, ꢀ75 8C, 20 h; (2) B(OMe) , ꢀ75 8C, 2 h, (3) CH CO H, 0 8C, 1 h, 96%; (d) K
LTMP, THF, ꢀ75 8C, 20 h; (2) dry ice, thaw to r.t., 89%; (f) DCC/NHS/MeNHCOCH(Me)NH , r.t., overnight, 58%; (g) Pd/H /Et
3
, ꢀ75 8C, 2 h, (3) CH
CO /MeI/acetone, reflux overnight, 97%; (e) (1)
N, 85%; (h) BBr , 0 8C to r.t., overnight, 63%.
3 3 2 3
CO H, 0 8C, 1 h, 80%; (b) K CO /
3
3
3
2
3
2
2
3
3

Y. Ma, R.C. Hider / Journal of Fluorine Chemistry 173 (2015) 29–34
31
Scheme 3. Synthesis of 1-alkyl-2-amido-5-fluoro substituted HPO. (a) DCC/NHS/MeNH
or BBr in dichloromethane, 0 8C to r.t., overnight, 68%.
2
, r.t., overnight, 61%; (b) Pd/H
2
/Et
3
N, 87%; (c) EtI/acetone, r.t., overnight, 85%; (d) BCl
3
3
Scheme 4. Synthesis of 1-alkyl-2-fluoro-5-amido 3-hydroxypyridin-4-one. (a) (1) LTMP, THF, ꢀ75 8C, 16 h; (2) CCl
2) dry ice, thaw to r.t., 82%; (c) DCC/NHS/MeNH , r.t., overnight, 61%; (d) Pd/H /Et
4%; (f) K CO /MeI/MeOH, reflux overnight, 35%; (g) BBr , 0 8C to r.t.; overnight, 73%.
2
FCClF
2
, ꢀ75 8C, 2 h, 85%; (b) (1) LTMP, THF, ꢀ75 8C, 16 h;
(
2
2
3
N, 90%; (e) (1) LTMP, THF, ꢀ75 8C, 20 h; (2) B(OMe)
3
, ꢀ75 8C, 2 h, (3) CH
3 3
CO H, 0 8C, 1 h,
6
2
3
3
pyridinium iodide salt. This salt will not be stable and simulta-
neously converts into the more stable 1-alkyl pyridin-4-one analog
and release ethyl iodide. Indeed, when 4-methoxy substituted 16
reacts with ethyl iodide, a mixture of 1-ethyl and 1-methyl HPO
analogs are produced. Therefore, in order to afford a clean
quantitative product 1-ethyl HPO, ethyl group must be used to
protect the 4-hydroxy group. Compounds 18 were deprotected to
afford the 1-alkyl-2-amido-5-fluoro HPO 19 (Scheme 3).
pathway for 3(5)-fluoro HPOs is slightly different from that of the
2-fluoro analogs, mainly due to the influence of the electronega-
tivity of the fluorine. Physicochemical characterizations and
metabolic studies of these ligands are currently in progress.
4. Experimental
General information: Fluorinated pyridines were purchased
from Fluorochem. Reagents were from Sigma–Aldrich and reagent
grade quality and were used without further purification. Column
chromatography purifications were performed on Merck silica gel
In contrast to the conversion from 3-fluoropyridine derivatives
1
6–18, the 2-fluoropyridine analog 25 could not be obtained by
treatment of compound 7 with methyl iodide. This may be due to
the presence of fluorine at C2, which by virtue of its strong
electronegativity, decreases the nucleophilicity of nitrogen.
Therefore a new synthetic strategy for 1-alkyl-2-fluoro-5-amido
substituted HPO 26 has been designed (Scheme 4). C4 of 2-fluoro-
1
13
19
60 (0.04–0.063 mm). H, C and F NMR spectra were recorded
on a Bruker Avance 400 (400 MHz) NMR spectrometer. Chemical
shifts (d) are reported in ppm downfield from the internal standard
1
13
tetramethylsilane (TMS) for H and C NMR. ESI mass spectra
were obtained by infusing samples into an LCQ Deca XP ion trap
mass instrument. HRMS were monitored on MicroMass Q-TOF
instrument.
3
-methoxypyridine 3 is first blocked with chlorine. Carboxylation
of the resulting compound 20 at C5 was achieved with LTMP/dry
ice. This step was followed with a coupling reaction with
methylamine in the presence of DCC/NHS, yielding 22, which
was hydrogenated to remove the chloro group at C4. Another
hydroxyl group was introduced at C4 by sequential lithiation,
electrophilic substitution and oxidation. Compound 24 has two
2-Fluoropyridin-3-ol (2):
A
solution of 2-fluoropyridine
was cooled to
(10 mmol) in anhydrous THF (20 ml) under N
2
ꢀ78 8C in a dry ice/acetone bath. To this solution was added a
solution of lithium diisopropylamide (LDA; 11 mmol) in hexane
slowly. The mixture was stirred for 0.5 h at ꢀ78 8C. To the mixture
was added trimethoxyborane (2.4 ml) and stirred for 2 h, followed
by an addition of peracetic acid (3.6 ml; 32% in dilute acetic acid).
The mixture was allowed to warm to 0 8C under stirring for 1 h.
After the mixture was cooled to ꢀ20 8C, sodium dithionite (4 g in
10 ml water) was added slowly. The mixture was extracted with
ethyl acetate and the extract was dried and concentrated. The
2 3
resonance forms and when it reacts with MeI/K CO , the methyl
group can be attacked by either N1 or the oxygen at C4. In order to
obtain the desired N-substituted product 25 in maximum yield, a
polar solvent MeOH was adopted. Similar to the reactions
mentioned above, the methyl protecting group can be removed
3
by BBr to afford the 1-alkyl-2-fluoro-5-amido substituted 3-
hydroxypyridin-4-one.
residue was purified by chromatography, eluting with 1:5
1
3
. Conclusion
EtOAc:hexane to give a white solid [19] (92%). H NMR (CDCl
3
):
d
9.46 (brs, 1H, OH), 7.45–7.47 (m, 1H, C
6 4
–H), 7.13–7.18 (m, 1H, C –
+
In conclusion, several fluoro- and amido-disubstituted 3-
H), 6.85–6.88 (m, 1H, C –H). ESI-MS: 114 (M+1) .
5
hydroxypyridin-4-ones with either hydrogen or an alkyl group
at N1 of the pyridine ring have been synthesized. The synthetic
2-Fluoro-3-methoxypyridine(3): 2-Fluoropyridin-3-ol(10 mmol),
methyl iodide (20 mmol) and potassium carbonate (20 mmol) in

3
2
Y. Ma, R.C. Hider / Journal of Fluorine Chemistry 173 (2015) 29–34
acetone (100 ml) was refluxed overnight. The inorganic salt was
filtered and the solvent was evaporated. The residue was purified on
the reaction by the addition of methanol (10 ml) and left to stir for
another half an hour. After removal of the solvents under reduced
column (eluent: EtOAc:hexane = 1:5) to afford a colorless liquid [19]
pressure, the residues were purified by recrystallization to afford a
1
1
(
C
ꢀ
95%). H NMR (CDCl
3
):
d
7.74–7.75 (m, 1H, C
6
–H), 7.26–7.31 (m, 1H,
white solid (70%). H NMR (d
6
-DMSO)
d
9.04 (br s, 1H, OH), 8.18 (s,
19
19
4
–H), 7.11–7.15(m, 1H, C
90.15 (s). ESI-MS: 128 (M+1) .
-Fluoro-3-methoxypyridin-4-ol (4): At ꢀ78 8C, 2,2,6,6-tetra-
5
–H), 3.91(s, 3H,OMe). FNMR(CDCl
3
):
d
1H, C
NMR (d
2
–H), 5.94 (br s, 1H, NH), 2.83 (d, J = 4.6 Hz, 3H, NHMe).
F
+
13
6
-DMSO): ꢀ84.19 (s). C NMR (d
6
-DMSO):
d
25.83 (s, CH
3
),
2
112.03 (s), 127.62 (d, J = 29 Hz), 135.79 (d, J = 18 Hz), 154.82 (d,
methylpiperidine (12 mmol) was added to a solution of n-
butyllithium (11 mmol; 2 M in hexane) in THF (20 ml) under N
J = 230 Hz), 158.41 (d, J = 10 Hz), 168.13 (s). HRMS: Calcd for
+
2
,
C
7
H
8
N
2
O
3
F (M+1) , 187.0519; Found, 187.0517.
after 15 min, followed by 2-fluoro-3-methoxypyridine (10 mmol).
After stirring for 0.5 h, to this solution was added trimethoxybor-
ane (2.4 ml) and stirred for 2 h, followed by an addition of peracetic
acid (3.6 ml; 32% in dilute acetic acid). The mixture was allowed to
warm to 0 8C under stirring for 1 h. After the mixture was cooled to
2-Chloro-3-fluoro-4-hydroxypyridine (10): A solution of 2-
chloro-3-fluoropyridine (2 mmol) in anhydrous THF (10 ml) was
cooled to ꢀ78 8C. To this solution was added a solution of lithium
diisopropylamide (LDA; 2.2 mmol) in hexane slowly at same
temperature. After 2 h at ꢀ78 8C, to the mixture was added
trimethoxyborane (0.48 ml) and stirred for 2 h, followed by an
addition of peracetic acid (0.72 ml; 32% in dilute acetic acid). The
mixture was allowed to warm to 0 8C under stirring for 1 h. After
the mixture was cooled to ꢀ20 8C, sodium dithionite (0.8 g in 2 ml
water) was added dropwise. The mixture was extracted with ethyl
acetate and the extract was dried and concentrated. The residue
ꢀ
20 8C, sodium dithionite (4 g in 10 ml water) was added slowly.
The mixture was extracted with DCM and the extract was dried
and concentrated. The residue was purified by chromatography,
1
eluting with 1:9 MeOH:DCM to give a white solid [19] (87%).
H
NMR (d
H, C –H). 3.86 (s, 3H, OMe). F NMR (d
MS: 144 (M+1) .
-Fluoro-3,4-dimethoxypyridine (5): To a solution of 2-fluoro-3-
6
-DMSO):
d
7.63 (d, J = 5.4 Hz, 1H, C
6
–H), 6.80 (d, J = 5.6 Hz,
19
1
5
6
-DMSO):
d
ꢀ83.03 (s). ESI-
+
was purified by chromatography, eluting with 1:19 MeOH:DCM to
1
2
give the expected product as a white solid [19] (80%). H NMR (d
6
-
methoxypyridin-4-ol (5 mmol) in acetone (20 ml) was added
potassium carbonate (10 mmol) and methyl iodide (10 mmol). The
mixture was refluxed overnight. Inorganic salt was filtered and the
DMSO):
J = 5.8 Hz, 1H, C
148 (M+1) .
d
11.86 (brs, 1H, OH), 7.89 (d, J = 5.3 Hz, 1H, C
6
–H), 6.95 (t,
1
9
5
–H). F NMR (d
6
-DMSO):
d
ꢀ141.29 (s). ESI-MS:
+
solvent was evaporated. The residue was purified on column
2-Chloro-3-fluoro-4-methoxypyridine (11): 2-Chloro-3-fluoro-4-
hydroxypyridine (10 mmol), methyl iodide (20 mmol) and potas-
sium carbonate (20 mmol) in acetone (100 ml) was refluxed
overnight. The inorganic salt was filtered and the solvent was
1
chromatography, eluting with EtOAc to afford oil [19] (40%).
NMR (CDCl ): 7.82 (dd, J = 0.7, 5.6 Hz, 1H, C
J = 5.6 Hz, 1H, C –H), 3.95 (s, 3H, 4-OMe), 3.93 (d, J = 1.3 Hz, 3H, 3-
OMe). ESI-MS: 158 (M+1) .
,5-Dimethoxy-6-fluoropyridin-3-carboxylic acid (6): At ꢀ78 8C,
,2,6,6-tetramethylpiperidine (12 mmol) was added to a solution
of n-butyllithium (11 mmol; 2 M in hexane) in THF (20 ml), after
5 min, followed by 2-fluoro-3,4-dimethoxypyridine (10 mmol).
After 20 h, to this solution was added excess dry ice and stirred for
h. The mixture was neutralized by HCl and extracted with DCM
H
3
d
6
–H), 6.76 (d,
5
+
evaporated. The residue was purified on column (eluent: ethyl
1
4
acetate:hexane = 1:5) to afford a colorless liquid [19] (52%).
NMR (CDCl ): 8.08 (dd, J = 1.0, 5.8 Hz, 1H, C
J = 5.7 Hz, 1H, C
(s). ESI-MS: 162 (M+1) .
H
2
3
d
6
–H), 6.88 (t,
1
9
5
–H), 3.97 (s, 3H, OMe). F NMR (CDCl ):
3
d
ꢀ143.49
+
1
2-Chloro-3-fluoro-5-hydroxy-4-methoxypyridine (12): At ꢀ78 8C,
2,2,6,6-tetramethylpiperidine (12 mmol) was added to a solution
of n-butyllithium (11 mmol; 2 M in hexane) in THF (20 ml), after
15 min, followed by 11 (10 mmol). After 20 h, to this solution was
added trimethoxyborane (2.4 ml) and stirred for 2 h, followed by
an addition of peracetic acid (3.6 ml; 32% in dilute acetic acid). The
mixture was allowed to warm to 0 8C under stirring for 1 h. After
the mixture was cooled to ꢀ20 8C, sodium dithionite (4 g in 10 ml
water) was added slowly. The mixture was extracted with ethyl
acetate and the extract was dried and concentrated. The residue
1
and the extract was dried and concentrated. The residue was
purified by chromatography, eluting with 1:4 MeOH:DCM to give
1
a white solid (87%). H NMR (CDCl
3
):
d
8.57 (d, J = 0.48 Hz, 1H, C
2
–
H), 4.20 (br s, 1H, COOH), 3.99 (s, 3H, 4-OMe), 3.97 (d, J = 1.73 Hz,
1
9
3
(
H, 5-OMe). F NMR (CDCl
3
):
d
ꢀ74.59 (s, 1F). ESI-MS: 202
+
+
M+1) . HRMS: Calcd for C
8
H
9
4
NO F (M+1) , 202.0516; Found,
2
02.0503.
,5-Dimethoxy-6-fluoro-N-methylpyridine-3-carboxamide (7):
To a solution of 4,5-dimethoxy-6-fluoropyridin-3-carboxylic acid
5 mmol) in dry dichloromethane (50 ml), dicyclohexylcarbodii-
4
was purified by chromatography, eluting with 1:1 EtOAc:hexane to
1
(
give a white solid [19] (96%). H NMR (CDCl
3
):
d
7.88 (d, J = 0.8 Hz,
19
mide (DCC) (1.1 g, 5.5 mmol, 1.1 equiv.) and N-hydroxysuccini-
mide (NHS) (0.69 g, 6 mmol, 1.2 equiv.) were added. The mixture
was allowed to stir for 20 min before methylamine (1 M in THF,
1H, C
(CDCl
6
–H), 5.88 (brs, 1H, OH), 4.22 (d, J = 4.0 Hz, 3H, OMe). F NMR
+
3
):
d
ꢀ139.00 (s). ESI-MS: 178 (M+1) .
2-Chloro-4,5-dimethoxy-3-fluoropyridine (13): 12 (10 mmol),
methyl iodide (20 mmol) and potassium carbonate (20 mmol) in
acetone (100 ml) was refluxed overnight. The inorganic salt was
filtered and the solvent was evaporated. The residue was purified
5
mmol, 1 equiv.) was added, and the reaction was left to stir at
room temperature overnight. The DCU was filtered, and the
organic layer was washed with 0.1 M NaOH (3ꢁ) and brine, dried
over anhydrous Na
2
SO
4
and concentrated under reduced pres-
on column (eluent: EtOAc:hexane = 1:3) to afford a white solid [19]
1
sure. The obtained residue was purified by column chromatogra-
(97%). H NMR (CDCl
3
):
d
7.80 (d, J = 0.9 Hz, 1H, C
6
–H), 4.14 (s, 3H,
ꢀ138.34 (s). ESI-
1
19
phy (eluent: ethyl acetate) to afford white solid (67%). H NMR
4-OMe), 3.95 (s, 3H, 5-OMe). F NMR (CDCl
MS: 192 (M+1) .
3
):
d
+
(
CDCl
3
):
d
8.64 (d, J = 0.7 Hz, 1H, C
2
–H), 7.62 (br s, 1H, NH), 3.96 (s,
3
H, 4-OMe), 3.94 (d, J = 1.7 Hz, 3H, 5-OMe), 3.00 (d, J = 4.9 Hz, 3H,
6-Chloro-5-fluoro-3,4-dimethoxy-pyridine-2-carboxylic acid (14):
At ꢀ78 8C, 2,2,6,6-tetramethylpiperidine (12 mmol) was added to a
solution of n-butyllithium (11 mmol; 2 M in hexane) in THF (20 ml),
after 15 min, followed by 2-chloro-4,5-dimethoxy-3-fluoropyridine
(10 mmol). After 16 h, to this solution was added excess dry ice
and the mixture was left to thaw to room temperature. The mixture
was neutralized by HCl and concentrated. The residue was
1
9
+
NHMe). F NMR (CDCl
HRMS: Calcd for
05.0834.
-Fluoro-1,4-dihydro-5-hydroxy-N-methyl-4-oxopyridine-3-car-
boxamide (8): 4-Ethoxy-6-fluoro-5-methoxy-N-pyridine-3-car-
boxamide (2 mmol) was dissolved into CH Cl (20 ml) and
flushed with nitrogen. Boron tribromide (1 M in CH Cl , 8 ml)
was slowly added and the reaction mixture was stirred at room
temperature for 20 h. The excess BBr was eliminated at the end of
3
):
d
ꢀ77.75 (s, 1F). ESI-MS: 215 (M+1) .
+
9 12 2 3
C H N O F (M+1) , 205.08325; Found,
2
6
2
2
2
2
purified by chromatography, eluting with ethyl acetate to give a
1
white solid (89%). H NMR (CDCl
3
):
d
4.24 (d, J = 3.6 Hz, 3H, 4-OMe),
):
ꢀ128.84 (s). ESI-MS: 236
1
9
3
4.02 (s, 3H, 5-OMe). F NMR (CDCl
3
d

Y. Ma, R.C. Hider / Journal of Fluorine Chemistry 173 (2015) 29–34
33
+
+
(
2
M+1) . HRMS: Calcd for C
36.0122.
-Chloro-5-fluoro-3,4-dimethoxy-pyridine-2-carboxylic acid (1-
8
H
8
NO
4
ClF (M+1) , 236.0126; Found,
was purified by column chromatography eluting with 1:9
1
MeOH:DCM to afford a white solid (85%). H NMR (CDCl
8.05 (br s, 1H, NH), 7.34 (d, J = 6.4 Hz, 1H, C –H), 3.96 (q, J = 7.0 Hz,
2H, CH ), 3.81 (s, 3H, 3-OMe), 3.02 (d, J = 4.5 Hz, 3H, NHMe), 1.46 (t,
J = 7.0 Hz, 3H, Me). F NMR (CDCl
3
): d
6
6
methylcarbamoyl-ethyl)-amide (15): To a solution of 6-chloro-5-
fluoro-3,4-dimethoxy-pyridine-2-carboxylic acid (5 mmol) in dry
dichloromethane (50 ml), DCC (1.1 g, 5.5 mmol, 1.1 equiv.) and NHS
2
1
9
3
):
d
ꢀ150.22 (s). ESI-MS: 229
+
+
(M+1) . HRMS: Calcd for C10
14 2 3
H N O F (M+1) , 229.0988; Found,
(
0.69 g, 6 mmol, 1.2 equiv.) were added. The mixture was allowed to
stir for 20 min before (L)-2-amino-N-methylpropanamide (0.5 g,
mmol, 1 equiv.) was added, and thereaction was leftto stirat room
229.0997.
1-Ethyl-5-fluoro-3-hydroxy-N-methyl-4-oxo-1,4-dihydropyri-
5
dine-2-carboxamide (19): A similar procedure of making compound
1
temperature overnight. Then, the DCU was filtered, and the organic
8 started from compound 18 with BBr
NMR (d -DMSO): 8.84 (brs, 1H, OH), 8.36 (d, J = 7.0 Hz, 1H, C
6.15 (brs, 1H, NH), 4.01 (q, J = 7.1 Hz, 2H, CH ), 2.78 (d, J = 4.6 Hz,
3H, NHMe), 1.33 (t, J = 7.1 Hz, 3H, Me). F NMR (d -DMSO):
16.34 (s), 25.83 (s),
3
gave white solid (68%). H
layer was washed with 0.1 M NaOH (3ꢁ) and brine, dried over
6
d
6
–H),
anhydrous Na
SO
2 4
and concentrated under reduced pressure. The
2
1
9
obtained residue was purified by column chromatography
6
d
1
13
(
MeOH:DCM = 1:19) to afford a white solid (58%). H NMR (CDCl
7.89 (d, J = 7.7 Hz, 1H, CHNH), 6.31 (br s, 1H, NHMe), 4.61 (m, 1H,
CH), 4.20 (d, J = 3.4 Hz, 3H, 4-OMe), 3.97 (s, 3H, 3-OMe), 2.83 (d,
3
):
ꢀ152.53 (d, J = 7.4 Hz). C NMR (d
6
-DMSO): d
d
50.30 (s), 125.60 (d, J = 35 Hz), 130.41 (s), 145.94 (d, J = 12 Hz),
149.53 (d, J = 236 Hz), 158.00 (d, J = 12 Hz), 160.29 (s). HRMS:
Calcd for C
1
9
+
J = 4.9 Hz, 3H, NHMe), 1.50 (d, J = 7.0 Hz, 3H, CHMe). F NMR
9
H
12
N
2
O
3
F (M+1) , 215.0832; Found, 215.0843.
+
(CDCl
3
):
d
ꢀ131.26 (s). ESI-MS: 320 (M+1) . HRMS: Calcd for
4-Chloro-2-fluoro-3-methoxypyridine (20): At ꢀ78 8C, 2,2,6,6-
+
C
12
H
16
N
3
O
4
ClF (M+1) , 320.0813; Found, 320.0830.
tetramethylpiperidine (12 mmol) was added to a solution of n-
6
-Chloro-4-ethoxy-5-fluoro-3-methoxy-N-methylpicolinamide
2
butyllithium (11 mmol; 2 M in hexane) in THF (20 ml) under N ,
0
1
(
15 ). H NMR (CDCl
H, CH
d, J = 7.2 Hz, 3H, Me). F NMR (CDCl
3
):
d
7.36 (br s, 1H, NH), 4.42 (dq, J = 2.2, 7.2 Hz,
after 15 min, followed by 2-fluoro-3-methoxypyridine (10 mmol).
After stirring for 16 h, to this solution was added 1,1,2-trichloro-
1,2,2-trifluoroethane (20 mmol) and stirred for 2 h. The mixture
was then extracted with ethyl acetate and the extract was dried
1
(
(
2
), 3.98 (s, 3H, 3-OMe), 2.97 (d, J = 5.2 Hz, 3H, NHMe), 1.43
19
3
):
d
ꢀ130.39 (s). ESI-MS: 263
+
+
M+1) . HRMS: Calcd for C10
63.0587.
-Fluoro-3,4-dimethoxy-pyridine-2-carboxylic acid (1-methylcar-
H N O ClF (M+1) , 263.0599; Found,
13 2 3
2
and concentrated. The residue was purified by chromatography to
1
5
give an oil (85%). H NMR (CDCl
3
):
d
7.83 (dd, J = 2.0, 5.2 Hz, 1H, C
6
–
bamoyl-ethyl)-amide (16): To a solution of 15 (1.5 mmol) in ethyl
acetate (20 ml), catalytic 10% Pd/C (0.2 g) and triethylamine
H), 7.12 (dd, J = 2.8, 5.2 Hz, 1H, C
5
–H). 3.95 (d, J = 2.8 Hz, 3H, OMe).
1
9
+
F NMR (CDCl
3
):
d
ꢀ81.98 (s). ESI-MS: 162 (M+1) . HRMS: Calcd
+
(2 mmol) were added. The mixture was hydrogenated at room
for C NOClF (M+1) , 162.0122; Found, 162.0106.
6 6
H
temperature and 3 atms for 24 h. Then the catalyst was filtered off
through celite, and the clear solution, taken to dryness, afforded
4-Chloro-6-fluoro-5-methoxynicotinic acid (21): A similar pro-
cedure of making compound 6 started from 4-chloro-2-fluoro-3-
1
the title compound. Column chromatography eluting with 1:3
methoxypyridine to afford white solid (82%). H NMR (CDCl
3
):
d
1
19
EtOAc:hexane yields a white crystal (85%). H NMR (CDCl
3
):
d
8.20
8.07 (d, J = 2.0 Hz, 1H, C
(CDCl ):
ꢀ81.07 (s). ESI-MS: 206 (M+1) . HRMS: Calcd for
NO
4-Chloro-6-fluoro-5-methoxy-N-methylnicotinamide (22): A sim-
ilar procedure of making compound 7 started from 4-chloro-6-
2
-H), 4.08 (d, J = 4 Hz, 3H, OMe). F NMR
+
(d, J = 2.0 Hz, 1H, C
6
–H), 8.09 (d, J = 7.6 Hz, 1H, CHNH), 6.43 (br s,
3
d
+
1
3
H, NHMe), 4.61–4.68 (m, 1H, CH), 4.17 (d, J = 3.2 Hz, 3H, 4-OMe),
.98 (s, 3H, 3-OMe), 2.82 (d, J = 4.9 Hz, 3H, NHMe), 1.49 (d,
C
7
H
6
3
ClF (M+1) , 206.0020; Found, 206.0039.
19
J = 7.0 Hz, 3H, CHMe). F NMR (CDCl
3
):
d
ꢀ140.71 (s). ESI-MS: 286
+
+
1
(
M+1) . HRMS: Calcd for C12
86.1225.
-Ethoxy-5-fluoro-3-methoxy-N-methylpicolinamide (16 ):
NMR (CDCl ): 8.15 (d, J = 2.0 Hz, 1H, C –H), 7.52 (br s, 1H,
NH), 4.40 (dq, J = 2.2, 7.2 Hz, 2H, CH ), 3.99 (s, 3H, 3-OMe), 2.98 (d,
J = 5 Hz, 3H, NHMe), 1.41 (d, J = 7.2 Hz, 3H, Me). F NMR (CDCl
H
17
N
3
O
4
F (M+1) , 286.1203; Found,
fluoro-5-methoxynicotinic acid to afford white solid (61%).
NMR (CDCl ): 8.04 (d, J = 2.0 Hz, 1H, C –H), 7.52 (br s, 1H, NH),
3.97 (d, J = 3.6 Hz, 3H, OMe), 2.98 (d, J = 5.2 Hz, 3H, NHMe). F
H
2
3
d
2
0
1
19
4
H
+
3
d
6
NMR (CDCl
ClF (M+1) , 219.0337; Found, 219.0340.
6-Fluoro-5-methoxy-N-methylnicotinamide (23): A similar pro-
cedure of making compound 16 started from 4-chloro-6-fluoro-5-
3
):
d
ꢀ82.44 (s). ESI-MS: 219 (M+1) . HRMS: Calcd for
+
2
8 9 2 2
C H N O
19
3
):
d
F
+
ꢀ
139.9 (s). ESI-MS: 229 (M+1) . HRMS: Calcd for C10
H
14
N
2
O
3
+
1
(
M+1) , 229.0988; Found, 229.0981.
-Fluoro-3-hydroxy-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid
1-methylcarbamoyl-ethyl)-amide (17): Compound 16 (5 mmol) was
Cl (20 ml) and flushed with nitrogen. Boron
tribromide (1 M in CH Cl , 20 ml) was slowly addedand the reaction
mixture was stirred at room temperature for 3 d. The excess BBr
waseliminatedattheendofthereactionbytheadditionofmethanol
10 ml) and left to stir for another half an hour. After removal of the
solvents under reduced pressure, the residues were purified by
methoxy-N-methylnicotinamide to afford white solid (90%).
NMR (CDCl ): 8.05 (d, J = 8 Hz, 1H, C –H), 7.50 (br s, 1H, NH), 7.37
(dd, J = 8, 9.6 Hz, 1H, C –H), 3.95 (s, 3H, OMe), 2.98 (d, J = 5.2 Hz,
H
5
3
d
2
(
4
+
dissolved into CH
2
2
3H, NHMe). ESI-MS: 185 (M+1) . HRMS: Calcd for C
8
H
10
N
2
O
2
F
+
2
2
(M+1) , 185.0726; Found, 185.0707.
3
6-Fluoro-4-hydroxy-5-methoxy-N-methylnicotinamide (24): A
similar procedure of making compound 12 started from 4-
chloro-5-methoxy-N-methylnicotinamide to afford white solid
(
1
(64%). H NMR (CDCl
3
):
d
13.1 (brs, 1H, OH), 8.05 (s, 1H, C
2
–H), 6.60
1
19
recrystallization to afford a white solid (63%). H NMR (d
6
-DMSO):
d
(brs, 1H, NH), 3.96 (s, 3H, OMe), 3.04 (d, J = 4.8 Hz, 3H, NHMe).
F
+
8
.90 (d, J = 7.5H, 1H, CHNH), 8.12 (q, J = 4.5 Hz, 1H, NHMe), 8.02 (d,
NMR (CDCl
F (M+1) , 201.0675; Found, 201.0686.
6-Fluoro-5-methoxy-N,1-dimethyl-4-oxo-1,4-dihydropyridine-3-
3
):
d
ꢀ77.53 (s). ESI-MS: 201 (M+1) . HRMS: Calcd for
+
J = 3.2 Hz, 1H, C
6
–H), 4.44–4.51 (m, 1H, CH), 2.62 (d, J = 4.6 Hz, 3H,
8 10 2 3
C H N O
19
NHMe), 1.35 (d, J = 7.0 Hz, 3H, CHMe). F NMR (d
6
-DMSO):
18.81 (s), 25.55 (s), 48.29 (s),
24.91 (s), 126.56 (d, J = 27 Hz), 149.07 (s), 149.36 (s), 150.49 (d,
d
13
ꢀ
146.89 (s). C NMR (d
6
-DMSO):
d
carboxamide (25): To a solution of 6-fluoro-4-hydroxy-5-methoxy-
N-methylnicotinamide (5 mmol) in methanol (20 ml) was added
potassium carbonate (10 mmol) and methyl iodide (10 mmol). The
mixture was refluxed overnight. Inorganic salt was filtered and the
solvent was evaporated. The residue was purified on column
1
+
J = 209 Hz), 164.18 (s), 171.46 (s). ESI-MS: 258.0 (M+1) . HRMS:
+
12 3 4
Calcd for C10H N O FNa (M+Na) , 280.0710; Found, 280.0693.
1-Ethoxy-5-fluoro-3-methoxy-N-methyl-4-oxo-1,4-dihydropyri-
dine-2-carboxamide (18): A solution of 4-ethoxy-5-fluoro-3-meth-
oxy-N-methylpicolinamide (5 mmol) in acetone (30 ml) was
added ethyl iodide (20 mmol) and the mixture was heated at
chromatography, eluting with 1:9 MeOH:DCM to afford white
1
solid (35%). H NMR (CDCl
3
):
d
8.26 (d, J = 0.7, 7.2 Hz, 1H, C
2
–H),
3.96 (s, 3H, OMe), 3.76 (d, J = 3.2 Hz, 3H, NMe), 2.95 (d, J = 5.2 Hz,
1
9
6
0 8C for 20 h. The solvent was then evaporated and the residue
3H, NHMe).
F NMR (CDCl
3
):
d
ꢀ113.15 (s). ESI-MS: 215

3
4
Y. Ma, R.C. Hider / Journal of Fluorine Chemistry 173 (2015) 29–34
+
+
(
2
M+1) . HRMS: Calcd for C
15.0820.
-Fluoro-5-hydroxy-N,1-dimethyl-4-oxo-1,4-dihydropyridine-3-
carboxamide (26). A similar procedure of making compound 19
9
H
12
N
2
O
3
F (M+1) , 215.0832; Found,
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started from compound 25 with BBr
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.79 (d, J = 3.6 Hz, 3H, NMe), 3.32 (brs, 1H, NH), 2.84 (d, J = 4.8 Hz,
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8.07 (d, J = 5 Hz), 114.49 (s), 132.42 (d, J = 4 Hz), 136.53 (s), 147.00
d, J = 260 Hz), 163.94 (s), 171.64 (d, J = 10 Hz). HRMS: Calcd for
3
gave white solid (73%).
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6
d
2
–H),
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0
2.005.