Synthesis of 5-Fluorocytosine Using 2-Cyano-2-fluoroethenolate as a Key Intermediate

Article abstract of DOI:10.1002/ejoc.201900629

There is an urgent demand for 5-fluorocytosine (5-FC) due to its activity against HIV-induced fungal infections as well as its use as a key intermediate in the synthesis of the clinically highly important anti-HIV drug emtricitabine (FTC). We report a simple, low-cost five steps synthesis of 5-FC starting from chloroacetamide. Overall yields up to 46 % were achieved and the route is devoid of any chromatographic purifications. The previously unknown key intermediate (Z)-2-cyano-2-fluoroethenolate is obtained through a Claisen-type condensation from fluoroacetonitrile. As the direct cyclization with urea only gave poor yields, 5-fluoro-2-methoxypyrimidin-4-amine, 5-fluoro-2-(methylsulfanyl)pyrimidin-4-amine and 5-fluoropyrimidine-2,4-diamine served as synthetic intermediates.

Full text of DOI:10.1002/ejoc.201900629

A Journal of
Accepted Article
Title: Synthesis of 5-Fluorocytosine using 2-Cyano-2-fluoroethenolate
as a Key Intermediate
Authors: Jule-Philipp Dietz, Brenden P. Derstine, Dorota Ferenc, Evan
T. Crawford, Anthony J. Arduengo, B. Frank Gupton, D. Tyler
McQuade, and Till Opatz
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using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900629
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900629
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10.1002/ejoc.201900629
European Journal of Organic Chemistry
FULL PAPER
Synthesis of 5-Fluorocytosine using 2-Cyano-2-fluoroethenolate
as a Key Intermediate
Jule-Philipp Dietz,[a] Brenden P. Derstine,[b] Dorota Ferenc, [a] Evan T. Crawford,[b] Anthony J. Arduengo,
III,[c] B. Frank Gupton,[b] D. Tyler McQuade,[b] Till Opatz*[a]
Abstract: There is an urgent demand for 5-fluorocytosine (5-FC) due
to its activity against HIV-induced fungal infections as well as its use
as a key intermediate in the synthesis of the clinically highly important
anti-HIV drug emtricitabine (FTC). We report a simple, low-cost five
steps synthesis of 5-FC starting from chloroacetamide. Overall yields
up to 46% were achieved and the route is devoid of any
chromatographic purifications. The previously unknown key
intermediate (Z)-2-cyano-2-fluoroethenolate is obtained through a
Claisen-type condensation from fluoroacetonitrile. As the direct
Figure 1: Structures of 5-FC (1), capecitabin (2) and emtricitabine (3).
cyclization with urea only gave poor yields, 5-fluoro-2-
methoxypyrimidin-4-amine, 5-fluoro-2-(methylsulfanyl)pyrimidin-4-
amine and 5-fluoropyrimidine-2,4-diamine served as synthetic
intermediates.
Unfortunately, 5-FC has not yet been registered for use in most
African countries and in wide parts of Asia. In addition to the lack
of generic manufacturers, this limits the availability of 5-FC in
world regions where it would be most beneficial.[6] New, affordable
and simple synthetic approaches to this indispensable compound
are therefore of great interest to encourage its generic production.
A synthetic challenge of this deceivingly simple target molecule
lies in the introduction of the fluorine atom. There are only a few
5-FC syntheses available and most of them use an electrophilic
fluorination with the highly expensive and aggressive gaseous
F2.[7,8] Handling of fluorine gas on an industrial scale poses
additional problems. Therefore, we opted for a nucleophilic
fluorination at an early synthetic stage. A different early-stage F-
introduction strategy was used by Duschinsky et al. (Scheme 1).[9]
This interesting approach furnishes 5-FC in 11% yield over five
steps but makes use of the relatively expensive S-
ethylisothiouronium bromide.
Introduction
The AIDS-associated Cryptococcus meningitis, a life-threatening
fungal infection in immunocompromised patients, causes about
15% of HIV-related deaths worldwide.[1] The first line treatment
consists in a combination of amphotericin B and 5-fluorocytosine
(5-FC) as the gold standard.[2] 5-FC 1 is on the World Health
Organization´s List of Essential Medicines and also serves as a
key intermediate in the synthesis of the cytostatic capecitabin (2,
Xeloda®)[3] and of the nucleoside reverse transcriptase inhibitor
(NRTI) emtricitabine (3, FTC, ingredient of Truvada®)[4], a highly
important anti-HIV drug (Figure 1).[5]
[a]
[b]
[c]
Prof. Dr. T. Opatz, J.-P. Dietz, D. Ferenc
Institute of Organic Chemistry
Johannes Gutenberg-University
Duesbergweg 10–14, 55128 Mainz, Germany
opatz@uni-mainz.de:
https://ak-opatz.chemie.uni-mainz.de/
Dr. B. F. Gupton, Dr. D. T. McQuade, Dr. B. P. Derstine, E. T. Crawford
Department of Chemical and Life Sciences Engineering
Virginia Commonwealth University
Richmond, Virginia 23284, United States
bfgupton@vcu.edu
https://egr.vcu.edu/directory/bfrankgupton/
Prof. Dr. A. J. Arduengo, III
Department of Chemistry
The University of Alabama
Scheme 1: 5-FC synthesis of Duschinsky et al.[9]
Tuscaloosa, Alabama 35487, United States
ajarduengo@ua.edu
https://chemistry.ua.edu/people/anthony-j-arduengo/
Following on Duschinsky´s concept for early introduction of
fluorine for the prepration of 5-FC, a Finkelstein reaction on a
different acyclic precursor was attempted to develop a new 5-
Supporting information for this article is given via a link at the end of the
document
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10.1002/ejoc.201900629
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FC synthesis. However, the approach required modifications in
order to utilize inexpensive and easily available chemicals for an
industrial scalable process. Thus, fluoroacetonitrile (FAN, 8)
appeared as an attractive intermediate. FAN is easily obtained
from chloroacetamide (7) in two steps (halogen exchange,
dehydration), both of which are known in literature.[10,11] For the
next step, the challenge was to introduce a C1-building block by
condensing 8 with either a) trimethyl orthoformate (TMOF, 9), b)
N,N-dimethylformamide dimethyl acetal (DMFDMA, 10), or c)
methyl formate (11) to generate a fluorinated C3 building block
required for reaction with urea or an equivalent thereof (Scheme
telescoped procedure was developed to access fluoroacetonitrile
(8) in a one-pot procedure. Starting from chloroacetamide (7),
fluoride was introduced in similar fashion as before using
potassium fluoride in p-xylene. Addition of dimethylformamide
followed by cyanuric chloride at room temperature, careful
distillation furnished 8 in 70% yield over two steps (Scheme 4).
2). Several examples exist for the direct cyclization with urea with
[12],[13],[14]
Scheme 4: Telescoped synthesis of fluoroacetonitrile (8).
similar non-halogenated C3-fragments (12a:
[15],[16],[17],[18], 12c:[19],[20]).
, 12b:
Preparation of C3 building blocks
For the following condensation, various screening experiments
were performed using TMOF under acidic conditions (Table 1).
There was no conversion in acetic anhydride (Ac2O) using TFA
as a Brønsted acid even at 150 °C (entry 1). Neither stronger
Brønsted acids nor the use of ZnCl2 as a Lewis acid (entry 4)
produced the desired reaction while the use of hydrochloric acid
led to hydrolysis of the nitrile.
Table 1: Attempted condensation of fluoroacetonitrile with TMOF.
Scheme 2: Proposed 5-FC synthesis through condensation of fluoroacetonitrile
entry
additive
TFA
eq.
0.1
0.2
0.1
0.2
0.1
solvent
Ac2O
temp [°C]
150b
80
time [h]
results
with different C1 reagents and subsequent cyclization with urea.
a
1
2
3
4
5
2
-
a
CH3SO3H
TMOF
TMOF
Ac2O
18
18
18
2
-
Results and Discussion
a
conc.
H2SO4
-
80
Synthesis of fluoroacetonitrile
a
-
Following a known procedure, fluoroacetamide (13) was prepared
in 67% yield by heating 7 with potassium fluoride in p-xylene.[10]
Dehydration with phosphorus pentoxide furnished 8 in 82% yield
ZnCl2
110
c
conc. HCl
TMOF
80
-
All reactions were performed using 0.2 g (3.4 mmol) FAN.
a no conversion (1H-NMR); b microwave reaction, c fluoroacetamide formed.
after
distillation
During the course of this work, a patent was published which
reported the condensation of 8 with DMFDMA to produce the
corresponding enaminonitrile 15 in 94% yield in DMF as well as
in DMSO (same conditions as in Table 2, entries 1 and 2).[23]
However, under a variety of conditions examined, no reaction
between 8 and DMFDMA could be observed (Table 2).
(
Scheme 3).[11]
Table 2: Attempted condensation of FAN with DMFDMA.
Scheme 3: Synthesis of fluoroacetonitrile (8) from chloroacetamide (7).
Due to the known toxicity of fluoroacetamide (13)[11,22], isolation of
this material can be problematic and is undesirable on an
industrial scale. Since phosphorous pentoxide is also undesirable
entry
1
solvent
temp [°C]
time [h]
result
in such
a setting, cyanuric chloride in combination with
b
DMF
110a
5
-
dimethylformamide was used as the dehydrating reagent.[21]
A
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10.1002/ejoc.201900629
European Journal of Organic Chemistry
FULL PAPER
KOtBu
(1.5)
KOtBu
(1.5)
KOtBu
(1.5)
b
b
-
-
HCO2Et
(4.0)
–15 °C
→ rt
72%
2
3
4
5
DMSO
toluene
DMFc
-
110a
5
10
11
12
13
14
15
16
17
THF
THF
THF
THF
THF
CPME
THF
THF
20
20
20
20
20
20
20
20
(60%d)
HCO2Et
(4.0)
–78 °C
→ rt
111
21
5
63%
77%e
75%
79%f
78%f
59%
79%
d
b
150a
150a
-
-
HCO2Et
(4.0)
–15 °C
→ rt
NaOtBu
1
HCO2Et
(4.0)
–15 °C
→ rt
(1.5)
NaOtBu
(1.5)
NaOtBu
(1.5)
NaOtAmyl
(1.5)
All reactions were performed using 0.2 g (3.4 mmol)
FAN and anhydrous solvents.
microwave reaction, no conversion (1H-NMR), 0.3 eq. pyrrolidine were
HCO2Et
(4.0)
–15 °C
→ rt
a
b
c
HCO2Et
(4.0)
–15 °C
→ rt
added,
d product mixture, enamine could not be detected by ESI-MS.
HCO2Et
(4.0)
–15 °C
→ rt
HCO2Et
(4.0)
NaHMDS
(1.5)
–15 °C
→ rt
The Claisen-type formylation with ethyl formate (11) that is
already known for chloroacetonitrile was investigated next.[24]
However, under the reported reaction conditions, only traces of
All reactions were performed using 0.2 g (3.4 mmol) FAN and anhydrous
solvents.
a isolated yields, b no conversion (1H-NMR), c product mixture (1H-NMR),
d work-up without hexane, e 3 g scale. f 5 g scale.
1
the desired product 16 were detected by H-NMR spectroscopy
(entries 1 and 2, Table 3). The use of alternative base/solvent
systems like NaH/Et2O and KOEt/THF also resulted in no or only
low conversion (entries 3 and 4). With KOtBu as the base, the
formation of potassium (Z)-2-cyano-2-fluoroethenolate 16a was
achieved in 41% yield (entry 5).[25] It was observed that the order
of addition of the reagents has a strong influence on yield and
progress. Only when the KOtBu/THF-solution was added
dropwise to the THF solution containing 8 and 11, 16a was formed
in significant amounts. Changing the order of addition induced
side reactions such as the Thorpe-condensation of two molecules
of fluoroacetonitrile[26] and the decomposition of 11 by KOtBu to
produce potassium formate became dominant. Nevertheless, the
crude product always contained some potassium formate (15 to
25 wt% as judged by 1H NMR). All yields stated herein are
corrected for the formate content since 16a could not be purified
without decomposition.
According to 1H-NMR spectroscopy, the (Z)-enolate is formed as
judged by the typical large trans H,F coupling constant (3JH-F
=
30.5 Hz).[27] Further optimizations were investigated to improve
the outcome of this reaction. Increasing the amounts of methyl
formate and KOtBu improved the yield to 60% (entry 6) which
likely reflects a better suppression of the side reactions. Switching
to the more stable ethyl formate led to a further improvement
(entry 7, 66%). Although enolate 16a starts to precipitate during
the addition of the KOtBu/THF solution, the reaction is still not
complete after 6 h (entries 8 and 9). Lowering the temperature to
–10 °C to achieve an additional suppression of side reactions,
gave the best result (entry 10, 72%). Cooling to –78 °C showed
no additional positive effect as the yield decreased. Hexane was
added in all cases to increase the precipitation of the product.
Omission of this step diminished the yield (entry 10, 60%). Using
the optimized conditions, 16a could be obtained in 77% yield on
a 3 g scale (entry 12). Replacement of potassium tert-butoxide
with sodium tert-butoxide under improved conditions led to
comparable results, the sodium enolate 16b was isolated in 75%
yield (entry 13). Under the same conditions, 16b was obtained in
79% yield on a 5 g scale (entry 14). Replacement of THF with the
process-friendly cyclopentyl methyl ether (CPME) afforded
enolate 16b in 78% yield, (entry 15). Switching the anion to tert-
amylate resulted in a diminished isolated yield (entry 16, 59%)
whereas if NaHMDS was used, 16b was obtained in a 79% yield
(entry 17). These yields are corrected for the presence of sodium
formate which varied in quantity from 5 wt% to 20 wt%.
Table 3: Condensation of fluoroacetonitrile with methyl/ethyl formate.
Reagent
(eq.)
Base
(eq.)
entry
Solv.
toluene
THF
Et2O
THF
THF
THF
THF
THF
THF
T [°C]
t [h]
20
48
20
20
20
20
20
2
yield a
HCO2Me
(2.0)
NaOMe
(1.1)
0 °C →
rt
b
1
2
3
4
5
6
7
8
9
-
HCO2Me
(2.0)
NaOMe
(1.1)
–5 °C
→ rt
traces
0 °C →
rt
HCO2Me
(2.0)
NaH
(1.1)
b
-
Synthesis of 5-fluorocytosine
The cyclization of 16a with O-methylisourea hemisulfate would
0 °C →
rt
HCO2Me
(2.0)
KOEt
(1.1)
KOtBu
c
-
lead
to
5-fluoro-2-methoxypyrimidin-4-amine
17.
2-
HCO2Me
(2.0)
0 °C →
rt
Methoxypyrimidines are known to undergo hydrolysis to the 2-
hydroxypyrimidines (or rather their oxo-tautomers) by heating in
aqueous acid. Stirring 16a with a small excess of O-methylisourea
hemisulfate in methanol/water furnished 17 in 41% yield.
Subsequent hydrolysis in boiling 6N hydrochloric acid gave a
highly pure 5-FC 1 in 57% yield (Scheme 5).
41%
60%
66%
35%
53%
(1.1)
KOtBu
(1.5)
KOtBu
(1.5)
KOtBu
(1.5)
KOtBu
HCO2Me
(4.0)
0 °C →
rt
HCO2Et
(4.0)
0 °C →
rt
HCO2Et
(4.0)
0 °C →
rt
HCO2Et
(4.0)
0 °C →
rt
6
(1.5)
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10.1002/ejoc.201900629
European Journal of Organic Chemistry
FULL PAPER
worked well for the less expensive guanidine carbonate (91%).
Diazotation of 20 finally furnished 5-FC in 83% yield (Scheme 8).
Scheme 5: Cyclocondensation of 16a with O-methylisourea hemisulfate.
The cyclization of enolate 16a with S-methylisothiourea
hemisulfate gave 5-fluoro-2-(methylsulfanyl)pyrimidin-4-amine 18
in 83% yield, the hydrolysis of which to 5-FC has already been
reported.[28] Boiling in concentrated hydrobromic acid produced 5-
FC in 51% yield (Scheme 6). Since the strongly acidic conditions
were presumably causing the low yield of hydrolysis, an
alternative route was pursued.
Scheme 8: Cyclization of 16a with guanidine.
The routes presented herein were conceived to be compatible
with the synthesis of 5-FC on an industrial scale using derivative
methodology. Initial optimizations of the route were investigated.
Regarding the Claisen-type condensation previously described in
Table 3, a significant portion of enolate 16 was observed to be
lost in the mother liquor during isolation.
Scheme 6: Cyclocondensation of 16a with S-methylisothiouronium hemisulfate.
Telescoped synthesis route
2-(Methylsulfanyl)pyrimidines are also known to easily undergo
oxidation to the corresponding sulfones which are particularly
prone to alkaline hydrolysis.[29],[30] The oxidation of 18 with H2O2
under tungstate catalysis afforded the corresponding sulfone 19
in 90% yield. The following hydrolysis in aqueous NaOH solution
furnished 1 in 66% yield. By telescoping both steps, 5-FC could
be obtained in 72% yield (Scheme 7).
A telescoped procedure was developed to afford the fluorinated
pyrimidine 20 in higher yields. After complete consumption of
fluoroacetonitrile, the reaction mixture was concentrated in vacuo.
Guanidine carbonate was dissolved in a methanolic solution of
sodium methanolate and the now concentrated solution of the
potassium (Z)-2-cyano-2-fluoroethenolate 16a was added
dropwise at room temperature. The reaction mixture was stirred
for 24 hours at rt until complete consumption of the starting
material was observed. After completion, the reaction mixture was
filtered through Celite, concentrated in vacuo, redissolved in
isopropanol and decolorized with activated charcoal.
Concentration in vacuo afforded the pyrimidine 20 in an 82 wt%
yield which was used without further purification. Using
diazotation at 40 °C, 5-FC was obtained in 80% yield. (Scheme
9).
Scheme 7: Oxidation and hydrolysis of 18 to 5-FC.
Another approach was to condense 16a with guanidine
hydrochloride to the corresponding 2,4-diaminopyrimidine 20.
These pyrimidines are known to undergo selective
diazotation/hydrolysis in 2-position.[31],[32],[33] Under the same
conditions as used for S-methylisothiourea hemisulfate, the
reaction with guanidine hydrochloride gave 20 along with
significant amounts of impurities. When the reaction was
performed in the presence of a base (NaOMe), 20 was instead
formed in high purity and 89% yield. This latter reaction also
Scheme 9: Telescoped 5-FC synthesis.
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10.1002/ejoc.201900629
European Journal of Organic Chemistry
FULL PAPER
= 106.8–108.0 °C (Lit.: 107 °C[34]). TLC (SiO2): Rf = 0.50 (ethyl acetate),
ninhydrin-reagent. 1H-NMR (300 MHz, DMSO-d6): δ = 7.59 (m, 2H, NH2),
4.72 (d, 2JH-F = 47.3 Hz, 2H) ppm. 13C-NMR (75 MHz, DMSO-d6): δ = 169.5
It is particularly noteworthy that all new routes from 7 require no
chromatographic steps. The use of 16 for the synthesis of other
fluorinated heterocycles are currently being investigated.
(d, JC-F = 18.7 Hz), 79.8 (d, JC-F = 180.5 Hz) ppm. 19F-NMR (282 MHz,
DMSO-d6): δ = -223.3 (td, 2JF-H = 47.3 Hz, 4JF-H = 4.20 Hz) ppm. IR (ATR):
ν = 3384, 3192, 1663, 1455, 1434, 1117, 1036 cm-1. ESI-HRMS: Calcd for
2
1
C2H4FNO ([M+H]+): m/z
= 78.0350, Found: m/z = 78.0346. The
spectrometric data are consistent with literature values.[35] CAUTION!
Fluoroacetamide is classified as highly toxic. Appropriate safety measures
to avoid exposure are required.
Conclusions
Fluoroacetonitrile 8. According to a modified procedure of Buckle et
al..[11] A mixture of fluoroacetamide (2.20 g, 28.5 mmol, 1.0 eq.) and
In summary, several short routes towards 5-fluorocytosine were
developed. No chromatographic steps were required and only
inexpensive chemicals were employed. The key step in each case
was the Claisen-type condensation of fluoroacetonitrile with ethyl
formate furnishing the hitherto unknown (Z)-2-cyano-2-
fluoroethen-1-olate. While its direct cyclocondensation with urea
gave only a moderate yield, isothiouronium and guanidinium salts
permitted the ring closure and the respective products could be
converted to 5-FC in high yield.
phosphorus pentoxide (5.7 g, 29 mmol, 1.0 eq.) were heated in
a
distillation apparatus to 110 °C at atmospheric pressure. The temperature
was continuously increased to 150 °C until no more product condensed.
Fluoroacetonitrile (1.38 g, 23.3 mmol, 82%) was collected as a colorless
liquid at 83–86 °C. TLC (SiO2): Rf = 0.40 (ethyl acetate), ninhydrin-reagent.
2
1H-NMR (300 MHz, CDCl3): δ = 5.02 (d, JH-F = 46.3 Hz, 2H) ppm. 13C-
2
1
NMR (75 MHz, CDCl3): δ = 113.8 (d, JC-F = 26.0 Hz), 66.9 (d, JC-F
=
=
180.3 Hz) ppm. 19F-NMR (282 MHz, CDCl3):
δ
=
-231.9 (t, JF-H
2
46.3 Hz) ppm. IR (ATR): ν = 2975, 2361, 1035 cm-1. The spectrometric
data are consistent with literature values.[36] CAUTION! While the toxicity
of 8 has been reported to be much lower than that of 13, there seems to
be a high species dependency for 8.[11,22,39] Avoidance of exposure is
prudent.
Experimental Section
General information: All employed chemicals were commercially
available and used without prior purification. Anhydrous THF, p-xylene and
toluene were freshly distilled over potassium under argon atmosphere.
Anhydrous MeOH, DMF, DMSO and Et2O were purchased from Acros
(AcroSeal™). NMR spectra were recorded on a Bruker Avance-III HD
instrument (1H-NMR: 300 MHz, 13C-NMR: 75 MHz, 19F-NMR: 282 MHz) or
Telescoped fluoroacetonitrile synthesis: To a 250 mL three-neck round
bottom flask, equipped with an internal temperature probe and overhead
stirrer was added anhydrous 2-chloroacetamide (30.0 g, 320 mmol, 1.0
eq.), anhydrous potassium fluoride (28.0 g, 480 mmol, 1.5 eq.), and p-
xylene (160 mL). The reaction mixture was heated to an internal
h
and monitored by 1H-NMR. After
a
Bruker Avance-III HD instrument (1H-NMR: 600 MHz, 13C-NMR:
temperature of 110 °C for 16
completion of the reaction as indicated by 1H-NMR, dimethylformamide
(40 mL) was added. The reaction mixture was cooled to room temperature
and cyanuric chloride (46.5 g, 164 mmol, 0.5 eq.) was added in portions.
The temperature increased to 30 °C and the mixture was stirred for 40
minutes. After completion of the reaction as indicated by 1H-NMR the
mixture was filtered through celite and transferred into a distillation
apparatus. The reaction mixture was distilled until no fluoroacetonitrile
remained in the mother liquor. The crude distillate was re-distilled through
a Vigreux column to afford fluoroacetonitrile (13.3 g, 225 mmol, 70% yield)
as a colorless liquid.
150 MHz, 19F-NMR: 565 MHz) with a 5 mm BBFO probe. The chemical
shift δ is expressed in ppm downfield from tetramethylsilane (1H-NMR, 13C-
NMR) or trichlorofluoromethane (19F-NMR) (δ = 0 ppm). Deuterated
solvents (CDCl3, DMSO-d6) serve as internal reference. The reported
signal splittings are abbreviated as follows: sb = broad singlet, s = singlet,
d = doublet, t = triplet. Coupling constants J are reported in Hz. For high
resolution (HR) mass spectra an Agilent 6545 Q-TOF spectrometer and a
suitable external calibrant was used. ESI-MS spectra were recorded on a
1260-series Infinity II HPLC-system (Agilent-Technologies) with a binary
pump and integrated diode array detector coupled to an LC/MSD Infinitylab
LC/MSD (G6125B LC/MSD) mass spectrometer. Analytical HPLC was
carried out with an Agilent 1260 Infinity system using an Atlantis T3 column
(5 µm, 4.6 mm x 150 mm) with isocratic elution with 1% methanol in pH =
7.6 phosphate buffered water at 1.0 mL/min at 30 °C. IR-spectroscopy
was conducted on a Bruker Tensor 27 FTIR-spectrometer using a diamond
ATR unit. Thin-layer chromatography was performed on Merck F254 silica
gel plates. Spots were visualized with UV-light (λ = 254 nm) or ninhydrin
reagent. Melting points are uncorrected and were taken by using a Krüss
KSP1N digital melting point apparatus.
Potassium (Z)-2-cyano-2-fluoroethenolate 16a. In
a flame-dried
Schlenk flask, KOtBu (9.1 g, 81 mmol, 1.5 eq.) was dissolved in dry THF
(26 mL) under argon atmosphere. The solution was cooled to –15 °C using
a cryostat. In a second flame-dried Schlenk flask, a solution containing
fluoroacetonitrile (3.0 mL, 54 mmol, 1.0 eq.), ethyl formate (17.4 mL,
21.6 mmol, 4.0 eq.) and dry THF (30 mL) was prepared under argon
atmosphere and cooled to –15 °C. By using
a syringe pump the
KOtBu/THF solution was added dropwise to the fluoroacetonitrile/ethyl
formate/THF solution at a rate of 1 mL/min while stirring vigorously. After
the addition was complete, the reaction mixture was cooled for a further
20 min. The colorless suspension was stirred overnight (20 h) at rt.
Afterwards, n-hexane (30 mL) was added and the slightly brown
suspension was cooled in an ice bath. After 5 min, the precipitate was
filtered off and washed with cold n-hexane. The obtained solid was dried
in a vacuum desiccator to yield a slight brownish solid (6.21 g) which
contains (Z)-2-cyano-2-fluoroethenolate (5.17 g 41.3 mmol, 77%,
estimated by 1H NMR) and potassium formate. The yield was corrected for
the content of potassium formate. Tm = 91 °C (decomposition). Attempted
separation resulted in decomposition of 16a. 1H-NMR (300 MHz, DMSO-
Procedures and analytical data:
Fluoroacetamide 13. According to a modified procedure of Bradley et
al.[10] In a flame-dried Schlenk-flask a suspension of chloroacetamide
(2.50 g, 26.7 mmol, 1.0 eq.) and potassium fluoride (3.10 g, 53.3 mmol,
2.0 eq.) in anhydrous p-xylene (40 mL) was stirred at 100 °C under argon
atmosphere for 15 h and for a further 5 h at 120 °C for complete
conversion (TLC monitoring). The flask was then equipped with a Claisen
bridge and p-xylene was distilled off at atmospheric pressure. During
distillation, a portion of p-xylene (20 mL) was added to the reaction mixture.
The distilled fraction was cooled in an ice-bath whereupon colorless
crystals precipitated. After filtration, the crystals were dried over conc.
sulfuric acid to afford fluoroacetamide in 67% yield (1.38 g, 17.9 mmol). Tm
3
d6): δ = 7.48 (d, JH-F = 30.5 Hz, 1H, H-1) ppm. 13C-NMR, HSQC, HMBC
3
(75 MHz, DMSO-d6): δ = 157.9 (d, JC-F = 9.0 Hz, C-1), 124.2 (2JC-F
=
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European Journal of Organic Chemistry
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1
33.5 Hz, CN), 120.5 (d, JC-F = 196.5 Hz, C-2) ppm. 19F-NMR (282 MHz,
1130 cm-1. ESI-MS: m/z = 191.9 (100%, [M+H]+). The spectrometric data
DMSO-d6): δ = -207.1 (d, 3JF-H = 30.5 Hz) ppm. IR (ATR): ν = 2180, 1593,
1350, 1323, 1206 cm-1. ESI-HRMS: Calcd for C3HFKNO ([M]-): m/z =
86.0046, Found: m/z = 86.0046.
are consistent with literature values.[38]
5-Fluoropyrimidine-2,4-diamine 20. In a flame-dried Schlenk flask,
guanidine carbonate (2.22 g, 24.7 mmol, 3.0 eq.) was dissolved in dry
methanol (18 mL) under argon atmosphere. A 5.4M methanolic sodium
methoxide solution (4.7 mL, 26 mmol, 3.1 Eq.) was dripped quickly into the
solution, before potassium (Z)-2-cyano-2-fluoroethenolate (1.03 g,
8.23 mmol, 1.0 eq.) was added portionwise over 5 min. The brownish
suspension was stirred at rt for 18 h. The solvent was evaporated at 40 °C
under reduced pressure and the residue was dissolved in water (20 mL).
The aqueous suspension was extracted with ethyl acetate (4 x 20 mL).
The combined organic phases were dried over sodium sulfate and the
solvent was evaporated in vacuo. 5-fluoropyrimidine-2,4-diamine (0.96 g,
7.5 mmol, 91%) was obtained as a colorless to slight brownish powder. Tm
= 157.6–160.8 °C. TLC (SiO2): Rf = 0.30 (ethyl acetate : MeOH = 20:1).
5-Fluoro-2-methoxypyrimidin-4-amine 17. In a flame-dried Schlenk
flask, O-methylisourea hemisulfate (0.32 g, 2.6 mmol, 1.5 eq.) was
dissolved in methanol/water (5:2, 7 mL). Crude potassium (Z)-2-cyano-2-
fluoroethenolate (0.22 g, 1.7 mmol, 1.0 eq.) was added portion-wise. The
brownish suspension was stirred for 23 h at rt before the solvent was
evaporated in vacuo at 40 °C. The residue was suspended in ice-cooled
water (3 mL) while cooling the mixture in an ice-bath. The insoluble solid
was filtered off and washed with small portions of ice water (3 x 1 mL). The
colorless solid was first dried in air, then overnight in a desiccator over
molecular sieves to obtain the title compound (0.10 g, 0.70 mmol, 41%).
Tm = 185.5–188.4 °C (Lit.: 191–192 °C[37]). TLC (SiO2): Rf = 0.58 (ethyl
acetate). 1H-NMR (300 MHz, DMSO-d6): δ = 7.93 (d, JH-F = 3.4 Hz, 1H,
H-6), 7.27 (sb, 2H, NH2), 3.74 (s, 3H, CH3) ppm. 13C-NMR, HMBC, HSQC
1H-NMR (300 MHz, DMSO-d6): δ = 7.65 (d, JH-F = 3.9 Hz, 1H, H-6), 6.64
3
3
(sb, 2H, NH2), 5.81 (sb, 2H, NH2) ppm. 13C-NMR, HMBC, HSQC (75 MHz,
4
2
(75 MHz, DMSO-d6): δ = 160.6 (d, JC-F = 1.6 Hz, C-2), 155.0 (d, JC-F
=
DMSO-d6): δ = 159.8 (d, 4JC-F = 3.0 Hz, C-2), 153.6 (2JC-F = 12.3 Hz, C-4),
1
2
1
2
13.8 Hz, C-4), 142.2 (d, JC-F = 245.2 Hz, C-5), 139.8 (d, JC-F = 20.2 Hz,
140.0 (d, JC-F = 239.5 Hz, C-5), 139.9 (d, JC-F = 18.4 Hz, C-6) ppm. 19F-
C-6), 54.2 (CH3) ppm. 19F-NMR (282 MHz, CDCl3): δ = -165.9 (d, JF-H
=
NMR (282 MHz, DMSO-d6): δ = -171.2 (d, JF-H = 3.9 Hz) ppm. IR (ATR):
3
3
3.4 Hz) ppm. IR (ATR): ν = 3145, 1654, 1520, 1459, 1394, 1354, 1038 cm-
1. ESI-HRMS: Calcd for C5H6FN3O ([M+H]+): m/z = 144.0568, Found: m/z
= 144.0571.
ν = 3408, 3330, 3139, 1671, 1590, 1442, 1213 cm-1. ESI-HRMS: Calcd for
C4H5FN4 ([M+H]+): m/z = 129.0571, Found: m/z = 129.0570.
Telescoped 2,4-diamino-5-fluoropyrimidine synthesis: In a 500 mL 3-
neck round bottom flask, KOtBu (26.6 g, 237 mmol, 1.4 eq.) was dissolved
in anhydrous THF (120 mL) under an atmosphere of nitrogen. The solution
was cooled to 0 °C in an ice bath. To a 3-neck round bottom flask equipped
with an internal temperature probe was added fluoroacetonitrile (9.50 g,
161 mmol, 1.0 eq.) and ethyl formate (50.2 g, 675 mmol, 4.0 eq.). The
solution was cooled to -15 °C in a dry ice/acetone bath maintained at that
temperature by addition of dry ice to the bath. The KOtBu/THF solution of
was added dropwise to the fluoroacetonitrile/ethyl formate solution at a
rate of 1 mL/min while stirring vigorously, keeping the internal temperature
at -15 °C. After the addition was complete, the reaction mixture was cooled
for a further 1 h, then warmed to room temperature over 20 hours. The
yellow mixture was concentrated in vacuo to one third of the original
volume.In a 500 mL 3-neck round bottom flask equipped with an internal
temperature probe and overhead stirrer was added guanidine carbonate
(21.3 g, 237 mmol, 1.4 eq.) and methanol (200 mL). A 5.4 M solution of
sodium methoxide in methanol (44 mL, 241 mmol, 1.5 eq.) was added
dropwise over 15 minutes. The mixture was stirred until a fine suspension
of sodium carbonate had formed and free base guanidine was in solution.
The concentrated solution of 16a was transferred using a peristaltic pump
over the course of 10 minutes. The reaction mixture was stirred at room
temperature for 24 hours. After completion of the reaction as indicated by
HPLC, the mixture was concentrated in vacuo and isopropanol was added.
The mixture was heated to 40 °C with stirring and filtered through a bed of
celite. The mother liquor was decolorized by the addition of activated
charcoal and filtered through a bed of celite to yield a light yellow solution.
The solution was evaporated in vacuo to yield 5-fluoropyrimidine-2,4-
diamine (17.7 g, 138 mmol, 82wt%) as a light yellow solid.
5-Fluoro-2-(methylsulfanyl)pyrimidin-4-amine 18. In
a flame-dried
Schlenk flask, S-methylisothiourea hemisulfate (1.58 g, 11.3 mmol, 1.5
eq.) was suspended in dry methanol (15 mL) under argon atmosphere.
Crude potassium (Z)-2-cyano-2-fluoroethenolate (0.94 g, 7.6 mmol, 1.0
eq.) was added portion-wise over 5 min. The brownish suspension was
stirred for 18 h at rt. The solvent was evaporated in vacuo at 40 °C. The
residue was suspended in water (7 mL) while cooling the mixture in an ice-
bath. The insoluble solid was filtered off and washed with small portions of
ice water. The yellow-brown solid was first dried in air, then overnight in a
desiccator over molecular sieves. The dried powder was suspended of
ethyl acetate (10 mL) and filtered again. After solvent evaporation of the
filtrate in vacuo at 40 °C, the title compound (1.00 g, 6.3 mmol, 83%) was
obtained as colorless to slight yellow crystals. Tm = 116.9–119.0 °C (Lit.:
114–115 °C[38]). TLC (SiO2): Rf = 0.65 (ethyl acetate:cyclohexane = 1:1).
1H-NMR (300 MHz, CDCl3): δ = 7.98 (d, 3JH-F = 3.1 Hz, 1H, H-6), 5.24 (sb,
2H, NH2), 2.49 (s, 3H, CH3) ppm. 13C-NMR, HMBC, HSQC (75 MHz,
4
2
CDCl3): δ = 166.2 (d, JC-F = 5.1 Hz, C-2), 152.9 (d, JC-F = 12.2 Hz, C-4),
1
2
143.8 (d, JC-F = 253.0 Hz, C-5), 140.4 (d, JC-F = 18.4 Hz, C-6), 14.7
(CH3) ppm. 19F-NMR (282 MHz, CDCl3): δ = -162.1 (d, 3JF-H = 3.1 Hz) ppm.
IR (ATR): ν = 3314, 3165, 1640, 1493, 1340, 1226 cm-1. ESI-MS: m/z =
160.1 (100%, [M+H]+). The spectrometric data are consistent with
literature values.[38]
5-Fluoro-2-(methylsulfonyl)pyrimidin-4-amine 19. In a round-bottomed
flask, 5-fluoro-2-(methylsulfanyl)pyrimidin-4-amine (0.30 g, 1.9 mmol,
1.0 eq.) and sodium tungstate dehydrate (30 mg, 0.091 mmol), 0.05 eq.)
were dissolved in acetonitrile/water (6 mL, 1:1). Aqueous hydrogen
peroxide (35 wt%) (0.40 mL, 4.7 mmol, 2.5 eq.) was quickly dripped into
the solution. After stirring for 3 h at 50 °C, the reaction mixture was
quenched with saturated sodium sulfite solution (1 mL). The reaction
mixture was extracted with ethyl acetate (3 x 7 mL) and the combined
organic layers were dried over sodium sulfate. Evaporation of ethyl acetate
in vacuo at 40 °C afforded the title compound (0.32 g, 1.7 mmol, 90%) as
colorless crystals. Tm = 156.2–159.1 °C (Lit.: 157–159 °C[38]). TLC (SiO2):
Rf = 0.48 (ethyl acetate). 1H-NMR (300 MHz, DMSO-d6): δ = 8.34 (d, 3JH-F
= 3.6 Hz, 1H, H-6), 8.10 (sb, 2H, NH2), 3.27 (s, 3H, CH3) ppm. 13C-NMR,
5-Fluorocytosine syntheses
Method 1: Hydrolysis of 19 with aqueous NaOH
In a round bottom flask, 5-fluoro-2-(methylsulfonyl)pyrimidin-4-amine 19
(0.25 g, 1.3 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (3 mL), before 2N
sodium hydroxide solution (7 mL) was added. After stirring for 3 h at rt, the
solution was cooled in an ice-bath and neutralized by using concentrated
hydrochloric acid. The formed colorless suspension was concentrated in
vacuo at 40 °C, cooled again and finally filtered. The colorless solid was
washed with small portions of ice water (3 x 1 mL), dried in air and finally
in a desiccator over molecular sieves. 5-fluorocytosine was obtained as a
colorless powder (0.11 g, 0.9 mmol, 66%).
4
HMBC, HSQC (75 MHz, DMSO-d6): δ = 160.4 (d, JC-F = 5.5 Hz, C-2),
2
1
154.7 (d, JC-F = 13.2 Hz, C-4), 145.7 (d, JC-F = 261.3 Hz, C-5), 139.1 (d,
2JC-F = 19.8 Hz, C-6), 39.2 (CH3) ppm. 19F-NMR (282 MHz, CDCl3): δ = -
149.1 (d, 3JF-H = 3.6 Hz) ppm. IR (ATR): ν = 3338, 1641, 1494, 1306, 1183,
Method 2: Telescoped oxidation and hydrolysis of 18
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10.1002/ejoc.201900629
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In a round bottom flask, 5-fluoro-2-(methylsulfanyl)pyrimidin-4-amine 18
(2.00 g, 12.6 mmol, 1.0 eq.) and sodium tungstate dehydrate (0.21 g,
0.63 mmol), 0.05 eq.) were dissolved in acetonitrile/water (32 mL, 1:1).
Aqueous hydrogen peroxide (35 wt%) (2.7 mL, 31 mmol, 2.5 eq.) was
added quickly. After stirring for 3 h at 50 °C, the reaction mixture was
quenched saturated sodium sulfite solution (3.6 mL), before 10N sodium
hydroxide solution (8 mL) was added. After stirring for 2 h at rt, the reaction
mixture was cooled in an ice-bath and neutralized using concentrated
hydrochloric acid (6.4 mL). The formed colorless suspension was
concentrated in vacuo at 40 °C, before it was cooled again in an ice-bath.
The precipitate was filtered and washed with small portions of ice water (3
x 3 mL). Drying in air and in a desiccator yielded the title compound
(1.17 g, 9.1 mmol, 72%) as a colorless solid.
Keywords:
cyclocondensation • fluorine • 5-fluorocytosine
nitrogen
heterocycles
•
nucleobases
•
[1]
[2]
R. Rajasingham, R. M. Smith, B. J. Park, J. N. Jarvis, N. P. Govender, T.
M. Chiller, D. W. Denning, A. Loyse, D. R. Boulware, Lancet Infect. Dis.
2017, 17, 873.
J. R. Perfect, W. E. Dismukes, F. Dromer, D. L. Goldman, J. R. Graybill,
R. J. Hamill, T. S. Harrison, R. A. Larsen, O. Lortholary, M.-H. Nguyen et
al., Clin. Infect. Dis. 2010, 50, 291.
[3]
[4]
Arasaki et al., U.S. Patent 5,472,949, December 5, 1995.
R. F. Schinazi, A. McMillan, D. Cannon, R. Mathis, R. M. Lloyd, A. Peck,
J. P. Sommadossi, M. St Clair, J. Wilson, P. A. Furman, Antimicrob.
Agents Chemother. 1992, 36, 2423.
Method 3: Diazotation and hydrolysis of 20
In a 3-neck round bottom flask equipped with an internal temperature
probe and overhead stirrer 5-fluoropyrimidine-2,4-diamine 20 (17.1 g,
137 mmol, 1.0 eq.) was dissolved in water (125 mL) then cooled to 0 °C.
A solution of sulfuric acid (9.83 mL, 344 mmol, 2.5 eq.) in water (15 mL)
was added dropwise while the internal temperature was maintained below
5 °C. After the addition of sulfuric acid was complete, the mixture was
heated to 40 °C. A solution of sodium nitrite (23.7 g, 344 mmol, 2.5 eq.) in
water (25 mL) was added to the reaction mixture dropwise over 15 minutes
at 40 °C. The mixture was stirred for an additional 30 minutes until
complete consumption of the starting material. After completion of the
reaction, the temperature was increased to 70 °C and activated charcoal
was added. The mixture was stirred for 2 hours at 70 °C then filtered
through celite. The clear solution was concentrated in vacuo to half of the
original volume. The reaction mixture was cooled to 10 °C and was
adjusted to pH = 8.4 through the addition of ammonium hydroxide (27 wt%)
whereupon a colorless to slight yellow suspension was formed. The
mixture was maintained at pH = 8.4 with stirring for 2 hours at 10 °C to
maximize precipitation. The precipitate was collected by suction filtration
and washed with several small portions of ice-cold water (3 x 10 mL). The
colorless to light beige solid was dried in vacuo at 40 °C to yield 5-
fluorocytosine (14.2 g, 115 mmol, 82%).
[5]
WHO Model List of Essential Medicines, "20th edition (March 2017)".
https://apps.who.int/iris/bitstream/handle/10665/273826/EML-20-
eng.pdf?ua=1; accessed on April 27, 2019.
A. Loyse, H. Thangaraj, P. Easterbrook, N. Ford, M. Roy, T. Chiller, N.
Govender, T. S. Harrison, T. Bicanic, Lancet Infect. Dis. 2013, 13, 629.
A. Harsanyi, A. Conte, L. Pichon, A. Rabion, S. Grenier, G. Sandford,
Org. Process Res. Dev. 2017, 21, 273.
[6]
[7]
[8]
[9]
a) Bayer AG, U.S. Patent 4,703,121A, October 27, 1987; b) Sniker, D. et
al., U.S. Patent 3,846,429, November 5, 1974.
R. Duschinsky, E. Pleven, C. Heidelberger, J. Am. Chem. Soc. 1957, 79,
4559.
[10] Bradley, C.H., U.S. Patent 2,403,576, April 18, 1945.
[11] F. J. Buckle, R. Heap, B. C. Saunders, J. Chem. Soc. 1949, 0, 912.
[12] R. B. Toche, M. N. Jachak, T. S. Dalvi, R. W. Sabnis, H. Junek, T. Kappe,
Org. Prep. Proced. Int. 1998, 30, 367.
[13] M. Deshmukh, M. Mittelbach, H. Junek, Monatsh. Chem. 1995, 126, 91.
[14] H. Bredereck, R. Sell, F. Effenberger, Chem. Ber. 1964, 97, 3407.
[15] C. K. Chu, U. Reichman, K. A. Watanabe, J. J. Fox, J. Org. Chem. 1977,
42, 711.
[16] v. Itter, F.-A., U.S. Patent 5,026,852, January 3, 1990.
[17] G. Sun, C. J. Fecko, R. B. Nicewonger, W. W. Webb, T. P. Begley, Org.
Lett. 2006, 8, 681.
Method 4: Hydrolysis of 18 with Hydrobromic acid
[18] D. Smirnow, P. B. Hopkins, Synth. Commun. 1986, 16, 1187.
[19] P. J. Tariso, L. Nicholl, J. Org. Chem. 1957, 22, 192.
[20] U. Létinois, J. Schütz, R. Härter, R. Stoll, F. Huffschmidt, W. Bonrath, R.
Karge, Org. Process Res. Dev. 2013, 17, 427.
[21] G. Olah, S. Narang, A. Fung, B. Balaram Gupta, Synthesis 1980, 1980,
657.
[22] F. L. M. Pattison, W. J. Cott, W. C. Howell, R. W. White, J. Am. Chem.
Soc. 1956, 78, 3484.
[23] Xinxiang Tuoxin Pharmaceutical Co., CN107793364, March 2018.
[24] a) A. Gangjee, A. Vidwans, E. Elzein, J. J. McGuire, S. F. Queener, R. L.
Kisliuk, J. Med. Chem. 2001, 44, 1993; b) Kelly, V., WO 2016/050806 A1,
April 2016.
[25] Opatz, T., U.S. Patent Appl. 16/279,501, February 2019.
[26] J. L. Barkin, M. D. Faust, W. C. Trenkle, Org. Lett. 2003, 5, 3333.
[27] S. Berger, S. Braun, H.-O. Kalinowski, J. Becconsall, NMR spectroscopy
of the non-metallic elements, Wiley, Chichester, 1997. Kinetics and
thermodynamics of the enolate equilibrium of 16 have however not been
studied.
[28] Heidelberger, C., U.S. Patent 2,802,005, August 6,1957.
[29] J. Solberg, K. Undheim, M. Nilsson, C. R. Enzell, J.-E. Berg, A.
Ljungqvist, Acta Chem. Scand. 1986, 40b, 381.
In a round bottom flask, a solution of 5-fluoro-2-(methylsulfanyl)pyrimidin-
4-amine 18 (0.36 g, 2.2 mmol, 1.0 eq.) in conc. hydrobromic acid (4 mL)
was heated to reflux for 4 h. After cooling to rt, the solution was cooled in
an ice-bath and neutralized using 12N sodium hydroxide solution. The
solution was concentrated in vacuo at 40 °C until a colorless solid
precipitated. The suspension was cooled in an ice bath and filtered. The
filtered solid was washed with small portions of ice water (2 x 1 mL) and
subsequently dried in air. Additional drying in a desiccator over molecular
sieves afforded the title compound (0.15 g, 1.2 mmol, 51%) as a colorless
powder. Tm = 295°C (decomposition) (Lit.: 295–300 °C, decomposition[7]).
TLC (SiO2): Rf = 0.29 (ethyl acetate : MeOH = 3:1). 1H-NMR (300 MHz,
3
DMSO-d6): δ = 7.60 (d, JH-F = 6.2 Hz, 1H, H-6), 7.34 (sb, 1H, NH) ppm.
13C-NMR, HMBC, HSQC (75 MHz, DMSO-d6): δ = 158.2 (d, JC-F
=
2
1
13.0 Hz, C-4), 155.3 (s, C-2), 136.0 (d, JC-F = 237.9 Hz, C-5), 127.0 (d,
2JC-F = 29.3 Hz, C-6) ppm. 19F-NMR (282 MHz, DMSO-d6): δ = -171.6 (d,
3JF-H = 6.2 Hz) ppm. IR (ATR): ν = 3337, 3126, 2724, 1678, 1542, 1460,
1227, 1123 cm-1. ESI-MS: m/z = 130.1 (100%, [M+H]+). The spectroscopic
data are consistent with literature values.[7]
[30] Y. Nezu, M. Miyazaki, K. Sugiyama, N. Wada, I. Kajiwara, T. Miyazawa,
Pestic. Sci. 1996, 47, 115.
Acknowledgments
[31] B. Lythgoe, L. S. Rayner, J. Chem. Soc. 1951, 2323.
[32] J. D. Bryant, N. J. Leonard, J. Org. Chem. 1978, 43, 511.
[33] Valet, A. et al., U.S. Patent 6,706,215 B1, March 16, 2004.
[34] L. Polgar, P. Halasz, E. Moravcsik, Eur J Biochem 1973, 39, 421.
[35] a) S. Pedersoli, C. F. Tormena, R. Rittner, J. Mol. Struct. 2008, 875, 235;
b) A. Mukherjee, S. Tothadi, S. Chakraborty, S. Ganguly, G. R. Desiraju,
CrystEngComm 2013, 15, 4640.
We thank Dr J. C. Liermann for NMR spectroscopy and Dr C. J.
Kampf for mass spectrometry as well as the Bill & Melinda Gates
Foundation (The Medicines for All Initiative) for financial support.
[36] J. Burdon, J. R. Knights, I. W. Parsons, J. C. Tatlow, J. Chem. Soc.,
Perkin Trans. 1 1976, 1930.
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10.1002/ejoc.201900629
European Journal of Organic Chemistry
FULL PAPER
[37] Biressi et al., Gazz. Chim. Ital. 1963, vol. 18, 1268,1275.
[38] Boebel et al., US2011/152300, June 23, 2011.
[39] P. Bey, F. Gerhart, V. van Dorsselaer, C. Danzin, J. Med. Chem. 1983,
26, 1551.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Fluorinated Heterocycles
Jule-Philipp Dietz, Brenden P. Derstine,
Dorota Ferenc, Evan T. Crawford,
Anthony J. Arduengo, III, B. Frank
Gupton, D. Tyler McQuade, Till Opatz*
Page No. – Page No.
The antifungal drug 5-fluorocytosine was synthesized in 5 steps starting from
chloroacetamide. Claisen-type-condensation from fluoroacetonitrile and ethyl
formate afforded 2-cyano-2-fluoroethenolate which could be cyclocondensed to
produce various 4-amino-5-fluoropyrimidines.
Synthesis of 5-Fluorocytosine using
2-Cyano-2-fluoroethenolate as a Key
Intermediate
*one or two words that highlight the emphasis of the paper or the field of the study
Fluorinated Heterocycles
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