Fluorine gas for life science syntheses: Green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters

Article abstract of DOI:10.1039/c5gc00402k

Optimisation and real time reaction monitoring of the synthesis of 2-fluoromalonate esters by direct fluorination using fluorine gas is reported. An assessment of green metrics including atom economy and process mass intensity factors, demonstrates that the one-step selective direct fluorination process compares very favourably with established multistep processes for the synthesis of fluoromalonates.

Full text of DOI:10.1039/c5gc00402k

Green Chemistry
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Fluorine gas for life science syntheses: green
metrics to assess selective direct fluorination
for the synthesis of 2-fluoromalonate esters†
Cite this: DOI: 10.1039/c5gc00402k
Antal Harsanyi and Graham Sandford*
Received 19th February 2015,
Accepted 17th March 2015
Optimisation and real time reaction monitoring of the synthesis of 2-fluoromalonate esters by direct
fluorination using fluorine gas is reported. An assessment of green metrics including atom economy and
process mass intensity factors, demonstrates that the one-step selective direct fluorination process com-
pares very favourably with established multistep processes for the synthesis of fluoromalonates.
DOI: 10.1039/c5gc00402k
www.rsc.org/greenchem
Recently, the concept of green chemistry has found wide-
spread recognition in the chemical industries and various
Introduction
Green metrics demonstrate for the first time that direct fluori- green chemistry related programs have been initiated both
nation processes using fluorine gas can compete favourably within and between major industrial companies. For example,
from an environmental point of view, with established halogen several pharmaceutical companies now provide publicly avail-
exchange methodology for the synthesis of important fluori- able information on their solvent and reagent selection guides
nated building blocks. Life-science products containing fluo- that were largely developed by their respective green chemistry
rine atoms are of increasing importance and many groups.4 To assess the green credentials of a reaction, various
commercially significant pharmaceuticals and agrochemicals mass balance based metrics have been developed and E factor,
owe their activity, in part, to the presence of fluorinated struc- reaction mass efficiency (RME) and process mass intensity
tural subunits.1 The FDA lists over 150 active pharmaceutical (PMI) are routinely assessed for process development cam-
ingredients which contain fluorinated motifs that are used in paigns. Such guides and metrics along with environmental,
many therapeutic areas2 because fluorine incorporation into health and safety assessments form the basis of green metrics
organic systems can lead to a variety of physical, chemical and packages for the comparative assessment of alternative syn-
biological activity changes depending upon the system such as thetic methods.5
increasing metabolic stability, increasing lipophilicity and
Large scale manufacture of most fluorinated systems are
carried out using inexpensive anhydrous hydrogen fluoride
changing pKa of adjacent receptor sites.1
Whilst many fluorinated life science products contain (aHF) by, for example, very well established multi-step Balz-
fluoro- or trifluoromethyl-aromatic units, drug development Schiemann6 and halogen exchange (Halex)7 processes respect-
programmes now require chemical entities where fluorine ively and subsequent functional group transformation of the
atoms are located at less accessible sites and, consequently, resulting fluorinated aromatic building blocks. Whilst the use
there continues to be great interest for the development of of aHF in industry is widespread, the highly corrosive, acidic
efficient, selective and economically viable fluorination meth- nature of this reagent precludes fluorination reactions to
odologies for industry.3 The commitment by many pharma- appropriate, structurally simple organic substrates that are pre-
ceutical companies to significantly reduce waste streams and functionalised by nitration or chlorination by, in many cases,
the associated carbon footprint during drug manufacture pro- multi-step procedures.
vides a further requirement for the development of more
In principle, the most direct, least wasteful and economi-
environmentally benign, process intensive and reliable fluori- cally viable method of fluorine introduction for large scale syn-
nation methods for large scale synthesis.
thesis is the selective conversion of carbon–hydrogen bonds
to carbon–fluorine bonds using inexpensive fluorine gas.8
However, despite advances in selective direct fluorination
methodology, involving both batch and flow protocols, the use
of fluorine gas for life science product manufacturing has so
far been limited to the synthesis of 5-fluorouracil9 and a key
intermediate for the synthesis of Voriconazole (V-Fend,
Pfizer).10 However, although electrochemical cells used for the
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK.
E-mail: graham.sandford@durham.ac.uk
†Electronic supplementary information (ESI) available: Green metrics calcu-
lations are contained within the supporting information file accompanying this
publication. CCDC 1050160. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c5gc00402k
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Scheme 1 2-Fluoromalonate esters used in the synthesis of Fluoxastrobin and TAK-733.
Scheme 2 Synthetic routes to 2-fluoromalonate esters.
production of fluorine gas11 are in operation in many silicon- utilising fluoromalonate as a substrate for the synthesis of a
wafer fabrication plants,12 precluding the use of fluorine gas range of biologically active systems have been published
in high pressure cylinders, selective direct fluorination recently20 and reviewed.19 For example, Fluoxastrobin
technology has not been widely adopted by the life science (Fandango®), a fungicide marketed by Bayer CropScience that
industries.
has achieved global annual sales of over €140 m since its
The Durham group has reported the selective fluorination launch in 2005,21 and TAK-733, an anti-cancer drug candi-
of various 1,3-diketones and ketoesters by both batch13 and date,22 employ 2-fluoromalonate esters as the key fluorinated
continuous flow processes.14 Additionally, the synthesis of starting material (Scheme 1).
diethyl 2-fluoromalonate by direct fluorination has been pre-
There are three realistic, low-cost synthetic strategies avail-
viously achieved in good conversion, but the selectivity of the able for the large scale manufacture of diethyl 2-fluoromalo-
reaction was reported to be relatively low.15 Dialkyl 2-fluoro- nate ester (Scheme 2) which involve reaction of ethanol
malonate esters could, in principle, be very useful fluorinated with hexafluoropropene (HFP),23 halogen exchange (Halex)24
building blocks for the synthesis of fluorinated derivatives, and selective direct fluorination15 processes. Other syntheses
and various alkylation,16 Michael addition17 and heterocycle of fluoromalonate esters using electrophilic fluorinating
formation18 processes have been described, providing an indi- agents such as Selectfluor™ are possible, but are not
cation of the potential synthetic utility of this multi-functional, sufficiently commercially attractive to be considered for manu-
selectively fluorinated system.19 A growing number of patents facture on the large scale.
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In this paper, we reassess and optimise the direct fluorina- fluorination process and replacement and/or reduction of all
tion of diethyl malonate, catalysed by copper nitrate, with a environmentally harmful solvents used.
view to intensifying this transformation and reducing its
Conventional batch direct fluorination reactions of malo-
overall environmental impact. Upon optimisation, a compar- nate esters were carried out in glassware vessels by introduc-
ison of the green metrics of selective direct fluorination with tion of fluorine gas, as a 10% or 20% mixture in nitrogen (v/v),
corresponding literature HFP and Halex routes for the at a prescribed rate via a gas mass flow controller into a solu-
synthesis of fluoromalonates to determine the relative merits tion of malonate ester and copper nitrate catalyst in aceto-
of the three possible routes.
nitrile using equipment described previously.15c
To better understand the relationship between fluorine gas
introduction and rate of conversion, real time IR spectroscopic
monitoring of the reaction was chosen as the most suitable
technique. The use of the ReactIR technique25 was enabled by
Results and discussion
a
sufficient difference in the carbonyl group stretching
frequencies (1734 cm−1 for diethyl malonate and 1775 cm−1
for diethyl 2-fluoromalonate) and provided an in situ reaction
profile (Fig. 1).
Before a comparison of the green metrics between the three
possible, economically viable large scale processes for the syn-
thesis of fluoromalonate esters (Scheme 2) could be carried
out, some primary goals for the optimisation of the process
were targeted: complete conversion of the starting material is
essential because it can be difficult to separate the starting
material from the desired monofluorinated product by simple
distillation; fluorine gas usage should be minimised because
neutralisation of excess reagent could potentially generate sig-
nificant amounts of waste; reduction in volumes of solvents
used to reduce waste streams and overall intensification of the
The real time reaction monitoring (Fig. 1 and 2) revealed
that the reaction begins instantly upon initiation of fluorine
introduction and the reaction conversion is directly pro-
portional to the amount of fluorine gas passed into the reac-
tion vessel. When the intensity of the fluoromalonate carbonyl
peak (1775 cm−1) reached a maximum, the introduction of
fluorine gas was stopped and the crude reaction mixture was
1
analysed by H and 19F NMR spectroscopy. Complete conver-
Fig. 1 IR spectra of the fluorination reaction at 0% (light blue), 50% (dark blue) and 100% (red) conversions.
Fig. 2 In situ monitoring of the fluorination of diethyl malonate.
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Table 1 Fluorination of diethyl malonate ester using fluorine gas catalysed by Cu(NO3)2·2.5H2O
Entry
no.
Cmalonate
Catalyst
(mol%)
F2 in N2
(% v/v)
Conversion
(1H NMR)
A/B/C ratio
(
19F NMR)
Isolated
weight
T/°C
(mol L−1
)
1
2
3
4
5
6
7
8
0–5
0–5
0–5
0–5
RT
0–5
0–5
0–5
1.0
1.5
1.0
1.0
1.0
1.0
1.0
2.0
10
10
5
2.5
10
10
10
5
10
10
10
10
10
15
20
20
100%
100%
97%
82%
56%
85%
100%
52%
93.5/4.5/2
94/4/2
95/4/1
3.37 g
3.30 g
3.53 g
3.51 g
3.33 g
3.47 g
3.50 g
3.40 g
95/4/1
97.5/1.5/1
97.5/1.5/1
94/3/3
92/5/3
sion of the starting material was observed and diethyl fluoro-
The concentration of fluorine gas, between 10–20% v/v in
malonate was formed with 93% selectivity after introducing nitrogen, does not affect the selectivity of the reaction and the
1.1 equivalents of fluorine into the reaction mixture. The small quality of the product either, as exemplified by the product
excess of fluorine explains the unexpectedly small amount of mixtures obtained from reactions 1, 2 and 7 which have identi-
difluorinated side products B and C (4.5 and 2.5% respectively) cal compositions. In contrast, carrying out fluorination reac-
which were the major impurities (6.5 and 9% respectively) tions at room temperature rather than cooling the reaction
when larger excess of fluorine gas (1.8 eq.) was used.
mixture to 0–5 °C leads to increased catalyst decomposition
The effect of concentration of fluorine in nitrogen, reaction which results in an insoluble copper species that on occasion
temperature, copper nitrate catalyst loading and concentration blocked the fluorine gas inlet tube. In addition, without
of malonate substrate in acetonitrile were varied to optimise cooling, the exothermic nature of this fluorination reaction led
the fluorination process (Table 1). Additionally, reactions to a slight reaction temperature increase (from 20 to 29 °C in a
described in Table 1 allowed an assessment of various factors small scale laboratory experiment) resulting in loss of some
that have a major influence on the environmental impact of solvent and some decomposition of the catalyst and product
the process such as solvent usage, reaction temperature and degradation.
the amount and composition of waste generated. In each case
Lowering the concentration of the copper nitrate catalyst
20 mmol (3.20 g) of diethyl malonate was used as substrate led to a significantly slower reaction as would be expected and
and the isolated mass balance of crude material obtained after required the use of a larger excess of fluorine gas to enable
work-up was recorded along with the conversion of starting sufficiently high conversion. For example, the reaction pro-
material and yield of fluorinated products (Table 1).
ceeded in the presence of only 2.5 mol% catalyst, but in this
In all cases, small quantities of side products were formed case 40% excess fluorine was required to reach 100%
which were identified by 19F NMR and these originate from conversion.
two different processes: 3,3-difluoromalonate is produced
Typical literature work-up procedures for direct fluorination
from enolisation of diethyl fluoromalonate which is much reactions15 involve pouring the reaction mixture into 3 to 5
slower than enolisation of the diethyl malonate substrate, volumes of water and extracting the resulting mixture three
while the fluoroethyl fluoromalonate is postulated to form via times with dichloromethane. The combined organic fraction is
an electrophilic process.26
typically washed with water, saturated sodium bicarbonate
The data in Table 1 suggest that the concentration of the solution and dried over sodium sulfate before evaporation of
malonate ester substrate in acetonitrile has no apparent effect the solvent to give the crude reaction product. We sought to
on the outcome of the reaction although solvent is required improve the work-up to enable recycling of the reaction solvent
for these reactions because diethyl malonate does not dissolve and substitute the use of environmentally harmful dichloro-
the catalyst. Additionally, the use of high dielectric constant methane in the reaction work-up stage. Upon completion of
media, such as acetonitrile, have been found to be beneficial fluorine gas addition, acetonitrile was evaporated for reuse
for the control of selectivity of electrophilic direct fluorination and then the residue was partitioned between ethyl acetate
processes.27 For convenience, a 1.5 M concentration of malo- and water, the organic phase was washed with water, saturated
nate in acetonitrile was chosen as the optimal conditions Na2CO3 solution and saturated brine and dried prior to evapor-
which is approximately 5 mL solvent per 1 mL of diethyl ation under reduced pressure. Modification of the workup pro-
malonate.
cedure in this manner enables the recovery of acetonitrile and
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Scheme 3 Fluorination of di-methyl and di-tert-butyl malonates.
Fig. 3 Dimethyl fluoromalonate crystal structure and packing.
ethyl acetate and significantly reduces the amount of aqueous the case of di-tert-butyl malonate, fluorination was carried out
waste generated. When direct reuse of the recovered aceto- on 12 g scale. 100% conversion was reached after the introduc-
nitrile was attempted, a copper containing precipitate was tion of 1.2 equivalents of fluorine gas and the desired product
formed presumably because of the high HF content of the was isolated in 96% yield. The purity of the crude product was
solvent (0.63 M by titration). Therefore, before reuse of the higher than 97% by 1H and 19F NMR spectroscopy without any
solvent, HF must be removed. Stirring the recovered reaction further purification and as expected, the only side product was
solvent with solid Na2CO3 lowered the acid content to an the 2,2-difluorinated product (Scheme 3).
acceptable level (0.04 M) and when a second fluorination reac-
tion was carried out in the recovered, neutralised acetonitrile, tives are preferable substrates compared to ethyl or other
no change in the fluorination reaction profile was observed. higher alkyl esters since they lead to smaller quantities of
From an atom economy point of view, methyl ester deriva-
Upon completion of these optimisation studies, selective waste and so the fluorination of dimethyl malonate was inves-
fluorination reactions of malonate esters were scaled up to tigated. Using 10% catalyst and 1.1 equivalent of fluorine, 20 g
40 g scale in the laboratory without experiencing any change of dimethyl malonate was fluorinated to afford dimethyl
in product profile. Isolation of significant quantities of mono- fluoromalonate in 97% yield and 95% purity after isolation by
fluoromalonate A crude product (99% yield, 95% purity) was simple work-up and no further purification. In this case, the
achieved which could be used in the subsequent cyclisation only side product was dimethyl 2,2-difluoromalonate which
processes described below without further purification or, was separated from dimethyl fluoromalonate by fractional dis-
if high purity material was required, could be purified by tillation to afford high purity dimethyl fluoromalonate which
fractional vacuum distillation (bp. 102–103 °C, 18 mbar) to crystallises at room temperature (Fig. 3).
produce 99% pure material in 77% yield.
Condensation of fluoromalonate esters with dinucleophiles
Related malonate esters were also subjected to direct fluori- is a convenient route to multifunctional fluorinated hetero-
nation using the optimised conditions established above. In cyclic scaffolds. A number of nitrogen dinucleophiles were
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with sulfuryl chloride is reasonably selective and pure diethyl
chloromalonate can be obtained in good yield30 after vacuum
distillation and it is reasonable to assume that this reaction is
suitable for large scale synthesis. The halogen exchange reac-
tion is also very efficient since HF.amine systems are con-
venient, reactive sources of fluoride ion and additionally, they
can be handled safely since they are less volatile than aHF
and are commercially available on the multi-tonne scale
(Table 3).
Table 2 Synthesis of fluorinated heterocycles using crude (95% pure)
diethyl fluoromalonate ester
Dinucleophile
Product
Yield/%
51
The first obvious advantage of the direct fluorination
process is that diethyl fluoromalonate is obtained in one syn-
thetic step in excellent yield and no purification is necessary to
achieve sufficiently pure material for subsequent synthetic
steps (99% yield, 95% purity). The yields of the HFP and Halex
methods are significantly lower and vacuum distillation pro-
cesses are reported to be used to obtain the desired purity. The
atom economy and reaction mass efficiency of the direct fluori-
nation reaction are significantly higher than those of the com-
peting synthetic processes mostly because fluorination only
requires a single synthetic step and the only significant side
product is one equivalent of HF. The low atom economy of the
halogen exchange is explained by the high molecular weight
reagents used for both the chlorination (SO2Cl2) and the
halogen exchange (Et3N·3HF) steps. The PMI metrics indicate
how much waste is generated during the production of 1 kg of
product, and solvents are key contributors. However, for the
direct fluorination process, solvents used in the reaction
(MeCN) and work-up procedure (EtOAc) may be recovered and
reused with no change in product profile.
86
64
68
reacted with the crude diethyl fluoromalonate product syn-
thesised above (∼95% purity) to afford pyrimidine and diaze-
pane derivatives which could be purified readily by
recrystallization and demonstrate the usefulness of 95%
purity fluoromalonate material for further synthesis. Yields
are unoptimised, but comparable to similar literature
procedures.
In particular, crude diethyl fluoromalonate prepared above
reacts efficiently with formamidine to give 5-fluoro-4,6-di-
hydroxypyrimidine, a key intermediate in the synthesis of
Fluoxastrobin, in good yield (64%), which is comparable with
previously reported 61–78% yields (Table 2).21a
To compare the metrics of the optimised direct fluorination
process with other methods for the synthesis of fluoromalo-
nate esters, a “first pass” metrics package, was implemented.28
Hexafluoropropene (HFP) is an important, inexpensive per-
fluorinated building block used for the synthesis of various
well known fluoropolymers and refrigerant gases and is, there-
fore, available on the industrial scale.29 Synthesis of fluoro-
malonates by reaction of HFP with ethanol and H2SO4 affords
good purity product in fair yield, but, from an environmental
impact point of view, this is a very wasteful and low-atom
economy process. Firstly, the synthesis of the starting material
requires many steps, ultimately by reaction of low molecular
weight hydrocarbons with chlorine gas and subsequent
halogen exchange in a very energy intensive process3b and,
secondly, a significant amount of hazardous, strongly acidic
waste is generated in the reaction of HFP with ethanol.
As described in the patent literature, Bayer’s halogen
exchange reaction24 is a very efficient process, the reaction
uses only a minimum amount of solvent and all process
metrics look very promising apart from low atom economy due
to the use of Et3N·3HF. A possible disadvantage of the halogen
exchange process is the reported possibility of several time
consuming vacuum distillation procedures, but this may not
be necessary on the manufacturing scale.
Conclusion
Selective direct fluorination (SDF) process for the synthesis of
2-fluoromalonate esters have been optimised on a reasonable
scale in the laboratory (40 g scale) both in terms of product
yield and purity (99% crude yield, 95% purity, after distillation
77% yield and 99% purity) and green reaction metrics. The
PMI value of the SDF process is, even at this relatively small
scale, under 10, a benchmark figure that demonstrates an
efficient and effective, environmentally benign chemical syn-
theses. A comparison of green metrics between the SDF process
and established multi-step syntheses derived from hexafluoro-
propene ethanolysis and halogen exchange chemistry shows
that SDF compares very favourably in terms of environmental
impact for the synthesis of important fluorinated building
blocks on larger scale.
The halogen exchange reaction requires the industrial syn-
thesis of high purity chloromalonate ester since the purity of
the final fluoromalonate product largely depends on the
efficiency and selectivity of this step. The chlorination reaction
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Table 3 Green metrics to compare methods for the synthesis of diethyl fluoromalonate
Cu catalysed direct
fluorination (distilled)
Fluoromalonate synthesis
HFP method
Halex cumulative
Yield [purity %]
52% [n/a]
39.1
20.6
62.1
18.0
48.8
44.1
77 [96%]
39.0
33.0
6.9
5.5
3.3
99 [95%] (77 [99%+])
89.9
88.6 (69.3)
9.0 (11.6)
4.6 (6.1)
6.7 (8.6)
4.3 (5.5)
Atom economy (AE)
Reaction mass efficiency (RME)
Step MI/PMI total
PMI/MI reaction
PMI/MI solvents
PMI/MI workup
3.3
Solvents
MeOH
Xylenes
Acetonitrile
Et2O
Ethyl–acetate
Catalyst
Critical element
Energy
—
—
High
—
—
High
Cu(NO3)2·2.5H2O
Cu (recoverable)
Low (medium)
Workup/purification
Health & safety
Extraction
Extraction
Multiple
Extraction
Evaporation
Evaporation
Vac.-Distill.
Corrosive
Toxic
Vac.- Distill.
Corrosive
Toxic
(Vac. Distill.)
Corrosive
Toxic
Flammable
—
Expensive
Oxidiser
Chemicals of environmental concern
Availability
—
Good
Good
The reactor was built from a standard glass bottle with GL 45
thread joint and a PTFE screw cap or a glass flange head,
equipped with a gas inlet/outlet head built of Stainless Steel,
Experimental
General
Proton, fluorine and carbon nuclear magnetic resonance PTFE and FEP Swagelok components as described in earlier
spectra (1H, 19F and 13C NMR) were obtained using a Bruker publications.15
400 Ultrashield spectrometer (1H NMR at 400 MHz, 19F NMR
Vacuum distillations were carried out using FISCHER®
at 376 MHz and 13C NMR at 101 MHz) using residual solvent micro SPALTROHR®-column MMS 255 with manual fraction
peaks as the internal standard (1H NMR; CHCl3 at 7.26 ppm, collection.
19F NMR; CFCl3 at 0.00 ppm and 13C NMR; CDCl3 at
77.16 ppm). NMR spectroscopic data are reported as follows:
Diethyl malonate fluorination: general reaction
chemical shift (ppm), integration, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling con-
stant (Hz) and assignment.
GC-MS data were obtained using a Trace GC-MS device
(Thermo-Finnigan Corporation) operating in electron impact
ionization (EI) mode. Accurate mass analysis was performed
on a Xevo QtoF mass spectrometer (Waters Ltd, UK) with an
accurate solids analysis probe (ASAP). Melting point data were
Diethyl malonate (3.20 g, 20 mmol) and copper nitrate hydrate
(Cu(NO3)2·2.5H2O; 0.46 g, 2 mmol) were dissolved in aceto-
nitrile (17 mL) and placed into the fluorination reactor and the
mixture was cooled to 0–5 °C. After purging the system with N2
for 5 minutes, fluorine gas (10% v/v in N2, 45 mL min−1
,
22 mmol) was passed into the stirred mixture for 2 h. The
reactor was purged with nitrogen for 10 minutes, the solvent
was removed in vacuo and the residue partitioned between
water (10 mL) and ethyl acetate (10 mL). The aqueous phase
was extracted with ethyl acetate (10 mL) and the combined
organic layers were washed with saturated brine (10 mL). After
drying over sodium sulfate, the solvent was evaporated to leave
diethyl 2-fluoromalonate (3.37 g, 94% yield, 93.5% purity) as a
colourless liquid. IR (neat, cm−1): 2986, 1747, 1243, 1187,
obtained using
a Gallenkamp apparatus at atmospheric
pressure and are uncorrected. Infra-red (IR) spectroscopy
was performed on a Perkin Elmer 1600 Series FTIR with an
ATR probe. In situ IR spectroscopy was performed using a
Mettler Toledo React IR instrument equipped with a diamond
probe.
3
Fluorinations were carried out in a glass fluorination
reactor (100 mL, 250 mL or 500 mL) unless otherwise stated.
1097, 1020; δH (CDCl3, 400 MHz) 1.31 (6H, t, JHH 7.2, CH3),
3
2
4.31 (4H, q, JHH 7.2, CH2), 5.26 (1H, d, JHF 48.3, CHF); δF
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2
(CDCl3, 376 MHz): – 195.58 (d, JHF 48.3, CH–F); δC (CDCl3, Di-tert-butyl 2-fluoromalonate
1
100 MHz) 14.04 (CH3), 62.80 (CH2), 85.39 (d, JCF 198.2, C–F),
Di-tert-butylmalonate (12.0 g, 55 mmol) and copper nitrate
catalyst (1.16 g, 5 mmol) were dissolved in acetonitrile
(50 mL), placed in a fluorination vessel and the mixture was
cooled to 0–5 °C. After purging the system with N2 for
2
164.20 (d, JCF 24.1, CvO); m/z (EI+) 179 (5%, [M + H]+), 133
(44%, [M − OEt]+), 105 (49%, [M − COOEt]+), 78 (100%,
[CH2FCOOH]+). Spectroscopic data were identical with those
previously reported15 and side products were identified from
their reported 19F NMR shifts.
5 minutes, fluorine gas (20% v/v in N2, 44 mL min−1
,
60 mmol) was introduced for 5 h. After purging with nitrogen
for 10 minutes, the solvent was removed under reduced
pressure and the residue was partitioned between water
(10 mL) and ethyl acetate (25 mL). The aqueous phase was
extracted with ethyl acetate (25 mL) then the combined
organic layer was washed with saturated brine (10 mL). After
drying over sodium sulphate, the solvent was evaporated
under reduced pressure to leave di-tert-butyl 2-fluoromalonate
(12.57 g, 96% yield, 97% purity) as a colourless liquid; IR
Diethyl fluoromalonate large scale fluorination
Diethyl malonate (40.0 g, 0.25 mol) and copper nitrate hydrate
(Cu(NO3)2·2.5H2O; 5.81 g, 25 mmol) were dissolved in aceto-
nitrile (200 mL) and placed in 500 mL fluorination vessel,
cooled to 0–5 °C and stirred at 650 rpm using an overhead
stirrer. After purging the system with N2 for 5 minutes, fluo-
rine gas (20% v/v in N2, 80 mL min−1, 265 mmol) was intro-
duced into the mixture for 6 hours and 30 minutes. The
reactor was purged with nitrogen for 10 minutes, the solvent
removed in vacuo and the residue partitioned between water
(50 mL) and ethyl acetate (50 mL). The aqueous phase was
extracted once more with ethyl acetate (50 mL) and the com-
bined organic layers were washed with saturated NaHCO3
(25 mL) and brine (20 mL). After drying over sodium sulfate,
the solvent was evaporated to leave diethyl 2-fluoromalonate
(44.4 g, 99% yield, 95% purity) as a light yellow, transparent
liquid. This crude product was distilled to afford high purity
fluoromalonate (34.7 g, 77% yield, 99%+ purity) as a colourless
liquid, bp. 102–103 °C (18 mbar), (lit.: 110–112 °C,
29 mbar),23b spectroscopic data as above.
(neat, cm−1
) 2980, 1744, 1369, 1252, 1143; δH (CDCl3,
2
400 MHz) 1.49 (18H, s, CH3), 5.01 (1H, d, JHF 48.9, CHF);
δF (CDCl3, 376 MHz): −193.79 (d, JHF 48.9, CH–F); δC (CDCl3,
2
1
100 MHz) 27.95 (CH3), 84.01 (C–CH3), 85.97 (d, JCF 196.5,
C–F), 163.32 (d, JCF 24.5, CvO); m/z (EI+) 162 (20%,
2
[M − OtBu + H]+), 57 (100%, [tBu]+).
5-Fluoro-4,6-dihydroxypyrimidine
Formamidine acetate (2.06 g, 20 mmol) was added to the solu-
tion of sodium (1.38 g, 60 mmol) in anhydrous ethanol
(40 mL) and the mixture was heated to reflux. Diethyl 2-fluoro-
malonate (3.20 g, 18 mmol) was added dropwise over
20 minutes and the mixture was heated at reflux for 6 h. After
cooling to room temperature, the solution was evaporated to
dryness, the residue was dissolved in water (20 mL), acidified
with HCl (5 mL), the precipitate was filtered, washed with
water (5 mL), ethanol (2 × 5 mL) and diethyl ether (2 × 5 mL).
After drying in vacuo, 5-fluoro-4,6-dihydroxypyrimidine (1.50 g,
64%) was obtained as a brown powder. m.p.: >300 °C;
([M + H]+, 131.0244, C4H4FN2O2 requires: [M]+, 131.0257); IR
(neat, cm−1) 3053, 2639, 1633, 1547, 1388, 1213; δH (DMSO d6,
400 MHz) 7.90 (1H, s, C–H), 12.38 (2H, bs, OH); δF (DMSO d6,
376 MHz): – 178.06 (s); δC (DMSO d6, 100 MHz) 132.79 (d,
Dimethyl 2-fluoromalonate
Dimethyl malonate (19.8 g, 0.15 mol) and Cu(NO3)2·2.5H2O
(3.50 g, 15 mmol) were dissolved in acetonitrile (85 mL), the
mixture was cooled to 0–5 °C and stirred at 650 rpm using an
overhead stirrer. After purging the system with N2 for
5 minutes, fluorine gas (20% v/v in N2, 50 mL min−1
,
170 mmol) was introduced into the reaction mixture for 7 h.
After purging with nitrogen for 20 minutes, the solvent was
removed in vacuo and the residue was partitioned between
water (30 mL) and ethyl acetate (20 mL). The aqueous phase
was extracted with ethyl acetate (2 × 20 mL) and the combined
organic layer was washed with saturated brine (20 mL). After
4
2
1JCF 235.6, C–F), 144.46 (d, JCF 7.7, C–H), 155.83 (d, JCF 15.0,
C–OH); m/z (ASAP) 131 (100%, [M + H]+).21a
2-Amino-5-fluoro-4,6-dihydroxypyrimidine
drying over sodium sulphate, the solvent was evaporated Guanidine sulfate (5.95 g, 55 mmol) was added to the solution
under reduced pressure to give dimethyl 2-fluoromalonate of sodium (2.50 g, 110 mmol) in anhydrous ethanol (100 mL)
(21.8 g, 97% yield, 95% purity) as a colourless oil; IR (neat, and the mixture was heated to reflux. Diethyl 2-fluoromalonate
cm−1) 2962, 1748, 1438, 1250, 1206, 1112, 1016; δH (CDCl3, (8.90 g, 50 mmol, 93% pure) was added dropwise over
2
400 MHz) 3.85 (6H, s, CH3), 5.31 (1H, d, JHF 48.0, CHF); δF 20 minutes and the mixture was heated at reflux for 6 h. After
2
(CDCl3, 376 MHz): −195.73 (d, JHF 48.0, CH–F); δC (CDCl3, cooling to room temperature, the solution was evaporated to
1
100 MHz) 53.48 (CH3), 85.19 (d, JCF 197.2, C–F), 164.39 dryness, the residue was dissolved in water (20 mL), neutral-
2
(d, JCF 24.0, CvO); m/z (EI+) 150 (3%, [M]+), 119 (42%, ised with HCl to pH 7, the precipitated product was filtered,
[M − OMe]+), 91 (73%, [M − COOMe]+), 59 (100%, [COOMe]+). washed with water (5 mL), ethanol (2 × 5 mL) and diethyl ether
Spectroscopic data in agreement with previously published (2 × 5 mL). After drying in vacuo, 2-amino-5-fluoro-4,6-dihydrox-
data.23b Crystallographic data has been deposited at the ypyrimidine (6.21 g, 86%) was obtained as a pink powder. m.p.:
Cambridge Crystallographic Database centre as file CCDC >300 °C ([M + H]+, 146.0357, C4H5FN3O2 requires: [M]+,
1050160.
146.0366); IR (neat,cm−1) 3343, 3100, 2916, 2731, 1600, 1557,
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1415, 1358, 1204; δH (DMSO d6, 400 MHz) 7.00 (2H, bs, N–H),
11.1 (2H, bs, OH); δF (DMSO d6, 376 MHz): – 197.05 (s); δC
(DMSO d6, 100 MHz) 125.13 (d, 1JCF 208.6, C–F), 149.26 (d, 4JCF
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Acknowledgements
The research included in this publication received funding
from the European Community’s Seventh Framework Pro-
gramme (FP7/2007–2013) and EFPIA companies’ in kind con-
tribution for the Innovative Medicine Initiative under Grant
Agreement no. 115360 (Chemical manufacturing methods for
the 21st century pharmaceutical industries, CHEM21). We
thank Dr D. S. Yufit for X-ray crystallographic analyses and
Dr C. R. McElroy for useful discussions regarding the use of
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