One-Step Continuous Flow Synthesis of Antifungal WHO Essential Medicine Flucytosine Using Fluorine

Article abstract of DOI:10.1021/acs.oprd.6b00420

In Africa around 625-000 mortalities per annum (20% of HIV/AIDS related deaths) are due to the affects of the Cryptococcal meningitis (CM) fungal infection. Recently, the World Health Organisation (WHO) and the Infectious Disease Society of America (IDSA) recommended that the first line treatment for CM is a combination of amphotericin B and flucytosine, both now WHO Essential Medicines. However, flucytosine is not even registered for use in any African nation due, in part, to its relatively high cost of manufacture and lack of generic manufacturers. Currently, flucytosine is manufactured by an expensive four-step manufacturing process. Here we report a one-step continuous flow process involving the reaction of inexpensive cytosine with fluorine gas using stainless steel tubular laboratory and pilot-scale silicon carbide reactor devices which is readily scaleable to a manufacturing process with a low initial capital expenditure.

Full text of DOI:10.1021/acs.oprd.6b00420

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Communication
One-step continuous flow synthesis of anti-fungal
WHO Essential Medicine Flucytosine using fluorine
Antal Harsanyi, Annelyse Conte, Laurent Pichon, Alain Rabion, Sandrine GRENIER, and Graham Sandford
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00420 • Publication Date (Web): 05 Jan 2017
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One-step continuous flow synthesis of anti-fungal WHO Essential Medicine Flucytosine
using fluorine
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Antal Harsanyi,a Annelyse Conte,b Laurent Pichon,b Alain Rabion,c Sandrine Grenierd and
Graham Sandforda*
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a Chemistry Department, Durham University, South Road, Durham, DH1 3LE, U.K.
b Maison Européenne des Procédés Innovants (MEPI), Site Safran-Herakles, Chemin de la
Loge – CS 27813, F-31078 Toulouse, France
c Chemistry and Biotechnology Department, Sanofi Aventis, Campus Val de Bievre, Gentilly
France
d Chemistry and Biotechnology Department, Sanofi Aventis, 371 Rue Pr Blayac, Montpellier
France
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In Africa around 625,000 mortalities per annum (20% of HIV/AIDS related deaths) are due to the affects of the
Cryptococcal meningitis (CM) fungal infection. Recently, the World Health Organisation (WHO) and the
Infectious Disease Society of America (IDSA) recommended that the first line treatment for CM is a
combination of amphotericin B and Flucytosine, both now WHO Essential Medicines. However, Flucytosine is
not even registered for use in any African nation due, in part, to its relatively high cost of manufacture and lack
of generic manufacturers. Currently, Flucytosine is manufactured by an expensive four step manufacturing
process. Here we report a one-step continuous flow process involving the reaction of inexpensive cytosine
with fluorine gas using stainless steel tubular laboratory and pilot-scale silicon carbide reactor devices which is
readily scaleable to a manufacturing process with low initial capital expenditure.
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Keywords: Cryptococcal meningitis, fungal infection, flucytosine, essential medicine, fluorine, continuous flow
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HIV/AIDS remains a major health issue in Africa where it is estimated that 2 million people
die per annum from HIV or related diseases. Indeed, 625,000 mortalities1,2 are due to the
affects of Cryptococcal meningitis (CM), a fungal infection that is of particular concern to HIV
patients with heavily compromised immune systems and the leading cause of meningitis in
Saharan Africa, responsible for 20% of HIV/AIDS related deaths world-wide.3 Recently, the
World Health Organisation (WHO) recommended that the first line treatment for CM is a
combination of amphotericin B and Flucytosine 1 that results in a 39% decrease in 10-week
mortality rate4 and enhanced long term survival rates.5 This led to a successful campaign
from various health organisations to include Flucytosine in the most recent 19th WHO Core
List of Essential Medicines (2015),6 which lists medicines that must be available meet the
minimum medical needs of a national health care programme. Flucytosine was approved by
the FDA in 1971 (Ancoban®, Valeant) for the treatment of fungal infections and the only
generic version was introduced to the US market in 2011 (Sigmapharm). In developed
nations, 9% of patients diagnosed with CM die but this mortality rate increases dramatically
to 70% of CM patients in sub-Saharan Africa where diagnosis and availability of suitable
therapy is far too limited. Unfortunately, Flucytosine is not even registered for use in any
African nation and, therefore, not available to prescribe for treatment.3 Consequently,
WHO, Medicines sans Frontieres and various national health organisations supported by
reports from the Eurpean Molecular Biology Organisation (EMBO) workshop7 have
highlighted the urgent requirement for the supply of Flucyctosine to African nations. An 10-
measure action plan has been suggested3,7 including better global assessment,
dissemination of best practice and diagnosis of the CM problem, increased registration,
preferential pricing, licensing and supply of Flucytosine at affordable levels, to raise
awareness and address this health issue. The recommended daily dosage of Flucytosine for
a CM patient is 50-150 mg/kg and so, for a two week programme, each patient (body mass
50 kg) requires around 70 g of Flucyctosine to complete the course. It has been estimated
that a 2-week inductive treatment of CM costs $62 for Flucytosine alone at the very least,8 a
prohibitive expense for low GDP nations.
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In addition, Flucytosine 1 is an important intermediate required for the synthesis of
Capecitabine 2 (anti-cancer) and Emtricitabine 3 (anti-HIV). Capecitabine (Xeloda®, Hoffman
la Roche) was the first FDA approved oral chemotherapy drug (1998) with annual sales of
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over $640 m and the first generic product was introduced in the US recently (September
2013, TEVA). Emtricitabine is also used in various formulations and combinational therapies
for the treatment of HIV, the two best selling products being Atripla® (BMS, $2.9 bn sales in
2012) and Truvada® (Emtricitabine and Tenofovir; Gilead, $2.3 bn sales in 2012).
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Figure 1: Flucytosine 1: related pharmaceuticals and synthesis
Increased availability of Flucytosine to patients in less developed nations requires a much
reduced cost of manufacture of Flucytosine. Market failure in Africa has, in part, been
attributed to the relatively high cost of Flucytosine because of a lack of generic competition
in low income markets9 possibly due to low profit margins associated with current costs of
Flucytosine manufacture. Reported currently used 4-step manufacturing routes10 to
Flucytosine that are described in the patent literature utilise 5-fluorouracil as the starting
material and require chlorination, amination and hydrolysis stages to complete the 4 stage
synthesis of Flucytosine from uracil.11,12 Fluorine gas is used for the large scale manufacture
of a fluoropyrimidine derivative as an intermediate in the synthesis of Pfizer’s V-Fend
(Voriconazole) antifungal agent13 as well for the production of 5-fluorouracil, a long
established effective anti-cancer drug for solid tumour treatment.14 Consequently, fluorine
gas is used on the manufacturing scale when appropriate reaction selectivity and cost
benefits for a given process can be achieved.
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A simplified method suitable for scale-up to manufacturing quantities of Flucyctosine could,
in principle, be the direct fluorination of inexpensive cytosine using cheap fluorine gas.
However, a suitable, scaleable direct fluorination synthesis of Flucytosine has not been
reported in the literature.15,16 In this paper, we describe an inexpensive and readily scaleable
method for the synthesis of Flucytosine from cytosine using fluorine gas as part of a long
term programme developing the use of fluorine gas as a reagent for organic chemistry using
both batch and continuous flow reaction techniques.17-20
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Initially, we examined fluorination of cytosine by fluorine using a conventional batch
process. Cytosine is very soluble in formic acid (160 g/L [1.45 M]), a preferred medium for
direct fluorination due to enhanced reaction control for electrophilic fluorination
processes.21 Batch fluorinations were conducted by passing fluorine gas (10% in nitrogen)
via a gas flow meter through a solution of cytosine in formic acid at room temperature.
Following work-up, a crude mixture that contained mainly flucytosine (approx. 50 % by 19F
NMR spectroscopy, δ -170 ppm, doublet) and one major difluorinated side product (δ – 114
(dd, 2JFF 279 Hz, 3JHF 6 Hz) – 131 ppm (dd, 2JFF 279 Hz, 3JHF 3 Hz)) along with several other side
products was obtained, consistent with earlier reports.16 Recrystallization of the crude
product mixture from water efficiently removed all difluorinated organic impurities, but the
separation of unreacted starting material from the desired flucytosine product proved to be
very difficult. Therefore, the reaction conditions were adapted to give 100 % conversion by
passage of an excess of fluorine gas through the rapidly stirred reaction mixture (Table 1).
Consequently, after addition of 1.75 equivalents of fluorine, work-up and simple
recrystallization from water, pure Flucytosine was isolated in reasonable yield (38 %).
Our preliminary results, therefore, demonstrated that batch fluorination processes can be
used to synthesise Flucytosine in moderate yield although the formation of significant
quantities of difluorinated product leads to considerable waste which would contribute to
higher production costs. As an alternative to batch manufacturing processes, there are
many advantages associated with using continuous flow reactors for chemical synthesis and
among those discussed widely22-24 including high throughput, reduced waste streams, low
manufacturing, operation and maintenance costs, low power consumption, increased
precision and process control. Flow reactors may also lead to increased reaction selectivity
due to optimisation of contact between reagents because of very rapid mixing in such
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devices and laboratory and manufacturing scale continuous flow systems are now
commercially available.24 Consequently, we studied the fluorination of cytosine using a
continuous flow reactor system where greater fluorination reaction control may be possible.
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While we have utilised various laboratory continuous flow reactors previously for direct
fluorination processes,19 for this application we used a narrow-bore stainless steel tube (1.4
mm ID, 1 m length) as the continuous flow reaction vessel that ensures good gas-liquid
mixing and is operationally simple. Consequently, fluorine gas (10% in nitrogen) was passed
through the steel tube via gas flow meter at the same time as a solution of cytosine in
formic acid was introduced into the tube reactor at a prescribed rate by syringe pump
(Table). After some optimisation, involving changing flow rates and equivalents of fluorine
gas added, 100% conversion of the starting material was observed and Flucytosine was
isolated (63%) by recrystallization indicating the feasibility of using flow reactors for
Flucytosine manufacture.
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Table 1: Synthesis of Flucytosine
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Scale-up of our initial laboratory scale experiments was conducted using a meso-scale
Boostec® flow reactor system25 fabricated from silicon carbide, a material that is both
resistant to the corrosive reaction medium (fluorine, HF and acidic solvent) and has
excellent heat exchange properties appropriate for controlling exothermic processes. For
the fluorination of cytosine, a reactor built from six process plates was used giving a 16 m
total channel length and 61 mL reactor volume. After process development studies, cytosine
solution in formic acid (10 wt%, 600 g/h) and fluorine (10 vol. % in nitrogen, 204 g/h) were
passed through the continuous flow silicon carbide reactor via flow meters (Figure 2) which
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was externally cooled to 10 C and, after reaching steady state (15 minutes), the product
liquid phase was collected over a 60 minute time period to yield a yellow solution (620 g). n-
Butanol was added to the product mixture to precipitate the product and, after filtration,
flucytosine was isolated (58.0 g, 99.8 % purity by HPLC, 83 % yield).
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Figure 2: Continuous flow reactor system for manufacture of Flucytosine
In summary, a one-step synthesis of Flucytosine from cytosine using continuous flow direct
fluorination techniques has been established and transferred to the pilot scale (60 g
production of pure Flucytosine per hour per single reaction channel). This operationally
simple procedure from inexpensive starting materials offers the only alternative
manufacturing procedure for Flucytosine to the currently operated expensive four step
process since flow reactors fabricated from silicon carbide are available that enable larger
scale production.25 We envisage that this one-step low cost synthesis of Flucytosine will help
to raise awareness of the neglected CM health epidemic and ultimately contribute to
meeting the urgent requirement for large quantities of Flucytosine for low income nations
as stated by WHO, IDSA and Medicins sans Frontieres.3,7
Methods
Pilot scale continuous flow fluorination synthesis of Flucytosine 1
Cytosine solution in formic acid (10 wt%, 600 g/h) and fluorine (10 vol. % in nitrogen, 204
g/h) were passed through the silicon carbide Boostec® flow reactor system25 at 10 C and
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after reaching steady state (15 minutes) the product liquid phase was collected for 60
minutes to yield a yellow solution (620 g). To this solution n-butanol (1000 g, 1.23 L) was
added in five portions (no exotherm observed) and the mixture was stirred at rt for 12 h.
After filtration, the solid was washed once with n-butanol (60 mL) and dried in air to leave
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Flucytosine (58.0 g, 99.8 % by HPLC, 83 % yield); M.p.: 295 - 300 °C (decomposes), ([M]+
129.0337, [M]+ requires: 129.0338); IR (cm-1): 3384, 3092, 2724, 1665, 1624, 1551, 1454,
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1216; H NMR (400 MHz, D2O+DCl) 7.83 (1H, d, JHF 4.8 Hz); F NMR (400 MHz, D2O+DCl) -
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169.7 (1F, d, JHF 4.8 Hz); C NMR (100 MHz, D2O+DCl): 130.67 (d, JCF 29.6 Hz), 135.25 (d,
1JCF 232 Hz), 147.88, 153.65 (d, JCF 23.4 Hz); MS (ASAP): 111 (37 %, [M+H-F]+), 129 (8 %,
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[M]+), 130 (100 %, [M+H]+); physical and spectral data consistent with an authentic sample
of Flucytosine.
Supporting Information.
Details of selective direct fluorination processes using conventional batch, stainless steel
tube and silicon carbide continuous Flow Reactor protocols and spectroscopic data
accompanies this paper.
Corresponding Author
Prof. Graham Sandford
Department of Chemistry
Durham University
South Road
Durham DH1 3LE
U.K
Tel: +44 (0)191 334 2039
E-mail: graham.sandford@durham.ac.uk
Author Contributions
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All authors conceived and designed the experiments: A. H. and A.C. performed the
experiments: A.H, A.C, and S.G. analyzed the data: A.H and G.S. co-wrote the paper.
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Competing Interests
The authors declare that they have no competing financial interests.
Acknowledgements
The research included in this publication received funding from the European Community´s
Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution
for the Innovative Medicine Initiative under Grant Agreement No. 115360 (Chemical
manufacturing methods for the 21st century pharmaceutical industries, CHEM21).
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