A new non-chloride method of synthesis of antibacterial antibiotic fosfomycin based on the principles of green chemistry

Article abstract of DOI:10.1134/S1070363216130077

A new non-chloride method for synthesis of antibacterial antibiotic fosfomycin, which is based on principles of green chemistry, has been developed.

Full text of DOI:10.1134/S1070363216130077

ISSN 1070-3632, Russian Journal of General Chemistry, 2016, Vol. 86, No. 13, pp. 2974–2977. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © V.V. Belakhov, A.V. Garabadzhiu, 2016, published in Ekologicheskaya Khimiya, 2016, Vol. 25, No. 2, pp. 74–78.
A New Non-Chloride Method of Synthesis
of Antibacterial Antibiotic Fosfomycin Based
on the Principles of Green Chemistry
V. V. Belakhova* and A. V. Garabadzhiub
a Schulich Faculty of Chemistry, Technion – Israel Institute of Technology, Haifa, Israel
*e-mail: chvalery@techunix.technion.ac.il
b St. Petersburg State Institute of Technology (Technical University), Moskovskii pr. 26, St. Petersburg, 190013 Russia
Received October 27, 2015
Abstract—A new non-chloride method for synthesis of antibacterial antibiotic fosfomycin, which is based on
principles of green chemistry, has been developed.
Keywords: green chemistry, non-chloride method, antibiotics, fosfomycin
DOI: 10.1134/S1070363216130077
INTRODUCTION
which is used for treatment of many infectious diseases
caused by gram-positive and gram-negative bacteria
[18–20]. In recent years, fosfomycin has been ex-
tensively applied for treating infections in combina-
tions with other antibacterial antibiotics (cephalo-
sporins, aminoglycosides, tetracyclines, and fluoro-
quinolones), whereby the therapeutic effect of these
agents is increased, and their toxicity, reduced [21–23].
Today, fosfomycin certainly remains popular among
clinicians [24–26], being, in particular, the drug of
choice for treatment of urinary tract infections,
especially acute cystitis [27–31].
Green chemistry is a new area of chemistry and
chemical engineering, which emerged in the 1990s and
is focused on redesigning chemical processes and
products in the manner that enhances the environ-
mental performance. Along these lines, new schemes
of chemical reactions and processes, intended to
drastically reduce the environmental impact of large
chemical plants, have been developed in many
laboratories around the world [1, 2]. Accordingly, the
underlying strategy of green chemistry is that of
careful selection of raw materials and process schemes
in which the use of substances hazardous to human
health and environment is avoided [3, 4]. Consistent
application of the green chemistry principles leads to
lower production costs due to elimination of the steps
involving destruction and processing of harmful
byproducts, spent solvents, and other wastes which are
formed in negligible amounts. Reduction in the number
of synthesis steps leads to energy saving, which also
contributes to better results of environmental and
economic assessment of the production [5–7].
There exist numerous synthetic routes to fos-
fomycin, mostly based on the use of highly toxic,
harsh chemicals such as phosphorus trichloride PCl3
[32–37] and its derivatives (BuO)2PCl [38] and
ClCH2P(O)Cl2 [ 39, 40]. Other halogenated reactants,
e.g., 2-chloropropionaldehyde [41], thionyl chloride
(SOCl2) [42–44], and epibromohydrin [45], also find
widespread use for fosfomycin synthesis.
The aim of this study was to develop a new method
for the synthesis of fosfomycin basing on the chlorine-
free chemistry approaches, with the use of nontoxic
chemicals in compliance with green chemistry principles.
Green chemistry principles are also successfully
used today in the chemical synthesis of drugs, above
all of antibiotics [8–12]. One known drug produced
EXPERIMENTAL
synthetically is
broad spectrum antibacterial antibiotic fosfomycin
[(–)-(1R, 2S)-(1,2-epoxypropyl) phosphonic acid] [13–17]
a
low-toxic organophosphorus
We used chemicals available from Sigma-Aldrich
(US) or Fluka (Switzerland) without further purifica-
2974

A NEW NON-CHLORIDE METHOD OF SYNTHESIS OF ANTIBACTERIAL ANTIBIOTIC
2975
Scheme 1. Synthesis of antibacterial antibiotic fosfomycin.
O
O
OH
H
ONEt3
ONEt3
a
b
CH2=C=CH−P
CH2=C=CH−P
H3PO2 + HC≡C−CH2OH
HPA PA
1
2
O
O
O
OCH3
OCH3
OCH3
OCH3
OH
OH
e
d
c
CH3−C=CH−P
CH2=C=CH−P
CH2=C=CH−P
3
4
5
O
P
O
3
2
1
CH
OH
OH
OH
OH
g
f
CH3−C=CH−P
CH3
HC
O
6
Fosfomycin
a: C6H6, 80°С; b: CCl4, Et3N, H2O, 20°С; c: Dowex H+, H2O, 20°С; d: CH2N2, diethyl ether–methanol, 0°С; e: H2, Pd/C,
MeOH, 20°С; f; HCl (10% aqueous solution), 60°С; and g: CF3CO3H, 0°С.
tion. Organic solvents were purified before use by the
techniques from [46].
to yield 1,2-propadienylphosphonous acid 1 as a result
of hydrophosphoryl acetylene-allene rearrangement
detected by us earlier [47–49]. As phosphorylating
compound we used hypophosphorous acid which is a
mild hydrophosphorylating agent [50]. The reaction
proceeded under vigorous stirring in benzene at 80°C
under reflux using a Dean–Stark trap. The second step
consisted in oxidation of the phosphorus-hydrogen
bond of 1 under the Atherton–Todd reaction conditions
[51, 52]. The resulting triethylammonium salt of 1,2-
propadienylphosphonic acid 2 was dissolved in
distilled water and passed through a column packed
with Dowex H+ cation exchange resin to obtain free
acid 3 which was further reacted with diazomethane to
synthesize 1,2-propadienylphosphonic acid methyl
ester 4 following the procedure from [53, 54]. The
reaction of hydrogenation of 4 with the use of Pd/C
catalyst in methanol at room temperature [55] led to
1,2-propenephosphonic acid methyl ester 5. Acid
hydrolysis of 5 with 10% hydrochloric acid under the
conditions described in [50, 56] yielded 1,2-propene-
phosphonic acid 6. The epoxidation reaction of 6 using
trifluoroperacetic acid [57] gave antibiotic fosfomycin
(Scheme 1).
1
The H and 13C NMR spectra were obtained on a
Bruker Avance III (FRG) instrument (operating
frequency 600 MHz) from 10–15% solutions in D2O or
MeOH-d4, with TMS as internal standard. For
31
recording the P NMR spectra we used a Bruker AC-
200 (FRG) instrument operating at 200 MHz
frequency; chemical shifts δ(31P) were referenced to
85% H3PO4 external standard. The MALDI–TOF mass
spectra were measured on a MALDI Micromass (US)
spectrometer with α-cyano-4-hydroxycinnamic acid
matrix. The IR spectra were recorded on a Bruker
vector 22 (FRG) instrument from samples pressed into
KBr pellets. To monitor the progress of the reaction
and the identity of the compounds obtained we used
the TLC technique on Silica Gel 60 F254 (0.25 mm,
Merck, FRG) plates in different solvent systems:
chloroform-methanol 9 : 1; chloroform–methanol 5 : 1;
and chloroform-methanol-ammonium hydroxide (25%
aqueous solution) 10 : 3 : 1. Substances were detected
in the chromatograms using UV light or iodine vapor,
with Silica Gel 60 sorbent (63–200 mm, Merck, FRG).
The melting point (decomposition temperature) was
determined on an Electrothermal IA9300 (UK) instrument.
[(–)-(1R, 2S)-(1,2-Epoxypropyl)phosphonic acid]
1
(fosfomycin). H NMR spectrum (D2O), δ, ppm: 1.47
d (3Н, J1,2 = 5.0 Hz, Н3), 2.83 d.d (1Н, J2,3 = 5.5 Hz,
RESULTS AND DISCUSSION
JН –Р
spectrum (D2O), δ, ppm: 16.35 (C3), 57.25 (C2), 57.67
d (C1, JC –P = 175 Hz). 31Р NMR spectrum (D2O), δ,
ppm: 11.17. Mass spectrum (MALDI TOF): calculated
1
= 19.0 Hz, Н1), 3.27 m (1Н, Н2). 13С NMR
The fosfomycin synthesis by the method developed
by us was started with propargyl alcohol (PA) which
reacted with hypophosphorous acid (HPA) (Scheme 1)
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 86 No. 13 2016

2976
BELAKHOV, GARABADZHIU
for C3H7O4NaP [M + Na]+, m/z 161.05, found 161.07.
14. Christensen, B.G., Leanza, W.J., Beattie, T.R., Pat-
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1
The H, 13C, and 31P NMR spectral parameters of
fosfomycin obtained by the method developed by us
were fully consistent with the published data [58–62].
The melting point of benzylammonium salt of
fosfomycin was 172–174°C (recrystallization from
methanol–water mixture, 1 : 1) against 170–174°C
reported in the literature [14].
CONCLUSIONS
Thus, the non-chloride method of synthesis of anti-
bacterial antibiotic fosfomycin, developed by us, employs
readily available technologically and environmentally
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