An improved method for preparation of cefpodoxime proxetil

Article abstract of DOI:10.1016/S0014-827X(03)00051-X

Cefpodoxime proxetil, a third-generation cephalosporin for oral administration, was synthesized by a method based on the following sequence of reactions: acylation of 7-aminocephalosporanic acid (7-ACA) with S-benzothiazol-2-yl(2-amino-4-thiazolyl)(methoxyimino)thioacetate (MAEM), chloroacetylation of the cefotaxime formed with chloroacetyl chloride, esterification of the acid function with 1-iodoethyl isopropyl carbonate and final cleavage of chloroacetamide protective group by treatment with thiourea in N,N-dimethylacetamide. The developed procedure allows us to obtain better yields of cefpodoxime proxetil and to eliminate the final purification step by column chromatography, necessary during the synthesis of this antibiotic by the previously reported methods.

Full text of DOI:10.1016/S0014-827X(03)00051-X

Il Farmaco 58 (2003) 363Á369
/
www.elsevier.com/locate/farmac
An improved method for preparation of cefpodoxime proxetil
Juan C. Rodr´ıguez a, Ricardo Herna´ndez a, Maritza Gonza´lez a, Zalua Rodr´ıguez a,
Blanca Tolo´n a, Herma´n Velez a, Ba´rbara Valde´s a, Miguel A. Lo´pez a, Adamo Fini b,*
a Department of Chemical Synthesis, Center of Pharmaceutical Chemistry, Ave. 200 y 21, Atabey, Playa, Ciudad de la Habana, Cuba
b Istituto di Scienze Chimiche, via San Donato 15, I-40127 Bologna, Italy
Received 18 December 2002; accepted 15 February 2003
Abstract
Cefpodoxime proxetil, a third-generation cephalosporin for oral administration, was synthesized by a method based on the
following sequence of reactions: acylation of 7-aminocephalosporanic acid (7-ACA) with S-benzothiazol-2-yl(2-amino-4-
thiazolyl)(methoxyimino)thioacetate (MAEM), chloroacetylation of the cefotaxime formed with chloroacetyl chloride, esterification
of the acid function with 1-iodoethyl isopropyl carbonate and final cleavage of chloroacetamide protective group by treatment with
thiourea in N,N-dimethylacetamide. The developed procedure allows us to obtain better yields of cefpodoxime proxetil and to
eliminate the final purification step by column chromatography, necessary during the synthesis of this antibiotic by the previously
reported methods.
´
# 2003 Published by Editions scientifiques et me´dicales Elsevier SAS.
Keywords: Cephalosporins; 7-Aminocephalosporanic acid; Cefpodoxime proxetil; Cefotaxime; Synthesis
1. Introduction
time, it contains a (Z)-2-(2-aminothiazol-4-yl)(methox-
yimino)acetamido moiety linked to the C-7 position.
This molecular fragment is associated with the potent
activity against Gram-negative bacteria and high b-
lactamase stability displayed by this antibiotic.
Cefpodoxime proxetil (Fig. 1), a relatively new broad-
spectrum third-generation cephalosporin, has very good
in vitro activity against Gram-negative bacteria, includ-
ing b-lactamase producers and many strains resistant to
other oral agents. It also has activity against Gram-
positive bacteria, especially streptococci. It is well
tolerated and is one of the first third-generation
cephalosporins to be available in oral form. This
antibiotic has been used widely in the treatment of
respiratory and urinary tract infections and also in the
treatment of skin structure infections, acute media otitis,
pharyngitis, tonsillitis and sexually transmitted diseases
The best current synthetic method to prepare cefpo-
doxime proxetil is outlined in Scheme 1.
The 3-acetoxymethyl derivative II prepared by acyla-
tion of 7-aminocephalosporanic acid (7-ACA) with the
acid chloride of (Z)-2-(2-chloroacetamido-4-thiazolyl)-
2-(methoxyimino)acetic acid (CATMA) is treated with
aqueous methanol in the presence of calcium chloride to
give the corresponding 3-methoxymethyl derivative III.
The chloroacetyl group of III is removed by treatment
with thiourea in aqueous solution to afford compound
IV. Finally, esterification of IV with 1-iodoethyl isopro-
pyl carbonate (VI) gives the corresponding ester VII
[1Á4].
/
From the structural point of view, cefpodoxime
proxetil has a methoxymethyl group linked to the C-3
position of the cephem nucleus and ethyl 1-(isopropox-
ycarbonyloxy) group linked to the acid function by an
ester-type bond. Both structural characteristics are
associated with its good oral absorption. At the same
(cefpodoxime proxetil) [5Á9].
/
Although this synthetic pathway allows to get good
overall yields (ca. 31% from 7-ACA) it has some
drawbacks:
a) The use of CATMA to introduce the (Z)-2-(2-
aminothiazol-4-yl)(methoxyimino)acetamido moi-
ety linked to the C-7 position increases the cost of
* Corresponding author.
E-mail address: fini@biocfarm.unibo.it (A. Fini).
´
0014-827X/03/$ - see front matter # 2003 Published by Editions scientifiques et me´dicales Elsevier SAS.
doi:10.1016/S0014-827X(03)00051-X

364
J.C. Rodr´ıguez et al. / Il Farmaco 58 (2003) 363Á369
/
a high price in the market (similar to that of 7-
ACA).
b) It is necessary to prepare the acylating agent (the
acid chloride of CATMA) by the reaction of
CATMA with phosphorous pentachloride or thio-
nyl chloride, and it is known that acid chlorides are
difficult to be purified because they are water
sensitive.
c) The yield of 7-ACA acylation reaction with the acid
chloride of CATMA is relatively low (70%). As a
consequence, the yield of cefpodoxime proxetil and
the production cost of this antibiotic become
negatively affected. Additionally, the acylation
with the acid chloride of CATMA must be carried
Fig. 1. Chemical structure of cefpodoxime proxetil.
the final product (cefpodoxime proxetil), because
although CATMA is a commercial raw material
used in cephalosporin chemistry, this compound has
out at very low temperatures (Â
/
ꢀ20 8C), an
/
Scheme 1. Synthesis of cefpodoxime proxetil as reported in the literature.

J.C. Rodr´ıguez et al. / Il Farmaco 58 (2003) 363Á
/369
365
important handicap from the technological point of
view.
d) The removal of the chloroacetyl group in aqueous
solution causes a lot of troubles, especially the
absolute necessity to purify the obtained cefpodox-
ime proxetil by column chromatography.
also a commercial raw material used in cephalosporin
chemistry) and cefotaxime (I) was obtained in very good
yields (95%) through a rapid and efficient procedure
previously developed in our laboratory [10]. In the
following step, it was necessary to block the free amino
group of I in order to carry out further replacement of
acetoxy group linked to C-3 position by the methoxy
group without side reactions. After evaluating some
options, it was decided to effect the protection of amino
function with chloroacetyl group. With this objective, a
rapid and efficient procedure was developed for chlor-
oacetylation of I by treatment with chloroacetyl chloride
in N,N-dimethylacetamide as the reaction solvent. The
chloroacetylated derivative II was obtained with high
purity and over 90% yields.
The objective of this paper is to find an alternative
procedure for the synthesis of cefpodoxime proxetil in
order to overcome the problems cited above.
2. Results and discussion
The proposed synthetic route is as follows (Scheme 2).
In this method, the CATMA used during the acyla-
tion of 7-ACA was replaced by S-benzothiazol-2-yl(2-
amino-4-thiazolyl)(methoxyimino)thioacetate (MAEM,
Although it was necessary to introduce an additional
synthetic step, compound II was prepared in 85.5% yield
calculated from 7-ACA, that is to say, a yield 15.5%
Scheme 2. Synthesis of cefpodoxime proxetil by the developed procedure.

366
J.C. Rodr´ıguez et al. / Il Farmaco 58 (2003) 363Á369
/
higher than that of the previously reported procedure. It
is known that in cephalosporin synthesis, the cost of the
final product (in this case cefpodoxime proxetil) depends
almost exclusively on the mass relationship between 7-
ACA and the final product, because the 7-ACA price is
many times higher than the price of the auxiliary
reagents used during the synthetic procedures. Thus,
whereas less 7-ACA quantity is needed to obtain a mass
unity of the final product, more economic is the
synthetic method. The use of MAEM in place of
CATMA during the acylation step provides an addi-
tional economic benefit, because MAEM price is two or
three times lesser than the price of CATMA in the
market. From the technological point of view, the use of
MAEM to prepare cefpodoxime proxetil improves the
synthetic process because it is not necessary to obtain
and purify the acylating agent, and the acylation step
can be carried out at room temperature, thus avoiding
the necessity of using very low temperatures (as in the
case of CATMA).
Following the developed synthetic procedure, in the
next step the 3-methoxymethyl derivative I was obtained
from II in 65% yield by reaction with aqueous methanol
in the presence of calcium chloride as catalyst, according
to the method reported in the literature [6,8].
The 1-iodoethyl isopropyl carbonate (VI) was synthe-
sized from ethyl chloroformate through the following
sequence of reactions (Scheme 3): radical chlorination
with sulfuryl chloride, alcoholysis of the 1-chloroethyl
chloroformate formed with isopropyl alcohol to obtain
V and final halogen exchange by treatment of V with
sodium iodide in the presence of a catalytic amount of
18-crown-6 ether. The resulting yield was the same as
reported and no changes were introduced to the
described method [8,9].
IV) produces a vigorous evolution of CO2 and the
formation of a gummy precipitate difficult to handle. In
consequence, poor yields are obtained and at the end of
the process an additional purification step by column
chromatography is necessary to obtain cefpodoxime
proxetil of a suitable purity.
In the present work, the reaction sequence was
reversed and compound III was esterified by treatment
with VI in N,N-dimethylacetamide in the presence of
dicyclohexylamine. The low polarity of the resulting
ester allowed the extraction of this compound from
reaction mixture with ethyl acetate and the elimination
of the impurities (dicyclohexylammonium iodide and
dicyclohexylamine in excess) by washing with water and
diluted hydrochloric acid, respectively. In consequence,
it was not necessary to isolate the ester and after
removing the organic solvent, it was possible to effect
the direct cleavage of the chloroacetyl protective group
by reaction with thiourea in N,N-dimethylacetamide.
The use of an organic solvent to effect the deprotection
allowed to overcome all the problems found when
carrying this reaction in aqueous solution (as reported
in the literature). The cefpodoxime proxetil formed was
extracted from the reaction mixture with ethyl acetate
and after evaporation of the solvent, the residue was
crystallized with isopropyl ether to give the pure
1
antibiotic as was demonstrated by H NMR and 13C
NMR spectroscopy. This result made an additional
purification of the product by column chromatography
unnecessarily, which is an advantage in comparison with
the reported method.
On the other hand, the overall yield calculated from 7-
ACA was 36.2%. It means that from 100 g of 7-ACA, it
was possible to obtain 11 g more of cefpodoxime
proxetil in comparison with the synthetic route reported
in the literature consulted. It is also possible to affirm
that the different procedure used in the first step
(synthesis of compound II from 7-ACA) and the
reversing of the reaction sequence (synthesis of com-
pound VII from II) improve the process for the
preparation of this antibiotic, both from the economic
and technological point of view. Another advantage that
results from the present research is the possibility to use
the same raw materials (7-ACA and MAEM) in the
synthesis of both antibiotics (cefotaxime and cefpodox-
ime proxetil).
Another objective of this work was to overcome the
problems found during the elimination of the chloroa-
cetyl protective group of compound III. In the reported
procedure (Scheme 1), this process is effected before the
esterification of the acid function with VI. Although
relatively high yields are reported (75.5%), we found
that it is very difficult to isolate the resulting compound
IV. During the purification procedure, it is necessary to
dissolve IV by treatment with concentrated hydrochloric
acid in order to remove reaction by-products. Further
addition of sodium hydrogen carbonate (to precipitate
Scheme 3. Synthesis of 1-iodoethyl isopropyl carbonate (VI).

J.C. Rodr´ıguez et al. / Il Farmaco 58 (2003) 363Á
/369
367
3. Experimental
with stirring triethylamine (TEA) (71 ml, 513 mmol)
followed by MAEM (89.6 g, 256 mmol) were added. The
mixture was stirred for 1 h at room temperature and
then extracted twice with water (320 and 160 ml). The
combined extracts were adjusted to pH 2.9 by the
addition of 6 M hydrochloric acid (ca. 47 ml). The
Melting points (m.p.) were determined using the
Gallenkamp capillary apparatus with a system of
measurement and temperature control. H NMR and
13C NMR spectra were recorded at 250 and 62.5 MHz,
respectively, on a Bruker AC 250F spectrometer, using
either deuterated dimethylsulfoxide (DMSO-d6) or deut-
erated chloroform (CDCl3) as solvent and tetramethyl-
silane (TMS) as an internal standard.
1
mixture was cooled to 0Á5 8C and the resulting pre-
/
cipitate was separated by filtration, washed successively
with cold water (60 ml), cold ethanol (60 ml), diethyl
ether (2ꢂ80 ml) and dried to obtain I (100 g, 95%
/
The mass spectra (MS) were recorded in a quad-
rupolar mass spectrometer TRIO 1000 (Fisons Instru-
ments) based on the electronic impact technique with
yield). TLC (FM A) 0.74; m.p.; 1H NMR (DMSO-d6) d
(ppm): 1.99 (3H, s, OCOCH3); 3.23 and 3.45 (1H, Abq,
H-2); 3.84 (3H, s, NOCH3); 4.76 and 4.98 (1H, ABq,
CH2O); 5.01 (1H, d, H-6); 5.6 (1H, dd, H-7); 6.73 (1H, s,
thiazol); 7.28 (2H, s, NH2); 9.61 (1H, d, NHCO); 13C
NMR (DMSO-d6) d (ppm): C-1, 25.37; C-2, 112.17; C-
3, 64.50; C-4, 134.87; C-5, 163.06; C-6, 57.34; C-7, 58.07;
C-8, 164.00; C-9, 162.21; C-10, 149.06; C-11, 61.88; C-
12, 142.57; C-13, 109.02; C-14, 168.47; C-15, 170.55; C-
16, 20.74.
EIꢁ70 eV and DMK 400 V.
/
Thin-layer chromatography (TLC) was performed on
pre-coated plates of silica gel GF-254 (Merck). In the
development of chromatograms, two mobile phases
were used; (FM A) ethyl acetateÁ
acid (60:25:15:1) and (FM B) ethyl acetateÁ
(3:1). The chromatograms were visualized in a Camag
UVÁVis lamp with a wavelength of 254 nm.
The synthesis of each compound was confirmed by
/
ethanolÁ
/
waterÁ/formic
/
n-hexane
/
1
1
3.2. 7b-[2-(2-Chloroacetamidothiazol-4-yl)-(Z)-2-
methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-
carboxylic acid (II)
comparison of registered H NMR spectra with the H
NMR data reported in the literature consulted [8]. In the
particular case of compound V, the mass spectrum was
also used with the same purpose.
To a solution of I (58.5 g, 128 mmol) in N,N-
dimethylacetamide (295 ml), chloroacetyl chloride
(15.4 ml, 193 mmol) was added, keeping the temperature
between 5 and 10 8C. The mixture was stirred for 1 h at
room temperature and then poured into ice water. The
resulting precipitate was collected by filtration and
washed successively with water (30 ml), ethanol (30
In Fig. 2, the base structures of the synthesized
compounds are shown with an arbitrary numeration of
carbon atoms, in order to support the assignment of 13
NMR chemical shifts given below for each compound.
C
3.1. 7b-[2-(2-Aminothiazol-4-yl)-(Z)-2-
methoxyiminoacetamido]-3-acetoxymethyl-3-cephem-4-
carboxylic acid) (I) (cefotaxime)
ml), diethyl ether (2ꢂ
/
30 ml) and dried to obtain II (61.6
178 8C; 1H
g, 90.2%). TLC (FM A) 0.83; m.p. 177Á
/
NMR (DMSO-d6) d (ppm): 2.05 (3H, s, CH3COO); 3.51
and 3.65 (2H, Abq, H-2); 3.92 (3H, s, NOCH3); 4.40
(2H, s, CH2Cl); 4.60 and 5.0 (2H, Abq, CH2O); 5.19
A suspension of 7-ACA (62.9 g, 231 mmol) in
dichloromethane (755 ml) was cooled to 5Á10 8C and
/
Fig. 2. Base structures for synthesized compounds.

368
J.C. Rodr´ıguez et al. / Il Farmaco 58 (2003) 363Á369
/
(1H, d, H-6); 5.85 (1H, dd, H-7); 7.48 (1H, s, thiazol);
9.74 (1H, d, NHCO); 12.95 (1H, s, NHCOchloroacetyl);
13C NMR (DMSO-d6) d (ppm): C-1, 25.73; C-2, 123.51;
C-3, 62.66; C-4, 126.33; C-5, 162.78; C-6, 57.41; C-7,
58.57; C-8, 163.71; C-9, 162.52; C-10, 148.49; C-11,
62.14; C-12, 141.62; C-13, 114.57; C-14, 157.89; C-15,
170.18; C-16, 20.53; C-17, 165.34; C-18, 42.16.
and the mixture was stirred for 30 min at the same
temperature. The reaction mixture was washed succes-
sively with water (170 ml), brine (170 ml) and 5%
potassium hydrogen sulfate aqueous solution (170 ml),
and the organic layer dried over anhydrous sodium
sulfate. The solvent was removed and the resulting
liquid distilled under reduced pressure at 55 mmHg to
give V (fraction boiling between 92 and 94 8C) (113.2 g,
46.2%). 1H NMR (CDCl3) d (ppm): 1.34 (6H, m,
(CH3)2); 1.84 (3H, d, CH3); 4.95 (1H, sept, CHO);
6.44 (1H, q, OCHCl); 13C NMR (DMSO-d6) d (ppm):
C-19, 21.60 and 21.55; C-20, 84.30; C-21, 152.22; C-22,
73.26; C-23 and C-24, 25.16.
3.3. 7b-[2-(2-Chloroacetamidothiazol-4-yl)-(Z)-2-
methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-
carboxylic acid (III)
To a solution of II (26.0 g, 49 mmol) and sodium
hydrogen carbonate (4.1 g, 49 mmol) in water (80 ml),
methanol (170 ml, 4.2 mol) and calcium chloride
dihydrate (375 g, 2.55 mol) were added. The mixture
was stirred for 75 min. at 70 8C and then poured into
500 ml of ice water. The mixture was acidified with 37%
hydrochloric acid (10 ml) and extracted with ethyl
3.5. 1-Iodoethyl isopropyl carbonate (VI)
To a solution of V (5.1 g, 30.6 mmol) in benzene (50
ml) were added, at room temperature, sodium iodide (10
g, 66.7 mmol) and 18-crown-6 ether (0.25 g, 0.95 mmol),
and the mixture was refluxed with stirring during 12 h.
acetate (2ꢂ500 ml). The extracts were combined and
/
the organic layer was extracted with 10% potassium
hydrogen phosphate aqueous solution (350, 150 and 100
ml). The aqueous layers were combined and extracted
The mixture was washed with water (3ꢂ15 ml) followed
/
by 5% sodium thiosulfate aqueous solution (10 ml). The
organic layer was dried over anhydrous sodium sulfate
and after filtration, the filtrate was concentrated in
with ethyl acetate (2ꢂ500 ml) after acidification with
/
1
concentrated hydrochloric acid. The organic extracts
were combined, washed with brine (100 ml) and dried
over anhydrous sodium sulfate. The mixture was filtered
and the filtrate was concentrated under reduced pressure
to about 1/5 of the initial volume to yield a precipitate.
The mixture was allowed to stand at room temperature
for 3 h. The resulting precipitate was separated by
filtration, washed with ethyl acetate (30 ml) and dried to
vacuo to give VI (6.7 g, 85%). H NMR (CDCl3) d
(ppm): 1.32 (6H, m, (CH3)2); 2.15 (3H, d, CH3); 4.85
(1H, sept, CHO); 6.70 (1H, q, OCHCl).
3.6. 1-(Isopropoxycarbonyloxy)ethyl-7b-[2-(2-
aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-
methoxymethyl-3-cephem-4-carboxylate (VII)
(cefpodoxime proxetil)
give III (16 g, 65% yield). TLC (FM A) 0.69; m.p. 208Á
/
210 8C; 1H NMR (DMSO-d6) d (ppm): 3.25 (3H, s,
CH3O); 3.51 and 3.62 (2H, Abq, H-1); 3.92 (3H, s,
NOCH3); 4.20 (2H, s, CH2Cl); 4.40 (2H, s, CH2O); 5.20
(1H, d, H-6); 5.84 (1H, dd, H-7); 7.48 (1H, s, thiazol);
9.75 (1H, d, NHCO); 12.95 (1H, s, NHCOchloroacetyl);
13C NMR (DMSO-d6) d (ppm): C-1, 25.53; C-2, 125.39;
C-3, 69.95; C-4, 126.14; C-5, 163.00; C-6, 57.59; C-7,
58.51; C-8, 163.62; C-9, 162.52; C-10, 148.48; C-11,
62.13; C-12, 141.64; C-13, 114.57; C-14, 157.85; C-16,
57.40; C-17, 165.32; C-18, 42.15.
To a solution of III (2.0 g, 3.97 mmol) in N,N-
dimethylacetamide (10 ml), dicyclohexylamine (0.9 ml,
4.52 mmol) was added, followed by VI (1.3 g, 5.04
mmol) under cooling (0Á5 8C). The mixture was stirred
/
for 45 min at the same temperature and ethyl acetate (50
ml) was added. The mixture was washed successively
with water (15 ml), 1 M hydrochloric acid aqueous
solution (15 ml) and brine (15 ml). The organic layer was
dried over anhydrous sodium sulfate and the solvent
was removed by vacuum distillation to give an oil (2.4
g).
3.4. 1-Chloroethyl isopropyl carbonate (V)
The oil was dissolved in N,N-dimethylacetamide (20
ml), thiourea (0.61 g, 1.97 mmol) was added and the
resulting solution was stirred for 3 h at room tempera-
ture. The mixture was poured into 5% sodium hydrogen
carbonate aqueous solution (50 ml) and extracted with
ethyl acetate (75 ml). The organic layer was washed
successively with 10% potassium bisulfate aqueous
solution (25 ml) and brine (25 ml), and dried over
anhydrous sodium sulfate. After filtration, the solvent
was removed under reduced pressure and the residue
was stirred with isopropyl ether (25 ml). The resulting
precipitate was separated by filtration, washed with
To a solution of ethyl chloroformate (140 ml, 1.47
mol) and sulfuryl chloride (130 ml, 1.61 mol) was added
benzoyl peroxide (0.5 g, 2 mmol). The mixture was
refluxed for 7.5 h and it was distilled at atmospheric
pressure to give 1-chloroethyl chloroformate (boiling
range 119Á140 8C). To a solution of the resulting 1-
/
chloroethyl chloroformate in dichloromethane (675 ml)
isopropyl alcohol (134 ml, 1.74 mol) was added, under
cooling (0Á
/
5 8C) and with stirring. Pyridine (78 ml, 0.96
mol) was added dropwise to the solution over 20 min

J.C. Rodr´ıguez et al. / Il Farmaco 58 (2003) 363Á
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369
isopropyl ether (10 ml) and dried to give VII (1.44 g,
1
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The use of MAEM as starting material for preparing
cefpodoxime proxetil allowed to obtain better yields
during the synthesis of this antibiotic. Previous ester-
ification of the chloroacetylated derivative III, followed
by cleavage of the chloroacetyl protective group,
allowed to eliminate the drawbacks of the classic route
of synthesis, especially the final purification of cefpo-
doxime proxetil by column chromatography.
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