An efficient method for the synthesis of sulbactam pivoxil

Article abstract of DOI:10.1016/S0014-827X(00)00005-7

Sulbactam pivoxil, a prodrug of the β-lactamase inhibitor sulbactam, was prepared in high yield by reacting the sodium salt of sulbactam with chloromethyl pivalate in a polar solvent, then diluting the reaction mixture with water and isolating the product by filtration. Dimethyl sulfoxide was found to be the solvent of choice among several aprotic organic solvents. Copyright (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(00)00005-7

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Il Farmaco 55 (2000) 134–135
An efficient method for the synthesis of sulbactam pivoxil
Lubomir S. Changov a,*, Blagina K. Vassileva b, Maya N. Confino b,
Nely N. Agapova c
a Uni6ersity of Chemical Technology and Metallurgy, 8 Kliment Ohridsky Boule6ard, 1756 Sofia, Bulgaria
b Chemical Pharmaceutical Research Institute, 3 Kliment Ohridsky Boule6ard, 1756 Sofia, Bulgaria
c National Drug Institute, 26 Yanko Sakazo6 Boule6ard, 1504 Sofia, Bulgaria
Received 10 August 1999; accepted 30 December 1999
Abstract
Sulbactam pivoxil, a prodrug of the b-lactamase inhibitor sulbactam, was prepared in high yield by reacting the sodium salt of
sulbactam with chloromethyl pivalate in a polar solvent, then diluting the reaction mixture with water and isolating the product
by filtration. Dimethyl sulfoxide was found to be the solvent of choice among several aprotic organic solvents. © 2000 Elsevier
Science S.A. All rights reserved.
Keywords: Sulbactam; b-Lactamase inhibitor; Prodrug; Chloromethyl pivalate
for 18 h at room temperature, then diluting the reaction
mixture with water and isolating the product by filtra-
tion (Scheme 1).
1. Introduction
Sulbactam pivoxil 2 (pivsulbactam, CP-47,904) [1] is
a prodrug of sulbactam 1 [2], the latter being a b-lacta-
mase inhibitor, poorly absorbed from the gastrointesti-
nal tract (Scheme 1). In contrast, pivsulbactam has a
better absorption than the parent drug and provides
high serum levels after oral administration [3].
Until now sulbactam pivoxil was prepared by react-
ing chloromethyl pivalate with sulbactam free acid [4,5]
in DMF or with its sodium salt [6] in acetone. In the
former case, pivsulbactam was obtained after extraction
with ethyl acetate and evaporation of the solvent under
reduced pressure, and in the latter, after concentration
of the reaction mixture and column chromatography.
There are also methods in which the esterification of
the carboxyl group was accomplished at an early stage
(prior to oxidation or dehalogenation) in the synthesis
of sulbactam [4,5,7–9].
2. Results and discussion
A number of aprotic solvents were used, with or
without sodium iodide as a catalyst (10% from the
weight of the sulbactam), added as a 25% solution in
water (Table 1). In all cases the sodium salt of sulbac-
tam was insoluble in the corresponding solvent and the
reaction seemed to be heterogeneous, between the solid
sulbactam and the chloromethyl pivalate in the
solution.
As can be seen the best results were obtained in
DMSO. The presence of NaI in this case did not affect
the yield of pivsulbactam. The use of 18-crown-6 as a
catalyst (10% from the weight of the sulbactam) in
DMSO as a solvent also did not affect the yield. In our
opinion the best yields of sulbactam pivoxil in DMSO
were due to its higher polarity, compared with the other
solvents (Table 1). Good yields were also obtained in
N,N-dimethylacetamide and in 1-methyl-2-pyrrolidone
in the presence of NaI. In less polar solvents (acetone,
THF, dioxan) the reaction did not proceed without a
catalyst, while in the presence of NaI the yields were
In all these cases however, the purity and the yields
of the isolated sulbactam pivoxil were unsatisfactory.
We report here a simple method for preparing sulbac-
tam pivoxil by reacting the sodium salt of sulbactam
with chloromethyl pivalate in a polar aprotic solvent
* Corresponding author.
E-mail address: lschangov@hotmail.com (L.S. Changov)
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00005-7

L.S. Chango6 et al. / Il Farmaco 55 (2000) 134–135
135
Scheme 1. Synthesis of pivsulbactam from sulbactam sodium salt.
Table 1
3.1. Sulbactam pi6aloiloxymethyl ester
Yields of sulbactam pivoxil in different solvents
Sulbactam sodium salt (20.0 g, 0.08 mol) was sus-
pended in DMSO (200 ml) and chloromethyl pivalate
(13.4 ml, 13.6 g, 0.09 mol) was added at one portion.
The mixture was stirred at 20–25°C for 18 h, than
cooled to 5°C and water (400 ml) was added dropwise.
After stirring for another 30 min the crystals were
filtered off and dried. Yield: 23.1 g sulbactam pivoxil
(85%).
a
Solvent
m
Yields of pivsulbactam (%)
Without catalyst With catalyst NaI
Dimethyl sulfoxide 48.9 85
85
58
83
Sulfolane
N,N-Dimethyl-
acetamide
44.0
37.0 62
3
Acetonitrile
N,N-Dimethyl-
formamide
1-Methyl-2-
pyrrolidone
Hexamethylphos-
phoric triamide
Acetone
37.5 traces (TLC)
36.7 35
7
64
To recrystallize the product, 96% ethanol (60 ml) was
heated to 60°C and sulbactam pivoxil (12.0 g) was
added portionwise. To the resulting clear solution was
added activated carbon (0.12 g), the mixture was stirred
5 min at 60°C and quickly filtered. The filtrate was
stirred for 30 min at room temperature and 1 h at 0°C.
The obtained crystals were collected by filtration,
washed with cold ethanol and dried. Yield: 10.7 g
pivsulbactam (90%), m.p. 90–92°C.
33
25
83
61
29.6 59
20.7 traces (TLC)
7.4
2.2
11
oil
oil
Tetrahydrofuran
1,4-Dioxan
a m, dielectric constant.
1
IR (KBr): w 2980, 1810–1745, 1320 cm−1. H NMR
(CDCl3): l 1.23 (s, 9H, ꢀC(CH3)3), 1.43 (s, 3H, 2-CH3),
1.59 (s, 3H, 2-CH3), 3.48 (m, 2H, J=16.3, J=4.0,
J=2.4 Hz, 6a- and 6b-H), 4.42 (s, 1H, 3-H), 4.64 (dd,
1H, J=2.4, J=4.0 Hz, 5-H), 5.72 (d, 1H, J=5.5 Hz,
ꢀCH2ꢀ), 5.96 (d, 1H, J=5.5 Hz, ꢀCH2ꢀ). Anal.
(C14H21NO7S) C, H, N.
poor. DMSO was also the solvent of choice in the
synthesis of pivsulbactam because of its low toxicity,
which is important for large-scale operations.
In all cases the isolated pivsulbactam had a high
purity (at least 98% by HPLC).
References
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Kellogg, J. Med. Chem. 33 (1990) 344.
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Chem. Abstracts, 94, 121511s; 1981.
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92,286; 1983. Chem. Abstracts, 100, 103056k; 1984.
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1987.
3. Experimental
Melting points were determined on Bu¨chi 512 ap-
paratus and are uncorrected. IR spectra (wmax, cm−1) in
KBr were recorded on a Schimadzu 435 spectrophoto-
1
meter. H NMR spectra (l, ppm; J, Hz) were deter-
mined on Bruker WM 250 spectrometer, using
3-trimethylsilylpropionic acid-d4 sodium salt (TSPA) as
an internal standard (for the numbering of the protons
see Scheme 1). The elemental analysis was carried out
on Perkin–Elmer 240 apparatus.
.