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
[1] Drugs Fut. 5 (1980) 123.
[2] A.R. English, J.A. Retsema, A.E. Girard, J.E. Lynch, W.E.
Barth, Antimicrob. Agents Chemother. 14 (1978) 414.
[3] M. Cole, Drugs Fut. 6 (1981) 697.
[4] W.E. Barth, DE 2,824,535; 1978. Chem. Abstracts, 90, 121589r;
1979.
[5] W.E. Barth, US 4,234,579; 1980. Chem. Abstracts, 94, 121521v;
1981.
[6] A.R. English, D. Girard, V.J. Jasys, R.J. Martingano, M.S.
Kellogg, J. Med. Chem. 33 (1990) 344.
[7] B.S. Moore, R.D. Carroll, R.A. Volkmann, DE 3,008,257; 1980.
Chem. Abstracts, 94, 121511s; 1981.
[8] P.W. Henniger, J.K. Van der Drift, J.C. Kapur, H.P. Fasel, EP
92,286; 1983. Chem. Abstracts, 100, 103056k; 1984.
[9] A.D.C. Stampa, ES 528,030; 1985. Chem. Abstracts 106, 18242x;
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.
.