A modified procedure for synthesis of the side chain of ceftazidime-activated thioester

Article abstract of DOI:10.1007/s11164-012-0583-0

A modified procedure for synthesis of the side chain of ceftazidime-activated thioester has been established. This key intermediate of ceftazidime was obtained by a more eco-friendly process than conventional methods, and the yield was much higher (up to

Full text of DOI:10.1007/s11164-012-0583-0

Res Chem Intermed (2013) 39:615–620
DOI 10.1007/s11164-012-0583-0
A modified procedure for synthesis of the side chain
of ceftazidime-activated thioester
Lei Li
Xilong Yan
•
Guangyuan Wang
Ligong Chen
•
Shanshan Wei
•
•
Received: 28 March 2012 / Accepted: 26 April 2012 / Published online: 18 May 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A modified procedure for synthesis of the side chain of ceftazidime-
activated thioester has been established. This key intermediate of ceftazidime was
obtained by a more eco-friendly process than conventional methods, and the yield
was much higher (up to 92.4 %). It was found that different organic bases (trieth-
ylamine or pyridine) used in this reaction had different effects. The reaction con-
ditions were also optimized to make the route more competitive and suitable for
large-scale industrial production.
Keywords Modified procedure ꢀ Synthesis ꢀ Intermediate ꢀ Ceftazidime-activated
thioester
Introduction
The discovery of penicillin in 1928 by Alexander Fleming initiated the use of
antibiotics to fight human diseases. As the third generation of the cephalosporin
antibiotics, ceftazidime is still extensively used in the treatment of many severe
inflammations, for example the septicemia and the lower respiratory tract infections
[
1, 2]. (Z)-2-Amino-a-[(2-tert-butoxy-1,1-dimethyl-2-oxo-ethoxy)imino]-4-thiazo-
leacetic-2-benzothiazolyl thioester (I), known, for brevity, as the side chain of
ceftazidime-activated thioester, is the key intermediate of ceftazidime. Intensive
attention has been devoted to improving the synthesis of I [3–8, 16, 17].
Conventional synthesis of I reported by Fu et al. [6] in 2002 was accomplished
by a condensation reaction, similar to the synthesis of other cephalosporin
intermediates [9–15]. This technique was used in the production of I and output
L. Li ꢀ G. Wang ꢀ S. Wei ꢀ X. Yan ꢀ L. Chen (&)
School of Chemical Engineering and Technology, Tianjin University,
Tianjin 300072, People’s Republic of China
e-mail: lgchen@tju.edu.cn
123

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L. Li et al.
S
S
S
S
S
2
H N
H
2
N
O
N
O
N
N
N
N
N
S
OH +
S
+ P(OCH3)3
S
N
N
3
CH CN
(H
3
C)
3
COOC(H
3
C)
2
C
O
O
3 2 3 3
C(CH ) COOC(CH )
II
DM
I
Scheme 1 Modified synthetic route of I
could meet the market demand at that time. Although the technique was
successfully established for synthesis of I, it suffered from several major
disadvantages from an industrial perspective, including high cost, environmental
pollution, and tedious work-up procedures. Another synthetic route for synthesis of
I was reported by Liang et al. [16] in 2008, with modification by Wang [17] in 2009.
In this advanced method, the shortcoming of high cost was solved by changing the
condensation agent from triphenylphosphine to triethylphosphite, but the yield was
low. In 2005 Li et al. [18] claimed that environmental pollution could be avoided by
recovering the by-product 2-mercaptobenzothiazole (M). However, this recovery
process was cumbersome and the purity of recovered M was unreported, making it
unsuitable for industrial applications.
In this paper, we propose a modified synthetic route to I (Scheme 1) and a
technique for recovery of M. This new method has potential for large-scale
industrial use.
Results and discussion
Previously, I was synthesized from (Z)-2-amino-a-[(2-tert-butoxy-1,1-dimethyl-
0
2
-oxo-ethoxy)imino]-4-thiazole acetic acid (II) via condensation with 2,2 -dib-
enzothiazyl disulfide (DM) in the presence of triphenylphosphine and triethylamine.
The solvent was toluene or dichloromethane [6–8]. According to the literature [16],
polarity increased from the reactants to the transition state during the reaction
process. Polar solvent could stabilize the transition state and reduce the activation
energy, which would accelerate the reaction effectively. In our study, trim-
ethylphosphite, instead of triphenylphosphine, was used as the condensation agent.
Although its boiling point is lower, trimethylphosphite is much more active and less
expensive than triphenylphosphine. Also, acetonitrile was chosen as solvent because
of its greater polarity than toluene and dichloromethane. After the reaction was
complete, the acetonitrile was recovered by distillation and reused; recovery was
9
3.2 %. The experimental results indicated that these modifications increased the
yield of I to 92.4 % (lit. [16]:81.0 %) and reduced the total cost, which made it
more competitive industrially.
An interesting phenomenon observed in our experiments was that different
organic bases (triethylamine or pyridine) used in this reaction had different effects.
In the traditional synthesis, triethylamine was treated as a reactant and it was used in
excess (the molar ratio of II to triethylamine was 1:1.2) [6–8, 16–18]. The literature
generally accepted that II reacted with triethylamine first, to give a carboxyl anion,
1
23

A modified procedure for synthesis of the side chain
617
Table 1 Yield and purity of product I with different molar ratios of reactants
a
Entry
Molar ratio
Yield/%
Purity/%
b
1
1.0:1.1:1.2:1.2
1.0:1.1:1.2:1.2
1.0:1.1:1.2:1.0
1.0:1.1:1.2:0.5
1.0:1.1:1.2:0.1
1.0:1.1:1.2:0.05
1.0:1.1:1.2:0
92.6
92.3
92.5
92.3
92.4
92.4
27.6
34.2
92.0
98.3
98.9
98.1
98.5
98.3
98.7
97.7
98.0
98.1
2
3
4
5
6
7
b
8
1.0:1.1:1.2:0.05
1.0:1.1:1.2:0.05
c
9
a
II:DM:trimethylphosphite:pyridine
b
c
The organic base was triethylamine
The solvent was recycled acetonitrile
and the organic base was consumed in the reaction [16]. Reducing the amount of
triethylamine substantially reduced the product yield, according to our experimental
results (Table 1, Entry 8). In our research, pyridine was selected as the organic base.
The experimental results showed that a catalytic amount of pyridine could initiate
the reaction effectively and give a satisfactory product yield (Table 1, Entry 6).
In this reaction pyridine acted as a catalyst and a modified reaction mechanism
(
Scheme 2) was proposed on the basis of the results.
Environmental protection has been emphasized in the modern chemical industry.
In traditional technology [6–8, 16, 17], the by-product M was discharged directly,
and this is now considered environmental unfriendly. M is a relatively weak acid,
because of the electron-withdrawing effect of benzothiazolyl, which enables it to
dissolve in aqueous sodium hydroxide. The impurities have low solubility in
aqueous sodium hydroxide, so M can be isolated from other impurities by filtration
of the alkaline solution. M precipitates as a solid when the alkaline filtrate is
acidified. The crude M was purified by recrystallization from methanol, with
recovery of 75.2 % and purity 99.5 %. As a result of these modifications, the new
technique is more eco-harmless. The recovered M could be used in other
applications, for example as a vulcanization accelerator, corrosion inhibitor, and
special metal agent.
Conclusions
In conclusion, in this modified method the target product I was obtained by an
environmental friendly process with a yield of 92.4 % and purity of 98.7 %. The by-
product M was recovered with a yield of 75.2 % and purity of 99.5 %. We observed
that different organic bases had different effects in this reaction; the results showed
that triethylamine was a reactant whereas pyridine was a catalyst. This synthetic
123

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L. Li et al.
S
H
2
N
S
O
N
2
H N
O
N
H
N
O
O
+
N
H
N
O
C(CH
3
)
2
COOC(CH
3
)
3
N
O
C(CH
3
)
2
COOC(CH
3 3
)
S
N
2
H N
H CO
O
3
OCH3
S
H
2
N
H
3
CO OCH
3
P
O
OCH
3
P
OCH
3
O
N
N
O
(H
3
C)
3
COOC(H
3
C)
2
C
O
N
S
S
O
3 2 3 3
C(CH ) COOC(CH )
N
N
S
S
S
2
H N
O
S
O
P
N
+
H
3
CO
OCH
3
S
N
OCH
3
N
O
3 2 3 3
C(CH ) COOC(CH )
S
N
N
S
S
H
SH
+
N
N
Scheme 2 Modified mechanism of the condensation reaction using pyridine
technique was also improved and optimized to be more effective, competitive, and
suitable for large-scale industrial production.
Experimental
General information
Reagents and solvents were obtained from commercial suppliers. Anhydrous
acetonitrile was distilled from phosphorus pentoxide. The purity of product was
determined by HPLC at 25 °C (Agilent 1100 equipped with a Zorbax Eclipse XDB-
C18, 5 lm, 4.6 9 250 mm column and an Agilent 1100 VWD detector, and with
acetonitrile as mobile phase). Melting points were measured on a YRT-3 Melting
Point Tester and are uncorrected. IR spectra were recorded as KBr pellets on a
Bruker-Tensor 27 spectrometer. NMR spectra were recorded on a Varian Inova-
400 MHz NMR spectrometer with residual solvent peaks as internal references. MS
were recorded on an LCQ Advanced MAX mass spectrometer.
General procedure for preparation of compound I
To stirred acetonitrile (80 mL) under dry N in a 250-mL four-necked flask were
2
added (Z)-2-amino-a-[(2-tert-butoxy-1,1-dimethyl-2-oxo-ethoxy)imino]-4-thiazole
1
23

A modified procedure for synthesis of the side chain
619
acetic acid (II, 9.87 g, 30.0 mmol), 2,2’-dibenzothiazyl disulfide (DM, 10.96 g,
3
2
3.0 mmol), and pyridine (0.12 g, 1.50 mmol). The mixture was stirred for 0.5 h at
5 °C. Trimethylphosphite (4.46 g, 36.0 mmol) was added very slowly to the
mixture, with stirring, over 1 h. The reaction mixture was stirred for 6 h at 25 °C.
Then the mixture was filtered and the filter cake was washed with acetonitrile
(
2 9 100 mL). The filter cake was dried under vacuum at 0.096 MPa for 3 h at
0 °C to give compound I (13.25 g).
5
(
2
Z)-2-amino-a-[(2-tert-butoxy-1,1-dimethyl-2-oxo-ethoxy)imino]-4-thiazoleacetic-
-benzothiazolyl thioester (I)
Faint yellow solid. Yield: 92.4 %, Purity: 98.7 %; Melting point: 137–139 °C (lit.
[
6]:138–140 °C). IR (KBr) 3296, 3136, 2991, 1733, 1657, 1543, 1456, 1368, 1312,
-
1 1
1
146, 760 cm . H NMR (400 MHz, CDCl ) d (ppm): 1.48 (9H, s), 1.58 (6H, s), 6.80
3
(
1H, s), 7.45–7.49 (1H, m), 7.52–7.55 (1H, m), 7.94 (1H, d, J = 8.0 Hz), 8.08 (1H, d,
1
3
J = 8.0 Hz). C NMR (100 MHz, CDCl ) d(ppm):185.2, 173.2, 170.4, 155.9, 152.0,
3
148.6, 140.5, 136.6, 126.7, 126.1, 123.4, 121.4, 110.9, 84.4, 82.1, 28.2, 23.8. MS (ESI)
m/z: calcd. for C H N O S 479.08 (positive ion), found 479.1 (positive ion).
2
0 23 4 4 3
General procedure for the recovery of compound M
The above filtrate was distilled and the fraction (acetonitrile) boiling at 81–82 °C
was collected. The volume of acetonitrile obtained was 261 mL, and the recovery
was 93.2 %. To the residual oil were added deionized water (100 mL) and 10 %
(
w/w) aqueous sodium hydroxide (25 mL) to adjust the pH to 10–11, the mixture
was stirred for 0.5 h, then the solid was isolated by filtration. To the filtrate was
added 2 mol/L HCl (35 mL) to adjust the pH to 1–2, and the mixture was stirred for
0
.5 h. The solid was isolated by filtration then recrystallized from methanol. The
mixture was cooled to room temperature, and the precipitated solid was isolated by
filtration. The filter cake was dried under vacuum at 0.096 MPa for 3 h at 50 °C to
give compound M (3.77 g).
2
-Mercaptobenzothiazole (M)
White solid. Yield: 75.2 %; Purity: 99.5 %. Melting point: 178–180 °C (lit.
[
19]:179–182 °C). IR (KBr) 3113, 3074, 3041, 2575, 1641, 1582, 1497, 1456, 1320,
-1 1
1
245, 751 cm
. H NMR (400 MHz, CD OD) d (ppm): 7.23–7.28 (2H, m),
13
3
7
.33–7.37 (1H, m), 7.51 (1H, d, J = 8.0 Hz). C NMR (100 MHz, CD OD) d
3
(ppm): 192.6, 142.5, 131.4, 128.1, 125.3, 122.4 and 113.1. MS (ESI) m/z: calcd. for
C H NS 165.98 (negative ion), found 166.3 (negative ion).
7
4
2
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