One-pot synthesis of cefpirome sulfate from GCLE

Article abstract of DOI:10.1080/00397911003629499

Cefpirome was synthesized in 37.7% overall yield from 3-chloromethyl-7- phenylacetylamino cephalosporanic acid p-methoxybenzyl ester (GCLE) by sequential substitution of C-3 chloride with iodide and 2,3- cyclopentenopyridine, followed by a one-pot procedure including deprotection of carboxyl group, hydrolysis of 7-phenylacetamido, and reaction with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (MAEM). The reaction conditions were as follows: obtained from GCLE at low temperature (-5 to 0°C) and absence of light, 3-iodomethyl-7- phenylacetylamino cephalosporanic acid p-methoxybenzyl ester (GILE) without purification was reacted directly with 2,3-cyclopentenopyridine, in which the molar ratio of GCLE, NaI, and 2,3-cyclopentenopyridine was 1:2:4, and the molar ratio of the resulting compound p-methoxybenzyl 7-phenylacetylamido-3-(2,3- cyclopenteno-1-pyridinio)methyl-3-cephem-4-carboxylate iodide and MAEM was 1:1.1. The structure of the intermediate and the target compound obtained were determined by nuclear magnetic resonance spectra and mass spectroscopy.

Full text of DOI:10.1080/00397911003629499

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One-Pot Synthesis of Cefpirome Sulfate
from GCLE
Xuemin Duan a , Yao Lu a , Juan Han b , Ligong Chen c & Pengwu
Zheng a
a School of Pharmacy, Jiangxi Science and Technology Normal
University, Nanchang, China
b School of Chemistry, University of Nottingham, Nottingham, United
Kingdom
c School of Chemical Engineering and Technology, Tianjin University,
Tianjin, China
Published online: 31 Jan 2011.
To cite this article: Xuemin Duan , Yao Lu , Juan Han , Ligong Chen & Pengwu Zheng (2011) One-Pot
Synthesis of Cefpirome Sulfate from GCLE, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 41:5, 629-636
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Synthetic Communications1, 41: 629–636, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911003629499
ONE-POT SYNTHESIS OF CEFPIROME SULFATE
FROM GCLE
Xuemin Duan,1 Yao Lu,1 Juan Han,2 Ligong Chen,3 and
Pengwu Zheng1
1School of Pharmacy, Jiangxi Science and Technology Normal University,
Nanchang, China
2School of Chemistry, University of Nottingham, Nottingham,
United Kingdom
3School of Chemical Engineering and Technology, Tianjin University,
Tianjin, China
Abstract Cefpirome was synthesized in 37.7% overall yield from 3-chloromethyl-7-
phenylacetylamino cephalosporanic acid p-methoxybenzyl ester (GCLE) by sequential
substitution of C-3 chloride with iodide and 2,3-cyclopentenopyridine, followed by a one-pot
procedure including deprotection of carboxyl group, hydrolysis of 7-phenylacetamido, and
reaction with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate
(MAEM). The reaction conditions were as follows: obtained from GCLE at low temperature
(ꢀ5 to 0 ꢁC) and absence of light, 3-iodomethyl-7-phenylacetylamino cephalosporanic acid
p-methoxybenzyl ester (GILE) without purification was reacted directly with 2,3-cyclopente-
nopyridine, in which the molar ratio of GCLE, NaI, and 2,3-cyclopentenopyridine was 1:2:4,
and the molar ratio of the resulting compound p-methoxybenzyl 7-phenylacetylamido-3-
(2,3-cyclopenteno-1-pyridinio)methyl-3-cephem-4-carboxylate iodide and MAEM was
1:1.1. The structure of the intermediate and the target compound obtained were determined
by nuclear magnetic resonance spectra and mass spectroscopy.
Keywords Antibiotics; cefpirome; GCLE; onepot
Received November 3, 2009.
Address correspondence to Xuemin Duan, School of Pharmacy, Jiangxi Science and Technology
Normal University, Nanchang, China. E-mail: duanxuemin@126.com or Ligong Chen, School of
Chemical Engineering and Technology, Tianjin University, Tianjin, China. E-mail: lgchen@tju.edu.cn
629

630
X. DUAN ET AL.
INTRODUCTION
Until now, the synthesis of cefpirome has always used cephalosporin com-
pounds containing the 7-aminocephalosporanic acid nucleus as starting materials,[1]
through the introduction of the 2,3-cyclopenteno-1-pyridinio group at the C-30
position and the 2-syn-methoxyimino-2-(amino-4-thiazolyl)-acetyl group at the 7b
position. These synthetic methods could be summarized in two approaches.
In one approach, cefotaxime 1 is obtained first by a coupling reaction of
2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate (MAEM)
and 7-aminocephalosporanic acid (7-ACA),[2] and then the 2,3-cyclopenteno-1-
pyridinio group is introduced at the C-30 (methods A, B, and C, shown in
Scheme 1). Among them, method A is applied generally for introducing C-30-
substituted pyridine homologs, but its yield was poor. Single-step yield was 10% to
30%, and the overall yield of cefpirome preparation was 23%. Despite the good yield
of method B in the preparation of cefpirome, more than 50% for pyridine homologs
with different substituents, it had disadvantages of the use of acetonitrile and the
requirement for expensive N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA)
Scheme 1. Synthesis of cefpirome from cefotaxime.

ONE-POT SYNTHESIS OF CEFPIROME SULFATE
631
Scheme 2. Synthesis of cefpirome from 7-ACP.
Scheme 3. Synthesis of 7-ACP.
Scheme 4. Synthesis of cefpirome from GCLE.

632
X. DUAN ET AL.
or bis(trimethylsilyl)trifluoroacetamide (BSTFA) as silylating agents. Methods B and
C had the same principle. Amino and carboxyl groups of cefotaxime were protected
with trimethylsilyl before the C-30 chloride was replaced by iodine, and then the
2,3-cyclopenteno side chain was introduced. However, with the less active iodide
reagent, the yields of method C had significant variation for pyridine homologs with
different substituents, which limited its universal application.
In the other approach, 7-ACP is prepared first and then reacted with
2-(2-aminothiazole-4-yl)-2-methoxyiminoacetic acid (ATMA) or its derivatives such
as acylchloride, acid anhydride, and active ester (Scheme 2). This method is easy to
operate. ATMA or its active ester, particularly the widely used MAEM, was com-
mercially available. The key to this approach was the effective synthesis of 7-ACP.
The current synthesis of 7-ACP from 7-ACA is shown in Scheme 3. Similar to
methods B and C, this method also depends on the use of MSTFA, BSTFA, or iodo-
trimethylsilane, so its prospect of application is very limited.
Because of the availability of raw materials, cost, and operational convenience,
cefpirome was synthesized from 3-chloromethyl-7-phenylacetylamino cephalospora-
nic acid p-methoxybenzyl ester (GCLE) in this article (Scheme 4). The scheme has
advantages of commercially available reactants, ease of operation, low cost, and so on.
DISCUSSION
Modification of the C-30 Position of GCLE
3-Iodomethyl-7-phenylacetylamino cephalosporanic acid p-methoxybenzyl
ester (GILE) could be prepared by the replacement of chlorine at the C-30 position
of GCLE with iodine. Because iodine is less electronegative than chlorine, which
enhanced the polarization degree of the C-I bond and made the iodine atom a better
leaving group, the activity of GILE was enhanced, and C-30 electrophilic substitution
with tertiary amines or pyridine derivatives could take place easily. The modification
of C-30 of GCLE is shown in Scheme 5.
Scheme 5. Modification of C-30 of GCLE.

ONE-POT SYNTHESIS OF CEFPIROME SULFATE
633
Scheme 6. Hydrolysis of ester bond of 7-ACA.
Methyl ethyl ketone,[3] methyl isobutyl ketone,[4] or acetone[5] could be used as
solvents in the iodine replacement reaction, and sodium iodide or potassium iodide
could be used as iodination agents. Acetone and sodium iodide were used in this study.
Deprotection of Ester
It is known that ester hydrolysis is a classic reaction that can be achieved in
many ways, including acid hydrolysis and alkaline hydrolysis. Different conditions
were adopted according to specific purposes in the synthesis of drugs or intermedi-
ates containing the b-lactam ring. For example, alkaline conditions were applied in
the hydrolysis of 7-ACA into 7-amino-3-hydroxymethyl-cephalosporin acid
(Scheme 6),[6] but acidic conditions were applied in the synthesis of tazobactam
(Scheme 7).[7]
It was reported that the use of formic acid=dilute hydrochloric acid[3] or
phenol=hydrochloric acid mixture to remove the methoxy benzyl group was easy
to operate and had a good yield. We studied phenol and acid=dilute hydrochloric
acid for the deprotection of the ester and successfully removed the ester by phenol
with good yield.
Removal of Phenyl Acetyl Side Chain
The phenyl acetyl side chain could be removed by chemical or enzymatic reac-
tions. Chemical reactions had many disadvantages such as more steps, longer reac-
tion time, higher cost, and serious waste pollution, while microbial enzymatic
methods could remove the acetyl side chain with high specificity and selectivity. In
this study, we used penicillin G acylase (PGA) to remove the phenyl acetyl side chain
and achieved good results.
Scheme 7. Synthesis of tazobactam.

634
X. DUAN ET AL.
EXPERIMENTAL
1H NMR and 13C NMR spectra were recorded on a Bruker AV400 spec-
trometer using tetramethylsilane (TMS) as internal standard. Gas chromatography=
mass spectrometry (GC=MS) analyses were carried out on an HP5890 gas chroma-
tograph, coupled with an HP5971A mass spectrometer. The purity analysis of cefpir-
ome was performed on an Agilent 1100 high-performance liquid chromatographic
(HPLC) system with a Zorbax SB-C18 column (5 mm, 4.6 ꢂ 150 mm). Melting point
(mp) was determined on a YRT-3 melting-point apparatus (Precision Instrument
Plant, Tianjin University) and is uncorrected. PGA was purchased from Hunan Flag
Biotechnology Co., Ltd., China.
p-Methoxybenzyl 7-Phenylacetylamido-3-(2,3-cyclopenteno-1-
pyridinio)methyl-3-cephem-4-carboxylate Iodide (3)
To a suspension of NaI (3.07 g, 20.5 mmol) in acetone (60 mL) at ꢀ5 ꢁC, GCLE
(5.00 g, 10.3 mmol) was added. The mixture was stirred at ꢀ5 to 0 ꢁC under N2 in the
dark for 5 h. Ethyl acetate (60 mL) and water (40 mL) were added. The two phases
were separated, and the aqueous phase was extracted with ethyl acetate (2 ꢂ 30 mL).
The combined organic phase was washed with 10% sodium thiosulfate solution
(2 ꢂ 80 mL) and saturated saline (80 mL), dried with Na2SO4, and filtered. The fil-
trate was cooled to ꢀ5 ꢁC, and a solution of 2,3-cyclopentenopyridine (4.90 g,
41.1 mmol) in ethyl acetate (10 mL) was added dropwise under N2 protection. The
resulting solution was stirred at ꢀ5 ꢁC for 10 h and filtered. The filter cake was
washed with ethyl acetate and dried in vacuo. Yield 5.04 g (75.4%) of a pale yellow
1
solid: H NMR (400 MHz, DMSO-d6) d: 2.10–2.17 (m, 2H), 3.10–3.17 (m, 4H),
3.48–3.57 (m, 4H), 3.75 (s, 3H), 5.15–5.17 (m, 2H), 5.29 (d, J ¼ 6.0 Hz, 1H), 5.48
(s, 2H), 5.79 (dd, J1 ¼ 4.8 Hz, J2 ¼ 8.0 Hz, 1H), 6.91 (d, J ¼ 4.2 Hz, 2H), 7.21–7.33
(m, 7H), 7.89 (t, J ¼ 7.2 Hz, 1H), 8.40 (d, J ¼ 4 Hz, 1H), 8.56 (d, J ¼ 3 Hz, 1H),
9.14 (d, J ¼ 4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d: 21.88, 25.33, 30.45,
31.33, 41.50, 55.15, 57.65, 58.13, 59.38, 67.81, 113.78 (2C), 119.44, 125.50, 126.45
(2C), 127.82, 128.15 (2C), 128.91 (2C), 130.56 (2C), 135.63, 141.00, 141.11, 145.31,
159.43, 161.11, 161.61, 165.06, 170.86.
Cefpirome Sulfate (4)
A solution of compound 3 (1.80 g, 2.58 mmol) in phenol (10 g) was stirred at
50 ꢁC for 4.5 h before acetone (10 mL) was added, and the mixture was poured into
a beaker. Ether (120 mL) was added slowly while stirring, during which time a pre-
cipitate formed. The resulting suspension was stirred for 30 min. The precipitate was
filtered and washed with a mixture of acetone (30 mL) and ether (60 mL). The filter
cake was dissolved in sodium acetate solution (20 mL, pH 8.2) and stirred. The pH
value of the mixture was adjusted to 8.0–8.5 at 37 ꢁC using 13% ammonia water.
PGA (1.50 g) was added, the pH value was maintained at 8.0–8.5 for 2 h using 5%
ammonia water, and then PGA was filtered. The filtrate and tetrahydrofuran
(THF, 50 mL) were added into a flask. After adjusting the pH value to 6.8–7.2 using
hydrochloride (2 mol=L), MAEM (1.00 g, 2.85 mmol) was added, and the reaction

ONE-POT SYNTHESIS OF CEFPIROME SULFATE
635
was stirred at 25 ꢁC for 6.5 h. The mixture was extracted with ethyl acetate
(2 ꢂ 40 mL). The aqueous phase was cooled to 5 ꢁC, and the pH value was adjusted
to 1–2 using 20% H2SO4. A large amount of ethanol was added while stirring. After
standing in a refrigerator for 2 h, the precipitate formed, was collected by filtration,
and was dried in vacuo. Yield 0.79 g (50.0%) of a white solid: mp > 200 ꢁC; analytical
HPLC: 98.72%; 1H NMR (400 MHz, DMSO-d6) d: 2.19–2.25 (m, 2H), 3.11–3.15 (m,
2H), 3.25–3.29 (m, 2H), 3.40 (s, 2H), 3.81 (s, 3H), 5.17 (d, J ¼ 2.4 Hz, 1H), 5.50 (AB,
J ¼ 15.2 Hz, 2H), 5.86 (dd, J1 ¼ 5.2 Hz, J2 ¼ 8.4 Hz, 1H), 6.72 (s, 1H), 7.25 (d,
J ¼ 3.6 Hz, 2H), 7.93 (t, J ¼ 7.2 Hz, 1H), 8.43 (d, J ¼ 3.8 Hz, 1H), 8.64 (d, J ¼ 3.2 Hz,
Hz, 1H), 9.62 (d, J ¼ 4.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) d: 21.99, 25.09,
30.51, 31.43, 57.53, 58.29, 58.90, 61.86, 108.84, 118.81, 125.61, 128.87, 141.14,
141.33, 142.12, 145.32, 148.75, 161.93, 162.82 (2C), 163.73, 168.39; MS:
m=z ¼ 612.6 (M þ H2SO4)þ.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support of the Foundation of Engin-
eering Centre of Jiangxi University for Fine Chemicals.
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