Design and synthesis of new cephalosporin antibiotics

Article abstract of DOI:10.1007/s00706-014-1152-6

Cephalosporins are important antibiotics. We synthesized new cephalosporin analogs containing novel side chains of methyl, propyl, benzyl, and phenoxy groups. Four synthetic methods with N-alkylation and N-acylation at position C-7 and esterification at position C-4 of 7-aminodesacetoxycephalosporanic acid are reported here. Graphical Abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-014-1152-6

Monatsh Chem
DOI 10.1007/s00706-014-1152-6
ORIGINAL PAPER
Design and synthesis of new cephalosporin antibiotics
•
Chunjing Liu Dinah Dutta Lester Mitscher
•
Received: 29 August 2013 / Accepted: 6 January 2014
Ó Springer-Verlag Wien 2014
Abstract Cephalosporins are important antibiotics. We
synthesized new cephalosporin analogs containing novel
side chains of methyl, propyl, benzyl, and phenoxy groups.
Four synthetic methods with N-alkylation and N-acylation
at position C-7 and esterification at position C-4 of
7-aminodesacetoxycephalosporanic acid are reported here.
been carried out by tert-butyl [9], ethyl [10], and acet-
oxymethyl ester groups [11].
In this work, we designed and synthesized novel cepha-
losporins with new side chains. N-Alkylation and
N-acylation of 7-aminodesacetoxycephalosporin (7-ADCA)
at position C-7 were performed with methyl, propyl, benzyl,
and phenoxy groups as amino and amido side-chain moie-
ties. Esterification of C-4 carboxylic acid was carried out
with methyl, propyl, and benzyl groups. We developed four
synthetic methods to achieve these formations. These
methods are simple and convenient for parallel synthesis,
which can be used for building compound libraries.
Keywords Cephalosporin Á Antibiotics Á Alkylation Á
Esterification Á Side chains
Introduction
Cephalosporins are b-lactam antibiotics for treatment of
infectious diseases. Chemical manipulation of cephalo-
sporin has led to development of important marketed
antibiotics [1–3]. Considerable interest has focused on
modification of the substituent at C-3 position and side
chains at position C-4 and C-7 of the cephem nucleus to
obtain a variety of cephalosporin analogs with enhanced
antibacterial activity. Alteration at C-3 position of the
cephem nucleus has been carried out with methyl [4],
propenyl [5], and imidazo[1,2-b]pyridazinium-1-ylmethyl
[6]. Modification at position C-7 of the cephem nucleus has
been undertaken with thiophene-2-acetamido [7], 2-amino-
2-phenoxyacetyl [8], and benzylacetyl groups [9].
Replacement at position C-4 of the cephem nucleus has
Results and discussion
Synthesis of cephalosporin secondary amino derivatives
from 7-ADCA was carried out with propyl iodide in the
presence of sodium bicarbonate (Scheme 1). The amino
group at C-7 and the carboxyl group at C-4 of 7-ADCA
become strong nucleophiles under basic conditions. C-4
carboxylate nucleophile conducted SN2 reaction with propyl
iodide to yield 7-ADCA ester. Simultaneously, C-7 primary
amine nucleophile attacked propyl iodide through an SN2
reaction to form the secondary amine 2. This is an effective
and convenient procedure for simultaneous N-alkylation at
C-7 position and esterification on the C-4 carboxyl group of
7-ADCA with sodium bicarbonate as base.
Treatment of 7-ADCA and sodium bicarbonate with two
equivalents of propyl iodide in dimethylformamide (DMF)
formed a carboxylate propyl ester crude product. The res-
idue was purified by silica gel column chromatography
with EtOAc/n-hexane as eluent to yield carboxylate propyl
ester 2. Only monoalkyl product 2 was obtained in this
reaction condition. Other polyalkyl products were not
C. Liu (&) Á D. Dutta
Higuchi Biosciences Center, The University of Kansas,
Lawrence, KS 66045, USA
e-mail: cjliu2@gmail.com
L. Mitscher
Department of Medicinal Chemistry, The University of Kansas,
Lawrence, KS 66045, USA
123

C. Liu et al.
in DMF (Scheme 3). After treatment of 4 in DMF with
methyl iodide at room temperature for 3 h, water was
added to the reaction mixture and extracted with diethyl
ether. The organic solvent was removed and the residue
was purified by silica gel column chromatography with
EtOAc/n-hexane as eluent to yield complete formation of
methyl carbamate methyl ester 4a, propyl carbamate pro-
pyl ester 4b, benzyl carbamate benzyl ester 4c, and
benzothiazole methyl carbamate benzothiazole methyl
Scheme 1
1
ester 4d. In H NMR spectra, for product 4a, the 3-proton
Scheme 2
singlet peak of methyl group attached to C-7 carbamate
appears at 3.85 ppm. The 3-proton singlet peak of methyl
group attached to C-4 carboxyl group centers at 3.75 ppm.
1
Products 4b, 4c, and 4d were identified by H NMR, 13C
NMR, and high resolution mass spectrometry.
Synthesis of cephalosporin with C-7 phenoxyacetyl
amide and C-4 propyl ester proceeded in three steps
(Scheme 4). The first step was N-acylation at C-7 to obtain
phenoxyacetyl amido 7-ADCA carboxylic acid. The sec-
ond step was to make potassium salt of carboxylic acid.
The third step was to make carboxylate ester by SN2
reaction between potassium salt and propyl iodide. To a
cooled aqueous solution of 7-ADCA containing sodium
bicarbonate, phenoxyacetyl chloride in acetone was added.
The clear aqueous solution was acidified with cold sulfuric
acid solution and extracted with methyl isobutyl ketone
(MIBK). The extracted solution was mixed with potassium
2-ethylhexanoate in 1-butanol. The resulting precipitated
white solid was collected by filtration to give product
7-ADCA phenoxyacetyl potassium salt 6 in 60 % yield. To
6 in DMF, propyl iodide was added and stirred at room
temperature for 12 h. The solvent was removed and the
residue was purified by column chromatography with
EtOH/n-hexane to get product 7a in 69 % yield. The car-
boxyl benzyl ester 7b was obtained with the same
procedures by using benzyl bromide in the last step SN2
reaction.
observed. Product 2 was identified by 1H nuclear magnetic
resonance (NMR), 13C NMR, and high resolution mass
spectrometry.
Synthesisofcephalosporintertiaryaminoderivativesfrom
7-ADCA was carried out with methyl iodide and benzyl
bromide in the presence of sodium bicarbonate (Scheme 2).
The amino group at C-7 and carboxyl group at C-4 of
7-ADCA are more nucleophilic under basic conditions. C-4
carboxyl nucleophile attacked alkyl halides to form 7-ADCA
esters. At the same time, two protons at C-7 primary amine
were both replaced by alkyl groups to obtain tertiary amine
products 3a and 3b. Treatment of 7-ADCA and sodium
bicarbonate with 3 equivalents of methyl iodide or benzyl
1
bromide in DMF yielded final products 3a and 3b. In H
NMR spectra, for product 3a, the 6-proton singlet peak rep-
resenting two methyl groups attached to the amino group was
found at 2.48 ppm. The 3-proton singlet of methyl group
attached to the carboxyl group appeared at 3.79 ppm. For
compound 3b, the 1H NMR spectra showed that two benzyl
groups connected to the amino group.
Phenoxyacetyl amide esters 7a and 7b were identified
1
by H NMR, 13C NMR, and high resolution mass spec-
1
trometry. In H NMR spectra, for product 7a, complex
C-7 N-acylation and C-4 carboxyl esterification of
7-ADCA to form cephalosporin amide esters can be
achieved in two steps (Scheme 3). The first step is carba-
mate formation. 7-ADCA was dissolved in water
containing five equivalents of sodium bicarbonate. The
reaction was completed by using microwave synthesizer
irradiation at 70 °C for 2 h. The concentrated aqueous
solution was then lyophilized overnight to obtain 7-ADCA
patterns of benzene ring protons were found at 7.20 ppm
and 2-proton singlet peak of methylene was visible at
4.57 ppm. The 2-proton of methylene in propyl group
attached to carboxyl group appears at 4.25 ppm as multiple
peaks. These findings confirm the presence of phenoxy-
1
acetyl and propyl side chains. For product 7b, H NMR
signals indicated the presence of phenoxyacetyl and benzyl
side chains.
1
carbamate 4, which was characterized by H NMR, 13C
Over the past six decades, numerous modifications of
side chains of cephalosporin have been undertaken and
many cephalosporins synthesized [1, 2], leading to the
marketing of several antibiotics [3, 5]. According to our
SciFinder search, the side chains selected in this work are
NMR, and high resolution mass spectrometry.
Synthesis of cephalosporin amide esters was achieved
through SN2 reactions in parallel between carbamate salt 4
with various aliphatic, aromatic, and heterocyclic bromides
123

Design and synthesis of new cephalosporin antibiotics
Scheme 3
Scheme 4
novel and nine cephalosporin analogs reported herein are
new. These compounds were deposited into the NIH
Molecular Library Small Molecule Repository. They were
screened, and their biological results were deposited into
PubChem.
Melting points were determined using a Barnstead Inter-
national MET-TEMPÒ capillary melting point apparatus,
1
model 1001D-120VAC. H NMR and 13C NMR spectra
were recorded on a 400-MHz spectrometer (400 and
100 MHz, respectively), or a 500-MHz spectrometer (500
and 125.5 MHz, respectively). Abbreviations are as fol-
lows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet. High resolution mass spectrometry (HRMS)
Conclusions
spectra were obtained on
spectrometer.
a double-focusing mass
Novel amino and amide side chains at C-7 position of
cephalosporin nucleus and ester side chains at C-4 position
were designed. Nine new cephalosporin analogs were
synthesized. Synthetic methods for N-alkylation and
N-acylation and esterification of carboxyl moiety of
cephalosporin nucleus were developed in this work.
The biological activity of the compounds can be found
in PubChem by using their compound identification num-
bers: 247935 (2), 25011655 (3a), 24816504 (3b),
24789294 (4a), 24789354 (4b), 25011056 (4c), 25011654
(4d), 25011659 (7a), and 25011657 (7b).
Propyl (6R,7R)-3-methyl-8-oxo-7-(propylamino)-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylate
Experimental
(2, C14H22N2O3S)
7-ADCA (1, 215 mg, 1.0 mmol) was dissolved in 10 cm3
of water containing 250 mg of sodium bicarbonate
(3.0 mmol, 3.0 equiv.). The yellow mixture solution was
treated with 2 equivalents of propyl iodide in DMF and
Column chromatography was carried out by employing
silica gel (230–400 mesh). Thin-layer chromatography
(TLC) was performed on a silica gel W/UV254 Uni-
plateTM. Anhydrous organic solvents were purchased.
123

C. Liu et al.
stirred at room temperature for 12 h. Water was added to
the reaction mixture and extracted with diethyl ether
(3 9 50 cm3). The organic layer was washed with water
and dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure. The residue was purified
by silica gel column chromatography (1:2 EtOAc/
n-hexane) to obtain carboxylate propyl ester 2 as colorless
n-hexane) to yield the complete formation of carboxylate
1
benzyl ester 3b as a colorless semisolid (35 %). H NMR
(400 MHz, CDCl3): d = 7.28–7.44 (m, 15H), 5.34–5.23
(m, 2H), 4.77 (d, J = 4.6 Hz, 1H), 4.70 (d, J = 4.6 Hz,
1H), 3.93–4.04 (m, 4H), 3.46 (d, J = 18.4 Hz, 1H), 3.18
(d, J = 18.4 Hz, 1H), 2.09 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d = 165.30, 162.36, 138.22, 135.27,
129.13, 129.05, 128.86, 128.64, 128.43, 128.40, 127.29,
71.82, 67.59, 58.66, 56.42, 30.64, 20.06 ppm; HRMS
(FAB): m/z calcd. for C29H29N2O3S [M?H]? 485.1899,
found 485.1902.
1
semisolid (25 %). H NMR (400 MHz, CDCl3): d = 5.24
(s, 1H), 4.92 (d, J = 4.6 Hz, 1H), 4.56 (d, J = 4.6 Hz,
1H), 4.24–4.12 (m, 2H), 3.51 (d, J = 18.2 Hz, 1H), 3.19
(d, J = 18.2 Hz, 1H), 2.78–2.67 (m, 2H), 2.10 (s, 3H),
1.74–1.69 (m, 2H), 1.55–1.51 (m, 2H), 0.98–0.92 (m, 6H)
ppm; 13C NMR (100 MHz, CDCl3): d = 162.66, 123.04,
69.70, 67.16, 58.37, 51.04, 29.93, 23.57, 21.88, 19.99,
11.52, 10.45 ppm; HRMS (FAB): m/z calcd. for
C14H23N2O3S [M?H]? 299.1429, found 299.1436.
Sodium (6R,7R)-7-(carboxylatoamino)-3-methyl-8-oxo-5-
thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
(4, C9H8N2Na2O5S)
7-ADCA (215 mg, 1.0 mmol) was dissolved in 10 cm3 of
water containing 300 mg of sodium bicarbonate
(3.5 mmol, 3.5 equiv.). The reaction was carried out in
microwave at 70 °C for 2 h. The concentrated aqueous
solution was then lyophilized overnight to obtain 300 mg
(99 %) yellow powder 4. M.p.: 218–220 °C; 1H NMR
(400 MHz, CDCl3): d = 5.28 (d, J = 4.6 Hz, 1H), 4.94 (d,
J = 4.6 Hz, 1H), 3.52 (d, J = 17.9 Hz, 1H), 3.12 (d,
J = 18.0 Hz, 1H), 1.81 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): d = 170.36, 169.25, 166.98, 163.03, 160.59,
126.43, 121.69, 61.47, 58.20, 28.16, 18.43 ppm; HRMS
(FAB): m/z calcd. for C9H9N2Na2O5S [M?H]? 303.0027,
found 303.0031.
Methyl (6R,7R)-7-(dimethylamino)-3-methyl-8-oxo-5-thia-
1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
(3a, C11H16N2O3S)
7-ADCA (1, 215 mg, 1.0 mmol) was dissolved in 10 cm3
of water containing 420 mg of sodium bicarbonate
(5.0 mmol, 5.0 equiv.). The yellow mixture solution was
treated with three equivalents of methyl iodide in DMF and
stirred at room temperature for 12 h. Water was added to
the reaction mixture and extracted with diethyl ether
(3 9 50 cm3). The organic layer was washed with water
and then dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue was
purified by silica gel column chromatography (1:3 EtOAc/
n-hexane) to yield the complete formation of carboxylate
General procedure for carbamate esters 4a–4d
1
methyl ester 3a as a colorless semisolid (30 %). H NMR
Methyl (6R,7R)-7-(methoxycarbonylamino)-3-
(400 MHz, CDCl3): d = 4.84 (d, J = 4.4 Hz, 1H), 4.03 (d,
J = 4.5 Hz, 1H), 3.85 (s, 3H), 3.48 (d, J = 18.4 Hz, 1H),
3.21 (d, J = 18.4 Hz, 1H), 2.45 (s, 6H), 2.12 (s, 3H) ppm;
13C NMR (100 MHz, CDCl3): d = 163.51, 162.85, 130.68,
122.68, 75.42, 57.22, 52.31, 44.75, 30.81, 19.96 ppm;
HRMS (FAB): m/z calcd. for C11H17N2O3S [M?H]?
257.0960, found 257.0969.
methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylate (4a, C11H14N2O5S)
To a suspension of 90 mg 4 (0.3 mmol) in 5 cm3 DMF was
added 0.4 cm3 methyl iodide (0.6 mmol). The reaction
mixture was stirred at room temperature for 3 h. Water was
added to the reaction mixture and extracted with diethyl
ether (3 9 10 cm3). The organic layer was washed with
water and then dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure and the residue was
purified by silica gel column chromatography (1:2 EtOAc/
n-hexane) to yield the complete formation of the methyl
carbamate methyl ester 4a as colorless semisolid (50 %).
1H NMR (400 MHz, CDCl3): d = 5.63 (m, 1H), 5.41 (d,
J = 5.6 Hz, 1H), 4.99 (d, J = 4.8 Hz, 1H), 3.85 (s, 3H),
3.76 (s, 3H), 3.53 (d, J = 18.0 Hz, 1H), 3.24 (d,
J = 18.2 Hz, 1H), 2.17 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d = 163.49, 162.61, 156.11, 130.69,
122.44, 75.41, 57.21, 52.41, 44.73, 30.80, 30.13,
20.01 ppm; HRMS (FAB): m/z calcd. for C11H18N3O5S
[M?NH4]? 304.0967, found 304.0990.
Benzyl (6R,7R)-7-(dibenzylamino)-3-methyl-8-oxo-5-thia-
1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
(3b, C29H28N2O3S)
7-ADCA (1, 215 mg, 1.0 mmol) was dissolved in 10 cm3
of water containing 420 mg of sodium bicarbonate
(5.0 mmol, 5.0 equiv.). The yellow mixture solution was
treated with three equivalents of benzyl bromide in DMF
and stirred at room temperature for 12 h. Water was added
to the reaction mixture and extracted with diethyl ether
(3 9 50 cm3). The organic layer was washed with water
and then dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure and the residue was
purified by silica gel column chromatography (1:3 EtOAc/
123

Design and synthesis of new cephalosporin antibiotics
Propyl (6R,7R)-3-methyl-8-oxo-7-(propyloxy-
carbonylamino)-5-thia-1-azabicyclo[4.2.0]
oct-2-ene-2-carboxylate (4b, C15H22N2O5S)
clear solution was extracted twice with 15 cm3 portion of
MIBK. The organic extracts were discarded. The clear
aqueous solution was cooled to 10–15 °C and acidified to
pH 2 with cold 5 M sulfuric acid solution. The acidified
solution was extracted with MIBK twice. The extracted
solution was mixed with 10 cm3 solution of potassium
2-ethylhexanoate in 1-butanol. After stirring for 5 min, a
white solid was precipitated and collected by filtration.
Washing the white solid with dry acetone and drying
in vacuo yielded 2.0 g product 6 (60 %). 1H NMR
(400 MHz, CDCl3): d = 7.32–7.25 (m, 2H), 7.00–6.87
(m, 2H), 5.54 (d, J = 1.6, 1H), 4.98 (d, J = 1.6 Hz, 1H),
4.45 (s, 2H), 3.46 (d, J = 18.5 Hz, 1H), 3.11 (d,
J = 18.5 Hz, 1H), 1.83 (s, 3H) ppm; 13C NMR
(100 MHz, CDCl3): d = 168.88, 163.98, 162.28, 157.08,
131.27, 129.83, 129.75, 122.36, 114.85, 67.43, 67.18,
58.39, 56.93, 30.32, 21. 09 ppm; HRMS (FAB): m/z calcd.
for C16H16KN2O5S [M?H]? 387.0418, found 387.0419.
1
Colorless semisolid (55 %); H NMR (500 MHz, CDCl3):
d = 5.62 (dd, J = 4.7, 9.6 Hz, 1H), 5.33 (d, J = 9.6 Hz,
1H), 4.97 (d, J = 4.7 Hz, 1H), 4.24–4.14 (m, 2H),
4.10–4.05 (m, 2H), 3.52 (d, J = 18.2 Hz, 1H), 3.23 (d,
J = 18.2 Hz, 1H), 2.14 (s, 3H), 1.71–1.54 (m, 4H),
0.96–0.92 (m, 6H) ppm; 13C NMR (125 MHz, CDCl3):
d = 163.70, 161.28, 154.75, 129.85, 121.70, 66.66, 66.55,
66.28, 59.88, 56.24, 51.95, 29.06, 21.15, 20.84, 19.04,
9.45, 9.24 ppm; HRMS (FAB): m/z calcd. for
C15H23N2O5S [M?H]? 343.1327, found 343.1338.
Benzyl (6R,7R)-7-(benzyloxycarbonylamino)-3-methyl-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
(4c, C23H22N2O5S)
1
Colorless semisolid (49 %); H NMR (400 MHz, CDCl3):
d = 7.42–7.35 (m, 10H), 5.62 (d, J = 4.5 Hz, 1H), 5.56 (d,
J = 9.6 Hz, 1H), 5.28 (s, 2H), 5.16 (s, 2H), 4.96 (d,
J = 4.6 Hz, 1H), 3.52 (d, J = 18.5 Hz, 1H), 3.22 (d,
J = 18.5 Hz, 1H), 2.15 (s, 3H) ppm; 13C NMR (100 MHz,
CDCl3): d = 164.64, 162.05, 155.47, 135.66, 135.12,
131.87, 128.80, 128.69, 128.63, 128.59, 128.48, 128.25,
122.46, 67.77, 67.64, 60.98, 57.24, 30.16, 20.13 ppm;
HRMS (FAB): m/z calcd. for C23H23N2O5S [M?H]?
439.1327, found 439.1336.
Propyl (6R,7R)-3-methyl-8-oxo-7-(2-phenoxyacetamido)-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
(7a, C19H21N2O5S)
To 386 mg 7-ADCA phenoxy potassium salt (6, 1.0 mmol)
in 10 cm3 DMF, 0.5 cm3 propyl iodide (3 mmol) was
added and stirred at room temperature for 12 h. Solvent
was removed and extracted with CH2Cl2 (3 9 50 cm3).
The organic layer was dried over sodium sulfate and
concentrated. The residue was purified by column chro-
matography with EtOH/n-hexane (1:1) to get 222 mg
(69 %) white solid. 1H NMR (400 MHz, CDCl3): d = 7.31
(m, 2H), 7.04 (t, 1H), 6.94 (m, 2H), 5.86 (dd, J = 1.6,
9.0 Hz, 1H), 5.02 (s, 1H), 4.57 (s, 2H), 4.24 (m, 2H), 3.51
(d, J = 18.5 Hz, 1H), 3.21 (d, J = 18.5 Hz, 1H), 2.15 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): d = 168.84,
163.93, 162.25, 157.01, 131.25, 129.81, 129.73, 122.33,
114.81, 67.33, 67.14, 58.36, 56.91, 30.14, 21.89, 20.02,
10.49 ppm; HRMS (FAB): m/z calcd. for C19H22N2O5S
[M?H]? 391.1338, found 391.1331.
Benzo[c][1,2,5]thiadiazol-5-ylmethyl (6R,7R)-7-[(benzo[c]-
[1,2,5]thiazol-5-ylmethoxy)carbonylamino]-3-methyl-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
(4d, C25H21N4O5S3)
1
Yellow semisolid (66 %); H NMR (400 MHz, CDCl3):
d = 8.04 (d, J = 6.8 Hz, 2H), 8.00 (d, J = 4.2 Hz, 2H),
7.67 (dd, J = 1.6, 9.0 Hz, 1H), 7.59 (dd, J = 1.6, 9.0 Hz,
1H), 5.44 (d, J = 2.6 Hz, 2H), 4.93 (d, J = 4.6 Hz, 1H),
4.66 (d, J = 4.6 Hz, 1H), 4.18 (s, 2H), 3.56 (d,
J = 18.5 Hz, 1H), 3.29 (d, J = 18.5 Hz, 1H), 2.21 (s,
3H) ppm; 13C NMR (100 MHz, CDCl3): d = 163.53,
160.71, 154.17, 153.46, 136.53, 135.59, 131.93, 128.85,
128.26, 121.02, 120.79, 119.74, 118.97, 106.60, 105.33,
66.64, 66.14, 65.78, 59.95, 56.16, 48.39, 29.21, 29.50,
22.88, 19.22 ppm; HRMS (FAB): m/z calcd. for
C23H17N6O5S3 [M-H]- 553.0579, found 553.0680.
Benzyl (6R,7R)-3-methyl-8-oxo-7-(2-phenoxyacetamido)-
5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
(7b, C23H21N2O5S)
To 386 mg 7-ADCA phenoxy potassium salt (6, 1.0 mmol)
in 10 cm3 DMF, 510 mg benzyl bromide (3 mmol) was
added and stirred at room temperature for 12 h. Solvent
was removed and the residue was dissolved in 150 cm3
CH2Cl2. The organic layer was washed with water several
times, dried over sodium sulfate, and concentrated. The
residue was purified by column chromatography with
EtOH/n-hexane (1:1) to get 268 mg white solid. Yield:
Potassium (6R,7R)-3-methyl-8-oxo-7-(2-phen-
oxyacetamido)-5-thia-1-azabicyclo[4.2.0]oct-
2-ene-2-carboxylate
(6, C16H15KN2O5S)
To a cooled and stirred solution of 3.0 g 7-ADCA in
60 cm3 water containing 6.0 g of sodium bicarbonate,
phenoxyacetyl chloride in 5 cm3 of acetone was added in
1 min. The resulting mixture was stirred vigorously during
20 min while the temperature was kept at 10–15 °C. The
1
66 %; H NMR (400 MHz, CDCl3): d = 7.33 (m, 9H),
7.04 (t, 1H), 6.95 (m, 2H), 5.86 (dd, J = 1.6, 9.0 Hz, 1H),
5.29 (s, 2H), 5.00 (s, 1H), 4.57 (s, 2H), 3.52 (d,
J = 18.2 Hz, 1H), 3.21 (d, J = 18.5 Hz, 1H), 2.15 (s,
123

C. Liu et al.
3H), 1.75 (m, 2H), 0.98 (t, 3H) ppm; 13C NMR (100 MHz,
CDCl3): d = 168.85, 164.06, 162.01, 157.04, 129.83,
128.72, 128.62, 128.52, 122.35, 114.83, 67.66, 67.16,
58.41, 56.96, 30.22, 20.12 ppm; HRMS (FAB): m/z calcd.
for C23H22N2O5S [M?H]? 439.1338, found 439.1335.
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