Precise Preparation of a High-Purity Key Intermediate of Tazobactam

Article abstract of DOI:10.1021/acs.oprd.0c00407

In situ IR was used to precisely prepare high-purity diphenylmethyl 6α-bromopenicillanate 8, a key intermediate of tazobactam. 8 was obtained when 6α-bromopenicillanic acid 2 reacted with diphenyldiazomethane (DDM). 2 is unstable and must therefore react

Full text of DOI:10.1021/acs.oprd.0c00407

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Precise Preparation of a High-Purity Key Intermediate of
Tazobactam
Yanan Zhou,† Chengjun Wu,† Hongzhi Ma, Jianchao Chen,* and Tiemin Sun*
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ABSTRACT: In situ IR was used to precisely prepare high-purity diphenylmethyl 6α-bromopenicillanate 8, a key intermediate of
tazobactam. 8 was obtained when 6α-bromopenicillanic acid 2 reacted with diphenyldiazomethane (DDM). 2 is unstable and must
therefore react immediately with DDM upon preparation. DDM is also unstable. As DDM decomposes rapidly upon preparation,
the DDM content cannot be precisely determined using high-performance liquid chromatography (HPLC) or gas chromatography
(GC). Therefore, good yield and purity are difficult to obtain, resulting in large batch-to-batch variations (yield 69.3−82.8%, purity
89.8−98.4%) for 8. The developed preparation method for 8 involved the use of in situ IR to monitor the reaction process and
achieved good results (82.7−83.1% yield and 97.3−98.5% purity). This method was also used to prepare the key intermediate for
the synthesis of cephalosporin derivatives, which have high industrial value.
KEYWORDS: diphenylmethyl 6α-bromopenicillanate, diphenyldiazomethane, purity drift, in situ IR, cephalosporin derivatives
Route A for large-scale processes.14 Route B consists of
1. INTRODUCTION
replacing BPH by DDM during esterification. This method
Tazobactam (1) is an orally effective penicillin antibiotic with a
does not have some of the drawbacks of existing routes, such as
broad spectrum of antibacterial activity against both Gram-
peracetic acid (40%) use, and has a considerably shorter
positive and Gram-negative organisms1−4 and is typically
reaction time. However, the instability of DDM prevents the
added to certain antibiotics to lower the antimicrobial
DDM content from being precisely ascertained using general
resistance of bacteria.5 For example, a combination of
high-performance liquid chromatography (HPLC) or gas
tazobactam and piperacillin can be used to treat infections
chromatography (GC).15−18 In addition, DDM must be
caused by Pseudomonas aeruginosa.6−8
synthesized immediately before use and cannot be stored.
Scheme 1 illustrates the most widely used synthetic route for
Ketone has been found to be the main byproduct during DDM
tazobactam.9,10
preparation. Therefore, the content of different DDM batches
One of the key intermediates in the preparation of
has been found to be variable. This result is shown in Table 2.
tazobactam is 6α-bromopentamidine sulfoxide dibenzoate 3.
That is, the 1.4 equiv of DDM is not always optimal.
3 was originally synthesized using a three-step process with 6-
Optimization of the reaction conditions for each DDM batch
aminopenicilanic acid (6-APA) as a starting material.9 The 6α-
reduces large-scale esterification efficiency. Route B also
bromopenicillanic acid 2 was isolated from the products of a
involves the synthesis of compound 2 by diazotization−
Sandmeyer reaction. 2 was oxidized by peracetic acid to
bromination of 6-APA. The absence of aromatic conjugation
sulfoxide 7. Peracetic acid and benzophenone hydrazine
results in an unstable diazonium salt, increasing the yield of
(BPH) were added to the reaction mixture, and the resulting
byproducts in the reaction system. In addition, the instability
esterification produced 3 without isolation. Although this
of 2 necessitates reaction with DDM without purification to
procedure is generally used in industry, several problems need
yield 8. The reaction mechanism shows that one molecule of 2
to be solved urgently. First, an overoxidation product (3′) is
reacts with one molecule of DDM to produce one molecule of
produced, irrespective of any countermeasures implemented.
8. When a 1:1 ratio of the two reactants cannot be guaranteed
Second, a very poor esterification yield is obtained using a low
(that is, there is an excess of either reactant), side reactions
concentration of peroxyacetic acid (20%). Therefore, a higher
occur that affect product purity, resulting in a purity range of
concentration of peracetic acid (40%) is needed, the
89.5−98.4% for 8.19 Thus, an accurate determination of the
preparation of which poses extreme safety hazards for
concentration of these two reactants is key to increasing
industrial production.11
Peracetic acid/BPH use has been circumvented by using
diphenylmethanol and diphenyldiazomethane (DDM) as
Received: September 14, 2020
effective alkylation reagents for carboxylic acids during
esterification;12,13 however, these alternative reagents have
not yet been used in industrial production (Scheme 2). The
difficulty of removing the byproduct 1,3-dicyclohexylurea (9)
from the reaction system diminishes the efficiency of using
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A

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Scheme 1. Synthetic Route for Tazobactam
Scheme 2. Alternative Routes to Produce Bromopentamidine Sulfoxide Dibenzoate (3)
product purity. The aforementioned problems have challenged
chemists for decades and motivated us to explore a new
strategy for the transformation of reactants.20−23
time tracking of changes in the contents of the reactants and
products. Precise quantities of DDM and compound 2 could
be added to the reaction system. The reaction endpoint could
be accurately controlled. Large fluctuations in the yield and
purity during esterification were effectively eliminated. The
method was also used to prepare a key intermediate for the
synthesis of cephalosporin derivatives, which have high
industrial value.
Recent developments in process analytical technology
(PAT),24,25 especially in situ infrared spectroscopy (IR),26,27
have made it possible to follow a reaction in real time, whereby
quality by design (QbD)28 principles are used to obtain an in-
depth understanding of chemical processes.29,30 To the best of
our knowledge, in situ IR has been used to observe a
multicomponent synthesis process for which the reactant
content cannot be accurately determined, whereas previous
studies have been fundamental in nature and have not been
applied to industrial production. We developed a preparation
method for 8 using in situ IR to monitor the reaction process,
with good results (82.7−83.1% yield and 97.3−98.5% purity)
at the kilogram scale. Online monitoring was used for the real-
2. RESULTS AND DISCUSSION
2.1. Optimization and Evaluation of the Esterification
Process. First, the existing synthetic method for compound 8
(Scheme 2B) was evaluated. Compound 2 was rapidly
consumed during the dropwise addition of DDM. The yield
of 8 was initially improved from 52.4 to 78.9% by increasing
B
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the DDM equivalent from 0.9 to 1.4 (Table 1, entries 1−5).
Oxidants can be used to prepare DDM from benzophenone
hydrazine. Various oxidants are available for this pur-
pose.21,32−34 Manganese dioxide was chosen in this study
because of its recyclability.
Further increase in the DDM equivalent to 1.5 did not improve
a
Table 1. Optimization of the Esterification Process
2.2. Process Improvements. In situ IR was used to
monitor the esterification process, enabling the precise
determination of the reaction endpoint and control of the
quantities of DDM and 2. Although in situ IR has been used to
monitor diazonane-related reactions, previous studies have
been fundamental in nature and have not been applied to
industrial production.35−37 In situ IR was used in this study to
obtain the spectra of the reactants and products to accurately
track the reaction evolution. Dichloromethane (CH2Cl2) was
placed in an oven-dried three-necked flask, which was fitted
with a DiComp probe; the infrared spectrum of CH2Cl2 was
then collected. Compound 2 was then added to the flask, and
the IR spectra of 2 were obtained by subtracting the solvent
background (CH2Cl2). The operations described above were
repeated to collect the IR spectra of DDM and compound 8.
The infrared absorption characteristic peaks of the collected
samples were processed within the 1750−900 cm−1 high
infrared absorption range using iC IR 4.0 operating software
(Figure 1).
entry
n
(DDM)/n(6‑APA)
solvent
temp. (°C) yield (%) purity (%)
b
1
0.9
1.0
1.2
1.3
1.4
1.5
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
EtOAc
20
20
20
20
20
20
20
20
20
20
0
52.4
58.2
68.5
75.2
78.9
78.4
78.6
78.2
77.7
77.9
71.4
69.7
71.7
69.3
79.0
82.8
76.1
85.4
89.5
94.0
95.2
98.2
90.6
97.7
97.2
98.3
97.3
96.4
92.2
89.5
98.4
97.1
89.8
93.6
b
2
b
3
b
4
b
5
6
7
b
b
b
8
b
9
THF
b
10
11
12
13
14
15
16
17
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
b
b
−10
35
20
20
20
20
b
c
c
c
c
a
Bold values indicate that the 1.4 equiv of DDM is not always optimal
b
reaction conditions. The same batch of DDM was needed for the
optimization conditions to reduce the variables in the experiment.
c
The different batches of DDM.
the yield, and the purity decreased, indicating that the optimal
DDM equivalent was 1.4. As the related byproduct benzhydryl
ethyl ether can form in a protic solvent,31 several aprotic
solvents (CH3CN, EtOAc, tetrahydrofuran (THF), and
toluene) were screened, none of which produced a clear
change in the yield (Table 1, entries 7−10). The results of a
temperature survey are presented in Table 1 (entries 11−13).
Low temperatures decreased the overall rate, whereas high
temperatures increased the DDM decomposition rate, both of
which decreased the yield. Finally, four identical experiments
were performed on different DDM batches under the optimal
conditions (Table 1, entries 14−17). The resulting significant
variations in the purity of compound 8 (89.8−98.4%, RSD =
4.07%) are not conducive to scale up production.
DDM instability was quantitatively assessed using both
stable 2-(3,4-dimethoxyphenyl)acetic acid 10 and benzophe-
none hydrazine to yield the corresponding acetic acid ester 11.
Although the experimental conditions were strictly controlled,
variations in the purity of compound 11 were still observed
(Table 2). This result confirmed the variable contents of
different DDM batches.
Figure 1. IR spectra of 6α-bromopenicillic acid 2 (red),
diphenylmethyl 6α-bromopenicillanate 8 (green), and DDM (blue):
the blue background represents areas for which characteristic peaks of
collected samples were within the 1750−900 cm−1 high infrared
absorption range.
The peak at 1792 cm−1 was assigned to the stretching
vibration of the CO bond in the β-lactam ring for both
compounds 2 and 8. The absorption peaks at vCO 1732 cm−1
and vCO 1748 cm−1 were assigned to the carboxylic acid in
compound 2 and the ester in compound 8, respectively. The
2035 cm−1 peak originating from CN stretching (the most
intense absorption for DDM) was masked by absorptions
Table 2. Yield and Purity of Product 11 in Different Batches
entry
n(BPH)/n(compound 10)
output (g)
total yield (%)
HPLC purity (% area)
1
2
3
1.0
1.0
1.0
2.58
3.0
2.80
69.91
81.3
75.88
96.79
99.12
97.47
C
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arising from diamond transmits IR (2200−1900 cm−1) of the
attenuated total refraction (ATR) probe, but the peaks of the
benzene ring in DDM could be tracked. The stretching
vibration peaks of the benzene ring in DDM appeared at 1596,
1499, and 1461 cm−1.
The complex composition of the reaction system resulted in
significant overlap among the absorption peaks, making it
difficult to accurately observe the characteristic peaks of the
three components in the original online infrared spectrum.
Second derivative infrared spectroscopy was applied to
distinguish among the characteristic peaks of the components
in the esterification reaction more clearly. The second
derivative spectrum is shown in Figure 2A,B. The objective
of this series of experiments was to use in situ IR to accurately
track the trends in the evolution of each component over time
(Figure 3).
DDM was added dropwise continuously at d, and the CO
stretching vibration peaks at 1748 and 1723 cm−1 plateaued at
point e. DDM addition was terminated at point e. To ascertain
whether point e was the reaction endpoint, DDM was then
added dropwise at point f. Figure 3A shows an increase in the
intensity of the CC stretching vibration absorption peak
from the DDM benzene ring at 1596 cm−1 (blue curve) but no
change in the absorption peaks related to compounds 8 and 2.
Therefore, point e was concluded to be the reaction endpoint,
as determined by in situ IR. Notably, the esterification process
between compound 2 and DDM was completed in 20 min,
with 60% of compound 2 being consumed in approximately 7
min, as shown by the superposition of the three IR spectra at 1,
7, and 17 min in Figure 3B,D,36 which was considerably less
than the 20 h reported in the literature13 and indicates a
considerably reduced energy consumption and the prevention
of impurity formation to the greatest possible extent.
To further confirm that point e was the reaction endpoint,
samples were collected at the d−e, e−f, and f−g segments, and
HPLC was used to determine the purity of product 8. When
the reaction was at the d−e segment, compound 2 remained,
and the purity of product 8 was 90.2% (Figure S1); the
maximum purity of 8 of 98.9% was obtained at the e−f section
(Figure S2). More impurities were found from HPLC of the
sample at the f−g segment, and the purity of 8 declined to
87.5%, mainly because of the presence of excess DDM (Figure
S3).
2.4. Thermogravimetric Analysis (TGA) of DDM. A
TGA experiment was performed to determine the feasibility of
using DDM in a scaled process (Figure 4). The DDM
thermograms contained two separate degradation steps, or
stages, with two maximum rate peaks that can be clearly seen
in the corresponding DTG curves. DDM weight losses of
10.6795 and 83.3573% occur over the temperature ranges of
85−145 and 235−350 °C, respectively. The first step
corresponds to the dissociation of the diazo into N2 gas and
a highly reactive carbene, along with other byproducts, whereas
the second step corresponds to the degradation of residues.
Therefore, DDM is thermally stable under the experimental
conditions.
2.5. Process Scale-Up. The efficiency of the developed
preparation method (Scheme 3) was verified using other
batches, and the results are presented in Table 3. The purity of
compound 8 was in the 97.3−98.5% range, with a relative
standard deviation (RSD) of 0.47%, showing the effective
elimination of large fluctuations in the product purity.
2.6. Application to Cephalosporin Derivatives. The
problems encountered in cefdinir preparation also exist in the
preparation of cephalosporin derivatives.38 The typical use of
excess DDM to yield diphenylmethyl 7β-phenylacetamido-3-
hydroxymethyl-3-cephem-4-carboxylate 13 both reduces the
purity of 13 and increases production costs. We extended this
method to prepare 13, an important intermediate for the
synthesis of cephalosporin derivatives, with satisfactory results,
as shown in Table 4 (RSD = 0.36%).
Figure 2. Online infrared three-dimensional spectrum acquired
during an esterification reaction as a function of time and wavelength
after second derivative treatment: (A) IR stack plot of the entire
reaction process and (B) IR stack plot of changes in the main
characteristic peaks.
2.3. Inline Monitoring of the Esterification Process by
In Situ IR. Figure 3A shows a plot of the peak heights at 1723
cm−1 (red curve) and 1748 cm−1 (green curve) (corresponding
to the CO stretch of the carboxylic acid in compound 2 and
the ester carbonyl group in 8, respectively) versus the reaction
time. Point a corresponds to the addition of compound 2
dissolved in CH2Cl2 to the reaction mixture. After the system
stabilized, DDM was added at point b. The red curve
decreased and the green curve increased upon DDM addition,
indicating that the reaction occurred immediately with the
consumption of compound 2 and the formation of product 8.
Figure 3C shows that DDM addition was accompanied by a
sharp increase in the temperature over the b−c section.
Considering the instability of compound 2 at high temper-
atures, the addition rate of DDM was slowed down at c, and
the temperature increase ceased. If the drop speed is not
adjusted in time, an explosion accident can easily occur during
industrial production.
3. CONCLUSIONS
Diphenylmethyl 6α-bromopenicillanate 8, a key intermediate
of tazobactam, was prepared using in situ IR to monitor the
reaction process, with good results (82.7−83.1% yield and
97.3−98.5% purity) at the kilogram scale. The effective
synthetic method was established for various contents of
several raw materials. The use of in situ IR is key for the
D
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Figure 3. (A) Changes in absorbance at 1723 cm−1 (red curve), 1748 cm−1 (green curve), and 1596 cm−1 (blue curve) plotted against reaction
time during formation of product 8; (B, D) time-domain ATR-IR spectra during esterification, where superimposed IR spectra at 1, 7, and 17 min
show conversion of compound 2 to product 8 (from 1723 to 1748 cm−1) upon DDM addition; and (C) reaction temperature as a function of time.
Table 3. Purity of Product 8 in Different Batches
batch size of 6-APA
(kg)
output
(kg)
total yield
(%)
HPLC purity
(% area)
a
entry
1
2
3
4
2.16
2.16
10.8
10.8
3.69
3.70
18.47
18.43
82.9
83.1
82.9
82.7
98.2
97.7
97.3
98.5
a
The different batches of DDM.
the esterification could be completed within 20 min using in
situ IR, which considerably reduced energy consumption and
prevented the growth of impurities. The developed method
was used to prepare the key intermediate in the synthesis of
cefdinir. The developed protocol can instantaneously detect
profiles of species that are otherwise undiscernible or cannot
be easily measured offline.
Figure 4. TGA (blue) and DGT (green) thermograms for DDM:
blue line, observed; and green line, calculated.
success of this process because the accurate control of the
DDM quantity and the precise determination of the reaction
endpoint circumvent the inconclusive determination of the
contents of DDM and compound 2. Moreover, we found that
Scheme 3. Overall Process Scheme
E
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Table 4. Purity of Product 13 in Different Batches
a
entry
batch size of 12 (g)
output (g)
total yield (%)
HPLC purity (% area)
1
2
3
4
5.0
5.0
20.0
20.0
6.27
6.18
24.83
24.34
85.0
83.7
84.9
83.2
98.83
99.06
98.27
98.98
a
The different batches of DDM.
combined organic phase was washed with a saturated aqueous
sodium chloride solution (1 × 12.5 kg) and then dried over
anhydrous Na2SO4 (14.0 kg). The solution was filtered, the
filtrate was placed in a 250-L stirred reactor, and used without
purification in the next step.
4.4. Preparation of Diphenyldiazomethane (DDM). A
solution of benzophenone hydrazone (15 kg, 76.43 mol) in
dichloromethane (70 kg) was cooled to 0 °C. Activated
manganese dioxide (19.93 kg, 229.29 mol) was added in three
portions. The reaction mixture was warmed to room
temperature and stirred continuously for 1.5 h. After the
centrifuge separated, the red filtrate was concentrated to one-
fifth of its original volume and used in the next step without
purification.
4.5. Preparation of Diphenylmethyl 6α-Bromopeni-
cillanate (8). In the 250 L reaction tank equipped with an in
situ IR ATR probe, the newly prepared DDM was added
dropwise to the filtrate through an overhead tank. Addition of
DDM was stopped when the in situ IR indicated reaction
completion. After the solution was concentrated to one-fifth of
its original volume, it was charged with CH3OH (125 L) over
2 h at 0 °C, resulting in a white slurry. The slurry was filtered
and the filter cake was washed with cold methanol (12.5 L),
and then dried under vacuum (45 °C, −0.095 mPa) for 4 h to
give 8 as a white solid (18.43 kg, 82.7%). 1H NMR (400 MHz,
CDCl3) δ 7.39−7.27 (m, 10H), 6.94 (s, 1H), 5.43 (d, J = 1.3
Hz, 1H), 4.80 (d, J = 1.4 Hz, 1H), 4.63 (s, 1H), 1.59 (s, 3H),
1.26 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 167.32, 166.06,
139.04, 128.68, 128.65, 128.46, 128.31, 127.51, 127.10, 78.62,
70.73, 70.02, 65.27, 49.56, 34.24, 25.50. IR (neat): 3030, 2977,
2919, 1778, 1744, 1495, 1454, 1293, 1203, 1180, 968, 745,
705, 593, 546 cm−1. ESI-MS: m/z 446.36.
4. EXPERIMENTAL SECTION
4.1. General. All chemicals were commercially available
and were used directly without further purification. The
EliteP230p series instrument (column: Hyper ODS2 C18 (250
mm × 20 mm); pump: P230p; detector: UV230II, Dalian Elite
Analytical Instruments Co., Ltd., China) was used to monitor
the reaction. Proton nuclear magnetic resonance (1H NMR)
spectra and carbon-13 nuclear magnetic resonance (13C NMR)
spectra were recorded using a Bruker 400 MHz spectrometer.
Infrared spectra were obtained on an FTIR spectrometer
(EQUINOX55, Bruker, Germany) at 1.0 cm−1 resolution and
are reported in wavenumbers. All in situ infrared spectra were
collected using an IN-SITU IR (ReactIR 15, Mettler Toledo,
Redmond, VA) equipped with an ATR diamond sensor probe
interfaced with the Mettler iC IR 4.0 synthesis workstation. A
TGA (TGA 2 (SF), Mettler Toledo, Switzerland) thermogra-
vimetric analyzer was employed for thermogravimetric analysis
at a heating rate of 5 K min−1 under nitrogen from 303.2 to
673.2 K.
4.2. Preparation of Diphenylmethyl 2-(3,4-
dimethoxyphenyl)acetate (11). A solution of benzophe-
none hydrazone (2.0 g, 0.01 mol) in dichloromethane (30 mL)
was cooled to 0 °C. Activated manganese dioxide (2.66 g, 0.03
mol) was added to the solution in three portions. The reaction
mixture was warmed to room temperature and maintained
under stirring for 1.5 h. The mixture was filtered, and the red
filtrate was used in the next step without purification.
2-(3,4-dimethoxyphenyl)acetic acid (2 g, 0.01 mol) was
added under stirring to a solution of the filtrate at room
temperature, which was then maintained under stirring for 1 h.
The solvent was evaporated, and the residue was crystallized
from ether/n-hexane(1:1 v/v) to yield 11 as a white solid (2.8
g, 75.88%). 1H NMR (400 MHz, dimethyl sulfoxide (DMSO)-
d6) δ 7.60−7.12 (m, 10H), 6.9 (1H, d, J = 5.5 Hz, ArH), 6.89
(1H, s, CHPh2), 6.80 (2H, ArH), 3.73 (s, 5H), 3.69 (s, 3H).
4.3. Scale-Up: 6α-Bromopenicillanic Acid (2). A
solution of KBr (30 kg, 252.1 mol) in water (117.5 kg) was
placed in a 500-L reactor, and 98% H2SO4 (8.75 kg, 87.43
mol), EtOH (95%, 21.4 kg), and 6-APA (10.8 kg, 50 mol)
below −5 °C with cold brine were added to the reaction vessel.
Next, a solution of NaNO2 (5 kg) in H2O (20 kg) was slowly
added over 1 h at −15 to −10 °C, and the reaction mixture
was maintained at this temperature for 4 h, at which point
HPLC analysis indicated <0.5% of 6-APA. The reaction
mixture was diluted with dichloromethane (50 kg). The
aqueous phase was washed with CH2Cl2 (12.5 kg × 2). The
4.6. Preparation of Diphenylmethyl 7β-phenylaceta-
mido-3-hydroxymethyl-3-cephem-4-carboxylate (13).
The esterification of the acid (12) (5 g) with diphenyldiazo-
methane was carried out as above to give 13 as a white solid
1
(6.27 g, 85.0%). H NMR (400 MHz, DMSO-d6) δ 9.12 (d, J
= 8.4 Hz, 1H), 7.66−7.16 (m, 15H), 6.90 (s, 1H), 5.72 (dd, J
= 8.3, 4.7 Hz, 1H), 5.15 (t, 1H), 5.11 (d, J = 4.8 Hz, 1H), 4.21
(d, 2H), 3.61 (s, 2H), 3.52 and 3.56 (m, 2H). 13C NMR (400
MHz, DMSO-d6) δ 171.43, 165.70, 161.34, 140.52, 140.45,
136.29, 134.87, 129.48, 128.98, 128.85, 128.69, 128.31, 128.24,
127.23, 127.03, 126.96, 122.45, 78.80, 60.24, 59.37, 58.18,
42.06, 26.04. ESI-MS: m/z 537.21 [M + Na]+.
F
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(4) Yang, Y.; Janota, K.; Tabei, K.; Huang, N.; Siegel, M. M.; Lin, Y.
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class A β-lactamases PC1 and TEM-1 by Tazobactam: Observation of
reaction products by electrospray ionization mass spectrometry. J.
Biol. Chem. 2000, 275, 26674−26682.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00407.
■
sı
(5) Livermore, D. M. β-Lactamases in Laboratory and Clinical
Resistance. Clin. Microbiol. Rev. 1995, 8, 557−584.
HPLC spectra of diphenylmethyl 6α-bromopenicillanate
8 (d−e as the reaction endpoint during the synthesis
process; e−f as the reaction endpoint during the
synthesis process; f−g as the reaction endpoint during
the synthesis process; large-scale experiment); HPLC
spectrum of diphenylmethyl 2-(3,4-dimethoxyphenyl)-
acetate 11 and diphenylmethyl 7β-phenylacetamido-3-
hydroxymethyl-3-cephem-4-carboxylate 13; infrared
spectrum, and 1H NMR and 13C NMR spectra of
diphenylmethyl 6α-bromopenicillanate 8; 1H NMR
spectra of diphenylmethyl 2-(3,4-dimethoxyphenyl)-
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1
acetate 11; and H NMR and 13C NMR spectra of
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3-cephem-4-carboxylate 13 (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(11) Kitis, M. Disinfection of wastewater with peracetic acid: a
Tiemin Sun − Key Laboratory of Structure-Based Drug Design
and Discovery, Shenyang Pharmaceutical University, Ministry
of Education, Shenyang 110016, P. R. China; orcid.org/
0000-0002-9981-0243; Email: suntiemin@126.com
Jianchao Chen − Key Laboratory of Structure-Based Drug
Design and Discovery, Shenyang Pharmaceutical University,
Ministry of Education, Shenyang 110016, P. R. China;
Email: chenjianchaosyphu@163.com
review. Environ. Int. 2004, 30, 47−55.
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Situ Generation, Separation, and Reaction of Diazomethane in a
Dual-Channel Microreactor. Angew. Chem., Int. Ed. 2011, 50, 5952−
5955.
Authors
Yanan Zhou − Key Laboratory of Structure-Based Drug
Design and Discovery, Shenyang Pharmaceutical University,
Ministry of Education, Shenyang 110016, P. R. China
Chengjun Wu − Key Laboratory of Structure-Based Drug
Design and Discovery, Shenyang Pharmaceutical University,
Ministry of Education, Shenyang 110016, P. R. China
Hongzhi Ma − Key Laboratory of Structure-Based Drug
Design and Discovery, Shenyang Pharmaceutical University,
Ministry of Education, Shenyang 110016, P. R. China
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Raines, R. T. Diazo compounds for the bioreversible esterification of
proteins. Chem. Sci. 2015, 6, 752−755.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00407
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of β-lactam Antibiotics. Curr. Sci. 2004, 87, 1684−1695.
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Tuning the Rotation Rate of Light-Driven Molecular Motors. J. Org.
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Author Contributions
†Y.Z. and C.W. contributed equally to this work.
Notes
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The authors declare no competing financial interest.
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