General Synthesis of Industrial Cephalosporin-Based Antibiotics Through Amidation with Tosyl Chloride as a Coupling Reagent

Article abstract of DOI:10.1002/ejoc.201900277

In this contribution we demonstrate the feasibility of a recently developed amidation method for a general synthesis of industrially important semi-synthetic cephalosporin antibiotics starting from readily available 7-aminocephalosporanic acid and derivatives thereof. The amidation process is based on the use of 4-toluene-sulfonyl chloride as an economically attractive coupling reagent in combination with methanol or ethyl acetate as one of the solvent components. A broad reaction scope was shown by the successful synthesis of three further cephalosporin antibiotics with different functionalities, which were obtained in high yields of 82–95 % in the reactions even under non-optimized conditions. It is noteworthy that also different oxime functionalities in the side chain of the 7′-position are tolerated as well as an ester moiety in 4′-position and a cationic functionality in 3′-position. Thus, this amidation process through an activated anhydride formed by means of 4-toluenesulfonyl chloride is a broadly applicable methodology for the synthesis of industrial semi-synthetic cephalosporin antibiotics.

Full text of DOI:10.1002/ejoc.201900277

A Journal of
Accepted Article
Title: General Synthesis of Industrial Cephalosporin-Based Antibiotics
through Amidation with Tosyl Chloride as a Coupling Reagent
Authors: Matthias Pieper, Herbert Schleich, and Harald Gröger
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900277
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10.1002/ejoc.201900277
European Journal of Organic Chemistry
General Synthesis of Industrial Cephalosporin-Based Antibiotics
through Amidation with Tosyl Chloride as a Coupling Reagent
Matthias Pieper,[a] Herbert Schleich,[b] and Harald Gröger*[a]
Dedicated to Professor Dr. Dietmar Kuck on the occasion of his 70th birthday
Abstract: In this contribution we demonstrate the feasibility of a
recently developed amidation method for a general synthesis of
industrially important semi-synthetic cephalosporin antibiotics starting
from readily available 7-aminocephalosporanic acid and derivatives
thereof. The amidation process is based on the use of 4-toluene-
sulfonyl chloride as an economically attractive coupling reagent in
combination with methanol or ethyl acetate as one of the solvent
component. A broad reaction scope was shown by the successful
synthesis of three further cephalosporin antibiotics with different
functionalities, which were obtained in high yields of 82-95% even
under non-optimized conditions. It is noteworthy that also different
oxime functionalities in the side chain of the 7’-position are tolerated
as well as an ester moiety in 4’-position and a cationic functionality in
3’-position. Thus, this amidation process through an activated
anhydride formed by means of 4-toluenesulfonyl chloride is a broadly
Scheme 1. Synthetic concept towards third generation cephalosporin antibiotics.
applicable methodology for the synthesis of industrial semi-synthetic
cephalosporin antibiotics.
Representative examples of the cephalosporin antibiotics of the
third generation, which are also graphically shown in Scheme 2,
are the commercial antibiotic drugs cefotaxime (3a), cefepime
Introduction
(3b), cefpodoxime (3c), cefpodoxime proxetil (3d), and
ceftriaxone (3e). Related products with a different substitution
pattern at the oxime group in the acyl moiety are cefixime (3f) and
ceftazidime (3g).[4]
The discovery of the antibacterial effect of penicillin and the
development of antibiotics represents one of the most important
achievements in medicinal history. Because of its successful use
in therapy for a wide range of different bacterial infections, the
development of antibiotics has been considered as one of “Nine
Ways That Changed the World”.[1] Besides penicillin antibiotics,
cephalosporin antibiotics emerged as the second main subclass
of β-lactam antibiotics, which are the largest types of antibiotics in
terms of production volume.[2] For the production of cephalosporin
antibiotics, 7-aminocephalosporanic acid (7-ACA, 2) serves as a
key intermediate, which can be obtained by an enzymatic
hydrolytic reaction from cephalosporin C (1) manufactured on
large scale via
a a low
fermentation process.[3] Due to
pharmaceutical activity of cephalosporin C (1) and 7-ACA (2),
various semi-synthetic derivatives of type 3 were designed, which
are currently used for therapeutic treatment. The general
synthetic concept for the production of these semi-synthetic
cephalosporin-derived antibiotics of type 3 are shown in Scheme
1. Typically the derivatization is done in 3’- and 7’-position, and in
the cephalosporin antibiotics of the third generation of type 3, the
amino function in 7’-position is amidated with (Z)-(2-aminothiazol-
4-yl)methoxyiminoacetic acid.
[a]
M. Pieper, Prof. Dr. H. Gröger
Chair of Industrial Organic Chemistry and Biotechnology
Faculty of Chemistry
Bielefeld University
Universitätsstr. 25, 33615 Bielefeld, Germany
E-Mail: harald.groeger@uni-bielefeld.de
http://www.uni-bielefeld.de/chemie/arbeitsbereiche/oc1/HG/
Dr. H. Schleich
[b]
Business Unit Anti-Infectives
Sandoz GmbH
Biochemiestrasse10, 6250 Kundl, Austria
Scheme 2. Overview about selected third generation cephalosporin antibiotics.
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10.1002/ejoc.201900277
European Journal of Organic Chemistry
COMMUNICATION
Results and Discussion
At first we defined various cephalosporin-based target molecules
with different types of different substitution pattern for our study
on the amidation scope using 4-toluenesulfonyl chloride. In detail,
we selected cefpodoxime (3c), cefpodoxime proxetil (3d) and a
tert-butylester precursor of ceftazidime (3h).
To start with cefpodoxime (3c), this compound was chosen as an
initial target molecule due to the structural similarity to cefotaxime
(3a), which we synthesized earlier in our proof of concept work.[4]
The first step of this amidation to form the desired compound 3c
consists again in the activation of the acid 4 needed for the
preparation of the side-chain in 3c (Scheme 4). The activation can
be carried out under smooth conditions at -11 °C using the cheap
commodity chemicals Tos-Cl and triethylamine, thus leading to
the mixed anhydride 5. Without isolation, then this in situ-formed
anhydride 5 is added at -30 °C to a clear solution of the
corresponding 7-ACA derivative with triethylamine in methanol.
We were pleased to find that even under non-optimized conditions
cefpodoxime (3c) was formed in excellent 95% yield (Scheme 4),
which was determined directly from the reaction mixture.
Scheme 3. Proof-of-concept work on amidation of 7-ACA with 4-toluenesulfonyl
chloride and methanol as a key solvent for the syntheses of cefotaxime (3a).
Today the most common process for the synthesis of cefotaxime
from 7-ACA is based on the use of the activated thioester S-
(benzo[d]thiazol-2-yl)-(Z)-(2-aminothiazol-4-yl)methoxyiminothio-
acetate.[5] Although being economically attractive, this process is
disfavored from a sustainability perspective as it leads to a large
amount of waste when producing this activated thioester, e.g.,
due to the need for the 2,2’-dithiobis-(benzothiazole) as well as
triphenylphosphane as reagents.[6]
Very recently, based on a literature methodology[7] we reported
an alternative method for such an amidation exemplified for the
amidation of 7-ACA (2) with (Z)-(2-amino-thiazol-4-yl)methoxy-
iminoacetic acid (4) under formation of the antibiotic drug
cefotaxime (3a).[4] This amidation is based on the utilization of 4-
toluenesulfonyl chloride (Tos-Cl) as a readily available and
economically attractive coupling reagent in combination with
methanol as one of the solvent components. Besides being a
readily available economical reagent produced by sulfonation of
toluene with chlorosulfonic acid,[8] a further advantage of Tos-Cl
is that in the desired amidation process nontoxic 4-toluenesulfonyl
acid is formed as a by-product.[4] This leads to a favorable process
considering atom economics. In detail, conceptually this
amidation reaction proceeds as follows: at first, 4-toluenesulfonyl
chloride forms a mixed anhydride with the (Z)-(2-aminothiazol-4-
yl)methoxyiminoacetic acid (needed for the formation of the side
chain) in the presence of triethylamine (NEt3) as a base and
dimethylacetamide as a solvent. In the subsequent step, this
mixed anhydride is added to a solution of 7-ACA in methanol (or
alternatively methylene chloride according to an earlier method)[7]
to form cefotaxime (Scheme 3). We could further demonstrate
that this process exemplified for cetoxamine works efficiently in a
batch as well as flow fashion.[4]
Due to the attractiveness of this process and successful proof-of-
concept for the preparation of cefotaxime we became interested
to study if this methodology could serve as a generally applicable
synthetic technology for preparing cephalosporin-based -lactam
antibiotic drugs, in particular the third generation cephalosporin
antibiotics of type 3. In the following we report our results about
the synthesis of commercial cephalosporin antibiotics other than
cefotaxime, which we prepared by means of this method using 4-
toluenesulfonyl chloride as a coupling reagent in batch processes.
Scheme 4. Expanded product spectra for the amidation reaction under
formation of various third generation cephalosporin antibiotics 3.
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10.1002/ejoc.201900277
European Journal of Organic Chemistry
COMMUNICATION
When conducting the same transformation again but replacing the
solvent methanol by methylene chloride, the resulting yield of 3c
dropped significantly to 81% (Scheme 4). This very positive result
antibiotics, we investigated the suitability of this method for the
preparation of ceftazidime tert-butylester (3h) due to the distinctly
different side chains compared to cefotaxime (3a). In detail, this
compound 3h has a pyridinium salt moiety in the side chain in 3’-
position as well as a tert-butylester-protected acid function in the
“oxime side chain” in 7’-position, and represents a well-known
precursor of ceftazidime (3g). So far the synthesis of ceftazidime
tert-butylester (3h) is again based on the use of a S-
(benzo[d]thiazol-2-yl) derivative as an activated form of the side-
chain based acid, thus raising environmental and waste
concerns.[12] For the synthesis of this target molecule 3h with the
amidation method based on Tos-Cl as an alternative, we used
again methanol as the preferred solvent. In this case, besides the
advantageous utilization of methanol in our previous studies a
further reason for using methanol was the good solubility of the
pyridinium starting material therein (whereas in contrast the
solubility of this compound is far too low in methylene chloride).
Starting from the acid 6 the mixed anhydride 7 was prepared as
before, and when adding this in situ prepared activated acid form
7 to the corresponding 7-ACA derivative, dissolved under
treatment with triethylamine in methanol, we were pleased to find
that the desired ceftazidime tert-butylester (3h) was afforded in a
high yield of 86% under again non-optimized conditions.
utilizing methanol as
a solvent is both, remarkable and
advantageous from a fundamental synthetic as well as application
perspective for various reasons:
(i) Typically one would assume that the stability of anhydride
should be much lower in a protic solvent such as methanol
compared to a non-protic hydrophobic solvent, thus leading to a
less satisfactory result when using methanol compared to the use
of methylene chloride as standard solvent for this transformation
and other related amide bond forming reactions. However, in the
case of cefpodoxime a higher and excellent yield of 95% was
achieved with methanol being superior to even the yield obtained
for methylene chloride as a solvent.
(ii) In comparison with our proof-of-concept work and earlier
results for cefotaxime (for which we obtained 100% yield in
methylene chloride and 95% yield in methanol)[4], the change in
the substitution pattern in 3’-position of the starting material led to
a higher yield when utilizing methanol, thus indicating that the
substitution pattern can also play a role for the solvent preference
in the amidation reaction for the formation of cephalosporin-based
antibiotics.
(iii) The high yield obtained with methanol is very attractive also
from the perspective of a technical application as methanol is
ranked as a recommended solvent in the “CHEM21 selection
guide of classical and less classical solvents”. This solvent guide
has been proposed by representatives from the Innovative
Medicines Initiative (IMI)-CHEM21 public private partnership as a
European consortium and is based on a set of Safety, Health and
Environment criteria in alignment with the Global Harmonized
System (GHS) and European regulations.[10] It should be added
that in contrast to methanol in this solvent guide the halogenated
solvent methylene chloride which is ranked as a hazardous
solvent.[10]
In addition to cefpodoxime (3c), we investigated the synthesis of
cefpodoxime proxetil (3d) in our study because the esterified acid
function in 4’-position leads to a different reactivity as well as to
different solvent needs for an efficient synthesis. As for the
synthesis of cefotaxime, today the use of the unfavored S-
(benzo[d]thiazol-2-yl)-(Z)-(2-aminothiazol-4-yl)methoxyiminothio-
acetate as an activated ester is the common strategy for
synthesizing cefpodoxime (3c) and cefpodoxime proxetil (3d),
thus representing the benchmark process.[9] For the synthesis of
cefpodoxime proxetil (3d) we decided to use ethyl acetate as
solvent for the amidation step as the β-lactam component could
be dissolved easily therein due to the esterified carboxylic moiety
in 4‘-position. Furthermore, because of the risk of an undesired
side reaction of esterified cephalosporins under basic conditions
we did not use a base in the amidation as the second reaction
step.[11] When conducting the two-step transformation starting
from the acid 4 and the corresponding 7-ACA derivative under
such conditions, even under non-optimized conditions we could
reach a yield of 82% (Scheme 4). For the future, we expect to
achieve a higher yield after process optimization, for example by
adjusting the amount of base in the two steps of this process.
As a third example for demonstrating the suitability of our
amidation method using 4-toluenesulfonyl chloride (Tos-Cl) as a
general tool for the synthesis of industrial 7-ACA-derived -lactam
Conclusions
In conclusion, we reported the suitability of an amidation method
based on an activated anhydride prepared by means of 4-toluene-
sulfonyl chloride as an economically attractive coupling reagent
for a general synthesis of semi-synthetic cephalosporin antibiotics
via formation of the amide bond in 7’-position. Starting from an
earlier proof-of-concept for cefotaxime, the generality of this
amidation method has now been exemplified by the successful
synthesis of cefpodoxime, cefpodoxime proxetil and ceftazidime
tert-butylester as a precursor for ceftazidime. It is noteworthy that
cefpodoxime was obtained in an excellent yield of 95% when
using methanol as a preferred beneficial solvent. Furthermore,
cefpodoxime proxetil was synthesized in a yield of 82% utilizing
ethyl acetate as a further preferred solvent for the amidation step.
In addition, the formation of ceftazidime tert-butylester proceeding
with a high yield of 86% shows that neither a cationic structure
nor an esterified oxime group in the respective side chains have
a significant negative influence on the product formation, thus
underlining the high tolerance of this methodology towards the
presence of various functionalities and substitution pattern being
typical for semi-synthetic cephalosporin antibiotics. As in this work,
the reaction steps for the cephalosporin-based target molecules
was addressed with the goal to achieve a high conversion, in
future work the development of an efficient isolation method
represents one of the next tasks.
Experimental Section
Cefpodoxime (3c)
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10.1002/ejoc.201900277
European Journal of Organic Chemistry
COMMUNICATION
4-Toluenesulfonyl chloride (Tos-Cl, 6.00ꢀg, 31.5ꢀmmol) is stirred in
dimethylacetamide (6.5ꢀmL) for 30 minutes to obtain a clear solution. (Z)-
(2-Aminothiazol-4-yl)-methoxyiminoacetic acid (4, 7.00ꢀg; 34.8ꢀmmol) is
and cooled to 0ꢀ°C. After adding triethylamine (6.30ꢀmL, 45.4ꢀmmol) a clear
solution is formed, which is cooled to -30ꢀ°C. The suspension of the mixed
anhydride is added dropwise under controlling the temperature being -
30ꢀ°C. After 30 minutes stirring a part of this solution (20ꢀµL) is added to a
and acetonitrile (1.00ꢀmL) for determination of yield via HPLC. Column:
Macherey-Nagel Nucleodur C18 HTec; Phase A: KH2PO4 (4.35ꢀg,
32.0ꢀmmol) and Na2HPO4 (0.18ꢀg, 1.28ꢀmmol) in H2O (1000ꢀmL); Phase B:
Acetonitrile; Flow rate: 1 mL/min; ϑ column: 25ꢀ°C; λ detection: 260ꢀnm; t1
= 0ꢀmin, 93.5%ꢀA; t2 = 20ꢀmin, 44.5%ꢀA; t3 = 26ꢀmin, 44.5%ꢀA; t4 = 27ꢀmin,
93.8%ꢀA; t5 = 30ꢀmin 10.5 % A.
suspended in dimethylacetamide (21ꢀmL). After
5 minutes stirring
triethylamine (4.70ꢀmL, 33.7ꢀmmol) is added dropwise to the suspension at
15ꢀ°C. After 5 minutes stirring the reaction mixture is cooled to -11ꢀ°C and
the solution of 4-toluenesulfonyl chloride is added dropwise. The
suspension is stirred for 90 minutes to form the mixed anhydride. (6R,7R)-
7-amino-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid (6.73ꢀg, 27.5ꢀmmol) is suspended in methylene chloride or
methanol (62ꢀmL) and cooled to 0ꢀ°C. After adding triethylamine (9.40ꢀmL,
67.4ꢀmmol) a clear solution is formed, which is cooled to -30ꢀ°C. The
suspension of the mixed anhydride is added dropwise under controlling
the temperature being -30ꢀ°C. After 30 minutes stirring a part of this
solution (2ꢀµL) is added to a mixture of water (500ꢀµL) and acetonitrile
(500ꢀµL) for determination of yield via HPLC. Column: Macherey-Nagel
Nucleodur C18 HTec; Phase A: KH2PO4 (wꢀ=ꢀ3.4%) in H2O; pHꢀ=ꢀ4.6);
Phase B: Acetonitrile; Flow rate: 1 mL/min; ϑ column: 25ꢀ°C; λ detection:
260ꢀnm; t1 = 0ꢀmin, 89.5% A; t2 = 6ꢀmin, 66.0% A; t3 = 9ꢀmin, 30.0% A; t4
= 11ꢀmin, 30.0% A; t5 = 13ꢀmin, 89.5% A; t6 = 15ꢀmin, 89.5% A.
Acknowledgments
The authors thank the German Federal Environmental
Foundation (Deutsche Bundesstiftung Umwelt, DBU) for
generous support within the funding initiative “Sustainable
Pharmacy” (Project AZ 31723-32).
Keywords: amidation
• antibiotics • cephalosporin-based
Cefpodoxime proxetil (3d)
antibiotics • cefpodoxime • ceftazidime
4-Toluenesulfonyl chloride (Tos-Cl, 6.01ꢀg, 31.5ꢀmmol) is stirred in
dimethylacetamide (6.5ꢀmL) for 30 minutes to obtain a clear solution. (Z)-
(2-Aminothiazol-4-yl)-methoxyiminoacetic acid (4, 7.00ꢀg; 34.8ꢀmmol) is
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[2]
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M. Tian, CN102453041, 2012.
suspended in dimethylacetamide (21ꢀmL). After
5 minutes stirring
[3]
[4]
[5]
triethylamine (8.30ꢀmL, 29.9ꢀmmol) is added dropwise to the suspension at
15ꢀ°C. After 5 minutes stirring the reaction mixture is cooled to -11 °C and
the solution of 4-toluenesulfonyl chloride is added dropwise. The
suspension is stirred for 90 minutes to form the mixed anhydride. 1-
((isopropoxycarbonyl)oxy)ethyl-(6R,7R)-7-amino-3-(methoxymethyl)-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (10.3ꢀg, 27.5ꢀmmol)
is solved in ethyl acetate (62ꢀmL) and cooled to -30ꢀ°C. The suspension of
the mixed anhydride is added dropwise under controlling the temperature
being -30ꢀ°C. After 30 minutes stirring a part of this solution (10ꢀµL) is
added to acetonitrile (1000ꢀµL) for determination of yield via HPLC.
Column: Macherey-Nagel Nucleodur C18 HTec; Phase A: ammonium
acetate buffer (pHꢀ5.0, 20ꢀmM); Phase B: Acetonitrile; 60%ꢀA, 40%ꢀB; Flow
rate: 1 mL/min; ϑ column: 25ꢀ°C; λ detection: 260ꢀnm.
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Antibiot. 1995, 48, 1375-1377. (c) R. Heymes, J. Jolly, P. Rizzi, PCT Int.
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[9]
Ceftazidime tert-butylester (3h)
[10] D. Prat, A. Wells, J. Hayler, H. Sneddon, C. R. McElroy, S. Abou-
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4-Toluenesulfonyl chloride (Tos-Cl, 4.00ꢀg, 21.0ꢀmmol) is stirred in
dimethylacetamide (4.4ꢀmL) for 30 minutes to obtain a clear solution. (Z)-
(2-Aminothiazol-4-yl)-2-(((1-tert-butoxy)-2-methyl-1-oxopropan-2-
yl)oxy)imino)acetic acid (6, 7.63ꢀg; 24.4ꢀmmol) is suspended in
dimethylacetamide (14ꢀmL). After 5 minutes stirring triethylamine (3.13ꢀmL,
22.6ꢀmmol) is added dropwise to the suspension at 15ꢀ°C. After 5 minutes
stirring the reaction mixture is cooled to -11 °C and the solution of 4-
toluenesulfonyl chloride is added dropwise. The suspension is stirred for
90 minutes to form the mixed anhydride.1-(((6R,7R)-7-amino-2-carboxy-8-
oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-pyridin-1-ium-
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hydroiodide-hydrate (8.00ꢀg, 18.3ꢀmmol) is suspended in methanol (42ꢀmL)
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201900277
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Cephalosporin antibiotics
Matthias Pieper, Herbert Schleich,
Harald Gröger*
Page No. – Page No.
General Synthesis of Industrial
Cephalosporin-Based Antibiotics
through Amidation with Tosyl
Chloride as a Coupling Reagent
The feasibility of an amidation method for a general synthesis of industrially
important semi-synthetic cephalosporin antibiotics starting from readily available 7-
aminocephalosporanic acid and derivatives thereof is demonstrated. The amidation
process is based on the use of 4-toluenesulfonyl chloride as an economically
attractive coupling reagent in combination with methanol or ethyl acetate as
preferred solvent component.
This article is protected by copyright. All rights reserved.