Commercial synthesis of cefprozil: Development and control of process impurity

Article abstract of DOI:10.1021/op5000545

A process impurity, ethoxycarbonylcefprozil (9), formed in the synthesis of cefprozil (1) was controlled with addition of a catalytic amount of methanesulfonic acid.

Full text of DOI:10.1021/op5000545

Technical Note
pubs.acs.org/OPRD
Commercial Synthesis of Cefprozil: Development and Control of
Process Impurity†
Bishwa Prakash Rai, Neera Tewari, Hashim Nizar,* Mohan Prasad, and Sony Joseph
Chemical Research Division, Ranbaxy Research Laboratory, Gurgaon, Haryana 122001, India
ABSTRACT: A process impurity, ethoxycarbonylcefprozil (9), formed in the synthesis of cefprozil (1) was controlled with
addition of a catalytic amount of methanesulfonic acid.
impurity. Our emphasis was to investigate the root cause and
control its formation during the reaction. The HPLC monitoring
showed the impurity in the reaction mixture with a range from
0.5 to 1.25%. Our studies revealed that this impurity is generated
during the mixed anhydride formation of 6. The formation of
impurity is possible by the reaction of phenolic OH with ethyl
chloroformate under the given conditions (Scheme 2). Experi-
ments were carried out to minimize this impurity formation
during reaction. It was found that the addition of a catalytic
amount of an organic acid along with a catalytic amount of NMM
reduced the formation of this impurity drastically. Different
organic acids were tried, and results are tabulated in Table 1.
Among the various organic acids tried, such as acetic acid,
formic acid, 3-(N-morpholino)propanesulfonic acid (MOPS),
and methanesulfonic acid (MSA), the best result was obtained
with MSA. MOPS did not have any impact in reduction of
impurity. In a typical experiment, MSA (5 mol %) and NMM (2
mol %) were added to Dane salt 6 and treated with ethyl
chloroformate. The mixed anhydride 7 thus formed is condensed
with silylated 7-APCA 5, and product is isolated as DMF solvate.
Cefprozil regenerated as monohydrate by desolvation of DMF
solvate in water with 77% yield and impurity 9 in the range of
0.04−0.07%.
INTRODUCTION
■
Cephalosporins are an important class of β-lactam antibiotics.
Cefprozil (1), cefadroxil (2), and cefatrizine (3) antibiotics have
a common side chain, namely p-hydroxy phenyl glycine.
Cefprozil, developed by Bristol-Myers-Squibb, is an effective
broad spectrum antibiotic useful in the treatment of respiratory
tract, ear, and skin infections, etc.1 It is a mixture of Z and E
isomers, with Z primarily responsible for the antibiotic activity.2
The synthetic process3 for the commercial production involves
condensation of the acid chloride of p-hydroxy phenyl glycine or
mixed anhydride of Dane salt 6 with 7-amino-3-(propen-1-yl)-3-
cephem-4-carboxylic acid (7-APCA, 4) (Scheme 1). The Dane
salt route was preferred over the amino acid chloride route due to
the commercial availability of Dane salt 7, better yield, and poor
stability of acid chloride.4
The ICH guidelines require all the process impurities to be
controlled either through the starting materials, isolated
intermediates or in the API. In the API all the known impurities
need to be controlled with a limit of not more than 0.15%.5 This
article reports the control of a process impurity ethoxycarbo-
nylcefprozil (9), which is formed during the reaction.
CONCLUSION
■
We have effectively controlled the formation of ethoxycarbonyl
impurity 9 during the reaction with the use of a catalytic amount
of methanesulfonic acid. With this improvement, high quality
cefprozil is manufactured.
RESULTS AND DISCUSSION
■
EXPERIMENTAL SECTION
■
Our methodology to manufacture cefprozil involves condensa-
tion of silylated 7-APCA 5 with the mixed anhydride of Dane salt
7 (Scheme 1). The limit for E isomer content in API as per U.S.
Pharmacopoeia is 8−11%, which is controlled through starting
material 7-APCA (4). A method to achieve the desired ratio is
disclosed in our earlier publication.6 The manufacturing process
for cefprozil involves formation of a mixed anhydride of Dane salt
(7) by the reaction of 6 with ethyl chloroformate in the presence
of catalytic amount of N-methyl morpholine (NMM). NMM
catalyzed the mixed anhydride formation to get complete
conversion.4 This is then condensed with silylated 7-APCA 5.
The analysis showed an impurity ethoxycarbonylcefprozil (9) in
API in the range 0.3−0.8%. Attempted purification of API did
not give the desired result; hence, there was a need to control this
General. Reagents were used as such without purification. 1H
NMR (400 MHz) spectra was recorded using a Bruker
spectrometer. The chemical shift data is reported as δ (ppm)
using tetramethylsilane as internal standard. Mass spectrum was
recorded using an API 2000 (MPS SCIEX) instrument. Infrared
spectrum was recorded using PerkinElmer FTIR (Spectrum
One) instrument. HPLC analysis was performed on a Waters/
Agilent instrument with a UV detector (220 nm) using Inertsil
ODS-3 V (250 mm × 4.6 mm, 5 μm) column. Column oven
temperature: 30 °C, Sample tray temperature: 4 °C Mobile phase
Received: February 14, 2014
Published: April 15, 2014
© 2014 American Chemical Society
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Organic Process Research & Development
Technical Note
Scheme 1. Formation of Cefprozil
Scheme 2. Impurity Formation Pathway
Part C: Condensation and Isolation of Cefprozil DMF
Solvate. The solution of silylated 7-APCA (part A) was added to
part B, mixed anhydride keeping the temperature below −40 °C
over a period of 10−15 min. After the addition, the mixture was
stirred for 1 h at −40 − −45 °C. Then the temperature was raised
to −30 °C and the reaction monitored by HPLC. The reaction
mixture was added to a mixture of conc. HCl and water (84 and
410 L), stirred for 15 min at 0−5 °C and separated the aqueous
layer. The aqueous layer then diluted with DMF (1200 L) and
acetone (360 L) at 0−10 °C. Activated carbon (12 kg) was
added, stirred for 15−20 min at 0−10 °C. The resulting mixture
was filtered, washed with DMF (600 L) and the pH of the filtrate
was adjusted to 5.0−5.5 using aqueous ammonia (25%) at 15−20
°C. This solution was seeded with cefprozil DMF solvate (0.250
kg) and stirred for 15- 20 min. Then the pH was adjusted to 6.4−
6.5 with aqueous ammonia and stirred for 1 h at 15−20 °C. The
product was filtered, washed with DMF (240 L) followed by
acetone (2 × 1200 L) and dried at 30−35 °C for 12−14 h under
vacuum to give DMF solvate in 88% yield (203 kg).
Part D: Preparation of Cefprozil Monohydrate (1). Cefprozil
DMF solvate (203 kg) from part C was added to water (825 L) at
30−35 °C in 40−60 min and stirred for 1.5 h. The slurry was then
cooled to 0−5 °C and stirred for 2 h. The product was filtered
and washed with chilled water (120 L) and acetone (2 × 300 L).
The wet material was dried under vacuum at 40−45 °C until
water content is 4−5% (w/w) to give cefprozil monohydrate
(158 kg) in 77% yield. HPLC Purity: 99.47%, Ethoxycarbonyl
impurity: 0.07%, MS: m/z = 390 [M + H]+; IR (KBr) (cm−1):
1762, 1681, 1560. 1H NMR (400 MHz, CF3COOD): 8.17−8.2
(d, 2 H), 7.78−7.81 (d, 2 H), 6.94−6.98 (d, 1 H), 6.61−6.68 (m,
1 H), 6.45−6.46 (d, 1 H), 6.18 (d, 1 H), 5.94−5.95 (d, 1 H),
4.05−4.24 (q, 2H), 2.39−2.41 (d, 3H).
Table 1. Effect of Acid in the Formation of 9
a
impurity 9
Z/E (%)
impurity in API 9
organic acid
Z/E (%)
-
-
1.19/0.13
0.66/0.1
0.65/0.09
0.34/0.13
0.12/ND
Not tested
0.1/ND
Acetic acid
0.14/0.02
1.31/0.26
0.09/0.01
0.07/0.01
MOPS
Formic acid
Methanesulfonic acid
0.04/ND
a
HPLC reaction monitoring, ND = not detected.
A [Aqueous Monobasic sodium phosphate (0.04% w/w
solution) adjusted pH to 4 0.05 with dilute ortho phosphoric
acid]: Mobile phase B [mixture of mobile phase A and
acetonitrile 50:50 v/v], flow rate: 1.0 mL/min, gradient 95:5
(0−20 min), 70:30 (20−40 min), 40:60 (40−50 min), 0:100
(50−62 min), 95:05 (60−70 min)
Preparation of Cefprozil (1). Part A: Silylation of 7-Amino-
3-(propen-1-yl)-3-cephem-4-carboxylic acid (7-APCA). 7-
APCA (5, 120 kg, 0.5 kmol) was added to methylene chloride
(420 L) followed by 1,1,3,3-hexamethylsilazane (60.36 kg, 0.375
kmol), chlorotrimethyl silane (42.25 kg, 0.39 kmol) and
imidazole (1.2 kg). The reaction mixture was then refluxed for
3−4 h and cooled to 0−5 °C.
Part B: Mixed Anhydride Formation 7. Potassium (D)-N-(1-
methoxycarbonyl-propen-2-yl-α-amino-p-hydroxy phenyl ace-
tate (Dane Salt, 6, 168.8 kg, 0.56 kmol) was added to methylene
chloride (720 L) and DMF (540 L) and stirred at −40 − −45 °C.
N- Methyl morpholine (1 kg, 2 mol %) and methanesulfonic acid
(2.4 kg, 5 mol %) were added followed by ethyl chloroformate
(67.68 kg, 0.62 kmol) and stirred for about 2 h at −38 to −48 °C.
Then cooled to −60 to −65 °C
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Organic Process Research & Development
Technical Note
AUTHOR INFORMATION
Corresponding Author
*E-mail: hashim.nizar@ranbaxy.com; Tel: (91-124)4011832.
■
Author Contributions
†A patent application incorporating parts of this report has been
filed.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Analytical Division of Ranbaxy Research
Laboratories for their analytical and spectral support.
■
REFERENCES
■
(1) Wiseman, L. R.; Benfield, P. Drugs 1993, 45, 295−317.
(2) Naito, T.; Hoshi, H.; Aburaki, S.; Abe, Y.; Okumura, J.; Tomatsu,
K.; Kawaguchi, H. J. Antibiot. 1987, 7, 991−1005.
(3) (a) Crast, L. B. Jr. U.S. patent (Bristol- Myers) 4694079, 1987.
(b) Kumar, Y.; Tewari, N.; Singh, S. K.; Rai, B. P. PCT Int. (Ranbaxy)
WO 2004/083172, 2004.
(4) Bruggink, A.; Roy, P. D. Industrial synthesis of Semisynthetic
Antibiotics. In Synthesis of β-lactum Antibiotics; Bruggink, A., Ed.;
Springer: Netherlands, 2001; pp 12−54.
(5) International conference on Harminization (ICH) Guidelines,
Q3A (R), Impurities in New Drug Substances (Revised Guidline); U.S.
Department of Health and Human Services, Food and Drug
Administration: Washington, DC, 2008.
(6) Kumar, Y.; Tewari, N.; Singh, S. K.; Rai, B. P.; Nizar, H. Org. Process
Res. Dev. 2003, 7, 196−197.
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