Identification and control of a process-related impurity in the chlorination of 3-hydroxy-3-carbacephem

Article abstract of DOI:10.1021/op034026x

A process for the synthesis of carbacephem key intermediate (4-nitrophenyl)methyl,7-amino-1-carba(dethia)-3-chloro-3-cephem-4-carboxylate, monohydrochloride (1) via chlorination and deacylation employing chlorotriphenoxyphosphonium chloride [(PhO)₃

Full text of DOI:10.1021/op034026x

Organic Process Research & Development 2003, 7, 758−761
Identification and Control of a Process-Related Impurity in the Chlorination of
3
-Hydroxy-3-carbacephem
Yatendra Kumar,* Neera Tewari, Hashim Nizar, Bishwa Prakash Rai, and Shailendra Kumar Singh
Chemical Research DiVision, Ranbaxy Research Laboratories, Gurgaon, Haryana - 122 001, India
2
b,c
Abstract:
deacylation using this reagent,
only N-deacylation is
2a
reported. However, another publication mentions the deacy-
lation and chlorination in a single step using the above
A process for the synthesis of carbacephem key intermediate
(4-nitrophenyl)methyl,7-amino-1-carba(dethia)-3-chloro-3-ceph-
2
d
2e
reagent. J. E. Burks et al. have studied the kinetic
differences in the chlorination of cephalosporins vs that of
carbacephems with this reagent and report that chlorination
of carbacephems requires higher temperatures compared to
that of cephalosporins. With our prior practical experience
with cephalosporin molecules using the Hatfield reagent, we
observed that carbacephem behaves differently and faced
problems in the preparation of pure intermediate 1. In this
report, we highlight the issues encountered during the process
development and describe a scalable process for synthesis
of intermediate 1 from intermediate 4.
em-4-carboxylate, monohydrochloride (1) via chlorination and
deacylation employing chlorotriphenoxyphosphonium chloride
+
-
3
[(PhO) P ClCl ] has been described. The most difficult problem
encountered during the process development was the formation
of an impurity 2, which has been isolated, identified, and
controlled by modifying the reaction conditions.
Introduction
Loracarbef (3a) is the first carbacephem antibiotic, an
analogue of the most widely used cephalosporin antibiotic
cefaclor (3b). It is an orally active broad-spectrum antibiotic
Results and Discussion
The intermediate 1 is prepared by the reaction of
intermediate 4 with chlorotriphenoxy phosphonium chloride
in the presence of pyridine in a mixture of ethyl acetate and
dichloromethane. Scheme 1 outlines the reaction pathway
for the conversion of enol 4 to the chloro intermediate 1
used in the treatment of infections of the respiratory system
and urinary tract and for skin infections.1
+
-
3
using chlorination reagent (PhO) P ClCl which involves
rapid, reversible chloride addition to an intermediate enol
phosphonium species followed by rate-limiting phosphate
2
e
departure.
It is observed during our development work that an
impurity at the level of 20-25% is formed and present in
the isolated product in 15-20% (as determined by HPLC),
which resulted in inferior yield and quality of intermediate
The carbacephems have been prepared by total synthesis
in contrast to cephalosporin antibiotics. Since these are
obtained by total synthesis, purity of the intermediates
involved plays an important role in the formation of the final
drug molecule. The conversion of (4-nitrophenyl)methyl,
1
1
. The above impurity is isolated and characterized by
different spectroscopic data and is assigned the structure as
, which shows a pyridyl substitution at the 3-position instead
2
of chlorine. The impurity 2 is formed by the attack of
pyridine instead of chloride ion in the above phosphonium
species 5. There is no literature report for a similar
nucleophilic attack of pyridine and formation of impurity 2.
The proposed mechanism is shown in Scheme 2.
7
4
-phenoxyacetamido-1-carba(dethia)-3-hydroxy-3-cephem-
-carboxylate (4) to intermediate 1 is the key step in the
total synthesis of loracarbef. Different synthetic methods are
2
reported in the literature for the above conversion. In the
preparation of intermediate 1, our strategy involves deacy-
lation and chlorination in single step, utilizing Hatfield
(
2) (a) Bodurow, C. C. (Eli Lilly). E.P. Patent 348,124, 1994. (b) Hatfield, L.
D.; Blaszczak, L. C.; Fischer, J. W. (Eli Lilly). U.S. Patent 4,226,986, 1980.
2
b,c
reagent.
triphenyl phosphite with chlorine gas, resulting in the
formation of chlorotriphenoxyphosphonium chloride [(PhO)
This reagent is prepared by the reaction of
(c) Hatfield, L. D.; Lunn, W. H. W.; Jackson, B. G.; Peters. L. R.; Blaszczak,
L. C.; Fisher, J. W.; Gardner, J. P.; Dunigan, J. M. In Recent AdVances in
the Chemistry of â-Lactam Antibiotics; Gregory, G. I, Ed.; The Royal
Society of Chemistry: London, 1980; p 109. (d) Bodurow, G. C.; Boyer,
D. D.; Brennan, J.; Bunnell, C. A.; Burks, J. E.; Carr, M. A.; Doecke, C.
W.; Eckrich, T. M.; Fisher, J. W.; Gardner, J. P.; Graves, B. J.; Hines, P.;
Hoying, R. C.; Jackson, B. G.; Kinnick, M. D.; Kochert, C. D.; Lewis, J.
S.; Luke, W. D.; Moore, L. L.; Morin, J. M., Jr.; Nist, R. L.; Prather, D.
E.; Sparks, D. L.; Valduchick, W. C. Tetrahedron Lett. 1989, 30, 2321.
(e) Burks, J. E., Jr.; Chelius, E. C.; Johnson, R. A., J. Org. Chem. 1994,
59, 5724.
3
-
+
-
P ClCl ]. During the attempted two-step chlorination and
*
Author for correspondence. E-mail: yatendra.kumar@ranbaxy.com. Tele-
phone (91-124) 234 2020. Fax (91-124) 501 1832.
(
1) (a) Kant, J.; Walker, D. G. In The Organic Chemistry of â-Lactams; Georg.
G. I., Ed.; VCH: New York, 1993; pp 121-196. (b) Metais, E.; Overman,
L. E.; Rodriguez, M. I.; Stearns, B. A. J. Org. Chem. 1997, 62, 9210.
7
58
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10.1021/op034026x CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/15/2003

Scheme 1
Scheme 2
To minimize the above impurity 2, we turned our attention
scale-up batches where addition of chlorination reagent
(PhO) P ClCl in one lot is not feasible, this reaction
3
condition is found to be more suitable.
+
-
to the optimization of reaction conditions. In a typical
experiment the chlorotriphenoxyphosphonium chloride
+
-
[
°
(PhO)
3
P ClCl ] prepared at low temperature (-20 to -30
Further, it is observed that slow addition of chlorination
+
-
C) in dichloromethane is added to a suspension of inter-
reagent (PhO)
3
P ClCl to the suspension of intermediate 4
mediate 4 in ethyl acetate in the presence of pyridine at low
temperature (-55 to -20 °C). The temperature is raised to
in ethyl acetate (Table 1, entry 3) and addition of intermediate
4 dissolved in CH Cl to the precooled (PhO) P ClCl in
2 2 3
+
-
20-25 °C and the intermediate 1 isolated from the reaction
dichloromethane in the presence of pyridine and ethyl acetate
(Table 1, entry 4) favour the formation of impurity 2. In
these cases the availability of pyridine is more for attack on
species 5, resulting in the formation of species 6 (Scheme
2). Similarly when the reaction is carried out only in
dichloromethane (Table 1, entry 5), due to higher solubility
of intermediate 4 in dichloromethane, the reaction medium
is homogeneous. These conditions are favourable for the
formation of species 6. The presence of ethyl acetate makes
the reaction medium heterogeneous due to insolubility of
mixture with the addition of isobutanol followed by an HCl
gas sparge.
It is found that the factors which are favourable for the
minimization of impurity 2 are the following: (1) addition
+
-
of chlorination reagent (PhO)
suspension of intermediate 4 in ethyl acetate (Table 1, entry
); (2) addition of pyridine in two portions to the reaction
3
P ClCl in one lot to the
1
mixture prohibits the formation of species 6 due to the
nonavailability of excess pyridine (Table 1, entry 2). During
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759

Table 1. Chlorination of intermediate 4 under different conditions
impurity 2 (%) in isolated
intermediate 1 (by HPLC)
yield (%)
(after methanol washing)
entry no
reaction conditions
a
1
2
3
4
5
typical experiment (see Experimental Section)
addition of pyridine in two portions
0.2
0.2
15
17
13
74
76
61
55
58
a
+
-
slow addition of (PhO)
addition of intermediate 4 to the (PhO)
reaction in dichloromethane (without ethyl acetate)
3
P ClCl complex
+
-
3
P ClCl (reverse addition)
a
No methanol washing.
intermediate 4 (Table 1, entries 1 and 2). It indicates that
the solubility factor also plays a role in the formation of
impurity.
From the above experiments, it is evident that the ideal
condition for minimization of impurity 2 is to carry out the
reaction in a mixture of ethyl acetate and dichloromethane
with pyridine addition in two portions, to keep excess
chloride ions in the reaction medium.
Impurity 2 present in isolated intermediate 1 can be
removed by washing with methanol to afford pure intermedi-
ate 1. It can be isolated from methanol washings, and its
structure has been identified by spectral data (see Experi-
mental Section).
to -25 °C for 30 min, the temperature is slowly raised to 0
°C, and the reaction is stirred for 60 min at 0-5 °C. The
temperature is further raised to 20 °C and stirring continued
for approximately 90 min at 20-25 °C; the reaction is
monitored by HPLC for completion. Isobutanol (127 g, 1.7
mol) is added and stirred for 15-20 min at 25-30 °C
followed by bubbling of HCl gas for 15-20 min at 25-30
°C. The reaction mixture is allowed to stir for 60 min at
ambient temperature, cooled to 5-10 °C, and filtered. The
wet cake is washed with dichloromethane (2 × 250 mL)
and dried to give the desired product 61.5 g (74%).
1
Chromatographic purity (by HPLC): 98%, H NMR
(DMSO-d
6
2 2
): 2.0 (m, 2H, CH ), 2.4 (m, 2H, CH ), 4.0 (m,
1
H, â-lactam), 4.8 (d, J ) 4.8 Hz,1H, â-lactam), 5.4 (s, 2H,
COOCH
Hz, 2H, ArH), 9.4 (br, 2H, NH
Table 1, Entry 2. In the above experiment pyridine is
added in portions. Initially 0.31 mol of pyridine is added to
the suspension in ethyl acetate, and the remaining quantity,
2
-), 7.7 (d, J ) 8.2 Hz, 2H, ArH), 8.2 (d, J ) 8.4
).
Conclusions
2
The above report describes a scalable process for the
conversion of intermediate 4 to 1. An impurity formed during
the conversion is isolated and identified. The reaction
conditions are optimized to minimize the impurity formation
and prepare intermediate 1 in good yield and quality.
0
4
.28 mol, is added to the reaction mixture after stirring for
5 min at 0-5 °C. The rest of the reaction is carried out as
mentioned above (yield: 76%).
Experimental Section
Isolation of Impurity 2: (4-Nitrophenyl)methyl, 7-
Amino-1-carba(dethia)-3-pyridyl-3-cephem-4-carboxyl-
ate Monohydrochloride. To a mixture of triphenyl phosphite
(232 g, 0.74 mol) in dichloromethane (1000 mL) and pyridine
General. Reagents were used as such without further
purification. HPLC was performed with a Waters instrument
1
using Kromasil C18 (150 mm × 4.6 mm, 5µm) column. H
(12 g, 0.15 mol) chlorine gas is bubbled at -30 to -15 °C
NMR spectra were recorded using Bruker 300 MHz in
until a light-yellow colour persists. Cyclohexene is added
to decolourise the yellow colour, and the mixture is stirred
at -30 to -35 °C for 10-15 min. Pyridine (47 g, 0.59 mol)
is added followed by intermediate 4 dissolved in dichlo-
romethane (500 mL) at -35 to -15 °C. The reaction mixture
is allowed to stir for 30 min at -20 to -25 °C, 0-5 °C for
DMSO-d . The chemical shift data is reported as δ (ppm)
downfield from tetramethylsilane which was used as an
internal standard. Mass spectra were recorded using API 2000
6
(MDS SCIEX) instrument.
Preparation of (4-Nitrophenyl)methyl, 7-Amino-1-
carba(dethia)-3-chloro-3-cephem-4-carboxylate monohy-
drochloride (1) (Typical Experiment: Table 1, Entry 1).
To a mixture of triphenyl phosphite (232 g, 0.74 mol) in
dichloromethane (1000 mL) and pyridine (12 g, 0.15 mol)
at ∼-30 to -15 °C, chlorine gas is bubbled until light-
yellow colour develops. Cyclohexene is added dropwise to
decolourise the yellow colouration and stirred at ∼-20 to
6
0 min and 20-25 °C for 90 min. Isobutanol (127 g, 1.7
mol) is added followed by bubbling of HCl gas at 25-30
C. It is stirred for 60 min and then cooled to 5-10 °C,
°
filtered, and washed with dichloromethane (2 × 250 mL) to
obtain the desired product 55 g (66%). The chromatographic
purity by HPLC shows 17.0% impurity 2. The above material
(55 g) is suspended in methanol (300 mL) and stirred at
ambient temperature for 30 min. It is filtered, washed with
methanol (100 mL), and dried to yield 45.6 g (55%) of
intermediate 1.
The methanol washings are combined and concentrated
to give a residue which is triturated with ethyl acetate (100
mL) and filtered, and the hygroscopic solid is washed with
ethyl acetate (50 mL) and dried under vacuum to obtain
-
25°C for 10-15 min. In a separate flask, (4-nitrophenyl)-
methyl, 7-phenoxyacetamido-3-hydroxy-1-carba(dethia)-3-
cephem-4-carboxylate 4 (100 g, 0.214 mol) is suspended in
ethyl acetate (400 mL) and pyridine (47 g, 0.59 mol). The
suspension is cooled to ∼-50 to -55 °C and chlorotriphe-
noxyphosphonium chloride solution in dichloromethane
added in one lot under nitrogen atmosphere and flushed with
dichloromethane (500 mL). The reaction is stirred at -20
760
•
Vol. 7, No. 5, 2003 / Organic Process Research & Development

1
2
1
4
5
.5 g of impurity 2. H NMR (DMSO-d
H, CH ), 2.1 (m, 1H, CH ), 3.0 (m, 2H, CH
.8 Hz, 1H, â-lactam), 5.1 (d, J ) 4.6 Hz, 1H, â-lactam),
.2 (s, 2H, -CH -COOPNB), 7.5 (d, 2H, ArH), 8.0 (m,
H, pyridyl H), 8.2 (m, 3H, ArH, pyridyl H), 8.9 (m, 2H,
6
+ D
2
O): 2.07 (m,
), 4.1 (d, J )
Acknowledgment
2
2
2
We are grateful to the Analytical Division of Ranbaxy
Research Laboratories for their analytical and spectral
support.
2
2
-
1
2
pyridyl H), 9.2 (br, 2H, NH ), IR (KBr cm ): 3419, 2881,
787, 1732, 1628, 1521, 1486, 1402, 1378, 1348, 1294, 1267,
51, 681, MS (m/e): 395.
Received for review February 13, 2003.
OP034026X
1
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