AN IMPROVED PROCESS FOR THE PREPARATION OF
CEFUROXIME AXETIL
Field of the invention
The present invention is in the field of chemistry and more particularly the
present invention relates to the preparation of cefuroxime axetil of formula (I)
using alcohol and water system for isolation in a very safe, simple, economical,
user-friendly process and in an industrially viable manner.
Background of the invention
Cefuroxime axetil of formula (I) is chemically known as (R,S)-1 -acetoxyethyl (Z)-
3-carbamoyloxymethyl-7-[2-(2-furyl)-2-(methoxyimino)-aceta mido]-8-oxo-5-thia-
1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, the 1-acetoxyethyl ester of
cefuroxime, a second-generation semisynthetic cephalosporin characterized by a
broad spectrum activity against Gram-positive and Gram-negative bacteria. It is
orally active and is marketed in the amorphous form, this physical state having
better pharmacokinetic/pharmacodynamic characteristics than the crystalline
product.
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The absorption of cephalosporin antibiotics which are poorly absorbed through
the digestive tract can be improved by preparing and administering the
corresponding ester derivatives at the 4-carboxylic acid position. The esters are
then readily and completely hydrolysed in vivo by enzymes present in the body to
regenerate the active cephalosporin derivative having the free carboxylic acid at
the 4-position.
Mobasherry et. al. in J. Org. Chem., 1986, 51, 4723 describe preparation of
certain A3-cephalosporin-4-carboxylic acid esters by reaction of the
corresponding 3-cephem-4-carboxylic acids with an haloester in presence of 1.1
eq. of sodium carbonate in the presence 1.2-1.5 eq. of an alkyl halide and in
presence of a solvent comprising of a mixture of N,N-dimethylformamide and
dioxane.
Shigeto et. al. in Chem. Pharm. Bull., 1995, 43(11), 1998 have carried out the
esterification of certain 7-substituted-3-cephem-4-carboxylic acid derivatives with
1-iodoethyl isopropyl carbonate in a solvent system containing a mixture of N,Ndimethylformamide
and dioxane in a 3:5 ratio. A conversion to the corresponding
3-cephem-4-carboxylate ester was achieved in only 34%.
H. W. Lee et. al. in Synthetic Communications, 1999, 29(11), 1873-1887
demonstrate a method for preparation of (3,7)-substituted-3-cephem-4-carboxylic
acid esters comprising reacting the corresponding (3,7)-substituted-3-cephem-4-
carboxylic acid derivatives with a base selected form cesium carbonate or
cesium bicarbonate either used alone or in combination with potassium
carbonate, sodium carbonate, potassium bicarbonate and sodium bicarbonate.
The authors established that the formation of A2-isomers could be minimised by
utilisation of a solvent combination of N,N-dimethyl formamide and dioxane. The
use of the latter mentioned solvent i. e. dioxane was expected to lower polarity of
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the reaction medium and thereby reduce the basicity of the transient 3-cephem-
4-carboxylate anion formed in the reaction and thus preventing the isomerisation
of the double bond from the 3-4 position to the 2-3 position.
Y. S. Cho et. al., in Korean J. Med. Chem., 1995, 5(1), 60-63 describe synthesis
of ester by reacting the corresponding cephalosporin-4-carboxylic acid derivative
with the respective haloester derivative in presence of cesium carbonate and
N,N-dimethylacetamide. The yields of the ester derivatives obtained are in the
range of only 25-56%, indicating formation of substantial amounts of impurities in
the reaction.
The conventional process for the preparation of cefuroxime axetil is the
esterification of cefuroxime of formula II with 1-acetoxyethyl bromide (1-
bromoethyl acetate), as disclosed in U.S. Pat. No. 4,267,320, to afford, in normal
conditions, a crystalline product. The latter is transformed into the amorphous
form using special techniques, as described, for example in U.S. Pat. Nos.
4,562,181; 4,820,833; 4,994,467 and 5,103,833. In the processes for the
conversion of the crystalline product into the amorphous one, such as spray
drying, freeze drying, roller drying or treatment with excipients, the chemical
quality of the amorphous product in terms of impurities and diastereomeric ratio
is directly related to that of the crystalline precursor, as such processes do not
comprise further purification steps.
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(II)
PL 173252 discloses a method of producing pharmaceutical^ acceptable forms
of cefuroxime ester as a result of a reaction of cefuroxime with 1-acetooxyethyl
bromide in N,N-dimethylformamide or N,N-dimethylacetamide.
US 5,498,787 discloses a method for preparation of (3,7)-substituted-3-cephem-
4-carboxylic acid prodrug esters, unaccompanied by the analogous 2-cephem
esters comprising reaction of the corresponding (3,7)-substituted-3-cephem-4-
carboxylic acid alkali metal salts with suitable haloesters in the presence of
catalytic amounts of a quarternary ammonium or quarternary phosphonium salt.
US 6,833,452 discloses a process for the preparation of crystalline (R,S)-
cefuroxime axetil of Formula I comprising: a) generating an amine salt of
cefuroxime in situ by reacting cefuroxime of Formula II, with an amine selected
from the group consisting of ethylamine, diethylamine, diisopropylamine,
dibutylamine, di-sec-butylamine, triethylamine, dicyclohexylamine, or
didecylamine, in an inert organic solvent, b) reacting the amine salt of cefuroxime
in situ with (R,S)-1-acetoxyethyl bromide in the presence of a base, and c)
followed by aqueous work-up to give crystalline (R,S)-cefuroxime axetil wherein
said work-up comprises extracting with an organic solvent followed by the
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addition of a polar solvent selected from the group consisting of a lower alkanol,
ketone, ester and mixtures thereof.
US 7,064,198 discloses a process for preparation of cefuroxime axetil of formula
(I) of at least 96% purity, comprising (a) reacting cefuroxime acid of formula (III)
with (R,S)-1-acetoxyethyl bromide of formula (IV), and a Group I or II metal
carbonate in the presence of a compound of formula (V), MmHnPqOr (V) wherein
M is Group I or II metal; m is 1, 2 or 3; n is 0, 1, 2 or 4; q is 1 or 2 and r is 4, 7 or
8; in the presence of a C1-4 alcohol and solvent, the solvent comprising N,Ndimethylacetamide,
N,N-dimethylformamide, N,N-dimetheylpropionamide, N,Ndiethylacetamide,
N,N-diethylformamide, or N,N-diethylpropionamide, at a
temperature ranging from about -30 to +30° C. and (b) purifying the product of
step(a).
CN 103435632 discloses a method for preparing esters of cefuroxime by
dissolving dimethylformamide cefuroxime acid in the copper chloride catalyst with
1 - bromoethyl acetate in the esterification reaction; hydrolyzed with sodium
chloride solution and ethyl acetate, and extracted after distillation under reduced
pressure and crystallized from cyclohexane, filtered, and dried to obtain high
purity cefuroxime axetil.
The commercial product consists of a mixture of two diastereoisomers which
should be present in a well-defined ratio: the ratio of A isomer to the sum of the
A+B isomers should range from 0.48 and 0.55 [A/(A+B)=0.48.div.0.55], as
reported in European and United States Pharmacopoeias.
Furthermore, known impurities, such as delta-2 and anti isomers, as well as any
unknown impurities should not be present or at least be present in very small
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amounts and anyway within the limits established by the various
pharmacopoeias.
Hence, there is unmet need to develop a simple and environment friendly
process for the preparation of cefuroxime axetil thereof, which is convenient to
perform on a commercial scale, operationally safe and provides the product in
pure form.
With our continued search and intense investigation, we finally achieved a
process for the preparation of cefuroxime axetil, which overcomes all difficulties
and makes the process industrially viable and yield the title compound in required
quantity and quality.
It should be pointed out that carrying out the said process without cyclohexane
provides remarkable advantages in the industrial processes for the production of
Cefuroxime axetil. In fact, the method of the present invention provides good
quality of Cefuroxime axetil with the elimination of cumbersome process for
solvent recovery and removal of hazardous residual solvent in the final product.
Objective of the invention
The main object of the present invention is to provide a process for the
preparation of cefuroxime axetil of formula (I), which is very safe, simple,
economical, user-friendly and commercially viable.
Another objective of the present invention is to provide a process for the
preparation of cefuroxime axetil of formula (I), which would be easy to implement
on commercial scale, and to avoid excessive use of reagent(s) and organic
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solvent(s) and to avoid hazardous and risky solvents, which makes the present
invention more safe and eco-friendly as well.
Yet another objective of the present invention is to provide a process for the
preparation of cefuroxime axetil of formula (I) in a greater yield with higher
chemical purity.
Still another objective of the present invention is to provide a process for the
preparation of cefuroxime axetil of formula (I), wherein the organic solvent used
during the reaction can be reusable and thereby recyclable, which makes the
process industrially more suitable.
Summary of the invention
The present invention provides a process for the preparation of cefuroxime axetil
of formula (I), which comprises the steps of:
i. dissolving cefuroxime acid in a polar solvent;
ii. adding metal carbonate to the reaction solution;
iii. adding 1-acetoxy ethyl halide into the reaction mass followed by
stirring;
iv. quenching the reaction mass by adding water and organic solvent;
v. separating the compound rich organic layer from the aqueous layer;
vi. washing the organic layer with sodium metabisulfite and hydrochloric
acid solution
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vii. optionally, washing organic layer with brine and sodium bicarbonate
solution;
viii. treating organic layer with activated carbon followed by filtration;
ix. concentrating the organic layer to get solid residue
x. suspending the solid residue in an alcohol followed by addition of
water;
xi. stirring the reaction mass to complete the crystallization and cooling
the precipitated material;
xii. filtering the product followed by washing with water to get
cefuroxime axetil.
Detailed description of the invention
All temperatures are in degrees Celsius unless specified otherwise. All
measurements made are at about 25°C and about atmospheric pressure, and all
percentages and ratios used herein are by weight of the total composition, unless
otherwise designated.
As used herein, "comprising" means the elements recited, or their equivalent in
structure or function, plus any other element or elements that are not recited. The
terms "having" and "including" are also to be construed in the same manner. All
ranges recited herein include the endpoints, including those that recite a range
"between" two values. Terms such as "about," "generally," "substantially," and the
like are to be construed as modifying a term or value such that it is not an
absolute term or value. Such terms will be defined by the circumstances and the
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terms that they modify as those terms are understood by those having skill in the
art. This includes the degree of expected experimental error, technique error, and
instrument error for a given technique used to measure a value.
Accordingly, the present invention provides a process for the preparation of
cefuroxime axetil of formula (I), which comprises the steps of:
i. dissolving cefuroxime acid in a polar solvent;
ii. adding metal carbonate to the reaction solution;
iii. adding 1-acetoxy ethyl halide into the reaction mass followed by
stirring;
iv. quenching the reaction mass by adding water and organic solvent;
v. separating the compound rich organic layer from aqueous layer;
vi. washing the organic layer with sodium metabisulfite and hydrochloric
acid solution;
vii. optionally, washing organic layer with brine and sodium bicarbonate
solution;
viii. treating organic layer with activated carbon followed by filtration;
ix. concentrating the organic layer to get solid residue;
x. suspending the solid residue in an alcohol followed by addition of
water;
xi. stirring the reaction mass to complete the crystallization and cooling
the precipitated material;
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xii. filtering the product followed by washing with water to get
cefuroxime axetil.
Accordingly in an embodiment of the present invention, the said polar solvent in
step (i) is selected from the group consisting of: dimethylformamide,
dimethylacetamide, dimethylsulphoxide, acetonitrile, acetone, monoglyme,
diglyme and the like or mixture thereof, more preferably dimethylacetamide.
In another embodiment of the present invention, the said metal carbonate in step
ii) includes, but are not limited to: sodium carbonate, sodium bicarbonate,
potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium
carbonate and the like, and any mixtures thereof. Preferably, a metal carbonate
in step i) is sodium carbonate.
In another embodiment of the present invention, the said 1-acetoxy ethyl halides
in step (iii) is selected from the group comprising of 1-aceoxy ethyl chloride, 1-
aceoxy ethyl bromide, 1-acetoxy ethyl iodide and the like, preferably 1-acetoxy
ethyl bromide.
In another embodiment of the present invention, organic solvent in step iv)
includes, but are not limited to: a ketone, e.g. methyl isobutyl ketone, and the
like; a halogenated hydrocarbon, e.g., dichloromethane, ethylene dichloride,
chloroform, and the like; an ester, e.g., ethyl acetate, n-propyl acetate, n-butyl
acetate, t-butyl acetate, and the like; an ether, e.g., tetrahydrofuran and the like;
and any mixtures thereof. Preferably, suitable solvent in step iv) is ester; and
most preferably suitable solvent in step iv) is ethyl acetate.
In another embodiment of the present invention, alcohol used in step x) is
selected from the group consisting of: methanol, ethanol, isopropyl alcohol, nbutanol
and the like and any mixture thereof. Preferably, alcohol used in step x)
is methanol.
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In another embodiment of the present invention, alcohol used in step x) followed
by water used for the isolation of cefuroxime axetil.
In the present invention starting material(s) for the preparation of a compound of
formula (I), were prepared according to the known processes in the prior art.
Table - 01
Comparative chart showing advantages of present invention for the preparation
of cefuroxime axetil.
Process
Process using prior-art
method (using ethyl acetate
and cyclohexane for
isolation)
Process of Inventive method
(using methanol/water for
isolation)
Yield
(gm)
106
114
Purity
(%)
98
99.8
Residual Solvent
(ppm)
Ethyl acetate = >30,000 ppm;
Cyclohexane = 10,000 - 20,000
ppm;
Dimethylacetamide = 200 - 500
ppm
Ethyl acetate = < 5,000 ppm;
Dimethylacetamide = Not
detected
Methanol = Not detected
Advantages of present invention for the preparation of Cefuroxime axetil:
1. Smooth work-up due to fast filtration.
2. Drying time reduced due to less retention of solvent in wet material.
3. Eliminating the formation of cyclohexane solvate of the final product.
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4. Reducing the level of residual solvent as per ICH recommendation.
5. Avoiding the use of extremely flammable solvent i.e. cyclohexane.
Certain aspects and embodiments of the present application are described in
further details by the examples below, which are provided only for the purpose of
illustration and are not intended to limit the scope of the application in any
manner.
Examples:
Example 01: Preparation of Cefuroxime axetil
Cefuroxime acid (100 gm) was dissolved in dimethylacetamide (400 mL) at 25°C
to 30°C. Sodium carbonate (16 gm) was added to it with stirring and the reaction
mass was cooled to -5°C. 1-acetoxy ethyl bromide (39 gm) was added into the
cooled reaction mass. After the completion of the reaction, the reaction mass
was poured into a mixture of ethyl acetate (1500 mL) and water (1200 mL) along
with continuous stirring. The layers were separated. Organic layer was treated
with sodium metabisulphite and hydrochloric acid solution followed by washing
with brine solution (50 gm NaCI and 100 mL water) and sodium bicarbonate
solution. Then, the organic layer was charcolized, filtered and the charcoal bed
was washed with ethyl acetate (100 mL). The filtrate was then concentrated upto
complete dryness to obtain a solid residue. To the solid residue, methanol was
added followed by slow addition of water at low temperature. The precipitated
material was cooled and filtered to get cefuroxime axetil (Yield = 114 gm, Purity =
99.80%).
Example 02: Preparation of Cefuroxime axetil
Cefuroxime acid (100 gm) was dissolved in dimethylacetamide (400 mL) at 25°C
to 30°C. Sodium carbonate (16 gm) was added to it with stirring and the reaction
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mass was cooled to -5°C. 1-acetoxy ethyl bromide (39 gm) was added into the
cooled reaction mass. After the completion of the reaction, the reaction mass
was poured into a mixture of ethyl acetate (1500 mL) and water (1200 mL) along
with continuous stirring. The layers were separated. Organic layer was treated
with sodium metabisulphite and hydrochloric acid solution followed by washing
with brine solution (50 gm NaCI and 100 mL water) and sodium bicarbonate
solution. Then, the organic layer was charcolized, filtered and the charcoal bed
was washed with ethyl acetate (100 mL). Distilled out 40% of ethyl acetate from
the organic layer and cyclohexane (1000 mL) was added to it, to precipitate the
product. The precipitated material was cooled to 0°C-5°C and filtered to get
cefuroxime axetil (Yield = 106 gm, Purity = 98.0%).
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14
We Claim: i ^ "^ "^
1. A process for the preparation of cefuroxime axetil of formula (I), which
comprises the steps individually or in the sequence recited:
(I)
dissolving cefuroxime acid in a polar solvent;
i. adding metal carbonate to the reaction solution;
ii. adding 1-acetoxy ethyl halide into the reaction mass followed by
continuous stirring;
iv. quenching the reaction mass with organic solvent and water;
V. separating the compound rich organic layer;
vi. washing the organic layer with sodium metabisulfite and hydrochloric
acid solution;
vii. optionally, washing organic layer with brine and sodium bicarbonate
solution;
viii. treating organic layer with activated carbon followed by filtration;
ix. concentrating the organic layer to get solid residue
15
y-
X. suspending the solid residue in alcohol followed by addition of
water;
xi. stirring the reaction to complete crystallization and cooling the
precipitated material;
xii. filtering followed by washing with water to get desired cefuroxime
axetil.
2. The process as claimed in claim 1, wherein the polar solvent used in step
i) is selected from the group consisting of dimethylformamide,
dimethylacetamide, dimethylsulphoxide, acetonitrile, acetone, monoglyme
and diglyme.
3. The process as claimed in claim 1, wherein the metal carbonate used in
step ii) is selected from the group consisting of sodium carbonate, sodium
bicarbonate, potassium carbonate, potassium bicarbonate, magnesium
carbonate and calcium carbonate
4. The process as claimed in step claim 1, wherein the 1-acetoxy ethyl halide
used in step ill) is selected from the group consisting of 1-acetoxy ethyl
chloride, 1-acetoxy ethyl bromide and 1-acetoxy ethyl iodide.
5. The process as claimed in claim 1, wherein the organic solvent used in
step iv) is selected from the group consisting of methyl isobutyl ketone,
dichloromethane, ethylene dichloride, chloroform, ethyl acetate, n-propyl
acetate, n-butyl acetate and t-butyl acetate.
6. The process as claimed in claim 1, wherein the alcohol used in step x) is
selected from the group consisting of methanol, ethanol, isopropyl alcohol
and n-butanol.
7. A process for the preparation of cefuroxime axetil of formula (I) comprising
a step of isolating cefuroxime axetil using methanol and water system.
of
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8. A process for the preparation of cefuroxime axetil of formula (I), which
comprises the steps in the sequence recited thereof:
II " ^
OMe 6^0 O
(I)
i. dissolving cefuroxime acid in dimethyacetamide;
ii. adding sodium carbonate to the reaction solution;
iii. adding 1-acetoxy ethyl bromide into the reaction mass followed by
stirring;
iv. quenching the reaction mass with ethyl acetate and water;
V. separating the compound rich organic layer;
vi. washing the organic layer with sodium metabisulfite and hydrochloric
acid solution;
vii. optionally, washing organic layer with brine and sodium bicarbonate
solution;
viii. treating organic layer with activated carbon followed by filtration;
ix. concentrating the organic layer to get solid residue and suspending
the solid residue in methanol followed by addition of water;
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X. stirring the reaction till complete crystallization and cooling the
precipitated material;
12 31 ^^
xi. filtering followed by washing with water to get desired cefuroxime
axetil.