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 of formula (I) and pharmaceutically acceptable salts or ester thereof using monoglyme or diglyme as a single solvent in a very safe, simple, economical, user-friendly and in an industrially viable manner.
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Background of the invention
Cefuroxime of formula (I) and pharmaceutically acceptable salts or ester thereof are valuable broad spectrum antibiotic and having activity against wide range of gram-positive and gram-negative microorganisms.
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The synthesis of cefuroxime disclosed in US 3,966,717 and US 3,974,513 comprises eight synthetic steps starting from 7-ACA. Such high number of steps, which causes low overall yield, is due to the introduction of two protecting groups.

A process for the preparation of cefuroxime starting from 7-ACA has been described in Chemistry and Industry 1984,217, which does not involve any protective groups. The preparation involves the condensation of 3-hydroxymethyl-7-amino cephalosporanic acid with (fur-2-yl)-2-methoxyimino acetic acid using an organic base to produce (6R,7R)-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid. Carbamoylation of resulting acid with isocyanate of formula RNCO wherein R is a labile substituent to get (6R, 7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid (cefuroxime acid).
WO 00/71547 describes a process for the preparation of cefuroxime, which involves enzymatic hydrolysis of 7-glutaryl ACA, which is not industrially viable.
It is important to know that cefuroxime acid of formula (I) is a key intermediate for the industrial synthesis of cefuroxime axetil (for the oral administration) and cefuroxime sodium (for the injection administration). These compounds have a valuable broad spectrum activity against wide range of gram-positive and gram-negative microorganisms. Their effectiveness is advantageously combined with remarkable resistance to ß-lactamases
Cefuroxime axetil of formula (IV), whose non-proprietary name is (R,S)-1-acetoxyethyl (Z)-3-carbamoyloxymethyl-7-[2-(2-furyl)-2-(methoxyimino)-acetamido]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, is 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 conventional process for the preparation of cefuroxime axetil is the esterification of cefuroxime 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; 4,994,567 and 4,810,833. 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.
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 amounts and anyway within the limits established by the various pharmacopoeias.
Cefuroxime sodium of formula (V) is physiologically acceptable non-toxic salt of cefuroxime and may be administered to human or used as a veterinary medicine. The preparation involves the condensation of 3-hydroxymethyl-7-amino

cephalosporanic acid with (fur-2-yl)-2-methoxyimino acetic acid to produce (6R, 7R)-7- [(Z)-2- (fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid. Carbamoylation of resulting acid with isocyanate of formula RNCO wherein R is a labile substituent to get (6R, 7R)-3-carbamoyloxymethyl-7-[Z-2- (fur-2-yl)-2-methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid (cefuroxime), followed by converting the cefuroxime into its sodium salt using mixture of water soluble sodium salt.
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US patent 4,277, 601 describes the process for the preparation of cefuroxime sodium as its tetrahydrofuran solvate in in-situ manner. The process described in this patent involves the usage of multiple organic solvent systems and thereby making the process complicated. Moreover, recrystallisation is needed to get the sterile cefuroxime sodium.
As far as carbamoylation step of the 3-hydroxymethylceph-3-em is concerned, the known synthetic routes for the preparation of cefuroxime make use of solvents, which involves potential risks connected with their inflammability and toxicity.
The method disclosed in US 3,966,717 comprises the conversion of diphenylmethyl-3 -hydroxymethyl-7S-(thien-2-yl)acetamidoceph-3 -em-4-carboxylate into the corresponding 3-carbamoyloxymethyl derivative by reaction with trichloroacetylisocyanate in acetone and subsequent hydrolysis.
On the other hand, the synthesis disclosed in US 4,284,767 comprises the reaction of (6R,7R)-7-[[2-furanyl(syn-methoxyimino)acetamido]-3-hydroxymethylceph-3-em-4-

carboxylic acid with dichlorophosphinylisocyanate in tetrahydrofuran and the subsequent recovery of the product in the form of the sodium salt.
US patent 4,775, 750 discloses the process for the preparation of the compound of formula (I), which involves carbamoylation of (6R,7R)-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid in methyl or ethyl acetate with chlorosulfonyl isocyanate and in situ preparation of cefuroxime sodium using sodium-2-ethylhexanote. The product obtained from this patent suffers in non-acceptable color and low purity.
Hence, there is unmet need to develop a simple and environment friendly process for the preparation of cefuroxime and pharmaceutically acceptable salts or ester thereof, which is convenient to perform on a commercial scale, operationally safe and provide the product in pure form.
With our continued search and intense investigation, we finally achieved a process for the preparation of cefuroxime and pharmaceutically acceptable salts or ester thereof, which overcomes all difficulties and makes the process industrially viable and yield the title compound in required quantity and quality.
It has now been found that cefuroxime 3-hydroxymethyl precursors can be carbamoylated by reaction with activated isocyanates such as chlorosulfonyl isocyanate, using monoglyme or diglyme as reaction solvents. It should be pointed out that said reaction with isocyanates in solvents such as monoglyme or diglyme has never been reported in the literature. Looking at the fluctuating market scenario of solvent acetonitrile, the present inventors were motivated to develop a method which involves a different solvent and should be sufficiently inactive to the reagent chlorosulfonyl isocyanate. Therefore, the present invention provides remarkable advantages in the industrial process for the production of cefuroxime. In fact, the method of the invention

provides good quality cefuroxime acid in yields quite comparable with those expected with the prior art methods.
Objective of the invention
The main object of the present invention is to provide a process for the preparation of a compound 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 a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic 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 a compound 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 a compound 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
Accordingly, the present invention provides a process for the preparation of cefuroxime acid of formula (I); comprising the steps of:

(Formula Removed)
(i) suspending (6R,7R)-3-hydroxymethyl-7-[2-(fur-2-yl)-2-methoxyimino
acetamido]-ceph-3-em-4-carboxylic acid of formula (II) in an organic solvent
such as monoglyme or diglyme; (ii) reacting chlorosulfonyl isocyanate of formula (III) with the suspension of step (i)
at a low temperature to get a clear solution; (iii) adding water to a clear solution as obtained from step (ii); (iv) diluting the reaction mass as obtained from step (iii) by further addition of water; (v) adjusting the pH of the resultant mixture as obtained from step (iv) with alkali
metal hydroxide to get a clear solution; (vi) optionally charcolizing and filtering the clear solution as obtained from step (v); (vii) adjusting the pH of the filtrate as obtained from step (vi) with an acid; and (viii) isolating cefuroxime acid of formula (I) in pure form.
The above process is illustrated in the following synthetic scheme:
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Detailed description of the invention
Accordingly in an embodiment of the present invention, the said organic solvent in step (i) is monoglyme or diglyme. Monoglyme or diglyme are the solvents of choice

which may be selected from the group of mono ethylene glycol dimethyl ether (monoglyme), mono ethylene glycol diethyl ether, mono ethylene glycol dibutyl ether, diethylene glycol dimethyl ether (diglyme), diethylene glycol diethyl ether, diethylene glycol dibutyl ether and the like or mixture thereof, more preferably monoglyme.
In another embodiment of the present invention, the said alkali metal hydroxide in step (v) is sodium hydroxide or potassium hydroxide and the like, more preferably sodium hydroxide.
In another embodiment of the present invention, the pH disclosed in step (v) is in the range of 5.0 to 10.0, more preferably 6.0 to 7.0.
In another embodiment of the present invention, the said acid in step (vii) is hydrochloric acid or sulfuric acid and the like, more preferably hydrochloric acid.
In another embodiment of the present invention, the pH disclosed in step (vii) is in the range of 1.0 to 4.0, more preferably 2.0 to 2.5.
In another embodiment of the present invention, all the steps are preferably performed at a temperature in the range of (-) 50° C to 50° C.
In yet another embodiment of the present invention, process for preparation of a compound of formula (I) may also be extended further in the making of cephalosporin antibiotics such as cefuroxime sodium of formula (V) and cefuroxime axetil of formula (IV) by conventional methods.
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.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Example (1) Cefuroxime acid of formula (I) using monoethylene glycol dimethyl ether (monoglyme)
(6R,7R)-7-[2-(Fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (150gm) was suspended in monoglyme (750mL) at 25 to 30°C, and cooled to (-) 40° to (-) 35°C. To the cooled solution chlorosulphonyl isocyanate (78gm) was added at (-) 40° to (-) 35°C and stirred at the same temperature for 50 to 60 minutes. After completion of reaction, 225 mL of water was added and the mass stirred at 10 to 18°C till completion of hydrolysis. The reaction mass was further diluted with 750 mL of water and cooled to 0 to 10°C; pH adjusted to 6.5 to 6.8 by adding caustic soda solution; and clear solution was subjected to charcoal treatment. The pH of the charcoal treated solution was adjusted to 2.0 to 2.3 using dilute hydrochloric acid to give white colored precipitated material. The product formed was filtered off, washed with water and dried to produce cefuroxime acid (151gm, HPLC purity > 98.0%).
Example (2) Cefuroxime acid of formula (I) using diethylene glycol dimethyl ether (diglyme)
(6R,7R)-7-[2-(Fur-2-yl)-2-methoxyiminoacetamido]-3-hydroxymethylceph-3-em-4-carboxylic acid (150gm) was suspended in diglyme (750mL) at 25 to 30°C, and cooled to (-) 40° to (-) 35°C. To the cooled solution chlorosulphonyl isocyanate (78gm) was added at (-) 40° to (-) 35°C and stirred at the same temperature for 50 to 60 minutes. After completion of reaction, 225 mL of water was added and the mass stirred at 10 to 18°C till completion of hydrolysis. The reaction mass was further diluted with 750 mL of water and cooled to 0 to 10°C; pH adjusted to 6.5 to 6.8 by adding caustic soda solution; and clear solution was subjected to charcoal treatment. The pH of the charcoal treated solution was adjusted to 2.0 to 2.3 using dilute hydrochloric acid to give white colored precipitated material. The product formed was filtered off, washed with water and dried to produce cefuroxime acid (142gm, HPLC purity > 98.0%).

Substantial Advantages and Industrial applicability
(1) The process of the present invention is very safe, simple and yields higher purity and greater yield of a compound of formula (1).
(2) The process of the present invention avoids excess usages of reagent(s) and organic solvent(s), thereby promoting green chemistry and ensuring a cleaner surrounding by putting lesser load on environment.
(3) The process of the present invention avoids excessive use of solvents like tetrahydrofuran, which is harmful for the environment and are very hazardous in nature.
(4) The process of the present invention using a solvent which can be recycled and reused thereby makes the process more economical, industrially and commercially viable.
(5) The process of the present invention is a simple process, which avoids more number of operations, thus resulting in shortening of reaction time and lowering of labor.
(6) The process of the present invention requires no separate procedure for additional purification which could involve an extra step and thus consume extra time.

We claim:
1. An improved process for the preparation of cefuroxime acid of formula (I); comprising the steps of:
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(i) suspending (6R,7R)-3-hydroxymethyl-7-[Z-2-(fur-2-yl)-
methoxyiminoacetamido]-ceph-3-em-4-carboxylic acid of formula (II) in an organic solvent;
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(ii) reacting chlorosulphonyl isocyanate of formula (III) with the suspension of step(i) at low temperature to get a clear solution;
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(iii) adding water to a clear solution as obtained from step (ii);
(iv) diluting the reaction mass as obtained from step (iii) by further addition of water;
(v) adjusting the pH of resultant mixture as obtained from step (iv) with alkali metal
hydroxide to get a clear solution;
(vi) optionally charcolising and filtering the clear solution as obtained from step (v);
(vii) adjusting the pH of the filtrate as obtained from step (vi) with an acid; and
(viii) isolating cefuroxime acid of formula (I) in pure form.
2. A process according to claim 1, wherein the said organic solvent in step (i) is preferably selected from the group consisting of mono ethylene glycol dimethyl ether, mono ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether and like or mixture thereof, more preferably mono ethylene glycol dimethyl ether.
3. A process according to claim 1, wherein the said alkali metal hydroxide in step (v) is preferably sodium hydroxide or potassium hydroxide and the like, more preferably sodium hydroxide.
4. A process according to claim 1, wherein the said acid in step (vii) is preferably hydrochloric acid or sulphuric acid and the like, more preferably hydrochloric acid.
5. A process according to claim 1, wherein the said pH in step (v) is in the range of 5.0 to 10.0, more preferably 6.0 to 7.0.
6. A process according to claim 1, wherein the said pH in step (vii) is in the range of 1.0 to 4.0, more preferably 2.0 to 2.5.
7. A process according to claim 1, wherein all the steps are preferably performed at a temperature in the range of (-) 50° C to 50° C.