Field of the invention
The present invention is in the field of chemistry and more precisely the present invention relates to the preparation of cefotaxime acid of formula (IV) and pharmaceutically acceptable salt thereof, such as cefotaxime sodium of formula (I) using aqueous glyme or aqueous cellosolve as a solvent in a very safe, simple, economical, user-friendly and in an industrially viable manner.
(Formula Removed)
Background of the invention
Cephalosporin antibiotics inhibit bacteria by interfering with the synthesis of essential structural components of the bacterial cell wall. They are considered as highly effective antibiotics with low toxicity and are used for treating a wide variety of bacterial infections. Cephalosporin C was isolated in 1952 from a mold of the genus cephalosporium. A decade later the nucleus (7-aminocephalosporanic acid) was isolated and used as the basis for a series of synthetic derivatives, including cephalothin, cephaloridine and cephaloglycin.
Research has produced many cephalosporin derivatives with increased potency and improved stability. For example, derivatives containing a 7-aminothiazolyl group such as cefotiam have been shown to have increased potency. Resistance to beta-lactamase has been found to be conferred by a methoximino group at the alpha carbon atom in the 7-acyl group. Several cephalosporins have been developed that have

combined these structural features to provide highly potent enzyme resistant compounds; e.g. cefotaxime, cefmenoxime, ceftizoxime, and ceftriaxone.
U.S. Patent No. 4,098,888 describes cephem compounds and processes for their preparation. Another U.S. Patent No. 4,152,432 (henceforth '432) describes 3-acetoxymethyl-7-(iminoacetamido) cephalosporanic acid derivatives, in particular cefotaxime, and processes for preparing the derivatives.
Cefotaxime acid of formula (IV) is chemically known as (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-l,3-thiazol-4-yl)-2-methoxyiminoacetamido]-8-oxo-5-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid and is commercially sold as its sodium salt of formula (I) for parenteral administration. Cefotaxime sodium of formula (I) is a semisynthetic, broad-spectrum, cephalosporin antibiotic.
(Formula Removed)
7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) of formula (II) is a well known compound which has been proposed as starting material in various syntheses, in particular in the synthesis of many cephalosporins.
(Formula Removed)
Various important cephalosporins are obtained through the following reaction steps,

(I) effecting an acylation of the 7-amino group of the cephalosporanic ring by an optionally substituted aminothiazolyl acetic acid whose amino group has been protected.
(II) deprotecting the amino protecting group; and
(III) optionally substituting the 3-acetoxymethyl group of the cephalosporanic ring by a nucleophilic agent.
The sequencing of these steps may optionally be varied case by case. In every case the acylation of the 7-amino group of the cephalosporanic ring is carried out with an optionally substituted aminothiazolyl acetic acid whose amino group has been protected, the amino group being then deprotected.
U.S. Patent No. 4,767,852 (henceforth '852) discloses a process for the preparation of known 2-oxyiminoacetamido-3-cephem-4-carboxylic acid derivatives, including cefotaxime and ceftriaxone, by acylating 7-amino-3-cephem-4-carboxylic acid derivatives already substituted at the 3-position with 2-mercaptobenzofhiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula (III), the latter being often referred to as MAEM, which has become the standard acylating agent for the preparation of cephalosporins having an oximino group and a 2-aminothiazolyl group in the 7-acylamido side chain.
(Formula Removed)
US patent '432 discloses the process for the preparation of cefotaxime sodium of formula (I), which involves treating the cefotaxime acid in aqueous solvent such as methanol, ethanol or acetone in the presence of base and sodium ions to give cefotaxime sodium.

US patent '852 discloses a process for the production of cephalosporin derivatives by acylating 7-amino-3-cephem-4-carboxylic acid with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of the formula (III), using solvents such as chlorinated hydrocarbon, or esters such as ethyl acetate or in a mixture of such solvent with water.
US patent number 5,574, 154 (henceforth '154) discloses and claims a process for the preparation of the different cephalosporin derivatives by the condensation of MAEM with different cephem moieties in the presence of a solvent and a base. The solvent used in the US patent ' 154 for the condensation is selected from acetone, acetonitrile, carbon tetrachloride, methylene chloride, toluene, methanol, ethanol, iso-propanol, dioxane, iso-propyl ether, N-methyl pyrrolidone and N,N-dimethylformamide and the base used is triethylamine.
It has now been found that the condensation 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-ACA) of formula (II) with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula (III) can be performed using glyme or cellosolve as reaction solvents. It should be pointed out that the said condensation reaction in solvents such as glyme or cellosolve has never been reported in the literature. In fact, the method of the invention provides good quality cefotaxime sodium of formula (I) in yields quite comparable with those expected with the prior art methods.
As discussed above none of the prior art references disclosed or claimed the use of glyme or cellosolve as a solvent for the preparation of compound of formula (IV) and formula (I), hence we focused our research to develop an improved and efficient process for the preparation of a compound of formula (I) along with substantially fair operational safety, satisfactory yield and high chemical purity, which makes the process more distinct and successful at industrial and commercial level.

Objective of the invention
The main object of the present invention is to provide a process for the preparation of a compound of formula (IV) and (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 (IV) and (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 (IV) and (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 (IV) and (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 cefotaxime sodium of formula (I); comprising the steps of:

(Formula Removed)

(i) condensing 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid of formula (II) with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminofhiazol-4-yl)-2-methoxyiminoacetate of formula (III) in an aqueous organic solvent in the presence of an organic base at a low temperature to get a clear solution;
(ii) adjusting the pH of solution as obtained from step (i) with an acid;
(iii) isolating cefotaxime acid of formula (IV) in pure form; and
(iv) optionally converting cefotaxime acid of formula (IV) to its pharmaceutically acceptable salt such as cefotaxime sodium of formula (I) using sodium ion source in an organic solvent.
The above process is illustrated in the following synthetic scheme:
(Scheme Removed)
Detailed description of the invention
Accordingly in an embodiment of the present invention, the said organic solvent in step (i) is monoglyme or diglyme or cellosolve. Monoglyme or diglyme or cellosolve are the solvents of choice which may be selected from the group consisting 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, 2-methoxy ethanol, 2-ethoxy ethanol and the like.
In another embodiment of the present invention, the said organic base in step (i) may be selected from the group consisting of triethylamine, pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4, 4 dimethylaminopyridine or mixtures thereof, more preferably triethylamine.
In another embodiment of the present invention, the said acid in step (ii) 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 (ii) is in the range of 2 to 4.
In another embodiment of the present invention, the organic solvent used in step (iv) is selected from an alcoholic solvent or substituted alcoholic solvent or an ester. The organic solvent may be selected from the group consisting of methanol, ethanol, isopropanol, 2-methoxy ethanol, 2-ethoxy ethanol, ethyl acetate, butyl acetate and the like or mixture thereof
In another embodiment of the present invention, all the steps are preferably performed at a temperature in the range of (-) 10oC to reflux temperature of the solvent used.
In yet another embodiment of the present invention, the process for preparation of a compound of formula (IV) may also be extended further in the making of cephalosporin antibiotics such as cefotaxime sodium of formula (1) by conventional methods.

In the present invention the 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) Preparation of cefotaxime acid
100 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid and 138 g of 2-mercapto-benzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-methoxyiminoacetate were suspended in 600 mL of aqueous monoglyme (1:5) and stirred at room temperature. 45 g of triethylamine was added to the stirred suspension at 0°C to (-) 5°C within 1.0 to 1.5 hrs. The reaction mixture was stirred at 0°C to (-) 5°C until the completion of reaction. The resulting clear solution was then stirred at 10°C to 12°C for 10 to 15 mins. Dilute hydrochloric acid was added to the reaction mixture to adjust the pH upto 2.6 to 2.8 at the same temperature for complete precipitation. The resulting precipitated material was stirred at the same temperature for 1.0 hr. The product was filtered and washed with isopropyl alcohol and dried completely to yield 160 g of white colored cefotaxime acid of 99.3 % purity by HPLC.
Example (2) Preparation of cefotaxime sodium
100g of cefotaxime acid was charged in 300 mL of prechilled methanol under stirring. The reaction mixture was cooled to (-) 8 C to (-) 10 C. 22 g of triethylamine was added to the stirred reaction mixture at the same temperature. Activated charcoal was added and stirred the solution for 30 mins. The charcoal was filtered through hyflo bed the bed was washed with 100 mL of chilled methanol. 100 mL of methyl isobutyl ketone was added to the filtrate at 0°C to (-) 5 C and stirred for 10 to 15 mins. The solution of 43.0 g of sodium-2-ethylhexanoate in 200 mL of ethyl acetate was added to the filtrate

within 1.0 to 1.5 hrs at 0 C to (-) 5 C under slow stirring and it was further stirred for 1 hr for precipitation at the same temperature. 1000 mL of ethyl acetate was added to the precipitated material at 10°C tol5°C for complete precipitation. The product was filtered and washed with chilled ethyl acetate and dried completely to yield 92 g of white crystals of cefotaxime sodium of 99.4% purity by HPLC.
Example (3) Preparation of cefotaxime acid
100 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid and 138 g of 2-mercapto-benzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-methoxyiminoacetate were suspended in 600 mL of aqueous 2-methoxy ethanol (1:5) and stirred at room temperature. 45 g of triethylamine was added to the stirred suspension at 0°C to (-) 5°C within 1.0 to 1.5 hrs. The reaction mixture was stirred at 0°C to (-) 5°C until the completion of reaction. The resulting clear solution was then stirred at 10°C to 12°C for 10 to 15 mins. Dilute hydrochloric acid was added to the reaction mixture to adjust the pH upto 2.6 to 2.8 at the same temperature for complete precipitation. The resulting precipitated material was stirred at the same temperature for 1.0 hr. The product was filtered and washed with isopropyl alcohol and dried completely to yield 160 g of white colored cefotaxime acid of 99.06 % purity by HPLC.
Example (4) Preparation of cefotaxime sodium
100 g of cefotaxime acid was suspended in 300 mL of 2-methoxy ethanol under stirring. Reaction mixture was cooled to 0°C to (-) 5°C. The solution of 43.0 g of sodium-2-ethylhexanoate in 200 mL of ethyl acetate was added slowly to the suspension within 1.0 to 1.5 hrs at the same temperature to get a clear solution. Activated charcoal was added and stirred the solution for 20 to 30 mins. The charcoal was filtered through hyflo bed and the bed was washed with 100 mL mixture of cellosolve and ethylacetate (1:1). 900 mL ethyl acetate was added to the clear solution under slow stirring at 5°C to 10°C

and it was further stirred for 1.0 to 1.5 hrs for complete precipitation to get white colored crystals. The product was filtered and washed with chilled ethyl acetate and dried completely to yield 94.0 g of cefotaxime sodium of 99.50 % purity by HPLC.

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 the use of solvents like carbon tetrachloride, N,N-dimethylformamide which are harmful for the environment and is very hazardous in nature.
(4) The process of the present invention uses a solvent which can be recycled and reused and thus makes the process more economical and viable industrially & commercially.
(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.

We claim:
(1) An improved process for the preparation of cefotaxime sodium of formula (I); comprising the steps of:
(Formula Removed)
(i) condensing 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid of formula (II) with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula (III) in an aqueous organic solvent in the presence of an organic base at a low temperature to get a clear solution;
(Formula Removed)
(ii) adjusting the pH of solution as obtained from step (i) with an acid; (iii) isolating cefotaxime acid of formula (IV) in pure form; and
(Formula Removed)
(iv) optionally converting cefotaxime acid of formula (IV) to it's pharmaceutically
acceptable salt such as cefotaxime sodium of formula (I) using sodium ion source in an organic solvent.
(2) A process according to claim 1, wherein the said organic solvent in step (i) is selected from the group consisting of mono ethylene glycol dimethyl ether, mono ethylene glycol diethyl ether, mono ethylene glycol dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, 2-methoxy ethanol, 2-ethoxy ethanol and the like.
(3) A process according to claim 1, wherein the said organic base in step (i) is preferably selected from the group consisting of triethylamine, pyridine, N-methylpiperidine,
1,8-diazabicycloundecene, 4,4 dimethylaminopyridine or mixtures thereof, more preferably triethylamine.
(4) A process according to claim 1, wherein the said pH in step (ii) is preferably in the range of 2 to 4, more preferably 2.5 to 3.0.
(5) A process according to claim 1, wherein the said acid in step (ii) is hydrochloric acid or sulfuric acid and the like.
(6) A process according to claim 1, wherein the said sodium ion source in step (iv) is sodium-2 -ethy lhexanoate.
(7) A process according to claim 1, wherein the said organic solvent in step (iv) is selected from an alcoholic solvent or substituted alcoholic solvent or an ester.
(8) A process according to claim 7, wherein the said alcoholic solvent or substituted alcoholic solvent may be selected from the group consisting of methanol, ethanol, isopropanol, 2-methoxy ethanol, 2-ethoxy ethanol and the like or mixture thereof.
(9) A process according to claim 7, wherein the said ester is ethyl acetate, butyl acetate and the like or mixture thereof.
(10) A process according to claim 1, wherein all the steps are preferably performed at a temperature in the range of (-) 10°C to reflux temperature of the solvent used.