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 (I) in presence of a base and using in an alcohol 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
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 (I) is chemically known as (Z)-(6R, 7R)-3-(acetoxymethyl)-7-[2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetami do]-8-0X0-5-thia-l-azabicyclo[4,2,0]oct-2-en-2-carboxylic acid and is commercially sold as its sodium salt which is a semisynthetic, broad-spectrum, cephalosporin antibiotic.for parenteral administration.
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7-Amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (7-AC A) 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.
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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 substituted 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 ever 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-mercaptobenzothiazolyl-(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.
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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.
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 an alcohol as a single solvent at a lower temperature. The risk involved by the use of said solvent is remarkably lower than those connected with the use of the solvents cited above. Furthermore, said alcohol solvent has remarkably lower toxicity than the solvents reported above such as carbon tetrachloride, N,N-dimethylformamide etc.
As discussed above none of the prior art references disclosed or claimed the use of an alcohol as a single solvent at a lower temperature for the preparation of compound of 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.
It should be pointed out that the said condensation, which is extremely aggressive, in solvent such as an alcohol at a lower temperature, has never before been reported in literature. The present invention provides remarkable advantages in the industrial processes for the production of cefotaxime acid of formula (I). In fact, the method of the invention helped the inventors to provide good quality cefotaxime 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 cefotaxime acid of formula (I); comprising the steps of:
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(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 the presence of a base in an alcoholic solvent at a lower temperature;
(ii) adding water to the reaction mass as obtained from step (i) and filtering the solution;
(iii) adjusting the pH of solution as obtained from step (ii) with an acid; and
(iv) isolating cefotaxime 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 alcoholic solvent in step (i) may be preferably selected from the group consisting of methanol, ethanol, isopropanol and the like or mixture thereof, more preferably methanol.
In another embodiment of the present invention, the said base in step (i) is an organic base which may be preferably selected from the group consisting of triethylamine, pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4,4-dimethylaminopyridine, dicyclo hexylamine, diphenylamine, diisopropylamine, N-tert-butylcyclohexylamine and N,N-dibenzylethylenediamine and the like or mixtures thereof, more preferably triethylamine.

In another embodiment of the present invention, the condensation of step (i) is preferably performed at a low temperature, more preferably in the range of (-) 10oC to 10°C.
In another embodiment of the present invention, the condensation of step (i) is accomplished relatively in a shorter time, which makes the process more useful against the prior art processes. The said condensation of step (i) is proceeding to completion in 1 to 4 hrs.
In another embodiment of the present invention in step (ii) the by product 2-mercaptobenzothiazole is removed by means of filtration, which is helpful for the better quality of the compound of formula (I).
In another embodiment of the present invention, the said acid in step (iii) preferably 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, all the steps except step (i) are preferably performed at a temperature in the range of (-) 10°C to reflux temperature of the solvent used.
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 pharmaceutically acceptable salts of cefotaxime such as cefotaxime sodium 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
50 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid and 77.3 g of 2-mercapto-benzothiazolyl-(Z)-(2-aminothiazol-4-yl)-2-methoxyiminoacetate were added in 250 mL of methanol and stirred at 25°C to 30°C. The reaction mixture was cooled down to 0°C to 5°C. 27.86 g of triethylamine was added to the reaction mixture at the same temperature within 15 mins. The reaction mixture was stirred at 0°C to 5°C until the completion of reaction. 1000 mL of water was added to the reaction mixture and the precipitated 2-mercaptobenzothiazole (by-product) was filtered off. Activated carbon was added to the filtrate and stirred for 30 mins. The carbon was filtered through hyflo bed. 2 g of hydros and 1 g of ethylenediaminetetraacetic acid (EDTA) were added to the filtrate and stirred for 10 mins at 28°C to 30°C. Dilute hydrochloric acid (1:1) was added to the reaction mixture to adjust the pH to 2.3 to 2.5 at 0°C to 5°C for precipitation. The resulting precipitated material was stirred at the same temperature for 1.0 hr. The product was filtered and washed with acetone and dried completely to yield 80 g of cefotaxime acid with 99.30% 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 industrially & 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.

We claim:
(1) An improved process for the preparation of cefotaxime acid of formula (I);
comprising the steps of:
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(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 the presence of a base in an alcoholic solvent at a lower temperature;
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(ii) adding water to the reaction mass as obtained from step (i) and filtering the solution; (iii) adjusting the pH of solution as obtained from step (ii) with an acid; and (iv) isolating cefotaxime acid of formula (I) in pure form.
(2) A process according to claim 1, wherein the said alcoholic solvent in step (i) is
preferably selected from the group consisting of methanol, ethanol, isopropanol and
the like or mixture thereof, more preferably methanol.
(2) A process according to claim 1, wherein the said base in step (i) is an organic base, and is selected from the group consisting of triethylamine, pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4,4-dimethylaminopyridine, dicyclo
hexylamine, diphenylamine, diisopropylamine, N-tert-butylcyclohexylamine and N,N- dibenzylethylenediamine and the like or mixtures thereof, more preferably triethylamine.
(4) A process according to claim 1, wherein the said pH in step (iii) is preferably in the range of 2 to 4.
(5) A process according to claim 1, wherein the said acid in step (iii) is hydrochloric acid or sulfuric acid and the like.
(6) 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.