Field of the invention
The present invention provides a "single pot" process for the preparation of highly pure cefixime of formula (I) in a very simple, economical, user-friendly and in an industrially viable manner. More particularly the present invention relates to an improved process for the preparation of cefixime of formula (I) and the trihydrate thereof.
(Formula Removed)
Background of the invention
U.S. Pat. No. 4,409,214 discloses 7-Acylamino-3-vinylcephalosporanic acid derivatives and pharmaceutically acceptable salts thereof. These compounds are antibacterial agents. Among them cefixime, chemically 7-[2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid is an orally active cephalosporin antibiotic and is more potent against gram-negative bacteria. Cefixime is represented by the following structure:
(Structure Removed)
Processes for the preparations of cefixime and related compounds were disclosed in many patents and publications such as U.S. Pat. No. 4,409,214 (henceforth '214), J. Antibiotics (1985), 38, 1738, WO 95/33753 (henceforth '753), U.K. Patent Application No. 2330140 (henceforth '140), U.K. Patent Application No. 2330141 (henceforth '141),

U.S. Pat. No. 6,313,289 (henceforth '289), WO 98/06723 (henceforth '723) and U.S. Pat. No. 6,800,755 B2.
U.K. Patent Application No. 2330141 (henceforth '141) describes the process for preparing cefixime by hydrolyzing in a halogenated aliphatic hydrocarbon (e.g., methylene chloride) the ester compound of formula-A, wherein R represents (Ci to C4) alkyl group; with potassium carbonate in the presence of phase transfer catalyst at ambient temperature for 30 to 90 minutes.
(Formula Removed)
U.K. Patent Application No. 2330140 (henceforth '140) describes a process for preparing cefixime by treating the compound of formula A with an inorganic base in dimethyl formamide and water for 1 hour 30 minutes to 2 hours and isolating cefixime.
U.S. Pat. No. 6,800,755 B2 (henceforth '755) describes a process for preparing cefixime by dissolving alkyl ester of formula A in water and water immiscible solvent such as ethyl acetate using sodium bicarbonate, hydrolyzing with sodium hydroxide at 0°C to 25 C and isolating cefixime by acidifying the reaction mass.
The processes described in patent applications '140, '141 and patent '755 suffer from any of the following problems: a) color and quality are poor, b) contamination of cefixime with high boiling point solvent such as dimethyl formamide. The removal of the residual solvents is difficult owing to sensitivity of cefixime to high temperature.
J. Antibiotics (1985), 38, 1738 describe the processes for preparing cefixime involving protection and deprotection steps. The processes described required purification of cefixime by column chromatography. Methods involving column

chromatographic purifications cannot be used for large-scale operations, thereby making the process commercially unviable.
Process for preparing cefixime described in patent '214 and '753 are lengthy involving many protecting and deprotecting steps and hence not commercially viable. The patent '289 describes the purification of cefixime by forming a crystalline amine salt of crude cefixime, converting the salt into sulfuric acid addition salt of cefixime and recovering pure cefixime from sulfuric acid addition salt of cefixime. The PCT application '723 is related to cefixime dicyclohexyl amine salt and purification of cefixime via dicyclohexyl amine salt. The purification of cefixime by the processes described in '289 and '723 are lengthy and complicated involving many crystallizations, neutralizations and salt formations.
U.S. Pat. Pub. No. 20080242858 describes the process for preparing cefixime, in which 7-amino-3-vinyl-3-cephem-4-carboxylic acid is reacted with 2-mercapto-1,3 -benzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-(methoxycarbonyl)-methoxyimino acetate in tetrahydrofuran and water at 4°C in the presence of triethylamine. The reaction mass is extracted with ethyl acetate. 7-[2-(2-Amino-4-thiazolyl)-2-(methoxycarbonylmethoxyimino)acetamido] -3 -viny 1-3 -cephem-4-carboxylic acid triethylamine salt present in the aqueous layer is hydrolyzed with sodium hydroxide in less than 30 minutes and aqueous hydrochloric acid is added immediately to adjust the pH to 4.8 to 5.2. Then, aqueous hydrochloric acid is added at 35°C to adjust the pH to 2.5 and cooled to crystallize cefixime trihydrate.
The present invention is an improved, commercially viable process solving the aforesaid problems associated with processes described in the prior art.

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 simple, economical, user-friendly and industrially 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), which makes the present invention 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 greater yield with higher chemical purity.
Still another objective of the present invention is that the by-products formed during the proposed process can be recycled, which makes the process more environment friendly as well as cost effective.
Summary of the invention
Accordingly, the present invention provides a process for the preparation of a compound of formula (I), comprising the steps of:
(Formula Removed)
(i) reacting 7-amino-3-vinyl-3-cephem-4-carboxylic acid of formula (III) with a thiazolyl acetic acid derivative of formula (II) in a substantially low amount of an aqueous organic solvent in the presence of a base such as an aqueous alkali metal hydroxide in a single pot reaction;

(ii) removing the byproduct by adding further water to the reaction mass and filtering
subsequently; (iii) optionally washing the filtrate of step (ii) by an organic solvent and then
separating the aqueous layer; (iv) treating the aqueous layer obtained in step (iii) with an aqueous alkali metal
hydroxide solution; (v) adjusting the pH of the reaction mass with an acid; (vi) optionally treating the solution obtained in step (v) with carbon and with
ethylenediaminetetraacetic acid and filtering the solution; (vii) optionally adding an organic solvent to the filtrate as obtained from step (vi); and (viii) crystallizing a compound of formula (I) by adjusting the pH of the resulting
solution of step (vii) with an acid and cooling if required.
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, in step (i) thiazolyl acetic acid derivative of formula (II) is used wherein the R is a lower alkyl, which may be selected from C1 to C4, preferably methyl.
In another embodiment of the present invention, the said organic solvent in step (i) is acetone.

In another embodiment of the present invention, the said alkali metal hydroxide in step (i) and (iv) is sodium hydroxide or potassium hydroxide and the like.
In another embodiment of the present invention, the said organic solvent in step (iii) is ethyl acetate or methylene chloride.
In another embodiment of the present invention, the said acid in step (v) and (viii) may be preferably selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and the like, more preferably hydrochloric acid.
In another embodiment of the present invention, the said pH in step (v) is in the range of 4.5 to 8.0 and in the step (viii) is 2.0 to 3.5.
In another embodiment of the present invention, the said organic solvent in step (vii) is ethyl acetate.
In another embodiment of the present invention, the step (i) of said reaction is completed in the range of 1 hr to 8 hrs, preferably in 3 hrs.
In yet another embodiment of the present invention, all the steps are preferably performed at a temperature in the range of (-) 10°C to reflux temperature of the solvent used.
In the present invention starting materials 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.
Examples
Example (1) Preparation of Cefixime trihydrate of formula (I)
7-amino-3-vinyl-3-cephem-4-carboxylic acid (500g) was suspended in acetone (2.50L) and water (1.0 L) at 20° to 22°C. 2-Mercapto-l,3-benzothiazolyl-(Z)-2-(2-

aminothiazol-4-yl)-2-(methoxycarbonyl)-methoxyimino acetate, 1.0 kg, was added under stirring to the reaction mixture. Sodium hydroxide solution (prepared by dissolving lOOg of NaOH in 1.25L of water) was added drop wise in one hour and the stirring was continued till the reaction was completed (3 hrs). Water (10.0L) was added; stirred for 15 mins; and the resulting precipitate of 2-mercaptobenzothiazole was filtered off.
The filtrate was washed with ethyl acetate. Charcolization was done by adding 50g of activated carbon and subsequent stirring. Filtration was done and charcoal bed washed with water. The combined filtrate was cooled to 0 to 4 °C. NaOH solution [prepared by adding 300g of NaOH in 3.75L of water] was added to the reaction mixture and stirred for 10 mins at 4 to 5°C. The pH was adjusted to 5.0 by using 3 % HC1 solution at 4 to 5°C and to the reaction mixture was added activated charcoal (50g), ethylenedi aminetetraacetic acid (EDTA 20g). The reaction mixture was filtered and charcoal bed washed with water and ethyl acetate was added to the filtrate. The temperature was raised to 30 to 32° C. Then the pH was adjusted to 2.1 by using 3 % HC1 solution at 30 to 32 °C to allow precipitation. It was further stirred for 2 hrs at 30 to 32°C; cooled down to 8 to 10°C and stirred for 30 mins. The precipitates were filtered and washed with water. The product was dried to obtain 1005g of creamish white crystals of 7-[2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido] -3 -vinyl-3 -cephem-4-carboxylic acid with a chromatographic purity of more than 99%.

Substantial Advantages and Industrial applicability
(1) The process of the present invention provides higher yield with greater purity of a compound of formula (I). Moreover, the said process is a single pot reaction free from more number of operations that results in shortening of reaction time and lowering of labor.
(2) The use of alkali metal hydroxide such as sodium hydroxide or potassium hydroxide makes the process more economical. The present invention uses substantially cheaper reagent(s) in substantially lower amounts and less organic solvent(s) thereby achieving better quality of a compound of formula (I).that is substantially free of impurities.
(3) Sodium hydroxide serves the dual purpose of carrying forward the reaction as well as working as a reagent for making of the water soluble sodium salt for the subsequent hydrolysis.
(4) The process of the present invention avoids the use of reagents like triethylamine or other organic bases, reported in the prior art thereby ensuring a clean reaction with better colour and quality. Moreover, the said process avoids excessive use of solvents like tetrahydrofuran, which is harmful to the environment. The said process 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.
(5) The process of the present invention separates and isolates the by-product, 2-mercaptobenzothiazole, which can be recycled, thus making it environment friendly as well as cost effective.
(6) The process of the present invention avoids distillation(s) thereby ensuring the good color and greater purity of the compound of formula (I).

We claim:
(1) An improved process for the preparation of a compound of formula (I), comprising the steps of:
(Formula Removed)
(i) reacting 7-amino-3-vinyl-3-cephem-4-carboxylic acid of formula (III) with a thiazolyl acetic acid derivative of formula (II) in a substantially low amount of an aqueous organic solvent in the presence of a base such as an aqueous alkali metal hydroxide in a single pot reaction;
(Formula Removed)
Wherein R is a lower alkyl, which may be selected from C1 to C4
(ii) removing the byproduct by adding further water to the reaction mass and filtering
subsequently; (iii) optionally washing the filtrate of step (ii) by an organic solvent and then
separating the aqueous layer; (iv) treating the aqueous layer obtained in step (iii) with an aqueous alkali metal
hydroxide solution; (v) adjusting the pH of the reaction mass with an acid; (vi) optionally treating the solution obtained in step (v) with carbon and with
ethylenediaminetetraacetic acid and filtering the solution;
(vii) optionally adding an organic solvent to the filtrate as obtained from step (vi); and (viii) crystallizing a compound of formula (I) by adjusting the pH of the resulting solution of step (vii) with an acid and cooling if required.
(2) A process according to claim 1, wherein R is methyl.
(3) A process according to claim 1, wherein the said organic solvent in step (i) is acetone.
(4) A process according to claim 1, wherein the said alkali metal hydroxide in step (i) and (iv) is sodium hydroxide or potassium hydroxide and the like.
(5) A process according to claim 1 wherein the said organic solvent in step (iii) is ethyl acetate or methylene chloride.
(6) A process according to claim 1, wherein the said acid in step (v) and (viii) is preferably selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and the like, more preferably hydrochloric acid.
(7) A process according to claim 1, wherein the said pH in step (v) is in the range of 4.5 to 8.0 and in the step (viii) is 2.0 to 3.5.
(8) A process according to claim 1, wherein the said organic solvent in step (vii) is ethyl acetate.
(9) 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.
(10) An improved process for the preparation of cefixime of formula (I) by reacting 7-amino-3-vinyl-3-cephem-4-carboxylic acid of formula (III) with 2-mercapto-l,3-benzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-(methoxycarbonyl)-methoxyimino acetate of formula (II) in a substantially low amount of an aqueous acetone in the presence of a base sodium hydroxide followed by hydrolysis in a single pot reaction.
(Formula Removed)