Field of the invention
The present invention is in the field of chemistry and more particularly it relates to the preparation of cefepime dihydrochloride monohydrate of formula (I), by reacting 7-amino-3-[(l-methyl-l-pyrrolidino)methyl]ceph-3-em-carboxylate monohydrochloride dihydrate of formula (II) with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate of formula (III) using an organic solvent or mixture thereof in a very safe, simple, economical, user-friendly and in an industrially viable manner.
(Formula Removed) Background of the invention
Cefepime is a valuable fourth generation injectable cephalosporin with antibacterial properties, which is used in the form of a dihydrochloride hydrate. Cefepime dihydrochloride monohydrate is chemically known as 7-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino) acetamido]-3-[(l-methyl-l-pyrrolidinium)methyl]-3-cephem-4-carboxylate dihydrochloride monohydrate. Cefepime dihydrochloride monohydrate is a cephalosporin that is active against a wide range of gram-positive and gram-negative aerobic organisms. Its chemical structure is depicted below:
(Formula Removed) The semi-synthetic antibiotic cefepime is a useful broad- spectrum antibiotic which was first described in U.S. Patent No. 4,406,899 wherein the cefepime was synthesized by a multistep process involving protection and deprotection steps thereby making the process lengthy and laborious.
US Patent No 4,754,031 describes a process in which (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid is activated by reacting with methanesulfonyl chloride to undergo acylation with 7-amino-3-(l-methyl-1-pyrrolidini um)methyl-3-cephem-4-carboxylate hydrochloride to obtain cefepime which is purified by column chromatography. Methods involving chromatographic purifications cannot be used for large-scale operations, thereby making the process commercially unviable.
US Patent No 5,594,129 and US Patent No 5,594,130 disclose the synthesis of cefepime which involves acylation of 7-amino-3-[(l-methyl-l- pyrrolidinio)methyl]ceph-3-em-4-carboxylate hydrochloride with syn 2-(2-amino-4-thiazolyl)-2-methoxyiminoacetic acid that is activated by converting to chloride by reacting with chlorinating agents such as thionyl chloride or phosphorous pentachloride etc.
In the process described in PCT application WO2004/037833 Al, 7-amino-3-[(l-methyl-l-pyrrolidinio)methyl]ceph-3-em-4-carboxylate hydroiodic salt was treated with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyimino acetate in a mixture of tetrahydrofuran, water and dimethyl acetamide to prepare cefepime. Ethyl acetate and acetone are used for isolating the product. The recovery of the solvents from mixture of solvents is difficult. Therefore the process is not economical.
The PCT application WO2004/092183A2 describes the preparation of cefepime dihydrochloride monohydrate by reacting 7-amino-3-[(l-methyl-1-pyrrolidine) methyl]ceph-3-em-carboxylate monohydrochloride with mercaptobenzothiazole 2-(2-aminothiazol-4-yl)-2-syn-methoxyiminoacetate in a mixture of water and acetone. The resultant yield is very low and the reaction is taking longer time for the completion.
In view of the above, there is a clear need to find an alternative industrially viable process for the production of cefepime dihydrochloride monohydrate. The present invention provides remarkable advantages in the industrial process for the production of cefepime dihydrochoride monohydrate of formula (I). In fact, the method of the invention helps the inventors to provide good quality cefepime dihydrochloride monohydrate as compared 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 with a greater yield and higher chemical purity
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, and thereby makes the present invention more safe and eco-friendly as well.
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 recycled and thereby reused, which makes the process industrially more suitable.
Summary of the invention
Accordingly, the present invention provides an improved process for the preparation of cefepime dihydrochloride monohydrate of formula (I); comprising the steps of:

(Formula Removed) (i) condensing 7-amino-3-[(l-methyl-1-pyrrolidino) methyl] ceph-3-em-carboxylate monohydrochloride dihydrate of formula (II) and 2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazol- 4-yl)-2-methoxyiminoacetate of formula (III) in presence of a base in an organic solvent or mixture thereof; and
(ii) isolating cefepime dihydrochloride monohydrate of formula (I) in pure form.
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) may be preferably selected from an alcoholic solvent such as methanol, ethanol, isopropanol alone or in combination with chlorinated solvent such as methylene chloride 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, dicyclohexylamine, diphenylamine, diisopropylamine, N-tert-butylcyclohexylamine and N,N-dibenzylethylenediamine and the like or mixture thereof, more preferably triethylamine.
The condensation reaction is carried out at a temperature preferably in the range of -20"Cto lO'^C, more preferably O^C to S^C. The condensation reaction is completed within 3 hrs to 4 hrs.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
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!
Preparation of cefepime dihydrochloride monohydrate
50.Og of 7-amino-3-[(l-methyl-l-pyrrolidino)methyl]ceph-3-em-carboxylate monohydrochloride dihydrate was added in 220mL of methyl alcohol and stirred for 10 minutes. The reaction mixture was cooled to O^C to S'^C and 20g of triethylamine was added dropwise into it. To the clear solution, 55.6g of 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate was added at O^C to 5*^0. The reaction was completed within 3 hrs to 4 hrs. After the reaction completion, temperature was raised to 25''C. The pH of reaction mass was adjusted to 0.5 with concentrated hydrochloric acid and stirred for 15 minutes. 5.0g of charcoal and l.Og of ethylenediaminetetraacetic acid (EDTA) were added to the reaction mixture and stirred for 10 minutes. The reaction mass was filtered through carbon pad and 0.45 micron filter. Ethyl acetate was added to the filtrate and stirred for 30 minutes for complete precipitation. The reaction mass was filtered, washed with ethyl acetate and suck dried to get 72g of the titled compound with chromatographic purity of 98.94%.
EXAMPLE-2
Preparation of cefepime dihydrochloride monohydrate
25.Og of 7-amino-3-[(l-methyl-l-pyrrolidino)methyl]ceph-3-em-carboxylate monohydrochloride dihydrate was added in 125mL of methyl alcohol at 0 C to 5 C and stirred for 10 minutes. 17.08g of triethylamine was added dropwise into it. To the clear solufion, 26.08g of 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate was added at O'^C to 5*'C. The reaction was completed within 3 hrs to 4 hrs. After the reaction completion, water and n-butyl acetate were added into it. Stirred the reaction mixture at 15°C to 20*'C and layers were settled, separated and charcolized. The pH of the aqueous layer was adjusted to 0.5 to 0.1 with concentrated hydrochloric acid at 0°C to SV. Acetone was added slowly to the aqueous layer at 0*^0 to S'^C and stirred for one hour at same temperature for complete precipitation. The reaction mass was filtered,

washed with acetone and dried in hot air oven for 3 hours at 40*'C to get 34.5g of the titled compound with chromatographic purity of 99.43%.
EXAMPLE-3
Preparation of cefepime dihydrochloride monohydrate
10.Og of 7-amino-3-[(l-methyl-l-pyrrolidino)methyl]ceph-3-em-carboxylate monohydrochloride dihydrate was added in a mixture of 1 OOmL of methylene chloride and 15mL of methyl alcohol and stirred at 0*^0 to 2'^C .4.0g of triethylamine was added dropwise into it. To the clear solution, 11.5g of 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate was added and stirred at 0°C to 5 C. After the reaction completion, 60mL of water was added into it, stirred for 30 minutes and layers were settled and separated. The aqueous layer was charcolized and filtered. The pH of filtrate was adjusted in the range of 0.5 to 0.7 with concentrated hydrochloric acid. Acetone was added to the filtrate and stirred for Ihour for complete precipitation. The reaction mass was filtered, washed with acetone and dried under vacuum to get 14g of the titled compound with chromatographic purity of 99.91 %.
EXAMPLE-4
Preparation of cefepime dihydrochloride monohydrate
50.Og of 7-amino-3-[( 1 -methyl-1 -pyrrolidino)methyl]ceph-3-em-carboxylate monohydrochloride dihydrate was added in 220mL of methyl alcohol and stirred for 10 minutes .The reaction mixture was cooled to 0°C to S^C and 20g of triethylamine was added dropwise into it. To the clear solution, 55.6g of 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate was added at O^'C to 5°C. The reaction was completed within 3 hrs to 4 hrs. After the reaction completion, temperature was raised to 25''C. The pH of reaction mass was adjusted to 0.5 with concentrated hydrochloric acid and stirred for 15minutes. 5 g of charcoal and 1 g of ethylenediaminetetraacetic acid (EDTA) were added to the reaction mixture and stirred for 10 minutes. The reaction mass
was filtered through carbon pad and 0.45 micron filter. Isopropyl alcohol was added to the filtrate and stirred for 30 minutes for complete precipitation. The reaction mass was filtered, washed with Isopropyl alcohol and suck dried to get 72g of the titled compound with chromatographic purity of 99.54%.
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 using a solvent which can be recycled and reused this makes the process more economical and industrially and commercially viable.
4. 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 cefepime dihydrochloride mono hydrate of formula (I); comprising the steps of:

(Formula Removed) (i) condensing 7-amino-3-[(l-methyl-l-pyrrolidino) methyl] ceph-3-em-carboxylate monohydrochloride dihydrate of formula (II) and 2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazol- 4-yl)-2-methoxyiminoacetate of formula (III) in the presence of a base in an organic solvent or mixture thereof; and
(Formula Removed) (ii) isolating cefepime dihydrochloride monohydrate 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 an alcoholic solvent such as methanol, ethanol, isopropanol alone or in combination with chlorinated solvent such as methylene chloride or mixture thereof, more preferably methanol.
(3) A process according to claim 1,wherein the said base in step (i) is an organic base which 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 condensation reaction is carried out at a temperature preferably in the range of-20°Ctol0V, more preferably 0°C to SV.
(5) A process according to claim 1, wherein the condensation reaction is completed within 3 hrs to 4 hrs.
(6) An improved process for the preparation of cefepime dihydrochloride monohydrate of formula (I) by condensing 7-amino-3-[(l-methyl-1-pyrrolidino) methyl] ceph-3-em-carboxylate monohydrochloride dihydrate of formula (II) and 2-mercaptobenzothiazolyl-(Z)-2- (2- aminothiazol- 4-yl)-2-methoxyiminoacetate of formula (III) in the presence of triethylamine in methanol.
(Formula Removed) (7) An improved process for the preparation of cefepime dihydrochloride monohydrate of formula (I) by condensing 7-amino-3-[(l-methyl-l-pyrrolidino) methyl] ceph-3-em-carboxylate monohydrochloride dihydrate of formula (II) and 2-mercaptobenzothiazolyl-(Z)-2- (2- aminothiazol- 4-yl)-2-methoxyiminoacetate of formula (III) in the presence of triethylamine in methanol and methylene chloride. (Formula Removed)