WO2011121389A1

WO2011121389A1 - Process for preparation of cefepime dihydrochloride monohydrate

Info

Publication number: WO2011121389A1
Application number: PCT/IB2010/002300
Authority: WO
Inventors: Prabhat Kumar Sahoo; Sivakumaran Sundaravadivelan; Senthil Kumar Surulichamy; Manoj Upadhyay
Original assignee: NECTAR LIFESCIENCES Ltd
Current assignee: NECTAR LIFESCIENCES Ltd
Priority date: 2010-03-29
Filing date: 2010-09-15
Publication date: 2011-10-06
Anticipated expiration: 2012-09-29

Abstract

A process for preparation of cefepime dihydrochloride monohydrate is provided. The process comprises condensing 7-amino-3-[(l -methyl- 1 -pyrrolidino)methyl]-3-cephem-4-carboxylate monohydrochloride dihydrate and 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetate in the presence of a base in an alcohol solvent.

Description

PROCESS FOR PREPARATION OF CEFEPIME DIHYDROCHLORIDE MONOHYDRATE

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-[( 1 -methyl- 1 -pyrrolidino)methyl]-3-cephem-carboxylate

monohydrochloride dihydrate of formula (II) with 2-mercaptobenzothiazolyl-(Z)-2-(2- aminothiazol-4-yl)-2- methoxyiminoacetate of formula (III) using an alcoholic solvent, optionally in combination with a chlorinated hydrocarbon solvent in a very safe, simple, economical, user-friendly and in an industrially viable manner.

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:

The semi-synthetic antibiotic cefepime is a useful broad- spectrum antibiotic which was first described in U.S. Patent No. 4,406,899 wherein 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-memoxyiminoacetic acid is activated by reacting with methanesulfonyl chloride to undergo acylation with 7-amino-3-(l -methyl- l-pyrrolidinium)methyl-3-cephem-4- carboxylate hydrochloride to obtain cefepime which is purified by column chromatography. Methods involving chromatographic purifications should not be preferably 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]-3- cephem-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-[( 1 -methyl- 1 -pyrroIidinio)methyl]-3-cephem-4-carboxylate hydroiodide salt was treated with 2-mercaptoberizotluazolyl-(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 WO2004/092183 A2 describes the preparation of cefepime dihydrochloride monohydrate by reacting 7-amino-3-[(l -methyl- 1-pyrrolidino) methyl] -3-cephem-4-carboxylate monohydrochloride with mercaptobenzothiazole 2-(2- ammothiazol-4-yl)-2-syn-memoxyiminoacetate in a mixture of water and acetone. The resultant yield is very low and the reaction is taking longer time for 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 to 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 making 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 solvent(s) 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:

(I)

(i) condensing 7-amino-3-[(l -methyl- 1 -pyrrol idino) methyl]-3-cephem-4- 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 alcoholic solvent, optionally in combination with a chlorinated hydrocarbon solvent; and

(ii) isolating cefepime dihydrochloride monohydrate of formula (I) in pure form. The above process is illustrated in the following synthetic scheme:

Detailed description of the invention

Accordingly in an embodiment of the present invention, the said alcoholic solvent in step (i) is preferably selected from the group consisting of methanol, ethanol or isopropanol, optionally in combination with chlorinated hydrocarbon solvent such as methylene chloride, more preferably methanol alone. 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, diethylamine, pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4,4-dimethylaminopyridine, dicyclohexylamine, diphenylamine, diisopropylamine, N- tert-butylcyclohexylamine and Ν,Ν-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°C to 10°C, more preferably 0°C to 5°C. The condensation reaction is completed within 3 hrs to 4 hrs.

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

Preparation of cefepime dihvdrochloride monohvdrate

50.0g of 7-amino-3 -[( 1 -methyl- 1 -pyrrolidino)methyl] -3-cephem-4-carboxylate monohydrochioride dihydrate was added into 220mL of methyl alcohol and stirred for 10 minutes. The reaction mixture was cooled to 0°C to 5°C and 20g of triethylamine was added dropwise into it. To the clear solution, 55.6g of 2-mercaptobenzothiazolyl- (Z)-2-(2-ammotrdazol-4-yl)-2-memoxyiminoacetate was added at 0°C to 5°C. The reaction was completed within 3 hrs to 4 hrs. After completion of the reaction, temperature was raised to 10°C 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 was 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 precipitated mass was filtered, washed with ethyl acetate and dried to get 72g of the titled compound with chromatographic purity of 98.94%.

EXAMPLE-2

Preparation of cefepime dihydrochloride monohydrate

25.0g of 7-amino-3-[( 1 -methyl- 1 -pyrrolidino)methyl]-3-cephem-4-carboxylate monohydrochloride dihydrate was added into 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 solution, 26.08g of 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2- methoxyiminoacetate was added at 0°C to 5°C. The reaction was completed within 3 hrs to 4 hrs. After completion of the reaction, water and n-butyl acetate were added into it. The reaction mixture was stirred at 15°C to 20°C and layers were settled, separated and the aqueous layer was charcolized. The pH of the aqueous layer was adjusted to 0.5 to 0.1 with concentrated hydrochloric acid at 0°C to 5°C. Acetone was added slowly to the aqueous layer at 0°C to 5°C and stirred for one hour at same temperature for complete precipitation. The precipitated 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

1 OO.Og of 7-amino-3-[( 1 -methyl- 1 -pyrrolidino)methyl]-3-cephem-4-carboxylate monohydrochloride dihydrate was added into 400mL of methyl alcohol and stirred. The reaction mixture was cooled to 0°C to 5°C and 33.4g of triethylamine diluted with lOOmL of methanol was added dropwise to get a clear solution. To the clear solution 105g of 2-mercaptobenzotlnazolyI-(Z)-2-(2-ammothiazol-4-yl)-2-memoxyiminoacetate was added at 0°C to 5°C and stirred till the completion of the reaction. After completion of the reaction, water and methylene chloride were added into it. The reaction mixture was stirred at 0°C to 10°C and layers were settled and separated. The pH of the aqueous layer was adjusted below 0.1 with concentrated hydrochloric acid at 0°C to 5°C. The aqueous layer was charcoalized and filtered through hyflo bed. 4000mL of acetone was added slowly to the filtrate at 10°C to 15°C and stirred for one hour at 0°C to 5°C. The precipitated mass was filtered, washed with 200mL of acetone twice and dried to get 138g of the titled compound with chromatographic purity of 99.90%.

EXAMPLE-4

Preparation of cefepime dihydrochloride monohydrate lO.Og of 7-amino-3-[(l -methyl- l-pyrrolidino)methyl]-3-cephem-4-carboxylate monohydrochloride dihydrate was added into a mixture of lOOmL of methylene chloride and 15mL of methyl alcohol and stirred at 0°C 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 completion of the reaction, 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 to the range of 0.5 to 0.7 with concentrated hydrochloric acid. Acetone was added to the filtrate and stirred for lhour for complete precipitation. The precipitated mass was filtered, washed with acetone and dried under vacuum to get 14g of the titled compound with chromatographic purity of 99.91 %. EXAMPLE-5

Preparation of cefepime dihydrochloride monohydrate

50. Og of 7-amino-3-[(l -methyl- l-pyrrolidino)methyl]-3-cephem-4-carboxylate monohydrochloride dihydrate was added into 220mL of methyl alcohol and stirred for 10 minutes .The reaction mixture was cooled to 0°C to 5°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 0°C to 5°C. The reaction was completed within 3 hrs to 4 hrs. After completion of the reaction, temperature was raised 10°C 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 was 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 precipitated 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 (I).

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 uses 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.

Claims

We claim:

An improved process for the preparation of cefepime dihydrochloride monohydrate of formula (I); comprising the steps of:

(i) condensing 7-amino-3-[(l -methyl- 1-pyrrolidino) methyl]-3-cephem-4- 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 alcoholic solvent, optionally in combination with chlorinated hydrocarbon solvent; and

(ii) isolating cefepime dihydrochloride monohydrate of formula (I) in highly pure form.

(2) A process according to claim 1 , wherein the said alcoholic solvent is selected from the group consisting of methanol, ethanol or isopropanol.

(3) A process according to claim 1, wherein the said chlorinated hydrocarbon solvent is methylene chloride. (4) A process according to claim 1, wherein the said base in step (i) is an organic base which is selected from the group consisting of triethylamine, diethylamine, pyridine, N-methylpiperidine, 1 , 8-diazabicycloundecene, 4,

4- dimethylaminopyridine or mixtures thereof.

(5) A process according to claim 1, wherein the condensation reaction is carried out at a temperature preferably in the range of -20°C to 10°C, more preferably 0 C to 5°C. (6) An improved process for the preparation of cefepime dihydrochloride monohydrate of formula (I) by condensing 7-amino-3-[(l -methyl- 1-pyrrolidino) methyl] -3 -cephem-4-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.

An improved process for the preparation of cefepime dihydrochloride monohydrate of formula (I) by condensing 7-amino-3-[(l -methyl- l-pyrrolidino) methyl]-3-cephem-4-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.

(I)

(III)