PROCESS FOR THE PREPARATION OF CEFPODOXIME ACID

Abstract: A new process is described for the preparation of cefpodoxime acid, which may then be converted into cefpodoxime proxetil by methods known in the art.

Description: PROCESS FOR THE PREPARATION OF CEFPODOXIME ACID FIELD OF THE INVENTION The present invention relates to a new process for the preparation of cefpodoxime acid, an antibiotic belonging to cephalosporin class of compounds. More specifically, the present invention relates to the preparation of cefpodoxime acid of high purity and yield. The cefpodoxime acid prepared according to the process of the present invention can be converted into its prodrug, cefpodoxime proxetil, by methods known in the art. Cefpodoxime proxetil is chemically an isopropyloxy carbonyl oxyethyl (proxetil) ester of cefpodoxime. It is a potent antibiotic and is of great therapeutic interest in the treatment of acute bronchitis, exacerbations, pneumonia, sinusitis, recurrence of chronic tonsillitis, pharyngitis, and acute otitis media. BACKGROUND OF THE INVENTION The process known for the preparation of cefpodoxime acid in the literature (Journal of Antibiotics, Vol. 40, p-370, 1987) involves conversion of 7-[2-(2- chloroacetyl amino thiazol-4-yl)-(Z)-2-(2- methoxyimino acetamido]-3-acetoxy- methyl-3-cephem-4-carboxylic acid into the corresponding 3-methoxymethyl derivative, which on deprotection at the 2-aminothiazolyl ring gives cefpodoxime acid. Esterification of the acid with iodides affords the corresponding esters. The process involves additional steps of protection and deprotection of the amino group resulting in lower yields. SUMMARY OF THE INVENTION It is an object of the present invention to provide an efficient process for the preparation of cefpodoxime acid of high purity and yield, and is economical from a commercial point of view. It is a further object of the present invention to provide a process which requires fewer steps and eliminates the use of additional protection and deprotection steps. Accordingly, the present invention provides a process for the preparation of Cefpodoxime acid having the Formula I FORMULA I comprising reacting 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2- benzothiazolyl thioester of Formula II FORMULA π (referred as MAEM) with 3-methoxymethyl-7-aminocephalosporanic acid of Formula III FORMULA m (referred as 7AMCA), in the presence of an organic solvent and an organic base as herein described and optionally in the presence of water, washing with a water-immiscible solvent as herein described, precipitating the product by adjusting the pH to an acidic pH, isolating and drying the product having the Formula I. Preferably the reaction between MAEM and 7AMCA is carried out at a temperature ranging from -5°C to about ambient temperature for about 2 to 12 hours. The organic solvent used is selected from tetrahydrofuran, N, N-dimethylaceta- mide, N,N-dimethylformamide, chlorinated hydrocarbons, ketones or a mixture thereof. Preferably, the reaction is carried out in tetrahydrofuran in the presence of water. The reaction is carried out in the presence of organic bases such as triethylamine, N-methylpiperidine, pyridine, 1 ,8-diazabicycloundecene, 4-dimeth- ylaminopyridine, or a mixture thereof. The water-immiscible solvent used is chlorinated hydrocarbon, aromatic hydrocarbon or ketones. The cefpodoxime acid having the Formula I prepared according to the process of the present invention is a syn-isomer of this compound. The present invention provides a method by which the syn-isomer of cefpodoxime acid is obtained in high purity and good yields without the necessity for protecting the amino group of acylating agent. The present invention is further illustrated by the following examples : DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1 Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid. To a stirred mixture of 2-benzothiazolyl(Z)-2-(aminothiazol-4-yl) methoxyimino- thioacetate (7.89g)and 7-amino-3-methoxymethyl-3-cephem-4-carboxyIic acid (5.0g) in tetrahydrofuran and water was added triethylamine (2.58g) in tetra- hydrofuran-water at 2-3-C. The reaction mixture was stirred at 2-3 Q C for 4 hours. After completion of the reaction, it was washed with methylene chloride. The aqueous layer was separated and its pH was adjusted to 2.75 with aqueous hydrochloric acid. The product thus separated was filtered, washed with water and isopropanol. The product was dried under reduced pressure to yield 6.65 gm (76%) of Cefpodoxime acid of 95.56% purity (HPLC). EXAMPLE 2 Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-(2-methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid. To a stirred mixture of 2-benzothiazolyl(Z)-2-(aminothiazol-4-yl)methoxyimino- thioacetate (8.6g) and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (5.0g) in methylene chloride (75ml) was added triethylamine (7.24g) at 2-3 9 C. The reaction mixture was stirred at 2-3 Q C for 3 hr. and water was added. The aqueous layer was separated and washed with methylene chloride. It was acidi- tied to pH 2.70 with aqueous hydrochloric acid. The product thus separated was filtered, washed and dried under reduced pressure to yield 6.2gm (70.8%) of Cefpodoxime acid of 94.30% purity (HPLC). EXAMPLE 3 Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid. To a stirred mixture of 2-benzothiazolyl(Z)-2-(aminothiazolyl-4-yl)methoxyimino- thioacetate (7.89g) and 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid in acetone and water, was added triethylamine (2.06g). The reaction mixture was stirred at 5-7 s C for 6 hrs. After completion of the reaction, it was washed with methylene chloride and aqueous layer was separated. The aqueous layer was acidified to pH 2.75 with aqueous hydrochloric acid. The product thus separated was filtered and washed with water and acetone. It was dried under reduced pressure at 45 Q C to afford 5.8gm (66%) of Cefpodoxime acid of 91.8% purity (HPLC). EXAMPLE 4 Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid. To a mixture of N,N-dimethylformamide and water, were added at 0-5 Q C, 7- amino-3-methoxymethyl-3-cephem-4-carboxylic acid (5.0g), 2-benzothiazolyl(Z)- (2-aminothiazol-4-yl)methoxyiminothioacetate (8.6g) and triethylamine (2.89g). The resulting mixture was stirred at 10-15 S C for 6 hrs. After completion of the reaction, the pH of the reaction was adjusted to 6.5 and stirred with methylene chloride (50ml). The aqueous layer was separated and acidified to pH 2.75 with aqueous hydrochloric acid. The product thus separated was filtered, washed with water and isopropanol, and dried under reduced pressure at 40 Q C to yield 4.9gm (56%) of Cefpodoxime acid of 94.92% purity (HPLC). EXAMPLE 5 Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyI-3-cephem-4-carboxylic acid. To a stirred mixture of 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (5.0g) in water (75ml) was added triethylamine (2.0 gm) at 2-5 s C. To this was added a solution of 2-benzothiazolyl-(Z)-2-(aminothiazol-4-yl)methoxyiminothio- acetate (7.88gm) in dimethylacetamide at 2-5-C. The resultant mixture was stirred at 20-25 s C for 12 hrs. After completion of the reaction, the reaction mixture was washed with methylene chloride. The aqueous layer was separated and pH was adjusted to 2.7 with aqueous hydrochloric acid. The solid thus separated was filtered and washed with cold water. The product was dried under reduced pressure at 40-45 Q C to yield 5.5gm (62%) of Cefpodoxime acid of 93.38% purity (HPLC). EXAMPLE 6 Preparation of 7-[(Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3- methoxy-methyl-3-cephem-4-carboxylic acid] (Via in situ-generated MAEM): A slurry containing triphenylphosphine (8.22g) and mercaptobenzothiazole disulphide (10.04g) in methylene chloride was stirred at 28-30 Q C for 1 hr. 2- (Aminothiazole-4-yl)- methoxyimino acetic acid (4.84g) and triethylamine (2.61 g) were added at 0 9 C and stirred at 0-2 5 C for 1 hr. 7-Amino-3-methoxymethyl-3- cephem-4-carboxylic acid (5.0g) and triethylamine (3.2g) were added and the resulting reaction mixture and further stirred for 2 hrs. After completion of the reaction, water was added and stirred for 10 min. Aqueous layer was separated and washed with methylene chloride. The aqueous layer was acidified to pH 2.75 with aqueous hydrochloric acid and the separated product was filtered. It was washed with water and dried under reduced pressure to yield 6.65gm (76%) of Cefpodoxime acid of 95.7% purity (HPLC).

Claims: LAIM : A process for the preparation of cefpodoxime acid having the Formula I FORMULA I which comprises reacting 2-[2-aminothiazol-4yl]-2-syn-methoxyiminoacetic acid -2-benzothiazolyl thioester of Formula II, FORMULA π with 3-methoxymethyl-7-aminocephalosporanic acid of Formula III, FORMULA ffl in the presence of an organic solvent and an organic base, precipitating the product by adjusting the pH to an acidic pH, isolating and drying the product having the Formula I. 2. The process of claim 1 , wherein after the reaction in the presence of an organic solvent and an organic base, before precipitation, the product is washed with a water-immiscible solvent. 3. The process of claim 1 , wherein cefpodoxime acid having the Formula I is a syn-isomer. 4. The process of claim 1 , wherein the organic solvent used is tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, chlorinated hydrocarbons, ketones or mixtures thereof. 5. The process of claim 4, wherein the organic solvent is methylene chloride. 6. The process of claim 1 , wherein the organic base is triethylamine, pyridine, N-methylpiperidine, 1 , 8-diazabicycloundecene, 4- dimethylaminopyridine or mixtures thereof. 7. The process of claim 1 , wherein the said reaction is carried out at a temperature in the range of -5 Q C to about ambient temperature for about 2 to 12 hours. 8. The process of claim 2, wherein the water-immiscible organic solvent is chlorinated hydrocarbon, aromatic hydrocarbon or ketones.

Inventors: ARORA RAKESH KUMAR, DE SHANTANU, KHANNA JAG MOHAN, KUMAR YATENDRA, NIZAR HASHIM, SINGH KAPTAN, ARORA, RAKESH, KUMAR, DE, SHANTANU, KHANNA, JAG, MOHAN, KUMAR, YATENDRA, NIZAR, HASHIM, SINGH, KAPTAN
Applicants: ARORA RAKESH KUMAR, KHANNA JAG MOHAN, KUMAR YATENDRA, NIZAR HASHIM, RANBAXY LAB LTD, SHANTANU DE, SINGH KAPTAN, ARORA, RAKESH, KUMAR, DE, SHANTANU, KHANNA, JAG, MOHAN, KUMAR, YATENDRA, NIZAR, HASHIM, RANBAXY LABORATORIES LIMITED, SINGH, KAPTAN
Application year: 2000
Main classification: C07D501
IPC codes: C07D501, C07D513