AN IMPROVED PROCESS FOR THE PREPARATION OF
CEFPODOXIME ACID
Field of the invention
The present invention is in the field of chemistry and more particularly the present invention relates to the preparation of cefpodoxime acid of formula (I) using alcoholic solvent in the presence or absence of water in a very safe, simple, economical, user-friendly and in an industrially viable manner.
(Formula Removed)
Background of the invention
Cefpodoxime acid of formula (I), is chemically known as 7-[ (Z)-2-(2-Amino-4-thiazolyl)-2-(methoxyimino)acetamido] -3 -methoxymethyl-3 -cephem-4-carboxylic acid which was first disclosed/claimed in its product patent US 4,409,215 (henceforth '215). The '215 patent of Fuzisawa discloses many processes for the preparation of cefpodoxime acid of formula (I), but these processes are not very suitable at industrial scale..
(Formula Removed)
The cefpodoxime acid prepared according to the process of the present invention can be converted into pharmaceutically acceptable salts or ester thereof. Most preferably cefpodoxime acid can be converted into its prodrug, cefpodoxime proxetil of formula (la), by methods known in the art, which is chemically an isopropyloxy carbonyloxyethyl 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.
(Formula Removed)
The process known for the preparation of cefpodoxime acid in the literature
(Journal of Antibiotics (1987), 40, 370 involves conversion of 7-[2-(2-
chloroacetylaminothiazol-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.
According to the disclosure of PCT publication WO 00/68234 (henceforth '234) of Ranbaxy, the preparation of cefpodoxime acid of formula (I), by reacting 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (II) with 3-methoxymethyl-7-aminocephalosporanic acid of Formula (III), in the presence of an organic solvent such as tetrahydrofuran, N,N-dimethylacetamide,
N,N-dimethylformamide, chlorinated hydrocarbons, ketones or mixtures thereof and an organic base such as triethylamine, pyridine, N-methylpiperidine, 1,8-diazabicycloundecene, 4,4-dimethylaminopyridine or mixtures thereof described therein and optionally in the presence of water, washing with a water-immiscible solvent such as chlorinated hydrocarbon, aromatic hydrocarbon or ketones, precipitating the product by adjusting the pH to an acidic pH, isolating and drying the product having the Formula (I).
It has now been found that the condensation 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (III) with 3-methoxymethyl-7-aminocephalosporanic acid of Formula (II) can be performed using alcoholic solvents as reaction solvents. The risks involved by the use of said solvents are remarkably lower than those connected with the use of the solvents cited above. Furthermore, said alcoholic solvents have remarkably lower toxicity than the solvents reported above such as tetrahydrofuran, N,N-dimethylformamide, etc.
As discussed above none of the prior art references disclosed or claimed the use of alcoholic solvents as a solvent 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) with substantially fair operational safety, satisfactory yield and high chemical purity, that would make the process more distinct, cost effective and successful at industrial and commercial level.
It should be pointed out that the said condensation, which is extremely aggressive, in solvents such as alcoholic solvents, has never before been reported in literature. The present invention provides remarkable advantages in the industrial processes for the production of cefpodoxime acid. In fact, the method of the invention provides good quality cefpodoxime acid of formula (I) in yields quite comparable with those expected with the prior art methods.
Moreover, the acid product can easily be converted into the corresponding pharmaceutically acceptable salt or ester thereof, preferably into cefpodoxime proxetil of formula (la), by using conventional techniques known to those skilled in the 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 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.
Summary of the invention
Accordingly, the present invention provides a process for the preparation of cefpodoxime acid of formula (I), which comprises the steps of:
(Formula Removed)
(i) suspending 3-methoxymethyl-7-aminocephalosporanic acid of Formula (II) in an alcoholic solvent in the presence or absence of water;
(ii) condensing 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (III) with the suspension of step (i) in the presence of a base to get a solution;
(iii) mixing the solution of step (ii) with water;
(iv) adjusting the pH of the solution as obtained from step (iii) with an acid;
(v) filtering the solution as obtained from step (iv);
(vi) optionally charcolizing the filtrate as obtained from step (v);
(vii) adjusting the pH of solution as obtained from step (vi) with an acid; and
(viii) isolating cefpodoxime acid of formula (I) in pure form.
Alternatively, the present invention provides a process for the preparation of cefpodoxime acid of formula (I), which comprises the steps of:
(Formula Removed)
(i) suspending 3-methoxymethyl-7-aminocephalosporanic acid of Formula (II)
in an alcoholic solvent in the presence or absence of water; (ii) condensing 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-
benzothiazolyl thioester of formula (III) with the suspension of step (i) in
presence of a base to get a solution; (iii) adding water and an organic solvent to the solution as obtained from step (ii)
and separating the organic layer and aqueous layer; (iv) adjusting the pH of aqueous layer as obtained from step (iii) with an acid; (v) optionally charcolizing the aqueous layer as obtained from step (iv);
(vi) adjusting the pH of aqueous layer as obtained from step (v) using an acid;
and (vii) isolating cefpodoxime acid of formula (I) in pure form.
The above process is illustrated in the following synthetic scheme:
(Formula Removed)
Detailed description of the invention
Accordingly in an embodiment of the present invention, the said alcoholic solvent in step (i) of both the processes, may be 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 (ii) of
both the processes is an organic base which may be selected from the group
consisting of triethylamine, pyridine, N-methylpiperidine, 1,8-
diazabicycloundecene, 4-dimethylaminopyridine or mixtures thereof, more preferably triethylamine.
In another embodiment of the present invention in step (iii) of the alternative second process, the said organic solvent is n-butyl acetate.
In another embodiment of the present invention, the pH disclosed in step (iv) of both the processes is in the range of 5.0 to 6.0, more preferably 5.0 to 5.5.
In another embodiment of the present invention, the said acid in step (iv), step (vi) and step (vii) of both the processes is hydrochloric acid or sulfuric acid.
In another embodiment of the present invention, in step (v) of the first process the byproduct 2-mercaptobenzothiazole is removed by means of filtration, which is helpful for the better quality of the compound of formula (I).
It is important to know that 2-mercaptobenzothiazole is a toxic byproduct, which is produced during the said condensation. It is very difficult to remove it completely. Moreover, the presence of 2-mercaptobenzothiazole in the final active pharmaceutical ingredient is not advisable in terms of requirement for pharmacopoeial substances.
In another embodiment of the present invention, the pH disclosed in step (vii) and step (vi) of both the processes is in the range of 2.0 to 2.5.
In 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 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
cephalosporin antibiotics such as cefpodoxime proxetil of formula (la) by conventional methods.
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 cefpodoxime acid
50.0g of dry 3-methoxymethyl-7-aminocephalosporanic acid (7-AMCA) and 79.0g of 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester (MAEM) were suspended in 250mL of methanol at 5°C. to 10°C. The reaction mixture was cooled to 0°C. to 5°C. and 31g of triethylamine was added drop wise into it. The resultant solution was stirred at 8°C. to 10°C. till the completion of the reaction. After the reaction completion, reaction mass was poured into water in another flask. A solid (mainly 2-mercaptobenzothiazole) separated out. The pH of the reaction mass was adjusted to 5.0 to 5.5 with 10% sulfuric acid solution and stirred for 15 min. 2-Mercaptobenzothiazole was filtered and washed with water. Sodium metabisulphite and activated carbon were added to the filtrate at 10°C. to 15°C. and stirred for 30 minutes. It was filtered and the carbon bed was washed with water. 10% of sulfuric acid was added to the filtrate to adjust the pH in the range of 2.4 to 2.5. The reaction mass was cooled and stirred for 30 min. The solid was filtered, washed with water and acetone, and dried to get 69.0 g of the title compound with chromatographic purity of 96.68%.
EXAMPLE-2
Preparation of cefpodoxime acid
88.0 g of wet 3-methoxymethyl-7-aminocephalosporanic acid (7-AMCA)
obtained from a reaction starting with 50 g of 7-ACA and 61.1 g of 2-[2-
aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester
(MAEM) were suspended in 300mL of methanol at 27°C. The reaction mixture was
cooled to 10°C. to 15°C. and 15.0 g of triethylamine was added dropwise into it. The
solution was stirred at 15°C. to 20°C. until the reaction was completed. After
completion of the reaction, the reaction mass was poured into 1250 mL of water in
another flask. The pH of the reaction mass was adjusted to 5.0 to 5.5 with 10%
sulfuric acid solution and stirred for 15 min.The precipitated 2-
mercaptobenzothiazole was filtered and washed with 150 mL of water. Sodium metabisulphite and activated carbon were added to the filtrate at 15°C. to 20°C. and stirred for 30 minutes. It was filtered and the carbon bed was washed with water. 10% sulfuric acid was added to the filtrate to adjust the pH in the range of 2.4 to 2.5. The reaction mass was cooled to 0°C. and stirred for 30 min. The solid was filtered, washed with 100 mL of water and dried to get 49.0g of the title compound with chromatographic purity of 97.13%
Preparation of 7-AMCA
In a typical experiment, wet 7-AMCA was prepared by reacting 50 g of 7-aminocephalosporanic acid with 110 mL of methanol in the presence of boron trifluoride in sulfolane. On completion of the reaction, the mass was poured into water and the resulting solution washed with methylene chloride. The washed aqueous layer was basified with triethylamine to precipitate a solid which was filtered and washed repeatedly with water to give 88 g of the product 7-AMCA.
EXAMPLE-3
Preparation of cefpodoxime acid
50.0g of dry 3-methoxymethyl-7-aminocephalosporanic acid (7-AMCA) and 79.0g of 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester (MAEM) were charged in 250mL of methanol at 5°C to 10°C. The reaction mixture was cooled to 0°C. to 5°C. and 31g of triethylamine was added dropwise into it. The solution was stirred at 8°C. to 10°C. until the reaction was completed. After the reaction completion, n-butyl acetate and water were added to the reaction mass and stirred for 15 min. The aqueous layer was separated and its pH was adjusted in the range of 5.0 to 5.5 with hydrochloric acid. The above aqueous layer was washed with n-butyl acetate by stirring for 20 minutes. The aqueous layer was separated and ethylenediaminetetraacetic acid and activated carbon were added to it and stirred for 30 minutes. It was filtered and the carbon bed was washed with water. 5% hydrochloric acid was added to the filtrate to adjust the pH at 2.3. The reaction mass was cooled to 10°C. tol5°C. The solid was filtered, washed with water and finally with 100 mL of acetone. It was dried to get 73.5g of the title compound with chromatographic purity of 98%.
EXAMPLE-4
Preparation of cefpodoxime acid
78.0 g of wet 3-methoxymethyl-7-aminocephalosporanic acid (7-AMCA) obtained from a reaction starting with 50 g of 7-ACA and 46.0 g of 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester (MAEM) were suspended in 250mL of methanol at 25°C. The reaction mixture was cooled to 8°C. to 10°C. and 14.5 g of triethylamine was added dropwise into it. The solution was stirred at 8°C. to 12°C. until the reaction was completed. After completion of the reaction, reaction mass was poured into 1000 mL of water in
another flask. The pH of the reaction mass was adjusted to 5.0 to 5.5 with 5% sulfuric acid solution and stirred for 15 min. The precipitated 2-mercaptobenzothiazole was filtered and washed with 100 mL of water. Activated carbon was added to the filtrate at 15°C. to 20°C. and stirred for 30 minutes. It was filtered and the carbon bed was washed with water. 5% sulfuric acid was added to the filtrate to adjust the pH in the range of 2.4 to 2.5. The reaction mass was cooled to 0°C. and stirred for 30 min. The solid was filtered, washed with 100 mL of water and finally with 100 mL of acetone. It was dried to get 52.0 g of the title compound with chromatographic purity of 98.10%
EXAMPLE-5
Preparation of cefpodoxime acid
78.0 g of wet 3-methoxymethyl-7-aminocephalosporanic acid (7-AMCA) obtained from a reaction starting with 50 g of 7-ACA and 46.0 g of 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester (MAEM) were suspended in 250mL of methanol at 25°C. The reaction mixture was cooled to 8°C. to 10°C. and 14.5 g of triethylamine was added dropwise into it. The solution was stirred at 8°C. to 12°C. until the reaction was completed. After the reaction completion, the reaction mass was poured into a mixture of water and methylene chloride in another flask and stirred for 15 min. The aqueous layer was separated and its pH is adjusted in the range of 5.0 to 5.5 with 5% sulfuric acid. The above aqueous layer was washed with methylene chloride by stirring for 20 minutes. The aqueous layer was separated and activated carbon was added to it and stirred for 30 minutes. It was filtered and the carbon bed was washed with water. 5% sulfuric acid was added to the filtrate to adjust the pH in the range of 2.4 to 2.5. The reaction mass was cooled to 0°C. and stirred for 30 min. The solid was filtered, washed with 100 mL of water and finally with 100 mL of acetone. It was dried to get 49.0 g of the title compound with chromatographic purity of 97.82%.
Substantial Advantages and Industrial applicability
(1) The process of the present invention is very safe, simple and gives 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 less load on environment.
(3) The process of the present invention avoids the use of solvents like tetrahydrofuran, N,N-dimethylformamide which are harmful to the environment and is very hazardous in nature.
(4) The process of the present invention using a solvent which can be recycled and reused which 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. A process for the preparation of cefpodoxime acid of formula (I),
(Formula Removed)
which comprises the steps of:
(i) suspending 3-methoxymethyl-7-aminocephalosporanic acid of Formula (II)
(Formula Removed)
in an alcoholic solvent in the presence or absence of water; and
(ii) condensing 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (III)
(Formula Removed)
with the suspension of step (i) in the presence of a base.
2. The process according to claim 1, wherein the preparation of cefpodoxime acid of formula (I),
(Formula Removed)
comprises the steps of:
(i) suspending 3-methoxymethyl-7-aminocephalosporanic acid of Formula (II)
(Formula Removed)
in an alcoholic solvent in the presence or absence of water;
(ii) condensing 2-[2-aminothiazol-4-yl]-2-syn-methoxyimino acetic acid-2-benzothiazolyl thioester of formula (III)
(Formula Removed)
with the suspension of step (i) in the presence of a base to get a solution;
(iii) mixing the solution of step (ii) with water;
(iv) adjusting the pH of the solution as obtained from step (iii) in the
range 5.0 to 6.0 with an acid selected from the group consisting of
sulfuric acid and hydrochloric acid; (v) filtering the solution as obtained from step (iv); (vi) optionally, charcolizing filtrate as obtained from step (v); (vii) adjusting the pH of solution as obtained from step (vi) in the range 2.0
to 2.5 with an acid selected from the group consisting of sulfuric acid
and hydrochloric acid; and (viii) isolating cefpodoxime acid of formula (I) in pure form.
3. The process according to claim 1, wherein the preparation of cefpodoxime acid of formula (I),
(Formula Removed)
comprises the steps of:
(i) suspending 3-methoxymethyl-7-aminocephalosporanic acid of Formula (II)
(Formula Removed)
in an alcoholic solvent in the presence or absence of water;
(Formula Removed)