DESC:FIELD OF INVENTION

The present invention relates to a process for the preparation of Cefpodoxime proxetil or pharmaceutically acceptable salts thereof.

Formula I
BACKGROUND OF THE INVENTION
Cefpodoxime proxetil is chemically known as l-isopropoxycarbonyloxyethyl (6R,7R)-7-[2-(2-aminothiazol-4-yl)-2-(Z)-(methoxyimino)acetamido]-3-(methoxymethyl)-3-cephem-4-carboxylate of Formula (I). Cephalosporin drugs such as Cefpodoxime proxetil is widely used for the treatment and prevention of various infectious diseases caused by pathogenic bacteria. Cefpodoxime proxetil is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum over the general gram positive and gram negative bacteria, especially against Streptococci. The activity is primarily due to the Cefpodoxime acid which is generated easily in-vivo by the hydrolysis of its proxetil ester.

Cefpodoxime acid (II) is disclosed in US 4,409,215. Cefpodoxime proxetil is disclosed in U.S. Patent No. 4,486,425.

US ‘425 discloses a process for the preparation of Cefpodoxime proxetil of formula (I), wherein Cefpodoxime acid (II) is reacted with 1-haloethyl isopropyl carbonate (III) in presence of a solvent and base. After completion of the reaction, the reaction mixture is preferably diluted with a water-immiscible solvent, washed successively with an aqueous solution of potassium bisulphate and an aqueous basic solution and then dried, after which the solvent is distilled off to give the desired product. This product may be further purified by conventional means, for example by chromatographic techniques.
The process is shown in Scheme-I below:

Scheme-I

wherein X is chlorine, bromine or iodine atom.

However, the above process is associated with formation of impurities, which have been removed by taking recourse to chromatographic separation techniques, which albeit provides the compound of formula (I) of desired quality, but is however, cumbersome and not practical on industrial scale.

U.S. Pat. No. 5,498,787 discloses a method of preparing Cefpodoxime proxetil from a Cefpodoxime salt using a quaternary ammonium salt phase transfer catalyst, e.g., tetrabutylammonium hydrogensulfate in an amount ranging from 35 to 120 mole % based on Cefpodoxime. The method can effectively inhibit the formation of the ?2-isomer, but has problems in that the yield of the desired products is very low in the range of 50 to 60%, and the use of expensive quaternary ammonium salts is required.

U.S. Pat. No.7,045,618 discloses the purification of impure Cefpodoxime proxetil thus obtained is carried out in two stages which comprises of:
i) dissolving impure Cefpodoxime proxetil or adding a solution containing Cefpodoxime proxetil into a polar organic solvent or mixture(s) thereof, optionally reducing the solvent by concentration, and adding into a non-polar organic solvent or mixture(s) thereof to precipitate the solid; and
ii) dissolving the solid obtained from the above step into a water miscible polar organic solvent, optionally reducing the solvent by concentration, and adding into water to obtain the pure Cefpodoxime proxetil.

However, this method involves a two-step isolation and purification, which moreover involves use of a combination of solvents for crystallization, rendering the method tedious and not commercially attractive.

The major disadvantage with above processes is during the manufacturing of Cefpodoxime proxetil, acetaldehyde forms as a degradation product by degradation of 1-iodoethyl isopropyl carbonate. Acetaldehyde reacts with Cefpodoxime proxetil and leads to formation of two impurities namely Hemiaminal ether of Cefpodoxime proxetil (IV) and Cefpodoxime proxetil acetaldehyde dimer (V). The structures of these two impurities are shown below:

Hence, there is a need for the preparation of pure Cefpodoxime proxetil, which is free from said impurities.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Cefpodoxime proxetil (I) with high purity on commercial scale.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of pure Cefpodoxime proxetil (I) or pharmaceutically acceptable salts thereof,

Formula I
which comprises:
(i) reacting Cefpodoxime acid of formula (II),

Formula II
with 1-haloethyl isopropyl carbonate of formula (III),

Formula III
in presence of a base and a solvent;
wherein X is chlorine, bromine or iodine;
(ii) treating the obtained reaction mass with a scavenger to produce Cefpodoxime proxetil (I);
(iii) optionally, purifying Cefpodoxime proxetil (I).

In other embodiment, the present invention provides an isolation process of Cefpodoxime proxetil (I) free of two impurities namely Hemiaminal ether of Cefpodoxime proxetil (IV) and Cefpodoxime proxetil acetaldehyde dimer (V),

the process comprises, treating a reaction mass containing Cefpodoxime proxetil (I) with a biphasic solution comprises scavenger, water and water immiscible solvent.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention provides a process for the preparation of pure Cefpodoxime proxetil.

The process comprises, Cefpodoxime acid is condensed with 1-iodoethyl isopropyl carbonate in presence of a base and a solvent. The reaction mass obtained after completion of the reaction is added to a scavenger to produce Cefpodoxime proxetil.

The base used in the above reaction comprises, potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, dicyclohexylamine, pyridine or N,N-dimethylaniline, 1,1,3,3-tetrarnethylguanidine (TMG), di-isopropylethyl amine (DIPEA), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) or 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like.

The solvent used in the above reaction comprises dimethyl formamide, dimethyl acetamide, dimethyl sulphoxide, hexamethyl phosphoric triamide, acetonitrile, toluene, ethyl acetate and the like or mixtures thereof.

In another embodiment of the present invention, after completion of the reaction, the reaction mass is added to a scavenger in a solvent system. The pH of precipitated slurry mass is adjusted to 6.0 - 6.5 with a base at a temperature about 10°C-35°C. The product is filtered to produce Cefpodoxime proxetil free of impurities namely, Hemiaminal ether of Cefpodoxime proxetil (IV) and Cefpodoxime proxetil acetaldehyde dimer (V).

The scavenger used in the above reaction comprises sodium sulfite or its hydrate, sodium thiosulfite or its hydrate, potassium sulfite or its hydrate, potassium thiosulfite or its hydrate, carbohydrazide, diethyl hydroxylamine (DEHA), methyl ethyl ketoxime (MEKO), hydroquinone hydroxylamine, hydroxylamine, hydrazine or salts thereof and /or mixtures thereof. The solvent system is water and water immiscible solvent comprises cyclohexane, carbon tetrachloride, chloroform, 1,2-dichloroethane, dichloromethane, diethyl ether, dimethyl formamide, ethyl acetate, heptane, hexane, toluene or mixtures thereof. The base used in the above reaction comprises, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

Yet another embodiment of the present invention, the hydrate comprises mono hydrate, dihydrate, trihydrate, sesqui hydrate, pentahydrate, deca hydrate, dodeca hydrate and the like; the salt comprises, hydrochloride, hydrobromide, sulfate, phosphate, sulfonic acid, formic acid, acetic acid, trifluoroacetic acid and the like.
In other embodiment, the present invention provides an isolation process of Cefpodoxime proxetil (I) free of two impurities namely Hemiaminal ether of Cefpodoxime proxetil (IV) and Cefpodoxime proxetil acetaldehyde dimer (V). The process comprises, treating a reaction mass containing Cefpodoxime proxetil (I) with a biphasic solution.

The biphasic solution comprises a scavenger, water and water immiscible solvent.

The scavenger comprises sodium sulfite or its hydrate, sodium thiosulfite or its hydrate, potassium sulfite or its hydrate, potassium thiosulfite or its hydrate, carbohydrazide, diethyl hydroxylamine (DEHA), methyl ethyl ketoxime (MEKO), hydroquinone hydroxylamine, hydroxylamine, hydrazine or salts thereof and /or mixtures thereof.

The water immiscible solvent comprises cyclohexane, carbon tetrachloride, chloroform, 1,2-dichloroethane, dichloromethane, diethyl ether, dimethyl formamide, ethyl acetate, heptane, hexane, toluene or mixtures thereof.

Yet another embodiment of the present invention, the hydrate comprises mono hydrate, dehydrate, trihydrate, sesqui hydrate, pentahydrate, deca hydrate, dodecahydrate and the like; the salt comprises, hydrochloride, hydrobromide, sulfate, phosphate, sulfonic acid, formic acid, acetic acid, trifluoroacetic acid and the like.

In another embodiment, Cefpodoxime proxetil is optionally purified by known methods, for example by dissolving in a solvent comprises, methanol, ethanol, propanol, isopropanol, ethyl acetate, methylene chloride, hexane, heptane, cyclohexane, acetone, THF, acetonitrile, water or mixtures thereof; and precipitating pure Cefpodoxime proxetil by cooling the solution or by adding an anti solvent comprises, cyclohexane, n-hexane, heptane, diisopropyl ether or water etc.

In another embodiment, Cefpodoxime acid used in the present invention is purified by a process, wherein Cefpodoxime acid is passed through a pre-loaded resin column. The resin comprises Diaion® HP-20 resin, Diaion® HP-21 resin and the like.

Another embodiment of the present invention provides a process for the preparation of 1-halo (i.e chloro, bromo or iodo) ethyl isopropyl carbonate. The process comprises, reacting another halo (i.e chloro, bromo or iodo) ethyl isopropyl carbonate with Sodium halide and 18-crown-6 in toluene with to produce 1-haloethyl isopropyl carbonate. After completion of the reaction, toluene layer is concentrated under vacuum to obtain 1-haloethyl isopropyl carbonate.

In another embodiment, Cefpodoxime acid used in the present invention is prepared by deacylating 7-aminocephalosporanic acid (7-ACA) to produce 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA), which is condensed with 2-mercaptobenzothiazoly(Z)-(2-aminothiazole-4-yl)-2-methoxyimino acetate (MAEM) to produce Cefpodoxime acid.
The process is as shown in Scheme-II below:

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:

A process for the preparation of Cefpodoxime proxetil

Stage-I: Preparation of (6R,7R)-7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid (7-AMCA-WET)

Methanol (259 g) was added to a solution of boron trifluoride (400 g) in sulfolane (1000 ml) over a period of ~45 min at 25-40°C. Thereafter, 7-ACA (100 g) was added in a single lot at 40°C and stirring of the reaction mass continued at 40-45°C till unreacted 7-ACA was <2% by HPLC analysis. The reaction mass was cooled to 25-30°C and poured into pre-cooled DM water (1000 ml, 10-15°C). The solution was stirred for 15 min at 25-30°C and then extracted with methylene chloride (2x1500 ml) for sulfolane recovery. Then, pH of the aqueous layer was adjusted to 3.0 – 3.5 by adding triethylamine (~450 g) in 1 h at 10-15°C, thereby 7-AMCA precipitates out. The product was filtered and washed with DM water (500 ml) to obtain ~200 g of 7-AMCA-wet.

Stage-II: Preparation of Cefpodoxime Acid
Step-1: Preparation of Cefpodoxime acid-crude:

7-AMCA-wet material (~200 g) was suspended in a mixture of acetone (500 ml) and DM water (350 ml) and cooled to 10±2°C. 2-Mercaptobenzothiazolyl 2-(2-amino-4-thiazolyl)-2-methoxyimino acetate (MAEM, 91.50 g) was added to the reaction mass at 10±2°C and adjusted the reaction mass pH to 7.0 – 7.5 by adding triethylamine (~36 g). The reaction mass was stirred for 6 h at 10±2°C and the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was poured in to DM water (1800 ml) and pH was adjusted to 5.8 with 15% aqueous sulfuric acid. 2-Mercaptobenzothiazole (MBT) by-product was precipitated, filtered and washed with DM water (200 ml). Then, pH of combined filtrate was adjusted to 2.8±0.2 with 15% aqueous sulfuric acid at 10-15°C, thereby Cefpodoxime acid was precipitated out. The product was filtered and washed with DM water (200 ml) to obtain ~140 g of Cefpodoxime acid-crude product which was purified in the next step.
Assay (by HPLC, on anhydrous basis): ~85% w/w

Step-2: Purification of Cefpodoxime acid-crude

Cefpodoxime acid-crude (~140 g, obtained in step-1) was suspended in DM water (1000 ml) and cooled to 2-5°C. The slurry mass pH was adjusted to 6.5 – 7.0 by slowly adding 15-20% w/w aqueous ammonia (~25 ml) at 2-5°C. Thereafter, the reaction mass was stirred at 2-5°C and pH was maintained at 6.5 – 7.0 till a clear solution results. This solution was passed through pre-loaded resin column (Diaion HP-20 resin, 300 g) and collected the eluant slowly in ~ 2 h. Thereafter, another 500 ml of DM water was passed through the column to complete the product elution. Then, pH of combined filtrate was adjusted to 2.8±0.2 with 15% aqueous sulfuric acid 9~90 ml) at 2-5°C, thereby Cefpodoxime acid was precipitated out. The product was filtered and washed with DM water (200 ml) followed by acetone (100 ml). The product was dried at 40-45°C under reduced pressure to obtain 85 g of pure Cefpodoxime acid.
Assay (by HPLC, on anhydrous basis): ~99% w/w

Stage-III: Process for the preparation of 1-iodoethyl isopropyl carbonate

1-Chloroethyl isopropyl carbonate (50 g) was added to a suspension of sodium iodide (51.8 g) and 18-crown-6 (2.62 g) in toluene (250 ml) at 103-105°C. The resulted suspension was vigorously stirred at 103-105°C till GC analysis shows unreacted 1-chloroethyl isopropyl carbonate <10%. The reaction mixture was cooled to 10-15°C and washed with 1%w/w aqueous sodium thiosulfate solution (250 ml). Toluene layer containing 1-iodoethyl isopropyl carbonate was concentrated at <40°C under vacuum to obtain ~100 g of pale yellow colored solution of 1-iodoethyl isopropyl carbonate in toluene.

Stage-IV: Process for the preparation of Cefpodoxime Proxetil:
1,1,3,3-Tetramethylguanidine (25.85 g) was added to a solution of Cefpodoxime acid (100 g) in N,N-dimethylacetamide (500 ml) in 30±5 min at 10-15°C. Further, the solution was cooled to -15 to -10°C and 1-iodoethyl isopropyl carbonate in toluene solution was added (95.66 g, Assay: 60% w/w, obtained from Part A) slowly at -15 to -10°C in ~15 min. Thereafter, the reaction mass was stirred at -15 to -10°C for ~2 h to complete the reaction (unreacted Cefpodoxime acid <10% by HPLC). After completion of the reaction, the reaction mass was added to a biphasic solution of, 4g Sodium thiosulfate pentahydrate, 1.0 g hydroxyl amine hydrochloride in 4000 ml of DM water and 1000 ml of cyclohexane in 1h±10 min at 20-25°C. Precipitated Slurry mass pH was adjusted to 6.0 – 6.2 with 5% w/w aqueous sodium bicarbonate at 20-25°C. The product was filtered and dried at 40-45°C under reduced pressure to obtain ~120 g of Cefpodoxime proxetil-crude.

Cefpodoxime proxetil-crude (~120 g) was dissolved in methanol (400 ml) and treated with carbon (10 g) at 20-25°C. Carbon was removed by filtration through hyflo and washed the residue with methanol (100 ml). Methanol filtrate was added to DM water (3500 ml) slowly in 30±5 min at 20-25 to precipitate the product. Slurry mass pH is adjusted to 6.0 – 6.2 with 5% w/w aqueous sodium bicarbonate at 20-25°C and stirred for ~30 min. Thereafter, pH was adjusted to 4.0- 4.5 with acetic acid and stirred another ~30 min at 20-25°C. The product was filtered and washed with DM water (250 ml) at 20-25°C. Wet material was dried at 40-45°C under vacuum to obtain 100 g of pure Cefpodoxime proxetil.
Purity by HPLC: >98.7%. ,CLAIMS:WE CLAIM:

1. A process for the preparation of pure Cefpodoxime proxetil (I) or pharmaceutically acceptable salts thereof,

Formula I
which comprises:
(i) reacting Cefpodoxime acid of formula (II),

Formula II
with 1-haloethyl isopropyl carbonate of formula (III),

Formula III
in presence of a base and a solvent;
wherein X is chlorine, bromine or iodine;
(ii) treating the reaction mass obtained with a scavenger to produce Cefpodoxime proxetil (I);
(iii) optionally, purifying Cefpodoxime proxetil (I).

2. The process as claimed in claim 1, wherein the base used in step-(i) comprises potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, dicyclohexylamine, pyridine or N,N-dimethylaniline, 1,1,3,3-tetramethylguanidine (TMG), di-isopropylethyl amine (DIPEA), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN) or 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like.

3. The process as claimed in claim 1, wherein the solvent used in step-(i) comprises dimethyl formamide, dimethyl acetamide, dimethyl sulphoxide, hexamethyl phosphoric triamide, acetonitrile, toluene, ethyl acetate and the like or mixtures thereof.

4. The process as claimed in claim 1, wherein the scavenger used in step-(ii) comprises sodium sulfite or its hydrate, sodium thiosulfite or its hydrate, potassium sulfite or its hydrate, potassium thiosulfite or its hydrate, carbohydrazide, diethyl hydroxylamine (DEHA), methyl ethyl ketoxime (MEKO), hydroquinone hydroxylamine, hydroxylamine, hydrazine or salts thereof and /or mixtures thereof.

5. The process as claimed in claim 1, wherein step-(ii) is carried out in presence of base comprises potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate and the like and solvent comprises water, cyclohexane, carbon tetrachloride, chloroform, 1,2-dichloroethane, dichloromethane, diethyl ether, dimethyl formamide, ethyl acetate, heptane, hexane, toluene or mixtures thereof.

6. The process as claimed in claim 1, wherein the purification step-(iii) is carried out in presence of solvent comprises methanol, ethanol, propanol, isopropanol, ethyl acetate, methylene chloride, hexane, heptane, cyclohexane, acetone, THF, acetonitrile, water or mixtures thereof; and precipitating pure Cefpodoxime proxetil by cooling the solution or by adding an anti solvent comprises, cyclohexane, n-hexane, heptane, diisopropyl ether, water and/ or mixtures thereof.

7. An isolation process of Cefpodoxime proxetil (I) free of two impurities namely Hemiaminal ether of Cefpodoxime proxetil (IV) and Cefpodoxime proxetil acetaldehyde dimer (V),

the process comprises, treating a reaction mass containing Cefpodoxime proxetil (I) with a biphasic solution comprises scavenger, water and water immiscible solvent.

8. The process as claimed in claim 7, wherein the scavenger comprises sodium sulfite or its hydrate, sodium thiosulfite or its hydrate, potassium sulfite or its hydrate, potassium thiosulfite or its hydrate, carbohydrazide, diethyl hydroxylamine (DEHA), methyl ethyl ketoxime (MEKO), hydroquinone hydroxylamine, hydroxylamine, hydrazine or salts thereof and /or mixtures thereof.

9. The process as claimed in claim 7, wherein the water immiscible solvent comprises cyclohexane, carbon tetrachloride, chloroform, 1,2-dichloroethane, dichloromethane, diethyl ether, dimethyl formamide, ethyl acetate, heptane, hexane, toluene or mixtures thereof.