Indian Patents. 278213:IMPROVED PROCESS FOR THE PREPARATION OF CEFORANIDE IN PURE FORM

Title of Invention	IMPROVED PROCESS FOR THE PREPARATION OF CEFORANIDE IN PURE FORM
Abstract	The present invention provides an improved process for the preparation of the compound of formula (I) and also provides N, N,-cyclohexyl ethylenediamine salt of compound of formula (I).

Full Text	Field of the Invention The present invention provides an improved process for the preparation of the compound of formula (I) and also provides novel salts of compound of formula (I). The compound of formula (I) is known as Ceforanide. The novel N,N- dicylcohexyl ethylenediamine salt of Ceforanide prepared according to this invention are stable and found to be useful in the purification of compound of formula (I). Background of the Invention Ceforanide is a semisynthetic second-generation cephalosporin, and is chemically known as 7-(2-Aminomethylphenylacetamido)-3-(l- carboxymethyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid. Ceforanide, which is administered intramuscularly or intravenously and is found to be useful to treat a wide variety of bacterial infections, such as respiratory tract infections, skin infections and urinary tract infections and is disclosed in US Patent No. 4,100,346. U.S. Pat. No. 4,118,563 describes the preparation of Ceforanide by the reduction with hydrogen and Raney nickel of the corresponding 2-azidomethyl compound. The Ceforanide thus prepared according to US 4,100,346 & US 4,118,563 are not suitable for injectable as it contains impurities and even starting material in the range up to 10% that are difficult to remove. Hence purification of Ceforanide is inevitable. In order to purify crude Ceforanide, prior art processes utilize column chromatography or extensive carbon treatment plus recrystallization. US patent No. 4,448,958 claims N,N-Dimethylbenzylammonium-7- [.alpha.-(2-aminomethylphenyl)acetamido)-3-[(l-carboxymethyltetrazol-5- ylthio)methyl]-3-cephem-4-carboxylate. Even though this salt is used in the purification of Ceforanide, this salt is not preferable due to the corrosive nature of N,N-Dimethylbenzylamine since it causes burns to the eye on contact and may cause permanent damage. Hence, because of this safety issue this amine is not found to be useful from industrial point of view. During our continued search we have identified certain novel salts, which yield the compound of formula (I) in good purity, and yield. Objective of the Invention The main objective of the present invention is to provide a process for the preparation and purification of the compound of formula (I) in good purity, and quantity. Another objective of the present invention is to provide a N,N-dicylcohexyl ethylenediamine salt of Ceforanide, which are safe to handle in industry. Summary of the Invention Accordingly, the present invention provide a process for the preparation of compound of formula (I) which comprises the steps of: i) reacting the compound (7-amino-3-[5-(l-carboxymethyl-l,2,3,4- tetrazolyl)thiomethyl]-3 -cephem-4-carboxylic acid) of formula (II) or its reactive derivative with compound of formula (III) or its active derivative wherein Rj denotes lower alkyl in the presence of organic solvent, ii) isolating the compound of formula (I), iii) forming N,N-dicylcohexyl ethylenediamine salt of compound of formula (I) in the presence of solvent, iv) isolating pure Ceforanide of formula (I) from N,N-dicylcohexyl ethylenediamine salt. The process is shown in Scheme-1 Detailed description of the invention In an embodiment of the present invention the compound of formula (II) is employed either in free form or in reactive form. The reactive form of compound of formula (II) includes 1) silyl reactive derivative; the silyl derivative was prepared by reacting the compound of formula (II) with silylation agents like hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS), trimethylsilyl iodide (TMSI), N,0-bis-(trimethylsilyl)-acetamide (BSA), methyltrimethylsilyltrifluoroacetamide (MSTFA), N,0-bis- (trimethylsilyl)trifluoroacetamide (BSTFA) or mixtures there of; 2) salt of compound of formula (II), the salts of compound of formula include trimethylamine, dimethylethylamine, triethylamine, N-methylmorpholine, pyridine, diisopropylethylamine, N-methylpiperidine, N-ethylpiperidine, tetramethylguanidine, pentamethylguanidine, tetraethylguanidine, tetramethylethyguanidine, tetramethylbenzylguanidine and methylarylguanidines, l,5-diazabicyclo(4,3,0)-non-5-ene (DNB) and l,8-diazabicyclo(5,4,0)-undec-7- ene (DBU) or mixtures there of. In another embodiment of the present invention compound of formula (III) is activated as acid halides, mixed anhydrides, active esters, and active amides. Mixed anhydrides of compound of formula (III) formed by reacting the carboxylic acid of formula (III) or its salt with a lower-alkyl chloroformate such as ethyl chloroformate, benzyl chloroformate, isobutyl chloroformate or pivaloyl chloride in the presence or absence of catalytic amount of pyridine hydrobromide, N,N- dimethyl amino pyridine. The mixed carboxylic-carbonic anhydride thus formed is usually used in situ to acylate the said compound of formula (II). Alternatively acylation of compound of formula (II) comprises contacting the said compound of formula (III) with the appropriate carboxylic acid in the presence of certain agents known in the art for forming peptide bonds. Such agents include carbodiimides, for example, dicyclohexylcarbodiimide. In still another embodiment of the present invention, the solvent used in step (i) is selected from methyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, acetone, diethyl ether, ethyl propyl ether, ethyl butyl ether, tetrahydrofuran, dioxane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, toluene, xylene, chlorobenzene and anisole, such as dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, hexane, heptane, cyclopentane, cyclohexane, cycloheptane and cyclooctane, dimethylformamide and dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, etc. These solvents are used singly or in admixture of at least two of them. These solvents may contain water as required. Optionally a base may be present during acylation. In yet another embodiment of the present invention, the solvent used in step (iii) is selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, DMAc, DMF, water or mixtures thereof. In one more embodiment of the present invention the N,N-dicylcohexyl ethylenediamine salt of Ceforanide is converted into Ceforanide by reacting the salt with acid such as HC1, sulfuric acid, formic acid, acetic acid, perchloric acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, trifluoro acetic acid, or cationic exchange resin like UBK530 resin in the solvent selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, DMAc, DMF, water or mixtures thereof. The N,N-dicylcohexyl ethylenediamine salt of Ceforanide is stable and do not have any safety issue that are associated with the known N,N- Dimethylbenzylammonium salt of Ceforanide. Apart from this, cost of preparation of N,N-dicylcohexyl ethylenediamine salt of Ceforanide is less as compared to the known N,N-Dimethylbenzylammonium salt of Ceforanide. In one more embodiment of the present invention, this invention further provides a process for preparing sterile Ceforanide which comprises dissolving the Ceforanide in water and optionally in the presence of solvent like methanol, acetone, isopropyl alcohol, tetrahydrofuran and the like using a base selected from ammonia, sodium bicarbonate, triethyl amine and the like, subjecting the clear solution to sterile filtration in sterile area, precipitating the product by adjusting the pH using formic acid or acetic acid. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention. Example I 7-(2-Aminomethylphenylacetamido)-3-(l-carboxymethyltetrazol-5- ylthiomethyl) -3-cephem-4-carboxylic acid (Ceforanide). Activation of compound of formula (III) Solution A: To the suspension of Dane salt of 2-aminomethyl phenyl acetic acid (AMPAA) (24.8g) {prepared according to US 4,100,346} in methylene chloride (125mL) were added pyridine hydrobromide (0.3g) followed by pivaloyl chloride (8.5g) at -15 to -20°C and stirred for 60 min. The reaction mass was cooled to -35 to -40°C and DMF (87.5mL) was added in drops at -35 to -40°C for 30 min. Q-salt of compound of formula (II) Solution B: To 7-amino-3-[5-( 1 -carboxymethyl-1,2,3,4-tetrazolyl)thiomethyl]-3 cephem-4-carboxylic acid (ACATAA) (25g) in methylene chloride (125mL) tetramethyl guanidine (16.3g) was added at -10°C and stirred for 30 min at 0 to 5°C to get a solution. It was cooled to -20 to -25°C. Condensation: The solution A was transferred into solution B and the resulting solution was stirred until completion of reaction at -35 to -40°C (ACATAA 7-(2-Aminomethylphenylacetamido)-3-(l-carboxymethyltetrazol-5- ylthiomethyl) -3-cephem-4-carboxylic acid (Ceforanide). Silylation of compound of formula (II) Solution B: To ACATAA (lOg) in DMF (50mL) BSA (21.9g) was added at 0 to 5°C. The temperature was increased to 20 to 25°C and stirred for 60 min to get a solution and then reaction mass was cooled to 0 to 5°C. Activation of compound of formula (III) Solution A: To the suspension of Dane salt of 2-aminomethyl phenyl acetic acid (10.32g) {prepared according to US 4,100,346} in methylene chloride (80mL) DMF (lOmL) N-methyl morpholine, ethyl chloroformate (4.1g) were added at -55°C. Condensation: The cooled solution B was added into solution A and the reaction mass was stirred at -45 to -55°C till completion of the reaction (ACATAA Preparation of N. N.-cvclohexvl ethylenediamine Ceforanide To the suspension of crude Ceforanide {which may contain 8.6% of ACATAA} (5.0g) in a mixture of acetone (25mL) and water (25mL), N,N'- dicyclohexylethylenediamine (2.16g) was added and stirred for 15 min to get a solution. To the clear solution acetone was added. The precipitated N, N,- cyclohexyl ethylenediamine Ceforanide was stirred for 30 min and filtered. This was washed with acetone (25mL) and dried under vacuum to get N,N'- dicyclohexylethylenediamine salt of Ceforanide. Yield: 5.1g; Purity: 98.26%- 99.5% Example 4 Preparation of Pure Ceforanide To water (50mL) N, N,-dicyclohexyl ethylenediamine Ceforanide salt was added and stirred in at 25°C to get a solution. The pH of the clear solution was adjusted to 2.5 using dil. HCl. The precipitated pure Ceforanide was stirred for an hour and then it was filtered and washed with water (25mL) followed by acetone (25mL). This was dried under vacuum. Example 5 Preparation of Sterile Ceforanide Ceforanide (100 g) was added to water (100 mL) and stirred at 15-20° C to get a solution. The pH of reaction mass was adjusted to about 7.8 using ammonia solution to get clear solution. The clear solution was subjected to carbon treatment followed by sterile filtration. The pH of the filtrate was adjusted to 2.5 using formic acid at 15-20° C. The precipitated Ceforanide was stirred for an hour and then it was filtered and washed with water followed by acetone. This was dried under vacuum (M/C Preparation of Sterile L-Lysine To Water (200 mL) Non-sterile L-lysine (100 g) was added stirred to get clear solution. The clear solution was subjected to carbon treatment followed by sterile filtration. After filtration the filtrate was added slowly into isopropyl alcohol (5000mL). The precipitated sterile L-Lysine was filtered washed with isopropyl alcohol dried under vacuum, (moisture content We Claim, 1) An improved process for the preparation of Ceforanide of formula (I) The said process comprises the steps of: i) reacting the compound (7-amino-3-[5-(l-carboxymethyl-l,2,3,4- tetrazolyl)thiomethyl]-3 -cephem-4-carboxylic acid) of formula (II) or its reactive derivative with compound of formula (III) or its active derivative wherein R^ denotes lower alkyl in the presence of organic solvent; ii) optionally isolating the compound of formula (I); iii) forming N,N-dicylcohexyl ethylenediamine salt of compound of formula (I) in the presence of solvent; and iv) isolating pure Ceforanide of formula (I) from N,N-dicylcohexyl ethylenediamine salt. 2) A process according to claim 1, wherein the solvent used in step (iii) is selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, DMAc, DMF, water or mixtures thereof. 3) A process according to claim 1, wherein the Ceforanide in step (iv) is isolated by reacting N,N-dicylcohexyl ethylenediamine salt of Ceforanide with an acid or cationic exchange resin in the presence or absence of solvent. 4) A process according to claim 3, wherein the acid used is selected from HC1, sulfuric acid, formic acid, acetic acid, perchloric acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, or trifluoro acetic acid, and cationic exchange resin is UBK530 resin; the solvent used is selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, DMAc, DMF, water or mixtures thereof. 5) N,N-dicylcohexyl ethylenediamine salt of Ceforanide of formula: 6) A sterile process for the preparation of Ceforanide, the said process comprising the steps of: i) dissolving Ceforanide in water and in the presence or absence of solvent using a base; ii) filtering through micron filtration; iii) adjusting pH using an organic acid to yield sterile Ceforanide. 7) A process as claimed in claim 6, wherein the base used is selected from ammonia, TEA, sodium bicarbonate. 8) A process as claimed in claim 6, wherein the organic acid used is selected from formic acid or acetic acid.

Full Text

Field of the Invention
The present invention provides an improved process for the preparation of the compound of formula (I) and also provides novel salts of compound of formula (I).

The compound of formula (I) is known as Ceforanide. The novel N,N- dicylcohexyl ethylenediamine salt of Ceforanide prepared according to this invention are stable and found to be useful in the purification of compound of formula (I).
Background of the Invention
Ceforanide is a semisynthetic second-generation cephalosporin, and is chemically known as 7-(2-Aminomethylphenylacetamido)-3-(l- carboxymethyltetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid. Ceforanide, which is administered intramuscularly or intravenously and is found to be useful to treat a wide variety of bacterial infections, such as respiratory tract infections, skin infections and urinary tract infections and is disclosed in US Patent No. 4,100,346.
U.S. Pat. No. 4,118,563 describes the preparation of Ceforanide by the reduction with hydrogen and Raney nickel of the corresponding 2-azidomethyl compound.
The Ceforanide thus prepared according to US 4,100,346 & US 4,118,563 are not suitable for injectable as it contains impurities and even starting material in the range up to 10% that are difficult to remove. Hence purification of Ceforanide is inevitable. In order to purify crude Ceforanide, prior art processes utilize column chromatography or extensive carbon treatment plus recrystallization.
US patent No. 4,448,958 claims N,N-Dimethylbenzylammonium-7- [.alpha.-(2-aminomethylphenyl)acetamido)-3-[(l-carboxymethyltetrazol-5- ylthio)methyl]-3-cephem-4-carboxylate. Even though this salt is used in the purification of Ceforanide, this salt is not preferable due to the corrosive nature of N,N-Dimethylbenzylamine since it causes burns to the eye on contact and may cause permanent damage. Hence, because of this safety issue this amine is not found to be useful from industrial point of view.
During our continued search we have identified certain novel salts, which yield the compound of formula (I) in good purity, and yield.
Objective of the Invention
The main objective of the present invention is to provide a process for the preparation and purification of the compound of formula (I) in good purity, and quantity.
Another objective of the present invention is to provide a N,N-dicylcohexyl ethylenediamine salt of Ceforanide, which are safe to handle in industry.
Summary of the Invention
Accordingly, the present invention provide a process for the preparation of compound of formula (I)

which comprises the steps of:
i) reacting the compound (7-amino-3-[5-(l-carboxymethyl-l,2,3,4- tetrazolyl)thiomethyl]-3 -cephem-4-carboxylic acid) of formula (II) or its reactive derivative with compound of formula (III) or its active derivative wherein Rj denotes lower alkyl in the presence of organic solvent,

ii) isolating the compound of formula (I),
iii) forming N,N-dicylcohexyl ethylenediamine salt of compound of formula (I) in the presence of solvent,
iv) isolating pure Ceforanide of formula (I) from N,N-dicylcohexyl ethylenediamine salt.
The process is shown in Scheme-1
Detailed description of the invention
In an embodiment of the present invention the compound of formula (II) is employed either in free form or in reactive form. The reactive form of compound of formula (II) includes 1) silyl reactive derivative; the silyl derivative was prepared by reacting the compound of formula (II) with silylation agents like hexamethyldisilazane (HMDS), trimethylchlorosilane (TMCS), trimethylsilyl iodide (TMSI), N,0-bis-(trimethylsilyl)-acetamide (BSA),
methyltrimethylsilyltrifluoroacetamide (MSTFA), N,0-bis-
(trimethylsilyl)trifluoroacetamide (BSTFA) or mixtures there of; 2) salt of compound of formula (II), the salts of compound of formula include trimethylamine, dimethylethylamine, triethylamine, N-methylmorpholine, pyridine, diisopropylethylamine, N-methylpiperidine, N-ethylpiperidine, tetramethylguanidine, pentamethylguanidine, tetraethylguanidine,
tetramethylethyguanidine, tetramethylbenzylguanidine and methylarylguanidines, l,5-diazabicyclo(4,3,0)-non-5-ene (DNB) and l,8-diazabicyclo(5,4,0)-undec-7- ene (DBU) or mixtures there of.
In another embodiment of the present invention compound of formula (III) is activated as acid halides, mixed anhydrides, active esters, and active amides.
Mixed anhydrides of compound of formula (III) formed by reacting the carboxylic acid of formula (III) or its salt with a lower-alkyl chloroformate such as ethyl chloroformate, benzyl chloroformate, isobutyl chloroformate or pivaloyl chloride in the presence or absence of catalytic amount of pyridine hydrobromide, N,N- dimethyl amino pyridine. The mixed carboxylic-carbonic anhydride thus formed is usually used in situ to acylate the said compound of formula (II). Alternatively acylation of compound of formula (II) comprises contacting the said compound of formula (III) with the appropriate carboxylic acid in the presence of certain agents known in the art for forming peptide bonds. Such agents include carbodiimides, for example, dicyclohexylcarbodiimide.
In still another embodiment of the present invention, the solvent used in step (i) is selected from methyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, acetone, diethyl ether, ethyl propyl ether, ethyl butyl ether, tetrahydrofuran, dioxane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, toluene, xylene, chlorobenzene and anisole, such as dichloromethane, chloroform, dichloroethane, trichloroethane, dibromoethane, propylene dichloride, carbon tetrachloride, hexane, heptane, cyclopentane, cyclohexane, cycloheptane and cyclooctane, dimethylformamide and dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, etc. These solvents are used singly or in admixture of at least two of them. These solvents may contain water as required. Optionally a base may be present during acylation.
In yet another embodiment of the present invention, the solvent used in step (iii) is selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, DMAc, DMF, water or mixtures thereof.
In one more embodiment of the present invention the N,N-dicylcohexyl ethylenediamine salt of Ceforanide is converted into Ceforanide by reacting the salt with acid such as HC1, sulfuric acid, formic acid, acetic acid, perchloric acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, trifluoro acetic acid, or cationic exchange resin like UBK530 resin in the solvent selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, DMAc, DMF, water or mixtures thereof.
The N,N-dicylcohexyl ethylenediamine salt of Ceforanide is stable and do not have any safety issue that are associated with the known N,N- Dimethylbenzylammonium salt of Ceforanide. Apart from this, cost of preparation of N,N-dicylcohexyl ethylenediamine salt of Ceforanide is less as compared to the known N,N-Dimethylbenzylammonium salt of Ceforanide.
In one more embodiment of the present invention, this invention further provides a process for preparing sterile Ceforanide which comprises dissolving the Ceforanide in water and optionally in the presence of solvent like methanol, acetone, isopropyl alcohol, tetrahydrofuran and the like using a base selected from ammonia, sodium bicarbonate, triethyl amine and the like, subjecting the clear solution to sterile filtration in sterile area, precipitating the product by adjusting the pH using formic acid or acetic acid.
The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.
Example I
7-(2-Aminomethylphenylacetamido)-3-(l-carboxymethyltetrazol-5- ylthiomethyl) -3-cephem-4-carboxylic acid (Ceforanide).
Activation of compound of formula (III) Solution A:
To the suspension of Dane salt of 2-aminomethyl phenyl acetic acid (AMPAA) (24.8g) {prepared according to US 4,100,346} in methylene chloride (125mL) were added pyridine hydrobromide (0.3g) followed by pivaloyl chloride (8.5g) at -15 to -20°C and stirred for 60 min. The reaction mass was cooled to -35 to -40°C and DMF (87.5mL) was added in drops at -35 to -40°C for 30 min. Q-salt of compound of formula (II) Solution B:
To 7-amino-3-[5-( 1 -carboxymethyl-1,2,3,4-tetrazolyl)thiomethyl]-3 cephem-4-carboxylic acid (ACATAA) (25g) in methylene chloride (125mL) tetramethyl guanidine (16.3g) was added at -10°C and stirred for 30 min at 0 to 5°C to get a solution. It was cooled to -20 to -25°C. Condensation:
The solution A was transferred into solution B and the resulting solution was stirred until completion of reaction at -35 to -40°C (ACATAA 7-(2-Aminomethylphenylacetamido)-3-(l-carboxymethyltetrazol-5- ylthiomethyl) -3-cephem-4-carboxylic acid (Ceforanide).
Silylation of compound of formula (II) Solution B:
To ACATAA (lOg) in DMF (50mL) BSA (21.9g) was added at 0 to 5°C. The temperature was increased to 20 to 25°C and stirred for 60 min to get a solution and then reaction mass was cooled to 0 to 5°C.
Activation of compound of formula (III) Solution A:
To the suspension of Dane salt of 2-aminomethyl phenyl acetic acid (10.32g) {prepared according to US 4,100,346} in methylene chloride (80mL) DMF (lOmL) N-methyl morpholine, ethyl chloroformate (4.1g) were added at -55°C.
Condensation:
The cooled solution B was added into solution A and the reaction mass was stirred at -45 to -55°C till completion of the reaction (ACATAA Preparation of N. N.-cvclohexvl ethylenediamine Ceforanide
To the suspension of crude Ceforanide {which may contain 8.6% of ACATAA} (5.0g) in a mixture of acetone (25mL) and water (25mL), N,N'- dicyclohexylethylenediamine (2.16g) was added and stirred for 15 min to get a solution. To the clear solution acetone was added. The precipitated N, N,- cyclohexyl ethylenediamine Ceforanide was stirred for 30 min and filtered. This was washed with acetone (25mL) and dried under vacuum to get N,N'- dicyclohexylethylenediamine salt of Ceforanide. Yield: 5.1g; Purity: 98.26%- 99.5% Example 4
Preparation of Pure Ceforanide
To water (50mL) N, N,-dicyclohexyl ethylenediamine Ceforanide salt was added and stirred in at 25°C to get a solution. The pH of the clear solution was
adjusted to 2.5 using dil. HCl. The precipitated pure Ceforanide was stirred for an hour and then it was filtered and washed with water (25mL) followed by acetone (25mL). This was dried under vacuum. Example 5
Preparation of Sterile Ceforanide
Ceforanide (100 g) was added to water (100 mL) and stirred at 15-20° C to get a solution. The pH of reaction mass was adjusted to about 7.8 using ammonia solution to get clear solution. The clear solution was subjected to carbon treatment followed by sterile filtration. The pH of the filtrate was adjusted to 2.5 using formic acid at 15-20° C. The precipitated Ceforanide was stirred for an hour and then it was filtered and washed with water followed by acetone. This was dried under vacuum (M/C Preparation of Sterile L-Lysine
To Water (200 mL) Non-sterile L-lysine (100 g) was added stirred to get clear solution. The clear solution was subjected to carbon treatment followed by sterile filtration. After filtration the filtrate was added slowly into isopropyl alcohol (5000mL). The precipitated sterile L-Lysine was filtered washed with isopropyl alcohol dried under vacuum, (moisture content

We Claim,
1) An improved process for the preparation of Ceforanide of formula (I)

The said process comprises the steps of:
i) reacting the compound (7-amino-3-[5-(l-carboxymethyl-l,2,3,4- tetrazolyl)thiomethyl]-3 -cephem-4-carboxylic acid) of formula (II) or its reactive derivative with compound of formula (III) or its active derivative wherein R^ denotes lower alkyl in the presence of organic solvent;

ii) optionally isolating the compound of formula (I);
iii) forming N,N-dicylcohexyl ethylenediamine salt of compound of formula (I) in the presence of solvent; and
iv) isolating pure Ceforanide of formula (I) from N,N-dicylcohexyl ethylenediamine salt.
2) A process according to claim 1, wherein the solvent used in step (iii) is selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, DMAc, DMF, water or mixtures thereof.
3) A process according to claim 1, wherein the Ceforanide in step (iv) is isolated by reacting N,N-dicylcohexyl ethylenediamine salt of Ceforanide with an acid or cationic exchange resin in the presence or absence of solvent.
4) A process according to claim 3, wherein the acid used is selected from HC1, sulfuric acid, formic acid, acetic acid, perchloric acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, or trifluoro acetic acid, and cationic exchange resin is UBK530 resin; the solvent used is selected from ethanol, methanol, isopropanol, acetonitrile, acetone, ethyl acetate, THF, DMAc, DMF, water or mixtures thereof.
5) N,N-dicylcohexyl ethylenediamine salt of Ceforanide of formula:

6) A sterile process for the preparation of Ceforanide, the said process comprising the steps of:
i) dissolving Ceforanide in water and in the presence or absence of solvent using a base;
ii) filtering through micron filtration;
iii) adjusting pH using an organic acid to yield sterile Ceforanide.
7) A process as claimed in claim 6, wherein the base used is selected from ammonia, TEA, sodium bicarbonate.
8) A process as claimed in claim 6, wherein the organic acid used is selected from formic acid or acetic acid.

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Patent Number

278213

Indian Patent Application Number

1245/CHE/2006

PG Journal Number

53/2016

Publication Date

23-Dec-2016

Grant Date

16-Dec-2016

Date of Filing

18-Jul-2006

Name of Patentee

ORCHID CHEMICALS & PHARMACEUTICALS LTD

Applicant Address

ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI-600 034. TAMILNADU, INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	PRABHAT KUMAR SAHOO	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119. TAMILNADU, INDIA
2	KONDA ATHRMARAM RAMESH	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119.
3	SIVAKUMARAN SUNDARAVADIVELAN	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119.
4	UDAYAMPALAYAM PALANISAMY SENTHILKUMAR	ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI-600119.

PCT International Classification Number

A61K31/545

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA