Title of Invention

"AN IMPROVED PROCESS FOR THE PREPARATION OF CEFOTETAN SODIUM"

Abstract The present invention relates to an improved process for the preparation of a cephalosporin antibiotic. More particularly, the present invention relates to a process for the preparation of Cefotetan and its derivatives of the formula (I). wherein Ri represents hydrogen, carboxylic acid ester or easily cleavable carboxylic protecting group or pharmaceutically acceptable salts.
Full Text

Field of the Invention
The present invention relates to an improved process for the preparation of a cephalosporin antibiotic. More particularly, the present invention relates to a process for the preparation of Cefotetan or its derivatives of the formula (I).

wherein Ri represents hydrogen, carboxylic acid ester or easily cleavable carboxylic acid protecting group or pharmaceutically acceptable salts.
The present invention also relates to an improved process for the preparation of a cephalosporin intermediate of formula (IX)

wherein X is selected from chloro or bromo; which is an important intermediate in the preparation of cephalosporin antibiotics like Cefotetan of formula (I) and Cefminox of formula (A).

Cefotetan and Cefminox is a class of cephamycin antibiotic. Cefotetan is a semi-synthetic injectable Cephalosporin antibiotic, and has an excellent

antibacterial activity, particularly against the gram-negative bacteria, compared to other oral antibiotics.
In view of the vital antibiotic activities of Cefotetan or its derivatives of the formula (I), various methods of preparation were reported.
In US patent No. 4,404,373 discloses a process for the preparation of a Cefotetan and its derivatives, which comprises treating the 7"0;-methoxy-3-heterocyclic thiomethyl-cephalosporin derivatives, with a base selected from sodium hydrogen carbonate, potassium hydrogen carbonate, and sodium carbonate. The invention also provides various processes for preparing the aforesaid cephalosporin compounds. The preparation of Cefotetan as depicted in the Scheme I.
According to the method described in U.S. Pat. No. 4,263,432 and in Chem. Pharm. Bull. 28, 2629-2636 (1980), Cefotetan is obtained from 7/3-(4-carboxy-3-

hydroxyisothiazol-5-yl)thioacetamido-7o;-methoxy-3-(l-methyltetrazol-5-yl)-
thiomethyl-cephem-4-carboxylic acid is prepared by reacting 7- /3 -
bromoacetamido-7a-methoxy-3-( 1 -methyltetrazol-5-yl)thiomethyl -cephem-4-
carboxylic acid with trisodium-4-carboxy-3-hydroxy-5-mercapto-isothiazole. The reaction mixture is adjusted to pH 8.0 with dilute HCl and a precipitate of the Cefotetan is obtained. The following scheme II depicts the preparation of Cefotetan and its derivatives as mentioned above.

The aforementioned literature teaches that the use of trifluoro acetic acid, trifluoro acetic acid /anisole, meta-cresol, is must for deprotecting the diphenyl methyl group of carboxylic group. Also most of the prior art involves purification step and hence makes the process cumbersome.
US patent No. 4,357,331 claims Cefminox of formula (A), also this patent discloses a process for the preparation of from the compound of formula (IX).

In view of the importance of the intermediate of formula (IX) and by considering the foregoing limitations, we undertook an investigation in our lab to develop a process, which involves less number of steps and succeeded with a process, which yield Cefotetan in good quality, quantity and eco-friendly. We have also obviated the use of toxic chemicals for the cleavage of diphenylmethyl group.
Objectives of the Invention
The main objective of the present invention is to provide an improved process for the preparation of Cefotetan sodium of formula (I) from 7-/3 -amino-3-(1 -methyltetrazole-5yl)thiomethyl-3-cephem-4-carboxylic acid (TETRACA).
Another objective of the present invention is to provide a commercially viable process for the preparation of Cefotetan or its derivatives of formula (I), which would be easy to implement on manufacturing scale.
Still another objective of the present invention is to provide a process that obviate usage of toxic chemicals like triflouroaceticacid (TFA), anisole, meta-cresol, phenol, phenol/TFA, formic acid, p-toluene sulphonic acid.
One more objective of the present invention is to provide a process for the preparation of cephalosporin intermediate of formula (IX), which is an useful intermediate in the synthesis of cephalosporin antibiotics like Cefotetan sodium, Cefminox sodium heptahydrate.
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of Cefotetan and its derivatives of the formula (I)


wherein Ri represents hydrogen or pharmaceutically acceptable salts thereof which comprising the steps of:
i) condensing 7-iS-amino-3-(l-methyltetrazole-5yl)thiomethyl-3-cephem
carboxylic acid (TETRACA) of formula (II)

with substituted or unsubstituted phenyl acetyl chloride of formula (III)
V

where in R2 is H, chloro, bromo, methoxy, nitro, amino, C1.3 alkyl and X is chloro or bromo in the presence of a base and an solvent to produce a compound formula (IV),
where in R2 is as defined above
ii) methoxylating the compound of formula (IV) in the presence of base,
chlorinating agent and an organic solvent to produce a compound of formula (V),


iii) esterfying the compound of formula (V) to obtain a compound of formula (VI) in presence of esterifying agent and organic solvent

where in R is selected from group comprising of p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, or t-butyl,
iv) deacylating compound of formula (VI) using a reagent and in the presence of solvent at a temperature in the range of -50 °C to 30 °C to obtain a compound of the formula (VII)
where in R is as defmed above v) reacting compound of formula (VII) with reactive derivative of haloacetic acid in presence of organic base and polar organic solvent to produce a compound of formula (VIII).

where in R and X are as defined above
vi) deesterifying the compound of formula (VIII) using hydrogen chloride in
presence of polar organic solvent to produce compound of formula (IX)


where in X is as defined above, and
viii) reacting the compound of formula (IX) with compound of formula (X) in
presence of base and an inert solvent to produce Cefotetan of formula (I)

where in R2 is H or alkali metal ion selected from sodium, potassium, lithium preferably sodium.
Detailed description of the invention
In an embodiment of the present invention, the solvent used in the condensation in step (i) is selected from water, alkyl ketone like ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, dimethyl ketone, methyl vinyl ketone, and the like or mixtures thereof. And base used in step (i) is selected from triethylamine, diethylamine, tributylamine, pyridine, N-alkylanilines, N-methylmorpholine.
In an another embodiment of the present invention, base used in step (ii) is alkali metal salts of the alcohol selected from lithium methoxide, potassium methoxide, sodium methoxide, the lithium, sodium and potassium salts of benzyl alcohol and the chlorinating agent is selected from t-butyl hypohalite, an N-haloamide, an N-haloimide, an N-halosulfonamide, an N-halohydantoin, and an N-halotriazine, wherein halo is chloro or bromo, preferably N-chlorosuccinamide.

In another embodiment of the present invention, the compound of formula (V) in step (iii) was esterified using esterifying reagents selected from p-methoxybenzyl chloride, p-nitrobenzyl chloride, diphenyldiazomethane, t-butyl cholride and preferably diphenyldiazomethane.
In another embodiment of the present invention, compound of formula (VI) can be directly obtained from TETRACA without isolating compounds intermediary compounds.
In another embodiment of the present invention, the reagent used for deacetylation is selected from PCl5/POCl3/pyridine, PClf/pyridine, triphenyl phosphite/Cl2 complexes; and the solvent employed is selected from methylene chloride, CCI4, CHCI3, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (CpCs) alcohol or mixtures there of.
In still another embodiment of the present invention, haloacetic acid used in step (v) for condensation is selected from bromo acetic acid, chloro acetic acid and the like.
In one more embodiment of the present invention the haloacetic acid used in step(v) is activated as acid halides, mixed anhydrides, active esters, active amides to yield reactive derivative of haloacetic acid such as bromoacetyl bromide ,chloroacetyl chloride, preferably bromoacetyl bromide.
In yet another embodiment of the present invention, solvent employed in step (v) is selected from dimethylacetamide, dimethylformamide, N-methyl pyrrolidine, ethylacetate, methylene dichloride, ethylene dichloride,(Ci.3 )alkanol, acetone, tetrahydrofuran, isopropylether, toluene, xylene or mixtures thereof, preferably in

toluene; and base employed in step (v) is selected from sodium methoxide, lithium methoxide, sodium tertiary butoxide.
In yet another embodiment of the present invention, the solvents used for deesterification of compound of (VIII) is selected from methylenechloride, CCI4, CHCI3, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3) alcohol and the like or mixtures thereof; and organic or inorganic acid is selected from sulphuric acid, hydrochloric acid, acetic acid and the like. The reaction is carried out at a temperature in the range of -20 °C to 50 °C. The one of the advantages of the present invention the de-esterification of present invention is done by passing HCl gas thereby avoids the hazardous acid like TFA.
In yet another embodiment of the present invention, Cefotetan of formula (I) is obtained by reacting compound of formula (IX) with compound (X) in presence of organic solvent selected from acetone, dimethylformamide, methanol, ethanol, water, and mixtures thereof and base selected from alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate preferably sodium bicarbonate.
In yet another embodiment of the present invention, the compound of formula (I) obtained is syn isomer.
In yet another embodiment, Cefotetan obtained can be optionally purified by recrystalisation in solvents selected from (CpCs) alcohol, (C1-C3) alkyl acetate, methylene chloride containing toluene, alkyl ketones like ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, dimethyl ketone, methyl vinyl ketone, and the like tetrahydrofuran, hexane, and acetonitrile and/or mixtures thereof

In one more embodiment of the present invention, the compound of formula (IX) is useful in the preparation of number of cephalosporin antibiotic, like Cefotetan sodium, Cefminox sodium heptahydrate and the like. In still another embodiment of the present invention the compound of formula (IX) is converted into compound of Cefminox sodium heptahydrate of formula by utilizing the conventional process, as depicted in scheme IV, described in prior art like US 4,357,331 and US 4,555,404, which is exemplified in reference example.

The foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from manufacturing viewpoint, and affords good quality of Cefotetan sodium of the formula (I).
Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure.

The present invention is exemplified by the following example, which is provided for illustration only and should not be construed to limit the scope of the invention.
Example: I
Preparation of Diphenvlmethvl 7i3-phenylacetamido-7a-methoxv-3-(l-methyltetrazol-5-vl)thiomethyI-3-cephem-4-carboxylate (VI) Process A (By isolating the intermediates)
Synthesis of 7j3-Phenylacetamido-3-( 1 -methvltetra2ol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (IV)
To acetone (5.0 It), 7j3-amino-3-(l-methyltetrazol-5-yl)thiomethyl-3-cephem"4-carboxylic acid (500 gm) were added at 0"5°C followed by water (500 ml) and triethyl amine (450 ml). To the resultant mass phenylacetyl chloride (360 gm) was added slowly by maintaining pH in the range of 7.0 to 8.0 After completion of the reaction, the reaction mass was added to chilled DM-water and pH of the solution was adjusted to 2.0-2.5 using dilute hydrochloric acid. The product was extracted into methylene chloride. The organic layer was concentrated under vacuum. To the residue di-isopropyl ether was added, the solid obtained was filtered and dried to give 580 gm (85.3% of theoretical) of title product.
Synthesis of 7)3-Phenylacetamido-7-a-methoxy-3-(l-methyltetrazol-5-
yl)thiomethyl-3-cephem-4-carboxylic acid (V)
To the mixture of methylene chloride (8.8 It) and methanol (0.92 It), 7/3-
phenylacetamido-3- (1 -methyltetrazol-5-yl) thiomethyl-3-cephem-4-
carboxylic acid (1.1kg) was added. To the clear solution N-chlorosuccinamide (334
gm) was added at-85 to -90°C, followed by sodium methoxide solution (30 % w/w,

4.18 kg, 23.22 moles, in methanol) was added slowly at -85 to -90°C. The reaction mixture was stirred at -85 to -90°C and monitored and again N-chlorosuccinamide (341.4 gms, 2.55 moles) was added. After completion of reaction, sodium metabisulphite ( 2.27 gms) was added to the reaction mixture followed by acetic acid (80%, 1.65 It.) and sodium chloride solution (14%, 15 It.) was added to the reaction mass and stirred for 15 minutes. The pH of the reaction mass was adjusted to 2.0-3.0 by dilute hydrochloric acid. The organic layer was separated and washed successively with water and brine solution, and concentrated under vacuum. To residue di-isopropyl ether (24 It) was added and solid obtained was filtered and dried to give 1.06 kg (90.28% of theoretical) of the title product. Synthesis of Diphenylmethyl 1- B- phenylacetamido-7-Q!-methoxy-3-( 1 -methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate (VI) To the clear solution of 7-jS-Phenylacetamido-7"Q;-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (1.04 kg) in methylene chloride (2.5 It), diphenyldiazomethane (7.5 It) in methylene chloride was added slowly at room temperature, by maintaining pH of the reaction mass below 5.0 using dilute hydrochloric acid. After completion of reaction, layers were separated and organic layer was concentrated under vacuum at 40-45°C. To residue di-isopropyl ether ( 35 It) was added, the material obtained was filtered and dried to give 1.30 kg (92.72% of theoretical) of the title product.
Process B {without isolating the compound of formula (IV & V)
Synthesis of Diphenylmethyl 7- j3 -phenvlacetamido-7-Q;-methoxy-3-(l -methyltetrazol-5-yl)thiomethvl-3-cephem-4-carboxylate (VI)

To the suspension of 7-/3-Amino-3-(l-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (750 gms, 2.286 moles) in acetone (7.5 It), water (750 ml) and triethyl amine (675 ml ) were added at 0-2°C followed by phenyl acetyl chloride (530 gms, 3.43 moles) was added drop wise, by maintaining pH in the range 7.0 to 8.0. After completion of the reaction, the reaction mass was added to chilled DM-Water and pH of the solution was adjusted to 2.0-3.0 by dilute hydrochloric acid. Layers obtained were separated, and organic layer was concentrated under vacuum till thick slurry was formed. The residue obtained was dissolved in methylene chloride (7.65 It) and methanol (0.90 It). To clear solution N-chlorosuccinamide (313.2 gms, 2.346 moles), sodium methoxide solution ( 30 % w/w, 3.88 kg, 21.55 moles) in methanol (1.8 It) were slowly added at -85 to -90*^0. After completion of reaction, sodium metabisulphite (210 gms), acetic acid (80%, 1.53 It) was added. Layers obtained were separated. To organic layer diphenyldiazomethane solution in methylene chloride (5.75 It) was added slowly at room temperature by maintaining pH below 5.0 using dilute hydrochloric acid. After completion of reaction layers were separated and organic layer was concentrated under vacuum at 40-45°C. To residue di-isopropyl ether (35 It) was added and solid obtained was filtered and dried to give 1.10 kg (74.93% of theoretical) of the title product.
Example 2
Synthesis of Diphenylmethyl 7-j8-bromoacetainido-7-a-methoxy-3-(l-
methyltetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate Process A {with isolation}
Synthesis of Diphenylmethyl 7-p-Amino-7-a-methoxv-3-(l-methvl tetra2ol-5-ynthiomethyl-3-cepham-4-carboxylate

To diphenylmethyl-7-P-phenylacetamido-7-a-methoxy-3-(l-methyltetrazol-5-yl) thiomethyl-3-cepham-4-carboxylate (10 gm) in methylene chloride, (50 ml) pyridine (3.38 gm) and phosphorous pentachloride (8.10 gm) were added at -5 to -10°C and reaction mixture was stirred at 18 to 22°C. After completion of reaction methanol (120 ml) was added slowly at -70 to -65°C, and stirred. To chilled saturated sodium bicarbonate solution (200 ml), reaction mass was added. The layer was separated and organic layer washed with water and concentrated under vacuum. To residue di-isopropyl ether (150 ml) was added and stirred, the solid obtained was filtered and dried to give 5.0 gms of the title product.
Synthesis of Diphenylmethyl 7-j3-bromoacetamido-7-a-methoxy-3-(l" methyltetrazol-5-ynthiomethyl-3-cephem-4-carboxylate
To Diphenylmethyl 7-p"Amino-7-a-methoxy-3-(l-methyltetrazol-5-yl)thiomethyl-3-cepham-4-carboxylate 25.0 gms,0.0476 moles) in methylene chloride (300 ml ) pyridine (6.02 gms, 0.076 moles) bromo acetyl bromide (13.45 gms, 0.067 moles) were added at -15 to -10°C. After completion of reaction, the reaction mass was poured into chilled water (1.0 It). The layer was separated and organic layer was successively washed with water and concentrated under vacuum till thick slurry was formed. To residue toluene (150 ml) was added and stirred, the solid obtained was filtered and dried to give 20.5 gm of the title product.
Process B {without isolation of formula (VII)
Synthesis of Diphenylmethyl 7-j8-bromoacetamido-7-a-methoxy-3-(l-methyl
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxyIate(VIII)
To Diphenylmethyl 7-|3-phenylacetamido-7-Q;-methoxy-3-( 1 -methyltetrazol-5-yl) thiomethyl-3"Cephem-4-carboxylate ( 50 gm) in methylene chloride (700 ml), pyridine (21.5 gm) and Phosphorous pentachloride (62.5 gm) were added to at -

15°C. After completion of reaction methanol (1.0 It) was added drop wise at -50 to -55°C and reaction mass was further stirred. To the reaction mass chilled saturated sodium bicarbonate solution (1.2 It) was added, and layers obtained was separated, and moisture content of organic layer was brought to less than 0.5%. To the organic layer, pyridine (10.75 gm) and bromo acetyl bromide (26 gm, 0.129 moles) were added at -25 to -30°C. After completion of reaction water was added, layers obtained were separated and organic layer containing product was washed with water. The organic layer was concentrated under vacuum, to the residue obtained, toluene (350 ml) was added and stirred, and the solid obtained was filtered and dried to give 35.0 gm of the title product. Example 3:
Synthesis of 7-i3-Bromoacetamido -7-a-methoxy-3-(l-methyItetrazoI-5-yl)thiomethyI-3-cephem-4-carboxylic acid (IX)
A) By using HCl gas
To diphenylmethyl 7-i8-bromoacetamido -7-a;-methoxy-3-( 1 -methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (100 gms, 0.155 moles) in a mixture of methylene chloride (1.8 It) and acetonitrile (150 ml) dry HCl gas (50 gms , 1.36 moles) was purged slowly at -30 to -35°C. After completion of reaction, aqueous sodium chloride solution (15%, 3.0 It) was added slowly at 0 to 5°C. The layers were separated. This organic layer concentrated; to the residue di-isopropyl ether was added. The solid obtained was filtered dried to give title product (50 gm).
B) By using m-Cresol
To meta-cresol (50 ml), diphenylmethyl 7- (3 -bromoacetamido -7-o;-methoxy-3-(l-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (10 gm) was added and the reaction mixture was stirred at 45 to 50°C. After completion of reaction, butyl acetate (140 ml) and aqueous sodium bicarbonate solution (5%, 50 ml) were added

to reaction mass. The reaction mixture was stirred for 15 minutes and layers were separated. The pH of the aqueous layer containing the product was adjusted 2.0-2.5 using dilute hydrochloric acid at 0 - 5°C. The product isolated was filtered and dried to give 5 gm of the title product.
Example (4):
Preparation of Cefotetan from compound of formula (IX)
To the solution of 7-bromo acetamido 7- alpha methoxy cephalosphorinic acid (25gm, 0.155 mole) in 375 ml of dichloromethane and 40 ml of acetonitrile, HCl gas was purged at -30 to -50 °C till completion of reaction. After completion of reaction organic layer was added into brine solution. The organic layer was separated and 150ml sodium bicarbonate solution (2-3% W/V) and 18g of sodium 3-carboxy 4-hydroxy 5-mercapto isothiazolate were added. The reaction mass was stirred till completion of reaction, after completion of reaction the layers was separated. The aqueous layer was stirred between 10°-30°C at pH between 6.5-8.5 for 48 hrs. The aqueous mass was acidified to yield Cefotetan acid 20g of 95% purity.
Purification of Cefotetan:
To the mixture of isopropyl alcohol and acetone (90:10) (300 ml) 25 g of Cefotetan acid was added at 45°C and stirred for 4 hours. Product was filtered at 45°C and washed with IPE. The wet soUd was subjected to same operation and dried under vacuum at 45°C for 10 hours to get dry solid (12.5 g) with isotetan content 0.31% on HPLC Purity.
The same said process with ethyl acetate / acetone yields Cefotetan with isotetan content 0.64%
Reference Example :

Preparation Cefminox Sodium from compound of formula (IX)
To the mixture of dichloromethane (1500ml) and acetonitrile (150ml) of 7-methoxy bromoacetamido diphenylmethyl ester (VIII) (lOOg) was added. To the clear solution, hydrogen chloride gas was purged at -30 to -50°C till completion of reaction. After completion of reaction Pass the till the reaction is complete. To the Organic layer containing the compound of formula (IX), water, D-Cysteine hydrochloride (29 g) was added at -10° tO 0°C and pH or the reaction mass was maintained at 6-7.5 using sodium carbonate solution. After completion of reaction, pH of the reaction was adjusted to 2-5 using mineral acid like hydrochloric acid. The layers obtained was separated, the pH of aqueous layer was adjusted to 6-8 using sodium carbonate soltion. The reaction mass cooled to -10° to 10°C, and solid obtained was filtered and dried to yield the Cefminox sodium as heptahydrate (75g; purity: 99%).





We claim:
1. An improved process for the preparation of Cefotetan and its derivatives of the formula (I)

wherein R\ represents hydrogen pharmaceutically acceptable salts thereof which comprising the steps of:
i) condensing 7-j8-amino-3"( 1 -methyltetrazole-5yl)thiomethyl-3-cephem
carboxylic acid (TETRACA) of formula (II)

with substituted or unsubstituted phenyl acetyl chloride of formula (III)

where in R2 is H, chloro, bromo, methoxy, nitro, amino, C1.3 alkyl and X is chloro or bromo in the presence of a base and an solvent to produce a compound formula (IV),

where in R2 is as defined above
ii) methoxylating the compound of formula (IV) in the presence of base,
chlorinating agent and an organic solvent to produce a compound of formula (V),

iii) esterfying the compound of formula (V) to obtain a compound of formula (VI) in presence of esterifying agent and organic solvent

where in R is selected from group comprising of p-methoxybenzyl, p-nitrobenzyl, diphenylmethyl, or t-butyl,
iv) deacylating compound of formula (VI) using a reagent and in the presence of solvent at a temperature in the range of -50 °C to 30 °C to obtain a compound of the formula (VII)

where in R is as defined above
v) reacting compound of formula (VII) with reactive derivative of haloacetic acid in presence of organic base and polar organic solvent to produce a compound of formula (VIII).

where in R and X are as defined above
vi) deesterifying the compound of formula (VIII) using hydrogen chloride in
presence of polar organic solvent to produce compound of formula (IX)

where in X is as defined above, and
vii) reacting the compound of formula (IX) with compound of formula (X) in
presence of base and an inert solvent to produce Cefotetan of formula (I)

where in R2 is H or alkali metal ion selected from sodium, potassium, lithium preferably sodium.
2. The process according to claim 1, wherein the organic base used in step (i) is selected from triethylamine, diethylamine, tributylamine, pyridine, N-alkylaniline, N-methylmorpholine or mixtures thereof; and solvent used in step (i) is selected from dimethyl ketone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methyl vinyl ketone, water and mixtures thereof.
3. The process according to claim 1 where in chlorinating agent used in step (ii) is selected from t-butyl hypohalite, an N-haloamide, an N-haloimide, an N-halosulfonamide, an N-halohydantoin, and an N-halotriazine, wherein halo is chloro or bromo, preferably N-chlorosuccinamide; and base used is selected from sodium methoxide, or lithium methoxide.
4. The process according to claim 1 where in step esterifying reagent used in (iii) is selected from p-methoxybenzylchloride, p-nitrobenzylchloride, diphenyldiazomethane, t-butyl choloride and preferably diphenyldiazomethane; and organic solvent used in step (iii) is selected from dimethylacetamide,

dimethylformamide, N-methyl pyrrolidine, ethylacetate, methylene dichloride, ethylene dichloride, acetone, toluene, tetrahydrofuran, xylene and mixtures thereof.
5. The process according to claim 1, where in organic solvent used in step (iv)
is selected from methylenechloride, CCI4, CHCI3, tetrahydrofuran, acetonitrile,
N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3) alcohol or
mixtures there of, preferably in methylenechloride and methanol; and reagent used
for deacylation is selected from PCls/POCls/pyridine, PCls/pyridine, or triphenyl
phosphite/Cl2.
6. The process according to claim 1, where in organic solvent used in step (v) is
selected from dimethyl acetamide, dimethylformamide, N-methyl pyrrolidine, ethyl
acetate, methylene dichloride, ethylene dichloride, (C1.3) alkanol, acetone,
tetrahydrofuran, isopropyl ether, toluene, xylene and mixtures thereof, preferably in
toluene; and halo acetic acid employed is bromoacetyl chloride.
7. The process according to claim 1, where in organic solvent used in step (vi)
is selected from methylene dichloride, ethylene dichloride, acetone, isopropylether,
acetonitrile, propionitrile, or mixtures thereof.
8. The process according to claim 1, where in organic solvent used in step (vii) is selected from acetone, dimethylformamide, methanol, ethanol, water, and mixtures thereof and base used is selected from alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogen carbonate preferably sodium bicarbonate.
9. An improved process for the preparation of cephalosporin intermediate of formula (IX),
i) condensing 7-/3-Amino-3-(l-methyltetrazole-5yl)thiomethyl-3-cephem
carboxylic acid (TETRACA) of formula (II) with substituted or unsubstituted

phenyl acetyl chloride of formula (III) where in R2 is H, chloro, bromo, methoxy, nitre, amino, C1.3 alkyl and X is chloro or bromo in the presence of a base and an solvent to produce a compound formula (IV),

where in R2 is as defined above
ii) methoxylating the compound of formula (IV) in the presence of base,
chlorinating agent and an organic solvent to produce a compound of formula (V),

iii) esterfying the compound of formula (V) to obtain a compound of formula (VI) in presence of esterifying agent and organic solvent

where in R is selected from group comprising of p-methoxybenzyl, p-nitrobenzyl,
diphenylmethyl, or t-butyl,
iv) deacylating compound of formula (VI) using a reagent and in the presence of
solvent at a temperature in the range of -50 °C to 30 °C to obtain a compound of the formula (VII)


where in R is as defined above
v) reacting compound of formula (VII) with reactive derivative of haloacetic acid in presence of organic base and polar organic solvent to produce a compound of formula (VIII).
where in R and X are as defined above, and
vi) deesterifying the compound of formula (VIII) using hydrogen chloride in
presence of polar organic solvent to produce compound of formula (IX)

where in X is as defined above.
10. A process as claimed in claim (9), fiirther comprising converting the
compound of formula (IX) in to Cefotetan or its salt, and Cefminox or its salt or
hydrate.


Documents:

1056-che-2004 amended claims 23-02-2011.pdf

1056-CHE-2004 FORM-13 23-02-2011.pdf

1056-CHE-2004 AMENDED CLAIMS 04-08-2010.pdf

1056-CHE-2004 CORRESPONDENCE OTHERS 23-02-2011.pdf

1056-CHE-2004 EXAMINATION REPORT REPLY RECEIVED 04-08-2010.pdf

1056-che-2004-abstract.pdf

1056-che-2004-claims.pdf

1056-che-2004-correspondnece-others.pdf

1056-che-2004-description(complete).pdf

1056-che-2004-description(provisional).pdf

1056-che-2004-form 1.pdf

1056-che-2004-form 5.pdf

1056-che-2004-other documents.pdf

abs-1056-che-2004.jpg


Patent Number 246884
Indian Patent Application Number 1056/CHE/2004
PG Journal Number 12/2011
Publication Date 25-Mar-2011
Grant Date 18-Mar-2011
Date of Filing 12-Oct-2004
Name of Patentee ORCHID CHEMICALS & PHARMACEUTICALS LTD
Applicant Address ORCHI TOWERS, 313 VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI-600 034, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 BALDEVRAJ BANSAL ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI, TAMILNADU, INDIA.
2 MANOJ KHALI ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI, TAMILNADU, INDIA.
3 JITENDRA BHAGWANDAS KEVAT ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI, TAMILNADU, INDIA.
4 SINGARAVEL MOHAN ORCHID CHEMICALS & PHARMACEUTICALS LTD, 476/14, OLD MAHABALIPURAM ROAD, SHOLINGANALLUR, CHENNAI, TAMILNADU, INDIA.
PCT International Classification Number A61K 31/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA