DESC:FIELD OF INVENTION
The present invention relates to a method for the purification of an intermediate Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) of formula (II) and its uses for the preparation of pure Cefixime (I).
BACKGROUND OF THE INVENTION
Cefixime (I), Chemically known as [6R-(6a,7B(Z)]-7-([(2-amino-4-thiazole)|(carboxymethoxy)imino]acetyl]amino)-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. It is a semisynthetic cephalosporin for the oral use, which exerts its antibioticaction by inhibiting the synthesis of the bacterium cell wall.

Cefixime (I) is known via various literature and U.S. Pat. No. 4,409,214 and U.K. Patent Application No. 2330141
U.S. Pat. No. 7,705,142 describes the process for preparing cefixime, in which 7-amino-3-vinyl-3-cephem-4-carboxylic acid is reacted with 2-mercapto-1, 3 -benzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2-(methoxycarbonyl) - methoxyimino acetate in tetrahydrofuran and water at 4°C in the presence of triethylamine followed by hydrolysis and pH adjustments to yield cefixime trihydrate.
It is always desirable to prepare pharmaceutical product of a high purity having a minimum amount of impurities, in order to reduce adverse side effects and to improve the shelf life of active ingredient,
The present invention is directed to provide an improved synthetic process for the preparation of Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate, having minimum amount of impurities.

SUMMARY OF THE INVENTION
The present invention provides the process for preparation of pure Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate referred as DATMA comprising treating crude DATMA with a base in presence of a solvent.
The present invention further provides conversion of Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) (II) to Cefixime (I) with high purity.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides the process for preparation of pure Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) (II A) comprising treating crude DATMA (II) with a base in presence of a solvent.

Crude DATMA refers to DATMA with a HPLC purity about 92%.
Pure DATMA refers to DATMA with a HPLC purity of greater than 99%, greater than 99.5%.
The base used in the purification of Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) (II) may be an organic base such as aryl amines, alkyl amines like Methyl amine, diethyl amine, trimethyl amine, aniline, 4-methoxyaniline, butyl amines, N,N-Dimethylaniline.
The base used in the purification of Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) (II) may be an inorganic base such as alkali metal or alkaline earth metal hydroxides like Potassium hydroxide, Sodium hydroxide, Lithium hydroxide, Magnesium hydroxide; alkali metal or alkaline earth metal carbonates such as Potassium carbonate, Sodium carbonate , Calcium carbonate, Potassium bicarbonate, sodium bicarbonate, Magnesium carbonate, Barium carbonate.
The solvent used in the purification of Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) (II) is water, organic solvents and mixtures thereof. The organic solvents such as alcohols like methanol, ethanol, propanol, isobuyl alochols, isopropyl alcohols, ethylene glycols; esters like ethyl acetate, benzyl acetate, ethyl benzoate, ethyl butyrate, ethyl formate; ethers like diethyl ether, dimethyl ether, methyl ethyl ether; nitriles like ethane nitrile, propane nitrile, butane nitrile, hexane nitrile; ketones like acetone, propanone, butanone, pentanone, hexanone; and halogenated hydrocarbons like methyl chloride, methylene chloride, chloroform, carbontetrachloride and their aqueous mixtures thereof.
The physical properties of DATMA includes color off white powder which is soluble in methylene chloride and methanol.
According to the present invention the DATMA having purity 99.5% is used in the preparation of pure cefixime.
The present invention further comprising converting DATMA to cefixime of formula (I) having HPLC purity greater than 99 %.

a) reacting 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-amino-3-ethenyl-8-oxo-, (4-methoxyphenyl)methyl ester, paratoulenesulphonic acid(1:1)(6R,7R) (7-AE) of the formula (III)

with DATMA-Pure of the formula II A,

to get intermediate diester compound of the formula (IV),

b) hydrolyzing the compound of formula IV and isolating cefixime (I) from the reaction mixture thereof.
c) recrystallizing by using aqueous ammonia and water to get pure cefixime having purity 99% or above.
The cefixime (I) obtained from step b is having purity less than 98% by HPLC.
The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.

EXAMPLES
Example 1 Purification of Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) (II)
A mixture of Acetone (200 ml) and Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) (20 gm.) was maintained at temperature of 20-30°C. To this reaction mixture Tri-n-butyl amine was added to get clear solution. Water (180 ml) was added to the reaction mixture and solid obtained was filtered and washed with Isopropyl alcohol (135 ml). The solid was dried under vacuum.
Purity 99.6% by HPLC
Example 2: Preparation of Cefixime (I) by using Diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) (II).
a) 5-Thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid, 7-amino-3-ethenyl-8-oxo-, (4-methoxyphenyl)methyl ester, paratoulenesulphonic acid(1:1)(6R,7R) (7-AE) (50gm) was charged with Dichloromethane (476 ml) and cooled to about -13°C, and DATMA (44.5 gm.) was added. To the reaction mixture N-methyl morpholine (7.5 gm) was dissolved in DCM (24.5 ml) was added at –15 to -5°C. After completion of water was added and the organic layer was separated and pH was adjusted to 3.5±0.5 with 10% HCl and separate organic layer.
To the organic layer methylene chloride (150 ml), AlCl3 (119 gm) and Anisol (48.4 gm) were added at a temperature of about -8°C in 120 min.
In another flask water (400 ml), methylene chloride (350 ml) and HCl (33 ml) mixture were prepared. This is added to the above organic layer. The precipitated solid was filtered and washed with methylene chloride followed by Methyl isobutyl ketone and finally with ethyl acetate (110 ml).The solid obtained was dissolved in ethyl acetate (55 ml) and pH adjusted to 5.8 to 6.2 with 4% sodium bicarbonate solution. The solution is charcolised in the presence of EDTA (0.59 gm) and filtered and the pH was adjusted to 2.4-2.6 with HCl solution (10%).The reaction mass was further diluted with ethyl acetate and water (1:1).The reaction mixture was stirred at 5°C for 1 hr. and then raised the temperature to 25±5°C.Stirred for 1 hr. and filtered and washed with water and ethyl acetate. the wet cake was dried under vacuum at 40°C.
Yield: 33 gm
Water content: 5.5%
b) Purification of Cefixime (I).
The cefixime was taken in water (375 ml) and cooled to 5°C.Adjusted the pH of reaction mass with ammonia solution (2.5%) to 5.5-5.8. To the reaction mixture charcoal (3.2gm) and EDTA (0.32 gm) were added and further stirred for 30 minutes. The solution was filtered and washed with water (250ml). In a separate flask mixture of water (560ml) and ethanol (640ml) were prepared and cooled to -10°C.To this solution above filtrate was added and the pH readjusted to 3.5 ±0.2 with HCl solution (10%).Temperature increases to 15°C stirred the mass for 1 hr. and filtered the precipitated solid.it was washed with water and ethanol and dried.
Purity: 99.74 % by HPLC.
,CLAIMS:1. The process for preparation of pure diethylthiophosphoryl (Z)-(2)-aminothiazol-4-yl)-2-(tert-butoxycarbonyl) methoxyimino acetate (DATMA) comprising

converting crude DATMA in to pure DATMA (II A) in the presence of base and solvent.
2. The process as claimed in claim 1, wherein the DATMA having purity greater than 99.0% by HPLC.
3. The process as claimed in claim 1, wherein the DATMA having purity greater than 99.5% by HPLC.
4. The process as claimed in claim 1, wherein the base is selected from organic or inorganic bases.
5. The process as claimed in claim 4, wherein the organic base is aryl amines, alkyl amines selected from methyl amine, diethyl amine, trimethyl amine, aniline, 4-methoxyaniline, butyl amines, N, N-dimethylaniline.
6. The process claimed in claim 4, wherein the inorganic base is alkali metal, alkaline earth metal hydroxides and carbonates selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, magnesium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, potassium bicarbonate, sodium bicarbonate, magnesium carbonate, barium carbonate.
7. The process as claimed in claim 1, wherein solvent is selected from water, organic solvent and mixtures thereof.
8. The process as claimed in claim 7, wherein organic solvent is selected from alcohol, ester, ether, nitrile, ketone and halogenated hydrocarbon.
9. The process as claimed in claim 1, further comprising converting DATMA to cefixime of formula (I) having HPLC purity greater than 99%.

I
a) reacting 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-amino-3-ethenyl8-oxo-, (4-methoxyphenyl)methyl ester, paratoulenesulphonic acid(1:1)(6R,7R) (7-AE) of the formula (III)


with DATMA-pure of the formula II

to get intermediate diester compound of the formula (IV),

a) hydrolyzing the compound of formula IV and isolating cefixime (I) from the reaction mixture.
b) recrystallizing by using aqueous ammonia and water .
10. The process as claimed in claim 9, wherein cefixime (I) having purity of greater than 99% by HPLC.