FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of highly pure 7-amino-[(p-hydroxyphenyl)acetamido]cephalosporins of formula I,

wherein R represents methyl or 1-propenyl. The compound of formula I is Cefadroxil when R represents methyl and is Cefprozil when R represents 1-propenyl.
BACKGROUND OF THE INVENTION
7-Amino-[(p-hydroxyphenyl)acetamido] cephalosporins such as Cefprozil and Cefadroxil are well known antibiotics having broad spectrum antibacterial activity. Cefprozil has been disclosed in US patent 4,520,022 whereas Cefadroxil has been disclosed in US 3,489,752. There are several methods reported for the preparation of Cefprozil and Cefadroxil, but generally these cephalosporin compounds are prepared by acylating a 7-aminocephalosporin derivative with a reactive derivative, such as acid chloride, activated ester and a mixed anhydride of 4-hydroxyphenylglycyl compound.
GB patent 1,240,687 discloses a process, which comprises reacting protected 4-hydroxyphenylglycine with ethyl chloroformate to obtain a carbonate derivative to acylate the 7-amino-3-cephem compound. However, this method gives a product of low purity.

US patent 5,608,055 discloses the process for the preparation of 7-aminoacyl cephalosporins by acylating the non-silylated 7-amino-3-substituted-3-cepheni-4-carboxylic acid of formula II,

wherein R represents H, halogen, alkoxy, ethyl, vinyl, propenyl etc.
with suitable mixed anhydride in non-halogenated solvents. The mixed anhydride has been prepared by reaction of N-protected-4-hydroxyphenyl compound with pivaloyl chloride, a-ethylhexanoyl chloride and benzoyl chloride. The presence of a small amount of a free C4-C9 acid or benzoic acid is recommended during mixed anhyride preparation.
US patent application US 2002/0120136 Al discloses the process for the preparation of 4-hydroxyphenylglycine derivative by acylating 7-amino-3-cephem compound of formula II with mixed anhydride of formula III or formula IV,


wherein R1 is an amino protecting group.
PCT application WO 2003/011871 A2 discloses a process for the preparation of Cefprozil, by reacting amidine salt of compound of formula II, with mixed anhydride. The mixed anhydride is prepared by acylating sodium or potassium D-N-(l-ethoxycarbonylpropen-2-yl)-amino-p-hydroxyphenylacetate with pivaloyl chloride, 2-ethylhexanoyl chloride, benzoyl chloride or ethyl chloroformate. In this patent also, the presence of a small amount of a free C4-C9 acid or benzoic acid is recommended during mixed anhyride preparation.
Recently published PCT application WO 2004/083172 discloses a process which comprises reacting silylated derivative of 7-amino-3"Cephem compound with mixed anhydride; mixed anhydride is prepared by the reaction of D-N-(l-alkoxycarbonyl-prope-2-yl)amino-p-hydroxyphenyl-acetate (Dane salt) with alkyl chloroformate in the presence of an acid and an amine. In the exemplified process, only methanesulfonic acid was used to minimize the formation of impurity of formula V,

wherein R represent methyl or 1-propenyl; Alkyl represents ethyl or methyl.
We have found that in addition to impurity of formula V, one more impurity of formula VI is formed during acylation reaction.


wherein R represent methyl or 1-propenyl;
Ri is -COOAlkyl, where Alkyl represents ethyl or methyl
Therefore, it is an object of the present invention to provide a simple process in which the formation of impurities of formula V and formula VI is minimized to prepare pure compound of formula I.
SUMMARY OF THE INVENTION;
Accordingly, the present invention relates to a process for the preparation of pure compound of formula I,

wherein R represents methyl or 1- propenyl;
which comprises:
reacting D-(-)-2-(4-hydroxyphenyl)glycine Dane salt of formula VII,


wherein R represents an alkyl group; M is sodium or potassium
with alkyl chloroformate in the presence of a phenolic compound and an amine, to prepare a mixed anhydride of formula VIII,

wherein R represents an alkyl group; alkyl being methyl or ethyl;
condensing the mixed anhydride of formula VIII with silylated derivative of 7-amino-3-cephem compound of formula II,

wherein R is methyl or 1-propenyl;
in the presence an organic solvent, to prepare the compound of formula I in high purity,
DETAILED DESCRIPTION OF THE INVENTION
The 7-amino-3-cephem compound of formula II may be prepared by following the methods known in the prior art such as reported in US patents 5,171,854 and 3,489,752.

The D-(-)-2-(4-hydroxyphenyl)glycine Dane salt of formula VII is commercially available or may be prepared by the known methods. The mixed anhydride is prepared by the reaction of Dane salt of formula VII with alkyl chloroformate in the presence of phenol and an amine.
We have observed that alkyl chloroformate partly reacts with 4-hydroxy group of phenyl ring or NH2 group, which leads to the formation of impurities of formula V and VI in the final compound. We have found that addition of suitably substituted phenol to the reaction mixture inhibits the competing reactions in which -OH and -NH2 groups are inevitably involved, both in mixed anhydride formation as well as in the acylation step.
The phenol used in the reaction can be selected from the compound of formula IX,

wherein Ri, R2, R3, may be same or different and are H, alkyl, alkoxy, CI, NO2, NH2, OH or the like.
The suitable phenol includes phenols, cresols, substituted phenols, and preferably p-nitrophenol and 2,4,6-tri-nitrophenol.
The amine used is selected from the group consisting of A^-methylmorpholine, picoline, lutidine, pyridine and preferably N-methylmorpholine is used.

The solvent used for the preparation of mixed anhydride can be selected from halogenated hydrocarbon, ketone, ester, ether, amide and the like or mixture thereof and preferably mixture of methylene chloride and N,N-dimethylformamide is used.
The reaction is conducted at a temperature of-70°C to 0°C and preferably at -50°C to- 20°C and it takes about one to three hours for completion of reaction.
The mixed anhydride prepared as above is useful for the preparation of 7-amino-[(p-hydroxyphenyl)acetamido]cephalosporins such as Cefprozil or Cefadroxil or any cephalosporin containing p-hydroxyphenyl amino side chain . Specifically the mixed anhydride of formula VIII is reacted with silylated 7-amino-3-cephem compound of formula 11. The 7-amino-3-cephem compound is silylated using silylating agent in an organic solvent under anhydrous conditions.
The silylating agent can be selected from A^,(9-bis(trimethylsilyl)acetamide, N-methyl-7V-trimethylsilyl acetamide, hexamethyl disilazane in combination with a halosilane such as trimethylchlorosilane. It is advantageous to use a catalyst such as imidazole, trichloroacetic acid or acetamide to facilitate the reaction.
The acylation reaction is carried out at a temperature of-70°C to 0°C and preferably at -60°C to -10°C. The completion of the reaction is monitored by HPLC. After completion of reaction, the reaction mixture is quenched and work-up is carried out in conventional manner. The compound of formula I is isolated in high purity greater than 99% and typically having impurity of formula V less than 0.15 and impurity of formula VI is less than 0.05% or absent.
Major advantage realized in the present invention is the preparation of compound of formula I in high purity by making use of phenolic compound during mixed anhydride formation.

Further the invention is illustrated by the following specific examples, which are not intended to limit the scope of the invention.
Example 1
PREPARATION OF CEFADROXIL MONOHYDRATE
Step-1: Preparation Of Silvlated 7-ADCA
To stirred slurry of 7-aminodesacetoxycephalosporanic acid (25 g, 0.1166 mole) in methylene chloride (150 ml) were added hexamethyldisilazane (12.8 g, 0.0793 mole), chlorotrimethylsilane (8.76 g, 0.0806 mole) and imidazole (0.19 g, 0.0028 mole) and the reaction mixture was refluxed for 7 hours. After refluxing the reaction mass was allowed to cooled to -30±5°C.
Step-2: Preparation Of Mixed Anhydride
To a stirred slurry of D-(-)-2-(4"hydroxyphenyl)glycine Dane salt (Methyl, Potassium, 38.24 g, 0.126 mole) in methylene chloride (155 ml) were added N,N-dimethylformamide (82.5 ml), N-methyl morpholine (0.15 g) and 4-nitrophenol (0.81 g, 0.0058 mole) at -60°C. Ethyl chloroformate (14.56 g), was added and the reaction mass was allowed to stir for 2 hours at -40±5°C and then cooled to -70±5°C.
Step-3: Preparation Of Cefadroxil DMF Solvate
The above silylated 7 ADCA was added into the mixed anhydride at -68 and stirred for 2-3 hours at -60±5°C. The progress of the reaction was monitored by HPLC. After completion of reaction (typically takes 135 min), the reaction was hydrolyzed with water (125 ml) and hydrochloric acid (13 ml) and stirred for 10 min. The aqueous layer was separated and diluted with A';A^-dimethylformamide (250 ml). The reaction mass was stirred for 15 min and the aqueous layer was filtered. The pH of aqueous layer was adjusted to 5.7 with ammonia solution at 25-30°C and stirred for 1

hour. The solution was filtered and washed with N,N-dimethylformamide (50 ml) followed by acetone (200 ml). The Cefadroxill dimethylformamide solvate was dried under vacuum at 35-40°C to obtain 49 g of the compound having purity 98.63% and impurity of Formula V is 0.13% and impurity VI is not detected by HPLC.
Step-4: Preparation Of Cefadroxil Monohvdrate
The Cefadroxil DMF solvate (20g) was added in portions and with stirring to DM water (20 ml) at 38-42°C. After the complete addition, stirring was continued for further one hour at 38-42°C and then reaction mass cooled to 15°C. The product was filtered, washed with DM water (40 ml) and acetone (40 ml) and dried under vacuum at about 40°C to obtain crystalline Cefadroxil monohydrate (12.5g) having purity 99.69% by HPLC and impurity of Formula V is 0.07% and impurity VI is not detected by HPLC.
Example 2
PREPARATION OF CEFPROZIL
Step-1: Preparation Of Silvlated 7-APRA
To a stirred slurry of 7-amino-3-[(Z/E)-l-propen-l-yl]-3-cephem-4-carboxylic acid (7-APRA) (20 g, 0.0832 mole) in methylene chloride (135 ml) were added hexamethyldisilazane (8.86 g, 0.0548 mole), chlorotrimethylsilane (5.96 g, 0.0548 moles), and imidazole (0.11 g, 0.0016 mole) and the reaction mixture was refluxed for 4 hours. Thereafter, the reaction mass was allowed to cool to -25±5°C.
Step-2: Preparation Of Mixed Anhydride
To a stirred slurry of D-(-)-2-(4-hydroxyphenyl)glycine Dane salt (Methyl, Potassium, 27.10 g, 0.0893 mole) in methylene chloride (150 ml) was added N,N-dimethylformamide (54.5 ml), AT-methylmorpholine (0.11 g, 0.001 mol) and 2,4,6-

trinitrophenol (0.95g, 0.0041 mole) at -50°C followed by ethyl chloroformate (9.93 g, 0.0915 mole) at -60°C. The reaction mass was allowed to stir for 2 hours at -40±5°C and then cooled to -60±5°C.
Step-3: Preparation Of Cefprozii DMF Solvate
The above silylated mass was added into the mixed anhydride at -60°C and then stirred for 2-3 hours at -40±5°C. The progress of the reaction was monitored by HPLC. After completion of reaction (2h), the reaction was hydrolyzed with water (80 ml) and hydrochloric acid (10 ml) and stirred for 10 min. The aqueous layer was separated and diluted with N,N-dimethylformamide (250 ml) and acetone (75 ml). This was stirred for 15 min and then aqueous layer was filtered. The pH of the aqueous layer was adjusted to 6.5 with aqueous ammonia at 20-25°C and stirred for Ih. The resulting white solid was filtered and washed with N,N-dimethylformamide (50 ml) followed by acetone (2x100 ml). The Cefprozii dimethylformamide solvate obtained was dried under vacuum at 35-40°C to give 38.5 g of the compound having purity 97.45% by HPLC and impurity of Formula V is 0.11% and impurity VI is not detected by HPLC.
Step-4: Preparation of Cefprozii
The Cefprozil DMF solvate (20 g) was added in portions into DM water (40 ml) with stirring in about 60 min at 38-42°C. After the complete addition the reaction mass was diluted with methanol (40 ml) and stirring was continued for one hour. The crystals were filtered and washed with water (40 ml) followed by acetone (40 ml) and dried under vacuum at about 40°C to obtain crystalline Cefprozil as monohydrate (12.5g) having purity 99.31% and impurity of Formula V is 0.05% and impurity VI is not detected by HPLC

WE CLAIM:
1. A process for the preparation of highly pure compound of formula I,

wherein R represents methyl or 1-propenyl;
which comprises:
reacting D-(-)-2-(4-hydroxyphenyl)glycine Dane salt of formula VII,

wherein R represents an alkyl group, M is sodium or potassium;
with an alkyl chloroformate in the presence of a phenolic compound and an amine, to prepare a mixed anhydride of formula VIII,

wherein R represents an alkyl group; alkyl being methyl or ethyl;
and condensing the mixed anhydride of formula VIII with silylated derivative of 7-amino-3-cephem compound of formula II,


wherein R is methyl or 1-propenyl;
in an organic solvent, to prepare the compound of formula I
2. The process according to claim 1, wherein alkyl chloroformate is ethyl
chloroformate or methyl chloroformate.
3. The process according to claim 1, wherein amine is selected from the group consisting of N-methylmorpholine, picoline, lutidine, pyridine
4. The process of claim 1, wherein the mixed anhydride formation is carried out at temperature from about - 70°C to about 0°C.
5. The process of claim 4, wherein the mixed anhydride formation is carried out at temperature from about -50°C to -20°C.
6. The process of claim 1, wherein the solvent comprises halogenated hydrocarbon, ketone, ester, ether, amide and the like or mixture thereof
7. The process of claim 1, wherein the phenolic compound comprises phenols, cresols, substituted phenols, nitrophenols.
8. The process of claim 7, wherein preferably 4-nitrophenol is used.
9. The process of claim 1, wherein the acylation is carried out at temperature from about- 70°C to about 0°C.

10. The process of claim 9, wherein the acylation is carried out at temperature from about-60°C to-10°C.