Claims:1. An improved process for preparation of p-nitrobenzyl ester of 3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thiol-1-aza-bicyclo[3,2,0] heptane -2-carboxylic acid (Pen-GESO) comprising :
a) Esterification of Pen-GK with p-nitrobenzyl halide in the presence of solvent and phase transfer catalyst to get Pen-G ester

b) oxidizing of Pen G ester in the presence of oxidizing agent, catalyst and phase transfer catalyst to get Pen-GESO.

2. The process according to claim 1, wherein the solvent of step a ) selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, formic acid, acetic acid, propionic acid or mixtures thereof.

3. The process according to claim 1, wherein the phase transfer catalyst of step a) selected from tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, tetraethyl benzyl ammonium chloride ( TEBAC), tetraethyl benzyl ammonium bromide ( TEBAB), tetraethyl ammonium bromide , tetraethyl ammonium chloride, benzyltriethyl ammonium chloride , benzyltriethyl ammonium bromide, trioctylmethylammonium chloride, trioctylmethylammonium bromide .

4. The process according to claim 1, p-nitrobenzyl halide of step a) can be selected from p-nitrobenzyl chloride, p-nitrobenzyl bromide and p-nitrobenzyl iodide.

5. The process according to claim 1, wherein the phase transfer catalyst of step b) selected from tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, tetraethyl benzyl ammonium chloride ( TEBAC), tetraethyl benzyl ammonium bromide ( TEBAB), tetraethyl ammonium bromide , tetraethyl ammonium chloride, benzyltriethyl ammonium chloride , benzyltriethyl ammonium bromide, trioctylmethylammonium chloride, trioctylmethylammonium bromide.

6. The process according to claim 1, wherein the oxidizing agent of step b) selected from hydrogen peroxide, cumene hydrogen peroxide, sodium hypochlorite, vanadium pentoxide, asymmetric sulphur oxide and mixtures thereof.

7. The process according to claim 1, wherein the catalyst of step b) selected from titanium isopropoxide, m-chlorosuccinimide, sodium tungsten dihydrate.

8. A process for the preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid (7-ACCA) by using Pen-GESO, wherein Pen-GESO is prepared according to Claim 1.
, Description:
Field of the Invention:
The present invention relates to an improved process for the preparation of p-nitrobenzyl ester of 3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thiol-1-aza-bicyclo[3,2,0] heptane -2-carboxylic acid which is a key starting material of 7-amino-3-chloro-3-cephem-4-carboxylic acid.

Background of the invention:
p-nitrobenzyl ester of 3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thiol-1-aza-bicyclo[3,2,0] heptane -2-carboxylic acid (hereafter referred as Pen-GESO) and is represented by formula (I) which is a key starting material for preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid (hereafter referred as 7-ACCA). 7-ACCA is a key intermediate in the synthesis of semi-synthetic cephalosporin antibiotics.

The manufacturing process of 7-ACCA starts with penicillin G potassium (hereafter referred as Pen-GK) which is esterified and further oxidized to Pen-GESO.

The schematic representation is as below:

CN 102757449 discloses esterification of Pen-GK with p-nitrobenzyl bromide in DMF solvent followed by oxidation in the presence of N-hydroxyphthalamide and hexanitrile solvent.

Synthesis, (1), 52-4; 1986 discloses esterification of Pen-GK with p-nitrobenzyl bromide in the presence of acetonitrile solvent and 18-crown-6 as catalyst.

Jingxi Huagong (2005), 22(7), 552-554 discloses preparation of Pen-GESO by reacting p-nitrobenzyl bromide with Pen-GK in the presence of DMF solvent followed by oxidation in the presence of hydrogen peroxide.

CN 102432627 discloses preparation of Pen-GESO by oxidation of penicillin ester in the presence of oxidizing agent’s mixture hydrogen peroxide and peracetic acid in the ratio of 1: 2 ~ 4: 1.

However, each of the methods known for preparation of Pen-G ester and Pen-GESO from literature are cumbersome, prolonged and desired compound cannot be obtained with supplementary purity. There are shortcomings such as use of expensive reagents like use of p-nitro benzyl bromide.

Use of DMF as solvent and per acetic acid in the oxidation requires caustic to neutralize the acetic acid before recovery of DMF which comes from per acetic acid and forms sodium acetate as residue, which is difficult to dispose. The recovery of high boiling polar solvents like DMF is quite cumbersome.

To improve quality and yield simultaneously with receding in cost of process from commercial aspect as well as environment friendly, inventors have developed a phase transfer catalytic approach for preparation of Pen-G ester and Pen-GESO.

The present invention uses phase transfer catalyst, low boiling solvents offers immense advantage in terms of cost, yield and purity. The present invention is environment friendly process for esterification of Pen-GK and oxidation of Pen-G ester to Pen-GESO using phase transfer catalyst.

Summary of the invention:
In one aspect, present invention provides an improved, environment friendly cost effective process for the preparation of Pen-GESO.

In another aspect, present invention provides environment friendly, cost effective process for the preparation of Pen-G ester using phase transfer catalyst.

In another aspect, the present invention provides an improved process for the preparation of 7-ACCA.

Detail Description of the Invention:
In one aspect, the present invention provides an improved, environment friendly cost effective process for the preparation p-nitrobenzyl ester of 3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thiol-1-aza-bicyclo[3,2,0] heptane -2-carboxylic acid (Pen-GESO) comprising :

a) Esterification of Pen-GK with p-nitrobenzyl halide in the presence of solvent and phase transfer catalyst to get Pen-G ester;

b) oxidizing Pen G ester in the presence of oxidizing agent, catalyst and phase transfer catalyst to get Pen-GESO.

In one embodiment, the solvent of step a ) can be selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, or mixtures thereof, more preferably methylene dichloride, ethylene dichloride and mixtures thereof, most preferably mixture of methylene dichloride DMF.

In another embodiment, the phase transfer catalyst of step a) and step b)can be selected from tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, tetraethyl benzyl ammonium chloride ( TEBAC), tetraethyl benzyl ammonium bromide ( TEBAB), tetraethyl ammonium bromide , tetraethyl ammonium chloride, benzyltriethyl ammonium chloride , benzyltriethyl ammonium bromide, trioctylmethylammonium chloride, trioctylmethylammonium bromide more preferably tetrabutyl ammonium bromide (TBAB) and tetraethyl benzyl ammonium chloride ( TEBAC).

The p-nitrobenzyl halide of step a) the halide can be selected from p-nitrobenzyl chloride, p-nitrobenzyl bromide and p-nitrobenzyl iodide; most preferably p-nitrobenzyl chloride.

The reaction of step b ) can be performed in the presence of solvent selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, formic acid, acetic acid, propionic acid or mixtures thereof, more preferably methylene dichloride, ethylene dichloride , most preferably methylene dichloride.

The oxidizing agent of step b) can be selected from hydrogen peroxide, cumene hydrogen peroxide, sodium hypochlorite, vanadium pentoxide, asymmetric sulphur oxide and mixtures thereof; more preferably hydrogen peroxide.

The catalyst of step b) can be selected from titanium isopropoxide, m-chlorosuccinimide, sodium tungsten dihydrate etc.; more preferably sodium tungsten dihydrate.

In another aspect, present invention provides an improved, environment friendly, cost effective process for the preparation of Pen-G ester.

a) Esterification of Pen-GK with p-nitrobenzyl halide in the presence of solvent and phase transfer catalyst to get Pen-G ester

The solvent of step a ) can be selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, t-butyl alcohol, 1- pentanol, 2-pentanol, amyl alcohol, ethylene glycol, glycerol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, t-butyl acetate, isobutyl acetate, methylene dichloride, ethylene dichloride, acetonitrile, tetrahydrofuran, 1 ,4-dioxane, 2-methoxyethanol, N,N-dimethylformamide, ?,?-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, or mixtures thereof, more preferably methylene dichloride, ethylene dichloride , most preferably mixture of methylene dichloride and DMF.

The phase transfer catalyst of step a) can be selected from tetrabutyl ammonium bromide (TBAB), tetrabutyl ammonium chloride, tetraethyl benzyl ammonium chloride ( TEBAC), tetraethyl benzyl ammonium bromide ( TEBAB), tetraethyl ammonium bromide , tetraethyl ammonium chloride, benzyltriethyl ammonium chloride , benzyltriethyl ammonium bromide, trioctylmethylammonium chloride, trioctylmethylammonium bromide more preferably tetrabutyl ammonium bromide (TBAB) and tetraethyl benzyl ammonium chloride (TEBAC).

The p-nitrobenzyl halide of step a) the halide can be selected from p-nitrobenzyl chloride, p-nitrobenzyl bromide or p-nitrobenzyl iodide more preferably p-nitrobenzyl chloride.

In another aspect, the present invention provides an improved process for the preparation of 7-ACCA by using Pen GESO, wherein Pen GESO prepared according to the method described above.

The advantage of the present invention is high yield and high purity of Pen-GESO. There are lesser byproducts formed, lower impurity formation, cost efficient which is necessary for the industrial scale production. Formation of byproduct such as sodium acetate is avoided, hazards associated with per acetic acid are avoided, oxidation process is simple, easy to handle and industrially feasible.

Examples:
1. Preparation of Pen-GESO

To a mixture of DCM/DMF ( 150ml/ 12ml) is added p-nitrobenzyl chloride ( 47gm, 0.273mol) followed by addition of tetraethyl ammonium bromide (TEAB) ( 5g, 5% w/w) and Pen-GK ( 100gm, 0.268mol ). Reaction mass was stirred and refluxed. After completion of the reaction, reaction mass was cooled to room temperature, water (50ml) was added and allowed to stir, the organic layer was separated from aqueous layer. Aqueous layer was washed with 50ml of DCM, and separated. The combined organic layer was used for next step. To the combined organic layer was cooled 0°C to -5°C added tetraethyl benzylammonium chloride (TEBAC) (2g, 2%w/w). In another flask tungsten complex was prepared adding (30.4 gm, 0.53 mol) of H2O2 (~60% solution) and (940 mg, 0.94 % w/w) sodium tungstate dihydrate at 0°C to -5°C. This tungsten complex was added slowly to the reaction mass at -5 °C to 0°C. The reaction mixture was maintained at same temperature till reaction completes. After completion of reaction add sodium metabisulphite solution (3%, 100ml) and stir it room temperature. Allow the reaction mass to settle, separate the aqueous layer and organic layer. Distill out organic layer add water (200ml), filter the mass and dry it under vacuum.
Yield: 126g
% Yield: 96.7 %