FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF TFIE INVENTION

An Improved Process For Preparing p-nitro Benzyl Ester Of Penicillin G Sulfoxide,
An Intermediate For 7-ACCA

2. APPLICANT
NAME : Frichem Private Limited
NATIONALITY : IN
ADDRESS : 12, Concord, Bullock Road, Band Stand, Bandra West, Mumbai -400 050, India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention
The present invention relates to an efficient preparation of p-nitro benzyl ester of 3,3-dimethyl-7-oxo-6-(2-phenylacetamido)-4-thiol-l-aza-bicyclo[3.2.0]heptane-2-carboxylic acid (hereinafter referred as Pen-GESO), a key intermediate for preparation of 7-amino-3-chloro-3-cephem-4-carboxylic acid., (hereinafter referred as 7-ACCA)
Background of the invention
Pen-GESO, which is chemically known as p-nitro benzyl ester of 3,3-dimethyl-7~oxo-6-(2-phenylacetamido)-4-thiol-l-aza-bicyclo[3.2.0]heptane-2-carboxylic acid and represented by formula (I), is a key intermediate for preparation of 7-ACCA.

Tetrahedron the Letters 1962, S. 381, describes method for preparation of Pen-GESO by oxidation of pen-GES with hydrogen peroxide solution in presence of acetic acid.
Farmatsiya (Sofia, Bulgaria) (1974), 24(6), 5-8 discloses the preparation of Pen- GESO by oxidation of the corresponding esters with C1-C3 percarboxylic acids prepared in situ with sulfo-cation-exchange resins, H2SO4, or p-MeC6H4SO3H.
Huaxue Shijie (2006), 47(12), 743-745 discloses the preparation of Pen-GESO by

oxidation of penicillin nitro benzyl ester with acetic hydro peroxide at the temperature less than 5°C in the molar ratio of 1:1.15.
Jingxi Huagong (2005), 22(7), 552-554 discloses preparation of Pen-GESO from reaction of P-nitro benzyl bromide with penicillin acid followed by oxidation with hydrogen peroxide instead of peroxyacetic acid.
FN 194016 discloses an improved process for preparation of sulfoxide compounds, by oxidation of the corresponding thioether or sulfide compounds selectively with a peroxyacid in the presence of DMSO, in an inert solvent or water, at a temperature ranging from 0°C to 60°C.
JP 53041160 discloses the preparation of Pen-GESO, useful as intermediates for cephalosporins, by oxidation of penicillin ester sulfide in acetic acid/DMSO-acetic acid with30%H2O2 at-10oC.
JP 51056484 discloses the preparation of Pen-GESO by oxidation of penicillins sulfide with an aqueous solution of H2O2 in the presence of maleic anhydride (III).
However, each of the methods known for the Pen-GESO from the literature are cumbersome, prolonged and drawbacks in that the desired compound can not be obtained with supplementary purity. There are also more shortcomings such as use of expensive reagents in vast quantity where the same are not eco-friendly. On the other hand the applied per acid/acids are hazardous, corrosive & require more quantity of RO water for removal of the acid from the product which raises the effluent at plant scale thus not environment friendly.
To improve quality and the yield simultaneously with receding in cost of the process from commercial aspects as well as environment friendly, inventors of the present invention have made catalytic approach for preparation of Pen-GESO by oxidation of Pen-GES.

In this context, use of catalyst along with oxidizing agent offers an immense advantage to obtain a product with excellent whiteness with less fraction of impurity.
Object and Summary of the Invention
The main object of the invention is to provide environment friendly, cost effective and scalable process for preparation of Pen-GESO for commercial aspects.
It is another object of the present invention to provide catalytic oxidation of Pen-GES which is more convenient and efficient than the known processes.
The above and other objects of the present invention are attained according to following preferred embodiment of the present invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.
In preferred embodiment, the present invention is directed to preparing Pen-GESO by catalytic oxidation under controlled conditions.
In the present invention, the term Pen-GK is referred to as monopotassium salt of Penicilin G; the term Pen-GES is referred to asp-nitro benzyl ester of penicillin G; and the term Pen-GESO is referred to as p-nitro benzyl ester of penicillin G sulfoxide.
Description of the invention
Thus the process of preparing Pen-GESO, which is characterized by the fact that the Pen-GK is reacted with p-nitro benzyl bromide in a solvent to attain Pen-GES and then its conversion to Pen-GESO by using oxidizing agent in the presence of catalyst as illustrated by the following scheme.


Suitable solvent may include but not limited to dimethylformamide, dimethylacetamide, dimethyl sulphoxide and the like. Suitable oxidizing agent to carry out above reaction may include but not limited to hydrogen peroxide, cummene hydrogen peroxide, sodium hypochlorite, vanadium pentoxide, asymmetric sulpher oxide or mixtures thereof. Suitable catalyst, to accelerate the oxidation, may include but not limited to titanium isopropoxide, m-chlorosuccinimide, sodium tungsten dihydrate and the like.
The reaction temperature during formation of Pen-GES is in the range of 25-40°C whereas during formation of Pen-GESO is less than 5°C.
The advantages of the present invention exist in the use of inexpensive reagents as well as the simple method of isolation of the final product with high purity and better quality.
Best mode for carrying out the invention
The production of the Pen-GESO by catalytic oxidation of this invention is now illustrated with reference to the following Example, to which this invention is not limited.

Example
To the solution of DMF (25 ml) and Pen GK (25 gm), P-nitrobenzyl bromide (15 gm) was added and stirred at room temperature for 2 hr. Thereafter reaction mass was filtered and cooled to 0-5°C followed by the addition of Tungsten complex (prepared by sodium tungstate dihydrate (0.1 gm) and hydrogen peroxide (8.0 ml)) with constant stirring for 30-60 min. The reaction mass was quenched with water (150 ml) at room temperature and stirred. The obtained solid was filtered and wash with water and methanol and dried in VTD at 40-45°C.

We Claim:
1. An improved process for preparing Pen-GESO, wherein process comprising the
steps of,
a) reacting Pen-GK with p-nitro benzyl bromide; and
b) Oxidizing the resultant compound of step (a) in presence of catalyst.

2. The process as claimed in claim 1, wherein solvent employed during step (a) are selected from the dimethylformamide, dimethylacetamide, dimethyl sulphoxide.
3. The process as claimed in claim 1, wherein oxidizing agent employed during step (b) are selected from hydrogen peroxide, cummene hydrogen peroxide, sodium hypochlorite, vanadium pentoxide, asymmetric sulphur oxide or mixtures thereof.
4. The process as claimed in claim 1, wherein catalyst employed for oxidation reaction are titanium isopropoxide, m-chlorosuccinimide, sodium tungsten dehydrate.
5. The process as claimed in claim 1, wherein temperature during step (a) in the range of 25-40°C whereas during catalytic oxidation is less than 5°C.
6. An improved process for preparing Pen-GESO wherein improvement comprising with oxidation of Pen-GES in presence of catalyst.
7. The process as claimed in claim 6, wherein oxidizing agent are selected from hydrogen peroxide, cummene hydrogen peroxide, sodium hypochlorite, vanadium pentoxide, asymmetric sulphur oxide or mixtures thereof.

8. The process as claimed in claim 6, wherein catalyst employed are titanium isopropoxide, m-chlorosuccinimide, sodium tungsten dehydrate.
9. A Pen-GESO as prepared by any of the preceding claims is useful intermediate for preparation of 7-ACCA.