The present invention relates to an improved process for the preparation of 7-phenylacetamido desacetoxycephalosporanic acid having the Formula V (R1 CH2C6H5) shown in the accompanied drawings.
The said compound having the Formula V is a key intermediate in the preparation of 7-amino desacetoxycephalosporin (7-ADCA) having Formula VI as shown in the accompanied drawings.
A large number of useful cephalosporin antibiotics involve 7-amino desacetoxycephalosporanic acid (7-ADCA) as a key intermediate in their commercial preparation. Due to its commercial importance and versatility as intermediate, 7-ADCA has attracted lot of attention. Commercially, 7-ADCA is produced by the ring expansion of penicillin starting materials. Penicillin G (Formula I wherein R, is CH2QH5) or Penicillin V (Formula I wherein R1is CH2OC6H5) is oxidized with peracids to form the corresponding sulfoxide (Formula II) which is silylated with N,N-bis trimethyl silyl urea to give the silyl ester of sulfoxide (Formula III, wherein R2 is alkyl silyl). The silyl ester is then in situ heated with acid catalyst to carry out ring expansion reaction i.e. conversion of penam to cephem ring (Formula IV) followed by hydrolysis to give 7-substituted desacetoxycephalosporanic acid (Formula V) which upon deacetylation by chemical or enzymatic method gives 7-ADCA (Formula VI).
The quality of 7-substituted desacetoxy cephalosporanic acid (when R1 is CH2C6H5)
obtained via this process is very poor as it involves heating of penicillin sulfoxide. The crude product is therefore, repurified prior to its conversion into 7-ADCA. Consequently the overall yield of 7-ADCA is adversely affected.
In the ring enlargement reaction i.e. the conversion of penam to cephem ring, slight changes in the acidity or basicity of the reaction caused due to release of inorganic acids from silylating agents, significantly affect the overall yield of the product. Excess amounts of alkyl silylating agents are required in order to prevent desilylation in alkyl silylated penicillin ester by water which is produced as a by-product in the ring expansion reaction. Consequently, the excessive use of the silylating agent under heat leads to decarboxylation of
cephalosporin giving decomposition products, with the result that there is a severe loss in the yield of the desired product.
It is therefore, necessary to minimize the formation of decarboxy-lated products to improve the yield. In view of this, a large number of acid catalysts have been reported. Most effective catalysts in the ring expansion reaction are inorganic acid salts of organic bases like pyridine and pyridine derivatives (European patent No. 0 169 144),(1986). The main drawback linked to the use of these catalysts is that silylating reagent reacts with inorganic salt, releasing organic basein the reaction medium, which

causes conversion of ∆3isomer into ∆2-isomerof cephalosporin and
the latter has no biological activity. To circumvent this,European patent No. 0 169 144 describes the use of sulphamide/ silylsulph-amide/silylsulphamoyl in the ring expansion reaction. These substances, however, do not produce significant effect on the overall yield, quality of product and are also not cost effective on commercial scale.
It is an object of the present invention to provide an improved process for the preparation of 7-phenylacetamido desacetoxycepha-losporanic acid having high yield and high purity as compared to the conventional process.
It is another object of the present inventionto provide an improved for the preparation of 7-phenylacetamido desacetoxycep-halosporanic acid which can be used without repurification, for the production of 7-ADCA in high yield and high quality.
Accordingly, the present provides an improved process for the preparation of 7-phenylacetamido desacetoxycephalosporanic acid of the Formula V (wherein R1s CH2C6H5) by heating the silylated esterof penicillin sulfoxide of the Formula III (wherein R1is as stated above and R2is Hydrogen or alkylsilyl) with pyridine hydro-bromide in the presence of sulphamic acid and an inert organic solvent to give a compound of the Formula IV (wherein R1and R2 are as stated above) which compound is hydrolysed with water and the pH of the mixture is adjusted to give the desired compound of the Formula V.
According to a preferred embodiment of the invention, the compound of the Formula III is heated to reflux at 100° - 120°C for 1 - 3 hours in the presence of sulphamic acid and the inert organic solvent.
Preferably, the quanitty of pyridine hydrobromide and sulphamic acid used are between 0.5 and 1 molar equivalent; more preferably 0.9 molar equivalent.
According to another preferred embodiment of the invention, the sulphamic acid is dried prior to use in the reaction. The preferred method of dehydration involves refluxing the sulphamic acid with toluene and azeotroping till moisture content less than 0.1 is achieved. The sulphamic acid is then filtered and oven dried at 40° to 45°C in vacuo.
Any inorganic acid salt of organic base may be used in the said reaction. Preferably as^ inorganic salt of organic base, pyridine hydrobromide is used.
Any inert organic solvent may be used in the said reaction. Preferably toluene is used as inert organic solvent.
The process according to the present invention causes expensaion of the penam ring in the penicillin to A3 cephem ring in the product which is obtained in high yield and high purity. The use of sulphamic acid in the ring expansion reaction considerably reduces undesirable decarboxylation and A2 cephem isomerization reactions. This significantly improves the yield and quality of 7-phenyrjacetamido desacetoxycephalosporanic acid prepared.
The preparation of the compound of Formula V, according to the present invention, is illustrated in the following examples.
EXAMPLE-I
PREPARATION OF 7-PHENYLACETAMIDO DESACETOXYCEPHALOSPO-RANIC ACID (FORMULA V) USING SULPHAMIC ACID
The silylatcd ester of penicillin sulfoxide of the Formula 111 is prepared by adding N,N-bis (trimethyl silyl) urea (45.5 g, 0.22 moles) to dry toluene (590 ml), followed by the addition of compound of the Formula II (35 g, 0.1 moles). The reaction mixture obtained was stirred at 50-55°C for about 1 hour. Pyridine hydrobromide (14.39g, 0.089 moles) followed by sulphamic acid (8.7g, 0.09 moles), was added and the contents were further refluxed at 109-110°C for about 2 hours. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to 100°C, poured in water, stirred at 45° for 15 minutes, and acidified to pH 2 by dil. H2SO4. It was then filtered, washed with water and dried in oven to give the titled compound in crystalline form having >97% purity.
Yield : 28.95 g
Colour absorbance : 0.10
EXAMPLE-II
PREPARATION OF 7-PHENYLACETAMIDO DESACETOXYCEPHALOSPO-RANIC ACID (FORMULA V)
This example was followed in the same way as for example-I except that sulphamic acid (0.24 mol. eq.) was used and the reaction was work up in the following manner :
After pouring the reaction mixture in water, the mixture was cooled to 35°C, a solution of potassium bicarbonate (25%) was added dropwise to maintain pH ~ 6.7. The organic layer was separated from aqueous one and later given carbon treatment. The aqueous layer was then reacidified with sulphuric acid (25%) to to precipitate out the product. The precipitates were stirred for 20 min. at pH 2, filtered, washed by chilled water, dried to afford the tilled compound (Formula V).
QUANTITY OF SULPHAMIC ACID VERSUS YIELD AND QUALITY OF 7-PHENYLACETAMIDO DESACETOXYCEPHALOSPORANIC ACID
(Table Removed)

We Claim
1. An improved process for the preparation of 7-phenylacetamido desacetoxycephalosporanic acid of the Formula V (wherein R1 is CH2C6H5-) by heating the silylated ester of penicillin sulfoxide of the Formula III (wherein R1 is as stated above and R2is Hydrogen or alkylsilyl) with pyridine hydrobromide in the presence of sulphamic acid and an inert organic solvent to give a compound of the Formula IV (wherein R1 and R2are as stated above) which compound is hydrolysed with water and the pH of the mixture is adjusted to give the desired compound of the Formula V.
2. The process as claimed in claim 1 wherein the compound of

the Formula III is heated to reflux at 100o - 120o for 1-3
hours in the presence of sulphamic acid and the inert
organic solvent.
3. The process as claimed in claims 1 and 2 wherein the quantity of pyridine hydrobromide and sulphamic acid used are between 0.5 and 1 molar equivalent.
4. The process as claimed in claim 3 wherein the quantity of pyridine hydrobromide used is 0.9 molar equivalent.
5. The process as claimed in the proceeding claims wherein the sulphamic acid used is dried by refluxing with toluene and
azeotroping till moisture content is less than 0.1, the
sulphamic acid is then filtered and oven dried at 40-45O C
in vacuo.
6. The process as claimed in the preceeding claims wherein the inert organic solvent is toluene.
7. The improved process for the preparation of 7-phenylacet-amido desacetoxycephalosporanic acid of the Formula V substantially as herein described and illustrated in the Examples herein.