Field of the invention
The invention relates to a new improved process to prepare (6R,7R)-3-[(acetyloxy) methyl]-8-oxo-7-[(thiophen-2-ylacetyl)amino]-5-thia-l-a2abycyclo[42.0]oct-2-ene-2-carboxylic acid of the following Formula I
Formula I
Background of the Invention
Cephalothin is a generic name assigned to 7-(thiophene-2-acetamido) cephalosporanic acid. Cephalothin is a semi synthetic cephalosporin having a broad spectrum of antibiotic activity that is administered parenterally and used especially to treat systemic infections caused by susceptible microorganisms. Cephalothin exhibits in vitro activity against both gram-positive and gram-negative bacteria. Cephalothin is also highly active against penicillinase producing staphylococci.


This patent also discloses that acylation can also be carried out with the corresponding heteromonocyclic substituted alkanoic acid, employed in conjunction with an equimolar proportions of a carbodiimide such as N,N' -diisopropylcarbodiimide, N,N' -dicyclohexylcarbodiimide, N,N'-bis(p-dimethylaminophenyl)carbodiimide etc. Most of these acylating agents are hazardous at industrial scale. The yields of this process are in the range of 65-70%.
US 3,792,047 discloses another process for the preparation of Cephalothin by condensation of 7-aminocephalosporanic acid with thiophene-2-acetyl chloride in presence of aniline and ethyl acetate. The use of aniline which is highly carcinogenic poses a health hazard. The yields obtained by this process are in the range of 70-75 %.
OBJECTIVES OF INVENTION
The objective of the present invention is to provide an improved process for the preparation of Cephalothin in high purity and high yield.
Another objective of the present invention is to provide an improved process for the preparation of Cephalothin sodium.
SUMMARY OF INVENTION
Accordingly, the present invention provides a process for the preparation of Cephalothin of Formula I
Formula I comprising acylating a compound of Formula II

Formula II
with a compound of Formula III
Formula III
in the presence of organic amine base in halogenated solvent to obtain a compound of Formula I
DETAILED DESCRIPTION OF INVENTION
The present invention relates to a process for preparing Cephalothin of Formula I.
The process comprises of treating 7-aminocephalosporanic acid with a thienylacetylating agent such as thienylacetyl halides, especially the chlorides or bromide and mixed anhydrides derived for example from the thienyl acetic acid and an alkyl haloformate, more preferably thiophene-2-acetyl chloride.
The inventors have found that acylation of compound of Formula II with compound of Formula III is achieved in the presence of an a organic amine base in halogenated solvent and the reaction proceeded very smoothly in lesser reaction time with improved yield and quality. The preferred organic amine bases used in this acylation are teritiary amine bases such as triethylamine, tributylamine, tripropylamine etc and more preferably triethylamine.

The halogenated solvents employed during acylation include chloroform, dichlormethane, 1,2-dichloroethane, trichloroethylene more preferably dichloromethane. The resulting final product of compound of Formula I was obtained with exceptionally high quality and high yield over the reported prior art acylations.
The advantage realized with the use of halogenated solvents like dichloromethane is the easy recoverability in comparison to ethyl acetate wherein the said ethyl acetate recovery is contaminated with large amounts of water.
The acylation is conveniently carried out in the presence of triethylamine and dichloromethane. After the completion of the reaction, the pH of the reaction mixture was adjusted with HC1 to 2.0 at 20-22 °C. The precipitated cephalothin was recovered by filtration and washed with cold water. The wet cake was dried at 45-50 °C under reduced pressure to obtain pure cephalothin acid.
The compounds of Formula II and Formula III are prepared by known methods in the literature.
The purity of the Cephalothin obtained by the process of the present invention is > 98.0 % by HPLC.
Cephalothin prepared by the process of the present invention can also be used in preparation of other cephalosporins derivatives such as Cefoxitin sodium.

EXPERIMENTAL
Example 1
Preparation of (6R,7R)-3-[(acetyloxy)methyl]-8-oxo-7-(thiophene-2-ylacetyl)amino-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
7-Aminocephalosporanic acid (125 g, 0.46 mol) was suspended in methylene chloride (1250 ml) and the suspension was cooled to -30° C. To this, triethylamine (92.83 g, 0.92 mol) was added slowly and stirring continued at -30° C to -25 ° C for 30 min to obtain a clear solution. Thereafter, thiophene-2-acetyl chloride solution (79.71 g, 0.5 mol in 125 ml methylene chloride) was added to this clear solution slowly at -30° C to -25 ° C and stirring continued at this temperature for 1 hr. After, completion of reaction, water (1875 ml) was added at 20-25 °C and organic layer was separated. The aqueous layer was treated with carbon and thereafter pH was adjusted to 2.0 by adding hydrochloric acid at 20-22 °C. The precipitated cephalothin acid was recovered by filtration and washed with cold water (750 ml). The wet cake was dried at 45-50 °C under reduced pressure to obtain 160.20 g of cephalothin aicd (88 % yield). Cephalothin acid thus obtained had a chromatographic purity of 98.66 % by HPLC.

WE CLAIM
1) A process for the preparation of Cephalothin of Formula I
Formula I
comprising acylating a compound of Formula II
Formula II
with a compound of Formula III
Formula III
in the presence of an organic amine base in halogenated solvent to obtain a compound of Formula I.
2) The process according to claim 1, wherein the organic amine base is selected from
triethylamine, tributylamine, tripropylamine, more preferably triethylamine.
3) The process according to claim 1, wherein the halogenated solvent employed is
selected from Chloroform, dichloromethane, 1,2-dichloroethane, trichloroethylene,
more preferably dichloromethane.

4) The process according to claim 1, wherein the compound of Formula I is further
converted to Cephalothin sodium.
5) The process according to claim 1, wherein the compound of Formula I is further
converted to Cefoxitin sodium.