Title of Invention

PROCESS FOR THE PREPARATION OF CEFAZOLIN INTERMEDIATE

Abstract The present invention relates to an industrially advantageous and cost effective process to prepare highly pure Cefazolin intermediate [(6^,7/?)-7-amino-3-[[(5-methyl-l,3,4-thiadiazol-2-yl)sulphanyl]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (TDA)] of Formula III. by reacting 7-aminocephalosporanic acid with 2-mercapto-5-methyl-l,3,4-thiadiazole in the pesence of boron trifluoride, ethyl acetate and acetic acid. TDA is a useful and important intermediate in the preparation of antibacterial agents like Cefazolin and Cefazedone.
Full Text

FIELD OF THE INVENTION
This invention relates to a process for the preparation of Cefazolin intermediate of Formula III.

BACKGROUND OF THE INVENTION
Numerous cephalosporin antibiotic compounds having heterocyclic ring bound to a sulphur atom attached to the 3-methylene group of cephalosporin ring system are known. Cefazolin of Formula I and Cefazedone of Formula II constitute such an example and represent such a category.

(67?7^)-7-amino-34[(5-me%l-l,3^^
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (TDA) of Formula III is a key intermediate in the preparation of antibacterial agents like Cefazolin of Formula I and Cefazedone of Formula H.
Several publications such as US 3,516,997; US 3,821,207; US 3,641,021; describe the preparation of TDA and its 7-amino substituted derivatives, which comprises reacting 2-mercapto-5-methyl-l,3,4-thiadiazole (MMTD) with acetoxy group at 3-position of 7-aminocephalopsporanic acid (7-ACA) or its 7-amino substituted derivatives. The above inventions also report that it is not desirable to effect the said reaction in an organic solvent free from water rather it is preferable to effect the reaction in water or an aqueous organic solvent at a pH of 6.0-7.0. However, under the said preferable conditions the product obtained is in very low yields (around 30-50%), extremely impure and possessed tan colour.

US patents 4,385,178 and 4,317,907 disclose the reaction of MMTD with acetoxy group at 3-position of 7-ACA in acetonitrile using boron trifluoride etherate complex in 86% yield. However, the major drawback of this invention is the low purity of product (80% maximum) due to the presence of unreacted 7-ACA and degradation products in unacceptable amounts.
US patent 5,387,679 teaches the method for the preparation of TDA by reacting 7-ACA with MMTD in the presence of dialkyl carbonate trifluoro borone complex and an aliphatic acid. Although this method is an improvement in yield and purity over prior art, several disadvantages such as use of expensive dialkyl carbonates, low purity (87-94%) and poor solvent recovery impart certain undesirable limitations on a commercial scale production.
Above discussion represents the difficulties with the current art of making TDA and it is in the light of these difficulties that the present invention describes a new route for making TDA in good yields and high purity (> 99%).
Accordingly, a process for the preparation of (6i?,7i?)-7-amino-3-[[(5-methyl-l,3,4-thiadiazol-2-yl)sulphanyl]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (TDA) of Formula III is described

in a suitable solvent / mixture of solvents such as herein described and purging the solvent / solvent mixture with a boron trifluoride in the presence of lower aliphatic acid, till the desired concentration of the said solvent is achieved at a temperature ranging from 0°C to 50°C, to obtain the solid TDA,
recovering the said TDA by conventional methods.

DETAILED DESCRIPTION OF THE INVENTION
Based on our related art disclosure in the background the present inventors have conducted extensive experimentation with an intention to overcome the difficulties of producing (6i?,7/?)-7-amino-3-[[(5-methyl-l,3,4-thiadiazol-2-yl)sulphanyl] methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (TDA) in high yields and high purity. We have unexpectedly found that such nucleophilic displacement proceeds well in the presence of boron trifluoride in ethyl acetate solvent in the presence of aliphatic acid and the said intermediate is obtained in high purity i.e. greater than 99%.
The invention further advantageously uses recovered ethyl acetate having water to the extent of 4% w/w. Use of such a solvent avoids the use of dehydrating agents to maintain strictly anhydrous conditions, simplifies process and increases productivity.
According to the present invention, there is provided a new process for producing TDA by reacting 7-aminocephalosporanic acid of Formula IV

in the presence of boron trifluoride. The reaction is effected in ethyl acetate in the presence of acetic acid in the temperature range of 0°C to 50°C preferably between 10°C to 35°C.
According to present invention, the boron trifluoride is purged into ethyl acetate till its content is about 30%. However, varying concentrations can be used depending upon the choice of solvent medium without affecting the final outcome of the process.
Typically, the solvents that can be used are methyl acetate, ethyl acetate, w-butyl acetate or isopropyl acetate in the presence of aliphatic acids such as acetic acid or formic acid. It is preferred to carryout the reaction by adding compound of Formula V to the catalytic solution of boron trifluoride in ethyl acetate and acetic acid, followed by 7-ACA addition at a temperature between 5-10°C. The reaction mass is stirred at 30-35°C till 7-aminocephalosporanic acid is less than 1%, usually reaction takes about three to five hours for completion. After completion of the reaction, the reaction mixture is cooled, diluted with water and subsequently pH of the biphasic system is adjusted to 0.8-1.2 with a suitable base such as alkaline hydroxides, preferably aqueous sodium hydroxide

solution is used. The product, thus precipitated is isolated by filtration in high yield and high purity.
Major advantages realized in the present invention are high purity (>99%), use of low cost solvents and their recovery and avoiding any anhydrous conditions. Ethyl acetate can be simply recovered from mother liquor by separating the layers followed by distillation. Ethyl acetate (distilled) containing upto 4% of dissolved water can be recycled in the process without affecting the yield and quality of TDA. The compound, (6R,7R)-7-amino-3-[[(5-methyl-l,3?4-thiadiazol"2-yl)sulphanyl]methyl]-8-oxo-5-thia-l-azabicyclo-[4,2,0] oct-2-ene-2-carboxylie acid (TDA) so obtained can preferably be used in the preparation of Cefazolin and Cefazedone.
Further the following examples represent our best mode of carrying out the reaction that serves to illustrate our invention without limiting it.
Example 1
Preparation of (6R,7R)-7-amino-3-[[(S'methyl-ly394-thiadiazol-2-yl)sulphanyl]methyl]' 8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (TDA)
151.25 g (2.22 mol) of boron trifluoride was purged into a solution of 500 ml of ethyl acetate and 73.70 g of acetic acid under stirring at 5-10°C for 20 minutes. To the resulting solution added 54.45 g (0.41 mol) of 2-mercapto-5-methyl-l,3,4-thiadiazole and 110 g (0.40 mol) of 7-aminocephalosporanic acid under nitrogen at 5-10°C. The mixture was maintained at 30-35°C for three hours, cooled to 0°C and 880 ml of water was added. pH was adjusted to 0.8-1.2 using 15% w/v aqueous sodium hydroxide solution. The slurry was stirred for 30 minutes at 0-5°C. The solid thus obtained was filtered, washed subsequently with water and acetone and thereafter dried under vacuum at 45-50°C to obtain 119 g (85.6% yield) of title compound having a purity of 99.22% by HPLC. Assay: 99.1 % by w/w.
Example 2
Preparation of (6R9 7R)-7-amino-3-[[(5-methyl-lf394-thiadiazol-2-yl)sulphanyl]m 8-oxo-5-thia-l-azabicyclo[4.2.0Joct-2~ene-2-carboxylic acid (TDA)
75.62 g (1.11 mol) of boron trifluoride was purged into a mixture of 250 ml of ethyl acetate and 36.85 g of formic acid under stirring at 5-10°C for about 20 minutes. To the resulting solution 27.28 g (0.20 mol) of 2-mercapto-5-methyl-l,3,4-thiadiazole and 55 g (0,20 mol) of 7-aminocephalosporanic acid were added under nitrogen at 5-10°C. The mixture was maintained at 30-35°C for three hours, cooled to 0°C and 440 ml of water was added. pH was adjusted to 0.8-1.2 using 15% w/v aqueous sodium hydroxide solution. The resulting slurry was stirred for 30 minutes at 0-5°C. The solid thus obtained was filtered, washed with water and acetone and thereafter dried under vacuum at 45-50°C to give 53 g (76.2% yield) of title compound having a purity of 99.6% by HPLC.



WE CLAIM:
1. A process for the preparation of Cefazolin intermediate [(6J?,77?)-7-amino-3-[[(5-
methyl-l,3,44hiadiazol-2-yl)sulphanyl]metty
oct-2-ene-2-carboxylic acid (TDA)] of Formula III

in a suitable solvent / mixture of solvents such as herein described and purging the solvent / solvent mixture with a boron trifluoride in the presence of lower aliphatic acid, till the desired concentration of the said solvent is achieved at a temperature ranging from 0°C to 50°C, to obtain the solid TDA,
recovering the said TDA by conventional methods.
2. The process as claimed in claim 1, wherein the solvent or a solvent mixture is chosen such that use of dehydrating agent(s) is avoided to maintain anhydrous conditions during the preparation of TDA.
3. The process as claimed in claim 1? wherein the solvent is chosen from methyl acetate, ethyl acetate, w-butyl acetate, isopropyl acetate or a mixture thereof.
4. The process as claimed in claim 1, wherein the lower aliphatic acid is selected
from acetic acid or formic acid.
5. The process as claimed in claim 1, wherein the solvent contains water from
0 to 4% w/w.

6. The process as claimed in claim 1, wherein the mixture of Formula IV,
Formula V, solvent(s) and the lower aliphatic acid is stirred at a temperature
ranging from 30-35°C to obtain solid TDA.
7. The process as claimed in the claim 6, wherein the stirring is carried out for a
period of 3 to 5 hours.
8. The process as claimed in claim 1, wherein the said 2-mercapto-5-methyl-1,3,4-
thiadiazole is added to the catalytic solution of boron trifluoride in ethyl acetate
and acetic acid, followed by the addition of 7-aminocephalosporanic acid.



Documents:

606-che-2003-abstract.pdf

606-che-2003-claims duplicate.pdf

606-che-2003-claims original.pdf

606-che-2003-correspondnece-others.pdf

606-che-2003-correspondnece-po.pdf

606-che-2003-description(complete) duplicate.pdf

606-che-2003-description(complete) original.pdf

606-che-2003-form 1.pdf

606-che-2003-form 19.pdf

606-che-2003-form 26.pdf

606-che-2003-form 3.pdf

606.bmp


Patent Number 207696
Indian Patent Application Number 606/CHE/2003
PG Journal Number 44/2007
Publication Date 02-Nov-2007
Grant Date 20-Jun-2007
Date of Filing 29-Jul-2003
Name of Patentee AUROBINDO PHARMA LIMITED
Applicant Address PLOT NO.2, MAITRIVIHAR COMPLEX(Regd.office) AMEERPET ANDHRA PRADESH HYDERABAD-500 038.
Inventors:
# Inventor's Name Inventor's Address
1 UTTAM KUMAR RAY AUROBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX(Regd.office) AMEERPET ANDHRA PRADESH HYDERABAD-500 038.
2 BOJU SREENIVASULU AUROBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX(Regd.office) AMEERPET ANDHRA PRADESH HYDERABAD-500 038.
3 MEENAKSHISUNDERAM SIVAKUMARAN AUROBINDO PHARMA LIMITED, PLOT NO.2, MAITRIVIHAR COMPLEX(Regd.office) AMEERPET ANDHRA PRADESH HYDERABAD-500 038.
PCT International Classification Number A 61 K 31/545
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA