Title of Invention

CEPHALOSPORIN COMPOUND AND A PROCESS FOR ITS PREPARATION

Abstract

A process for the preparation of cephalosporin compound of the following formula I by the reaction of 7- aminocephalosporanic acid with 2-thiofuroic acid of the following formula III in the presence of baron trifluoride in an organic solvent,such as herein described,and precipitating the reaction product after completion of the reaction to obtain the said cephalosporin compound. by the reaction of 7-aminocephalosporanic acid with 2 thiofuroic acid of the following formula in the presence of boron trifluoride in an organic solvent selected from ethyl acetate, methyl acetate, n-butyl acetate and isopropyl acetate; the reaction being continued until unrelated 7-aminocephalosporanic acid is les5than 1% by HPLC analysis;

Full Text

The present invention relates to preparation of 7-amino-3-(2-furanylcarbonylthiomethyl) -3-cephem-4-carboxylic acid (Formula I; herein referred as Furaca). A key intermediate useful in the manufacture of heftier ( Ref U.S. Patent 4, 464,367 by Labeeuw et al) a cephalosporin antibiotic useful for treating a bovine respiratory disease. The only known method for the preparation of 7-amino-3-(2-ftiranylcarbonylthiomethyl) -3-cephem-4-carboxylic acid (herein referred as Furaca; of formula I) is described by Sacks et al. in U.S. Patent 4937330. In this process, aqueous solution of sodium 2-thiofiiroate of Formula II is reacted with 7- aminocephalosporonic acid at 65 degree C at pH 6.4 + 0.2 And the resuilting slurry is adjusted to pH 5.0, filtered, washed successively with acetone and heptane to obtain a light coloured product (yield not given); This procedure is associated with certain disadvantages, in that it results in impure Furaca in low yield. Further, the product obtained is coloured and contains unreacted 7- 7- aminocephalosporonic acids as a rule not suited or only ill-suited for subsequent 7- acylation to produce ceftiofor. The displacement of the acetoxy group of a cephalosporin by a slurs nucleophile or its salt in aqueous medium at elevated temperature (65 degree C) and near neutral to basic pH is generally destructive to the cephalosporin nucleus and is accompanied by formation of highly coloured impurities. The product d in this manner often requires extensive purification. Displacement of acetoxy group of a cephalosporanic acid by a sulftir nucleophile in an organic solvent under essentially anhydrous conditions is well documented in literature ( Ref US Patent 4,144391). Further, it is known from German Offenlegungsschriit 2, 804,896 that 7-amino- 3- (substituted thiomethyl) - 3- cephem-4-carboxylic acids can be prepaared by reacting 7-amino cephalosporanic acid with thiol compound in the presence of boron trifluoride. If 2-thiofIuoric acid (Formula III) is employed as a thiol compound In the process, with the usual acetone nitrile solvent, the reaction is complicated by formation of desacetyl-7-aminocephalosporanic acid Based on the above mentiotted background the present inventors have conducted extensive experimentation with an intention of developing a process to produce Furaca in high yield with ease in industry, and consequently have unexpectedly found that such a nucleophilic displacement proceeds clean in presence ofborontrifluoride in ethyl acetate solvent giving cefWofur intermediate of high purity (normally of 98.99 %).with a colour rating of 0.04 - 0.08 (1 % solution 420 nm). The invention further advantageously uses solution of 2-thiofuroic acid in ethyl acetate having water to the extent of 4% w/w. Use of the said solution avoids isolation of labile 2-thiofuroic acid in an " anhydrous form which means fewer industrial operations resulting in safety and cost effectiveness. In accordance with the present invention, there is provided anew process for producing Furaca by reacting 7-aminocephalosporanic acid with 2-thiofuroic acid in the presence of boron trifluoride. As a rule, boron trifluoride is used in molar excess e.g. 3 to 7 moles per mole of 7-aminocephalosporanic acid. The reaction is effected in ethyl acetate at 10 degree C to 50 degree C and preferably at 30 degree C to 35 degree C. According to the present invention, boron trifluoride content in ethyl acetate is about 32 % w/v. However varying concentrations can be used depending upon the solvent medium without affecting the final outcome of the process. Typical solvents that can be used are methyl acetate, ethyl acetate, n-butyl acetate, isopropyl acetate etc. The reaction is continued until 7-aminocephalosporanic acid left unreacted is less than 1% by HPLC analysis. This typically takes 1 to 5 hours. After completion of the reaction, the reaction mixture is diluted with cold water and subsequently tlie pH value is adjusted with a suitable base such as triethylamine, tributylamine, but preferably with aqueous ammonia whereby the reaction product precipitates. Accordingly the present invention has accomplished the purpose of obtaining Furaca of high purity (98-99%) in good yield (85-88%) by a distinctive use of boron trifluoride in ethyl acetate. Furaca so obtained can preferably be used for the preparation of antibacterial ceftiofur. The process, according to this invention, is for the preparation of cephalosporin compound of the following formula: by the reaction of 7-aminocephalosporanic acid with 2-thiofuroic acid of the following formula in the presence of boron trifluoride in an organic solvent selected from ethyl acetate, methyl acetate, n-butyl acetate and isopropyl acetate; the reaction being continued until unreacted 7-aminocephalosporanic acid is les than 1% by HPLC analysis; diluting the reaction mixture with with cold water and adjusting the pH value by a base; precipitating the reaction product after completion of the reaction to obtain the said cephalosporin compound. The following examples illustrate the invention without limiting it EXAMPLE I 7- AMINO-3-(2-FURANYLCARBONYLTHIOMETHYL)-3-CEPHEM-4-CARBONYLIC ACID (FURACA) Step A: 2- THIOFUROIC ACID 35.65 g of sodium sulfide (55%) is dissolved in 545 ml of water at 25-27 degree. The pH of the solution is adjusted to 9.8 - 10 with 8.5 % othophosphoric acid. 29.1 g of 2- Furoylchloride is added slowly in 30 min. while maintaining the pH of the solution at 9-9.5 with 25 % sodium hydroxide solution.The reaction mass is stirred for 1 hour at 28-30 degree C. Thereafter pH of the reaction mass is lowered to 1.0 with 6 N hydrochloric acid. Thiofuroic acid is extracted in 250 ml of ethyl acetate. Step B: FURACA PREPARATION A solution of 73.3.g of boron trifluoride in 225 mL of ethyl acetate (32% w/v solution) is prepared at 0-5 degree C. Thiofuroic acid solution obtained in step A is added followed by 50g of 7-aminocephalosporanic acids at 10-15 degree C. Thereafter the reaction is continued for 3-4 hours at 30-35 degree C till qualitative HPLC analysis shows 7-aminocephalosporanic acid not more than 1%. The mixture is cooled to 15 degree and 285 mL of cold water is added followed by freshly prepared solution of 5g of sodium metabisulphite in 20 mL water and 0.5 g of EDTA disodium in 20 mL water. Immediately the pH of the reaction mass is brought to 2.0 with aqueous 15% ammonia and then the pH of the reaction mass is slowly adjusted to 5.0 in 30 min. at 20-25 degree whereby the product precipitates. After stirring for 30 minutes, at 20-25 degree the product is filtered off under suction and washed with 200 mL ethyl acetate followed by 200 mL water. The crystals are dissolved in 625 mL of water at pH 9.0 to 9.5 by adding 29 mL of triethylamine slowly in 30 min. at 4-5 degree. The aqueous solution is treated with 5 g activated carbon. The carbon is removed and the filtrate is brought to pH 5.8 very slowly in about 2 hours at 28-30 degree with addition of 15 % aqueous orthophosphoric acid. The product is filtered off and washed with 125 mL water followed by 100 mL acetone and dried under reduced pressure to obtain 53.75 g. Furaca (yield : 86 %). Purity: 99.4% 7-ACA:0.07?/o in accordance with the HPLC analysis, colour 0.05 (1% solution, 420 nm.) Example 2: The procedure reported in Example 1 has been repeated with 34 % w/v solution of boron trifluoride in n-butyl acetate. Yield: 52.5g (84%) purity 99.3 % 7-ACA: 0.18 % by HPLC. Permeation of Furaca has been carried out as described in Example 1 using 22% w/v solution of boron trifiuoride in isopropyl acetate. Yield: 53.3 g (85.3 %) HPLC purity: 99.5 % 7-ACA: 0.1%. We Claim: 1. A process for the preparation ofcephalosporin compound of the following formula: by the reaction of 7-aminocephalosporanic acid with 2 thiofuroic acid of the following formula in the presence of boron trifluoride in an organic solvent selected from ethyl acetate, methyl acetate, n-butyl acetate and isopropyl acetate; the reaction being continued until unrelated 7-aminocephalosporanic acid is les5than 1% by HPLC analysis; diluting the reaction mixture with cold water and adjusting the pH value by a base; precipitating the reaction product after completion of the reaction to obtain the said cephalosporin compound. 2.A process as claimed in Claim 1 wherein the pH value is adjusted by a base selected from triethylamine, tributylamine, aqueous ammonia. 3. A process as claimed in any one of the preceding Claims wherein the reaction is carried out with ethyl acetate as solvent, at a temperature of 10- 50 degree C. 4. A process as claimed in any one of the preceding Claims wherein the boron trifluoride is present in molar excess with respect to 7-aminocephalosporanic acid. 5. A process as claimed in airy one of the preceding Claims wherein the boron trifluoride is present in 3 to 7 moles per mole of 7- aminocephalosporanic acid. 6. A process as claimed in any one of the preceding Claims wherein the 2-thioiuroic acid solution in ethyl acetate has water up to 4% w/w. 7. A process torn the preparation of cephalosporanic compound of the following formula I

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