CS252884B1 - Process for preparing 7 - [(1H-tetrazol-1-yl-acetamido) -cephalosporanic acid triethylammonium salt - Google Patents

Abstract

A simple and economical process for the production of the triethylammonium salt of 7-[(1H-tetrazol-1-yl)-acetamido]-cephalosporanic acid, a basic intermediate in the production of the broad-spectrum antibiotic cefazolin, by acylating the triethylammonium salt of 7-aminocephalosporanic acid in acetone containing 0.7 to 25% by weight of water relative to acetone, with an acetone solution of the equivalent of the mixed anhydride of 1-(1H-tetrazol-1-yl)-5,5,5-trimethyl-3-oxapentane-2,4-dione in the presence of 7 to 90% by weight of triethylammonium chloride based on the weight of water present at temperatures of -10 to 25°C for 1 to 5 hours.

Description

The invention relates to the economical production of triethylammonium salt of 7 - [(1H-tetrazol-1-yl) -acetamido] -cephalosporanoic acid, which is a preferred basic intermediate in the production of the broad-spectrum antibiotic cefazoline.

The prior art processes most commonly employ acylations of 7-aminocephalosporanoic acid or its salts with 1H-tetrazol-1-yl-acetic acid derivatives such as chlorides, mixed anhydrides, often under the action of organic or inorganic bases.

Acylation of 7-aminocephalosporanoic acid with 1H-tetrazol-1-yl-acetic acid chloride is carried out in acetone-water at 0 to 30 ° C by J. Antlbiotic, 3 (23, 1970, 131). In methanol at -50 to -20 ^and C in the presence of triethylamine stage DE - OS 2,264,861 (1971) and MS. AO č. No. 185 615 (1972), optionally DE-OS 2 730 579 (1976) in water in the presence of an organic solvent of alkoxy is dichloromethane or toluene in the presence of inorganic or organic bases at pH 7-8 and temperature 0-30 ° C.

Acylation of 7-aminocephalosporanoic acid or its salts with mixed-1H-tetrazol-1-yl-acetic anhydride and pivalic acid is carried out in tetrahydrofuran at -20 ° C in the presence of triethylamine, sodium bicarbonate or phosphate buffer according to US 3,516,997 (1968), DE-OS 1 953 861 (1969), S. African Pat. 6,907,800 (1971). The mixed anhydride obtained by the reaction of 1H-tetrazol-1-yl-acetic acid with benzoyl chloride uses Anal. Profiles Drug. Suhst. 4 (1-20), 1975.

Both methods of acylation of 7-aminocephalosporanoic acid with both chloride and mixed 1-H-tetrazol-1-yl-acetic anhydride in various solvents such as tetrahydrofuran, acetone, isobutyl chloroformate or mixtures thereof are used in the DE-OS 2617 processes. 442 (1976).

The prior art processes either provide low yields, or require extremely temperature and feedstock conditions, or employ complicated technological operations such as e.g. alternation of solvents and the associated isolation of the crystalline thermolabile product by evaporation of the solvents under high vacuum to dryness, all of which hinder the economy and operational reliability of production.

The process according to the invention has succeeded in reducing the shortcomings of the prior art processes to a minimum, at the same time achieving high yields and quality, moderate irrational conditions and the advantages of simplicity of the one-step process.

SUMMARY OF THE INVENTION The process according to the invention is characterized in that 1 to 1.3 equivalents of mixed 1- (1H-tetrazol-1-yl) -5,5,5-thirimethyl-3-oxapentane-2,4-dione anhydride in dry acetone is treated with the equivalent of triethylammonium salt of 7-aminocephalosporanoic acid in the form of an aqueous acetone solution at -10 to 25 ° C, characterized in that the acetone solution of triethylammonium salt of 7-aminocephalosporanoic acid contains 0.7 to 25% by weight. of water to the weight of acetone is reacted with 1- (1H-tetrazol-1-yl) -5,5,5-trimethyl-3-oxapentane-2,4-dione in the presence of triethylammonium chloride in an amount of 7 to 90% ihm. to the weight of water present for 1 to 2 hours at -10 to 0 ^° C and 0.5 to 3 hours at a temperature of 10 to 25 ° C.

The resulting triethylammonium salt of 7 - [(1H-tetrazol-1-yl) -acetamido] -cephalosporanoic acid crystallizes from the reaction mixture and is isolated in the usual manner;

The advantages of the process according to the invention are up to 92% yield, ease of reaction, simple recovery of the solvent used and high purity of the product.

The process according to the invention is illustrated by the following examples.

Example 1

6.7 kg of 1-H-tetrazol-1-yl-acetic acid and 7.3 l of anhydrous triethylamine are dissolved in 120 l of dry acetone with stirring. After cooling the mixture to -10 ° C, a solution of 6.4 L of pivaloyl chloride in 23 L of dry acetone was added. The resulting triethylamine hydrochloride crystallizes from the mixture by reaction.

A solution of 11.25 kg of 7-aminocephalosporanoic acid in 140 L of acetone, 15 L of water and 6.7 L of triethylamine, cooled to -10 ° C at such a rate that the reaction temperature did not exceed -6 ° C, was then added to the reaction mixture. After this operation, the mixture became clear and further cooled and stirred at -10 ° C for 1 hour. The mixture was slowly warmed to 18-22 ^° C with stirring for an additional hour and stirred at this temperature for an additional hour. Shortly after clarification from the reaction mixture, triethylammonium salt of 7 - [(1H-tetrazol-1-yl) acetamido] -cephalosporanoic acid crystallizes as the product.

Centrifugation of the reaction mixture, washing of the crystal with 40 to 60 L of acetone containing 3% water and drying of the crystal yielded 16.3 to 17.6 kg of product, which is 85 to 92% of theory, with a content of 94 to 98%. The pollutant is only triethylammonium chloride except traces of unreacted 7-aminocephalosporanoic acid. Triethylammonium hiloride generally does not prevent further processing of the product.

Example 2

6.7 g of 1H-tetrazol-1-yl-acetic acid and 7.3 ml of anhydrous triethylamine are dissolved in 120 ml of dry acetone. After the mixture has cooled to -10 ° C, a solution is added

6.4 ml of pivaloyl chloride in 24 ml of acetone. After 60 min. with stirring, the precipitate formed is filtered off. To the filtrate containing, in addition to the mixed anhydride, about 0.9 g of triethylammonium chloride at -10 ° C is added a solution

11.25 g of 7-aminocephalosporanoic acid in 140 ml of acetone, 1 ml of water and 6.7 ml of triethylamine so that the temperature does not exceed -6 ^° C. The reaction mixture is stirred at -10 ° C for 1 hour, gradually warming for 1 hour. The mixture was stirred at 15 to 18 ° C for 1 hour. After filtration and drying of the product, 13.8 to 14.5 g of 7 - [(1H-tetrazol-1-yl) -acetamido] -cephalosporanoic acid triethylammonium salt are obtained, which is 72 to 75% of theory with a content of 98 to 100% .

Example 3

The procedure is as in example no. 2, but a solution of 11.25 g of 7-aminocephalosporanoic acid, 140 ml of acetone, 6.7 ml of triethylamine contains 12.5 ml of water. The procedure of Example no. 2, the final temperature of the mixture is 10 to 15 ^C C. The yield is 70-75% of theory.

Claims (2)

SUBJECT Process for preparing triethylammonium salt of 7 - [(1H-tetrazol-1-yl) acetamido] -cephalosporanoic acid by subjecting an acetone solution of 1 to 1.3 equivalents of 1- (1H-tetrazol-1-yl) -5,5,5-mixed anhydride trimethyl-3-oxapheman-2,4-diome per equivalent of triethylammonium salt of 7-aminocephalosporanoic acid in aqueous acetone solution at -10 ° C to 25 ° C, characterized in that it is a tonic solution of triethylammonium salt of 7-aminocephalosporanoic acid containing 0.7 to 25% by weight of water per weight of acetone reacts with 1- (1H-tetrazol-1-yl) -5,5,5-trimethyl-3-oxapentam-2,4-dione in the presence of 7 to 90% by weight triethylammonium chloride to the weight of water present for 1 to 2 hours at -10 to 0 ° C and 0.5 to 3 hours at + 10 to 25 ° C.