KR810000909B1 - Process for preparing cephalosporin derivatives - Google Patents

Abstract

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Description

Method for preparing cephalosporin derivative

The present invention relates to a novel method for preparing a cephalosporin derivative represented by the following general formula (I).

Z in formula (I) is hydrogen or a 3'- or 4'-N- (hydroxy loweralkyl) -carbamoyl group.

Especially important among cephalosporin derivatives of general formula (I) is cephaloridine, which has been the subject of much research as an antibiotic and has stronger antimicrobial activity against gram-positive and gram-negative bacteria than the precursor cephalosporin C. It was found to have.

Conventional methods for preparing cephalosporin derivatives containing cephaloridine include U.S. Patent 3,270,012, J, Am, Chem, Soc, 32 500-501 (1967), and U.S. Pat. An improved process for the preparation of amido-3-pyridinomethyl-3-cepem-4-carboxylic acid, the improvement being of 7-α-acylamido in aqueous media with thiocyanate or iodide Separation of the thiocyanic acid or hydroiodic acid addition salt of 7-acylamido-3-pyridino methyl-3-cepem-4-carboxylic acid by reacting sephalosporranic acid with pyridine and adding acid to the reaction mixture It relates to a method for producing cephalosporin C _A antibiotic.

In addition, the process for obtaining acid addition salts of Documents J, Am, Chem, Soc, 32, 500-501 (1967) is the same as US Pat. No. 3,270,012. In contrast to the precipitation by the addition of the method of J, Am, Chem, Soc, 32,500-501 (1967), the method of precipitation using an ion exchange resin in water is different.

However, cephaloridine prepared by the method of US Pat. No. 3,270,012 has some problems.

First: very fine crystals are obtained due to the rapid formation of cephaloridine crystals, making it difficult to separate the product by filtration.

Secondly, white crystals cannot be obtained due to coloration during precipitation.

Third, it is inconvenient to use as an injection because of low solubility in water.

Fourth: When methanol is used as a precipitant, separated crystals are unstable, such as moisture absorption in air.

In addition, the method of the documents J, Am, Chem, Soc, 32, 500-501 (1967) has a low yield, there is also a problem in industrialization.

The present inventors have conducted various studies to solve these problems, and include cephaloridine as an intermediate in the preparation of the cephalosporin derivative including cephalosidin as an intermediate in the preparation of cephalosporin derivatives containing cephaloridine. By generating and separating the N, N-dimethyl acetamide adduct of the cephalosporin derivative, it has been found that the problems of the conventional method can be solved and the target can be obtained with high yield.

Examples of using N, N-dimethylacetamide as a solvent in a method for preparing a cephalosporin derivative are already known from US Pat. No. 3,502,665 and US Pat. No. 3,954,745, while US Pat. No. 3,502,665 is a 7-aminocephalosporin or 3-position. In the acylation reaction of 7-amino cephalosporin derivatives and acyl halides in which the acetoxy group of is substituted with another nucleophilic group, US Pat. No. 39,547,45 describes Sol-5-yl) hydrochloride of thiomethyl-3-cepem-4-carboxylic acid, solvate of N, N-dimethylformamide and acylation of 1H-tetrazol-1-acetyl chloride, which is used in the present invention. In the nucleophilic substitution of pyridine instead of the 3-position acetoxy group of cephalotin, it is different from the method of generating and separating N, N-dimethyl acetamide adduct of cephaloridine.

The present invention will be described in more detail as follows.

First, cephalotin 3-acetoxy of cephalotin or its salt and pyridine or 3- or 4-N- (hydroxy lower alkyl) -carbamoylpyridine are reacted under relatively mild conditions in an aqueous solution. The methyl group is substituted with 3-pyridinomethyl or 3'- or 4'-N- (hydroxy loweralkyl) -carbamoylpyridino methyl group.

At this time, an excess of N, N-dimethyl acetamide is added together with pyridine or 3- or 4-N- (hydroxy lower alkyl) -carbamoyl-pyridine, so that N, N-dimethyl acetamide represented by the general formula (II) An adduct is formed. The resulting adduct is separated by crystallization of the residue obtained by concentrating the reaction solution under reduced pressure in a mixed solvent of acetone and water.

Wherein Z is hydrogen or a 3'- or 4'-N- (hydroxy loweralkyl) -carbamoyl group.

However, depending on the reaction conditions, side reactions such as decomposition of (II) material in the reaction mixture and attack of water molecules on carbonium ions in which acetoxy groups are dropped may occur. It can be avoided by giving or using an excess of pyridine or 3- or 4-N- (hydroxy loweralkyl) -carbamoylpyridine.

In the second step, the compound represented by the general formula (II) can be easily stripped of N, N-dimethylacetamide under mild conditions in a mixed solvent of acetonitrile and water to obtain a target represented by the general formula (I). .

As described above, in the preparation of the cephalosporin derivative (Formula I) containing cephalosidine as the final object in the present invention, after the N, N-dimethylacetamide amide adduct (Formula II) is produced, Therefore, better results can be obtained in terms of yield, purity, water solubility, colorability, hygroscopicity, and the like of the final object (Formula I) than the conventional method.

As is well known, the most important use of the cephalosporin derivative (formula I) as an antibiotic is cephaloridine. The cephaloridine of the present invention was found to be much better in terms of coloration, UV, purity, reusability, moisture content, etc., and the yield of the cephaloridine was found to be excellent in the overall process.

TABLE 1

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example 1

(1) Preparation of N, N-dimethylacetamide adduct of 7-α-chienylacetamido-3-pyridinomethyl-3-cepem-4-carboxylic acid

4.19% of 7-α-chienylacetamido cephalosporanic acid natrium salt was added to 3.2 ml of water and suspended. A solution of 3.2 ml of pyridine diluted in 30 ml of N, N-dimethyl acetamide was added dropwise at room temperature. .

0.2 ml of 85% phosphoric acid is added, warmed and stirred at 37 ° C. for 16 hours. Concentrate to about 15ml under reduced pressure and crystallize by adding 30ml of acetone and water (V / V 10:90) mixed solvent.

The precipitate was separated by filtration, washed with a mixed solvent of N, N-dimethyl acetamide and water (V / V 40:60), and dried for 12 hours at 40 ° C. or lower under reduced pressure. The target product was 4.13 g (yield: 82.2%). Get)

Elemental Analysis for Target C ₂₃ H ₂₆ O ₅ N ₄ S ₂

Calculated Value (%): C54.96, H5.21, N11.15, S12.76

Found (%): C54.98, H5.17, N11.27, S13.02

(2) Preparation of 7-α-chienylacetamido-3-pyridinomethyl-3-cepem-4-carboxylic acid (cephaloridine).

4.0 g of the product of (1) was added to a mixed solvent of 10 ml of acetonitrile and 5 ml of water. 0.5 g of sodium bicarbonate was added to the suspension to dissolve it.

After cooling to 0 ° C., the pH of the solution was adjusted to pH 6.0 with 6N hydrochloric acid, and stirred for 1 hour to precipitate a white precipitate.

The precipitate was separated, dried under reduced pressure, and dried at 35 ° C. or lower to obtain 2.97 g (yield 89.7%) of the target cephaloridine.

Example 2

(1) Preparation of N, N-dimethylacetamide adduct of 7-α-chienylacetamido-3-pyridinomethyl-3-cepem-4-carboxylic acid, 7-α-chienylacetami 3.97 g of cephalosporranic acid is added to 40 ml of phosphate buffer (PH 6.4), suspended, and then a solution of 3.2 ml of pyridine diluted in 30 ml of N, N-dimethylacetamide is added dropwise.

After heating, the mixture was stirred at 37 ° C. for 16 hours, concentrated to 20 ml under reduced pressure, and crystallized by adding 40 ml of acetone and water (V / V 10: 90) mixed solvent.

The precipitates were separated and washed with a mixed solvent of N, N-dimethylacetamide and water (V / V 40:60), followed by drying for 12 hours at 40 ° C. or lower under reduced pressure. Get

Elemental Analysis for Target C ₂₃ H ₂₆ O ₅ N ₄ S ₂

Calculated Value (%): C54.96, H5.21, N11.15, S12.76

Found (%): C55.08, H5.15, N11.25, S13.11

(2) Preparation of 7-α-chienylacetamido-3-pyridinomethyl-3-cepem-4-carboxylic acid (cephaloridine).

By using 3.0 g of the product of (1) in the same manner as in (2) of (Example 1), 2.15 g (yield 86.7%) of the target cephaloridine was obtained.

Example 3

4.19 g of 7-α-thienylacetamide cephalosporane acid natrium salt as a starting material was used as in Example 1 using 3- or 4-N- (hydroxy methyl) -carbamoylpyridine instead of pyridine. Treatment with the method yields the following materials.

That is, as one of the compounds of general formula (I), 1.09 g of 7-α-chienylacetamido-3- (3'-N-hydroxymethylcarbamoyl) -pyridino methylcarboxylic acid (yield 22.3%) or 7 0.95 g (yield 19.4%) of -α-chienyl acetamido-3- (4'-N-hydroxy methylcarbamoyl) -pyridinomethyl carboxylic acid was produced.

Claims (1)

The following general formula (III) compound and the following general formula (IV) compound are reacted in the presence of excess N, N-dimethyl acetamide to produce the next general formula (II) N, N-dimethyl acetamide adduct as an intermediate. A process for preparing the following compound of formula (I), characterized by separation.

Z in the general formulas (I), (II) and (IV) is a hydrogen atom or a 3'- or 4'-N- (hydroxy loweralkyl) -carbamoyl group, and M in the general formula (III) Is an alkali metal of Na and K, or a hydrogen atom.