KR960000359B1 - The process for the preparation of cefoperazone sodium - Google Patents

Abstract

adding a solution of 1.0-2.0 vol.% water, 2.0-4.0 vol.% tetrahydrofurane and 1wt.% sodium cephopherazone to a solution of 15-30 vol.% acetone and 4-8 vol.% isobutyl methyl ketone at 0-3≰C; and 3)separating the produced sodium cephopherazone. The above cephopherazone free acid is cephopherazone dihydrate or cephopherazoneN,N-dimethylacetamide. The water/tetrahydrofurane sodium cephopherazone solution is prepared by mixing tetrahydrofurane solution of cephopheranzone free acid with an aqueous solution containing one equivalent base selected from hydrous or anhydrous sodium acetate.

Description

Method for preparing Ceferrazon Sodium

The present invention relates to a novel method for preparing sodium cepharazone, by adding a water / tetrahydrofuran / cepharazone sodium solution to acetone / isobutylmethylketone solution at low temperature and separating the resulting cepharazone sodium. The present invention relates to a method for producing high density, high crystallinity of ceperazone sodium.

Ceperazone is a third generation cephalosporin-based antibiotic administered parenterally in the form of sodium and can be prepared as an amorphous solid by British Patent No. 1508071. Such amorphous compounds are not preferred because of their low stability during long-term storage, severe changes over time, discoloration, and strong absorbency. Korean Patent Publication No. 83-1970 discloses a method for producing cephaperazone sodium by lyophilization, but the product by this method is also obtained as an amorphous compound, and it is disadvantageous that impurities cannot be removed at all in the sodium salt manufacturing process. have.

In addition, Korean Patent Publication No. 86-1495 discloses acetone-methylene chloride (95: 5, v / v) solution at a temperature of about 15 to 23 ° C. to a water-acetone solution containing sodium cepharazone to crystallize and isolate it. A method for drying crystalline cellular ferrazone sodium with little residual organic solvent is described.

In addition, Korean Patent Publication No. 87-1071 discloses a highly crystalline cytoperazone, in which acetone is added to a water-acetone solution containing sodium cepharazone at a temperature of about 18 to 25 ° C. to crystallize and separated and dried, thereby hardly remaining organic solvent. A method for producing sodium is described. However, in the case of Ceferrazone Sodium prepared according to the methods described in the above-mentioned Korean Patent Publication Nos. 86-1495 and 87-1071, the solid density is very low (0.24 to 0.28 g / cm 3), resulting in an increase in volume. There was a problem during charging.

Therefore, the present inventors have long researched to overcome the problems of the prior art when the water / tetrahydrofuran / cell perazone sodium solution is crystallized by adding to acetone / isobutyl methyl ketone solution at a low temperature of 0 ~ 3 ℃ 0.45 The present invention has been completed by discovering the fact that a high density, high crystallinity of ceraprazone sodium of ˜0.53 g / cm 3 can be prepared.

It is an object of the present invention to provide a novel method for producing high density, high crystallinity of ceperazone sodium.

Hereinafter, the present invention will be described in detail.

The present invention provides a water / tetrahydrofuran / cephaperazone sodium solution containing 1.0-2.0 vol. Of water, 2.0-4.0 vol. Of tetrahydrofuran and 1 part of c. It is characterized in that it is added to an acetone / isobutylmethylketone solution containing 15-30 vol. Parts of acetone and 4-8 vol. Of isobutyl methyl ketone at a low temperature of 0 to 3 ° C. to separate the resulting cytoperazone sodium.

Referring to the present invention in more detail as follows.

The present invention relates to a novel method for producing high density, high crystallinity of cephaperazone sodium. In the present invention, the initial water / tetrahydrofuran / cephaperazone sodium solution is tetrahydrofuran of ceperazone free acid. The solution may be prepared by mixing with an aqueous solution containing about 1 equivalent of a base selected from sodium acetate and sodium acetate hydrate. In this case, as the cell perazone free acid, cephaperazone dihydrate or cephaperazone N, N-dimethylacetamide solvate may be used, wherein the content of each component of the water / tetrahydrofuran / cephaperazone sodium solution is Outside the range, there is a problem that the density of the solid decreases, which is not easy to remove impurities.

In addition, it is preferable to dropwise add an initial water / tetrahydrofuran / cephaperazone sodium solution to the acetone / isobutylmethylketone solution cooled at a low temperature of 0 to 3 ° C., if the crystallization temperature is less than 0 ° C. There is a problem that the removal is difficult, and if higher than 3 ℃ there is a problem that the solid density decreases, which is not preferable. In addition, if the order of dropping is reversed, it is not preferable because low density absorbent cytoperazone sodium is obtained.

If the content of acetone in each component of the acetone / isobutyl methyl ketone solution is less than 15 parts by volume, there is a problem that a strong absorbent target is obtained, and if it exceeds 30 parts by volume, impurities are difficult to be removed, which is not preferable. In addition, if the content of isobutyl methyl ketone is less than 4 parts by volume, there is a problem that the solid density is reduced, and if it is more than 8 parts by volume, it is difficult to remove impurities.

When the crystallization is completed, stirring and maintaining for 1 to 6 hours, preferably 1.5 to 3 hours while maintaining a low temperature of 0 ~ 3 ℃ can be separated from the produced cell perazone sodium. At this time, when the temperature rises, since a low density product is obtained, it is not preferable.

High-density, highly crystalline cytoperazone sodium can be separated by filtration or centrifugation and dried for 15 to 30 hours at 25 ° C to 40 ° C under high vacuum (6 mmHg or less) to obtain a target with little residual solvent. have.

Ceferrazon sodium obtained by the method of the present invention has a high density of 0.45 to 0.53 g / cm 3 of solids, is obtained in high crystallinity with little amorphous material, and has the advantage of little change with time, discoloration and hygroscopicity in long-term storage. Have.

Hereinafter, the present invention will be described in detail with reference to Examples. The present invention is not limited by these Examples.

Example 1

A solution of 2.0 g of cell perazone dihydrate was dissolved in 6 ml of tetrahydrofuran and 0.4 g of sodium acetate and trihydrate dissolved in 3 ml of purified water was added thereto for 10 minutes. In another vessel, a solution of 44 ml of acetone and 11 ml of isobutyl methyl ketone was cooled to 0 to 3 ° C, and the anticorrosive solution prepared above was added thereto for 10 minutes. When crystals were formed, the mixture was stirred at 0-3 ° C. for 2 hours, filtered, washed with 5 ml of acetone and 5 ml of ethyl ether, and dried to obtain the target product as a white solid.

Yield: 1.86 g (95%)

Moisture: 1.5% (Kalfitsha Method)

Titer: 968 µg / mg (HPLC method)

Solid Density: 0.51g / cm3

Example 2

20 g of cell perazone-dihydrate was dissolved in 60 ml of tetrahydrofuran, and a solution of 2.4 g of sodium acetate anhydride in 30 ml of purified water was added thereto for 10 minutes and stirred for 30 minutes. In another vessel, a solution of 440 ml of acetone and 110 ml of isobutyl methyl ketone was cooled to 0-3 ° C., and the reaction solution prepared above was added thereto for 10 minutes. When crystals were formed, the mixture was stirred at 0-3 ° C. for 2.5 hours, filtered, washed sequentially with 50 ml of acetone and 50 ml of ethyl ether, and dried in vacuo (2 mmHg, 35 ° C., 18 hours) to give a target as a white solid. Got it.

Yield: 18.23 g (93%)

Moisture: 0.9% (Kalfitsha method)

Titer: 959 µg / mg (HPLC method)

Solid Density: 0.49g / cm3

Example 3

A solution obtained by dissolving 2.0 g of cell perazone-N and N-dimethylacetate amide in 6 ml of tetrahydrofuran and 0.24 g of sodium acetate and anhydride in 3 ml of purified water was added for 10 minutes and stirred for 30 minutes. In another vessel, a solution of 60 ml of acetone and 15 ml of isobutyl methyl ketone was cooled to 0-3 ° C., and the reaction solution prepared above was added thereto for 10 minutes. When crystals were formed, the mixture was stirred at 0-3 ° C. for 1.5 hours, filtered, washed sequentially with 5 ml of acetone and 5 ml of ethyl ether, and dried in vacuo (2 mmHg, 35 ° C., 20 hours) to obtain the target product as a white solid. Got it.

Yield: 1.70 g (93.4%)

Moisture: 1.2% (Kalfitsha Method)

Titer: 942 µg / mg (HPLC method)

Solid Density: 0.46g / cm3

Claims (4)

In preparing Ceferrazon sodium, a water / tetrahydrofuran / Ceperazone sodium solution containing 1.0-2.0 vol. Water, 2.0-4.0 vol. Tetrahydrofuran and 1 part c. It is added to an acetone / isobutylmethylketone solution containing 15 to 30 vol. Acetone and 4 to 8 vol. Isobutyl methyl ketone at a low temperature of c., And the resulting cell perazone sodium is separated. Method of producing sodium. The water / tetrahydrofuran / cephaperazone sodium solution is mixed with an aqueous solution containing about 1 equivalent of a base selected from tetrahydrofuran solution of ceferrazone free acid, sodium acetate anhydride and sodium acetate hydrate. Method for producing cephaperazone sodium, characterized in that the production. [Claim 3] The method of claim 2, wherein the cepharazone free acid is cepharazone dihydrate or cepharazone N, N-dimethylacetamide. [Claim 2] The method of claim 1, wherein the solid density of the cepharazone sodium is 0.45 to 0.53 g / cm3.