KR102188689B1 - Process for preparing cefmetazole sodium - Google Patents

Abstract

The present invention relates to a method for preparing Cefmetazole sodium, by dissolving Cefmetazole acid and sodium salt in an organic solvent, and then performing crystallization of the product after reaction using a crystallization solvent. The present invention relates to a method of preparing Cefmetazole sodium by crystallization without using freeze-drying, which is a manufacturing method of, and without additional equipment while shortening time.

Description

Method for producing cefmethazole sodium TECHNICAL FIELD {PROCESS FOR PREPARING CEFMETAZOLE SODIUM}

The present invention relates to a method for preparing cefamycin or Cefmetazole Sodium classified as a second-generation cephalosporin antibiotic through a crystallization method.

Cefmethazole sodium, a product developed by Sankyo (Japan), has a strong bactericidal effect on bacterial infections such as bacteroids and staphylococcus, and is known to exhibit a broader spectrum of antibiotic effects than the first generation cephalosporin antibiotic .

These cephalosporin antibiotics act as an inhibitory action in forming cell walls of bacteria, and cells are destroyed due to changes in osmotic pressure within the cells of the bacteria.

As described in patent GB 1449420, the corresponding carboxy-protected 7β-amino-7α-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cefem-4-ic acid Is subjected to a condensation reaction with 2-(cyanomethylthio)acetic acid, and the carboxy-protecting group is deprotected to obtain Cefmetazole acid.

The synthesized cefmetazole acid is crystallized in the form of a sodium salt to prepare cefmetazole sodium.

At this time, the pH of the solution is adjusted using sodium hydrogen carbonate as a salt change material, and then freeze-dried and marketed.

In addition, a method of preparing cefmethazole sodium by a freeze-drying method is described in Chinese Patent Application Publication No. 200910014972.5 .

This freeze-dried manufacturing method has the advantage of removing residual solvent and obtaining crystals in a stable state, but it requires a separate facility due to the nature of the process, has a long process time and high facility operating cost.

GB 1449420 A CN 200910014972 A

The present invention is to provide an economical manufacturing method of high yield through a crystallization method without the use of freeze-drying that requires a high unit cost and additional equipment for cefmethazole sodium currently sold.

In order to solve the above technical problem, the present invention dissolves Cefmetazole acid in an organic solvent and reacts by adding an organic sodium salt, and then adding the reaction product to a crystallization solvent to obtain Cefmetazole sodium. It provides a manufacturing method for crystallizing.

The manufacturing method of Cefmetazole sodium using freeze-drying requires removal of water due to the nature of the manufacturing process, so the process time is lengthened and the equipment operation cost is high.

According to the method for preparing Cefmetazole sodium according to the present invention, by using a specific organic sodium salt, the process time is shortened by crystallization in a general cepha-based antibiotic manufacturing facility, and a high yield of Cefmetazole sodium It has a very economical effect because it can be manufactured.

Hereinafter, the present invention will be described in more detail with reference to examples and the like.

In the method for preparing Cefmetazole sodium of the present invention, as shown in Formula 1 below, after dissolving Cefmetazole acid, the main component, in an organic solvent, it is possible to dissolve in an organic solvent. The product reacted by adding sodium salt is crystallized using a crystallization solvent.

<Formula 1>

Specifically, in the present invention, after dissolving Cefmetazole acid in an organic solvent, an organic sodium salt is added and reacted with stirring.

The reaction solution is added dropwise to the cooled crystallization solvent, and then stirred and crystallized while maintaining the temperature for an appropriate time.

The crystals are filtered in the crystallization solution and washed with the same solvent.

The filtered crystals were dried under reduced pressure to prepare off-white solid Cefmetazole sodium.

Acetone, acetonitrile (ACN), dimethylsulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc) as an organic solvent used to dissolve Cefmetazole acid in the manufacturing method of the present invention. ), tetrahydrofuran (THF), methanol, and ethanol may be used, and acetone is preferably used.

In the production method of the present invention, the weight ratio of the solvent to cefmetazole acid may be 9 to 13 times, preferably 9.5 to 12.5 times, and most preferably 10 to 11 times.

If the amount of the solvent is less than the above numerical range, the solubility of Cefmetazole acid may be insufficient, so that the sodium salt reaction may be insufficient, and if the amount of the solvent is greater than the above numerical range, high yield, etc. The effect cannot be obtained.

The organic sodium salt used in the manufacturing method of the present invention is sodium 2-ethyl hexanoate, sodium acetate, sodium formate, sodium propionate , Sodium butylate, sodium benzoate, sodium octanoate, sodium lactate, sodium malonate, sodium isovalerate, Sodium 2-oxo butyrate (sodium 2-oxo butylate), sodium pyruvate (sodium pyruvate), sodium trimethylacetate (sodium trimethylacetate), sodium oleate (sodium oleate), etc. can be used, preferably sodium 2-ethyl Use hexanoate.

In the production method of the present invention, 1.0 equivalent to 1.5 equivalents of organic sodium salt, preferably 1.0 to 1.3 equivalents, more preferably 1.1 equivalents of 1.05 equivalents based on 1 equivalent of cefmethazole acid may be used.

When the content of the organosodium salt is less than the above range, the reaction does not sufficiently occur, so that the final cefmethazole sodium is not produced, and the cefmethazole acid insoluble in water remains as a solid.

If it is more than the above range, the sodium salt remaining after the reaction is precipitated as crystals, so that the content of cefmethazole is lowered.

In the production method of the present invention, the solvent used for crystallization after the sodium salt reaction is ethyl acetate, n-Hexane, dichloromethane, cyclohexane, isopropyl Ether (Isopropyl ether), pentane (Pentane), toluene (Toluene), t-butylmethyl ether (t-butylmethyl ether), isopropanol (Isopropanol) and the like can be used.

In the manufacturing method of the present invention, the reaction temperature may be performed at 0°C to 20°C, and preferably at 5°C to 10°C.

If the reaction temperature is lower than the above range, the reaction does not occur sufficiently, the solubility is also lowered, and the final Cefmetazole sodium is not properly produced, resulting in a water-insoluble residue.

If the value is higher than the above range, the stability of cefmethazole acid may decrease, and impurities may occur.

The present invention will be described in more detail through the following examples.

However, the scope of the present invention is not limited to these.

After dissolving 20 g of cefmetazole acid in 240 mL of acetone at 5°C, 7.40 g of sodium 2-ethylhexanoate was added. While stirring this, the reaction temperature is maintained at 5° C. and reacted for 1 hour. Thereafter, the reaction solution was added dropwise to 720 mL of pentane cooled to 5°C. After that, the mixture is stirred while maintaining the temperature for 1 hour. The crystals were filtered and washed with pentane. The filtered crystals were dried under reduced pressure at 40° C. for 12 hours to obtain an off-white solid cefmetazole sodium (Cefmetazole sodium, yield: 93.8%).

After dissolving 20 g of Cefmetazole acid in 240 mL of acetone at 5° C., 7.75 g of sodium 2-ethylhexanoate was added. While stirring this, the reaction temperature is maintained at 5° C. and reacted for 1 hour. Thereafter, the reaction solution was added dropwise to 720 mL of pentane cooled to 5°C. After that, the mixture is stirred while maintaining the temperature for 1 hour. The crystals were filtered and washed with pentane. The filtered crystals are charged with nitrogen at room temperature for about 1 hour to remove the solvent. Thereafter, it was dried under reduced pressure at 40° C. for 12 hours to obtain an off-white solid cefmetazole sodium (Cefmetazole sodium, yield: 95.7%).

After dissolving 10 g of Cefmetazole acid in 120 mL of acetone at 5°C, 5.28 g of sodium 2-ethylhexanoate was added. While stirring this, the reaction temperature is maintained at 5° C. and reacted for 1 hour. Thereafter, the reaction solution was added dropwise to 720 mL of pentane cooled to 5°C. After that, the mixture is stirred while maintaining the temperature for 1 hour. The crystals were filtered and washed with pentane. The filtered crystals were dried under reduced pressure at 40° C. for 12 hours to obtain an off-white solid cefmetazole sodium (Cefmetazole sodium, yield: 93.6%).

After dissolving 10 g of cefmetazole acid in 120 mL of acetone at 10° C., 3.70 g of sodium 2-ethylhexanoate was added. While stirring this, the reaction temperature was maintained at 10° C. and reacted for 0.5 hours. Then, the reaction solution was added dropwise to 280 mL of ethyl acetate cooled to 10°C. After that, the mixture is stirred while maintaining the temperature for 1 hour. The crystals were filtered and washed with 50 mL of ethyl acetate. The filtered crystals were dried under reduced pressure at 40° C. for 12 hours to obtain an off-white solid cefmetazole sodium (Cefmetazole sodium, yield: 93%).

After dissolving 10 g of cefmetazole acid in 140 mL of acetone at 10° C., 3.70 g of sodium 2-ethylhexanoate was added. While stirring this, the reaction temperature was maintained at 10° C. and reacted for 0.5 hours. Then, the reaction solution was added dropwise to 280 mL of ethyl acetate cooled to 10°C. After that, the mixture is stirred while maintaining the temperature for 1 hour. The crystals were filtered and washed with 50 mL of ethyl acetate. The filtered crystals are charged with nitrogen at room temperature for about 2 hours to remove the solvent.

Thereafter, it was dried under reduced pressure at 40° C. for 12 hours to obtain an off-white solid cefmetazole sodium (Cefmetazole sodium, yield: 93%).

After dissolving 110 g of cefmetazole acid in 140 mL of acetone at 10° C., 40.71 g of sodium 2-ethylhexanoate was added. While stirring this, the reaction temperature was maintained at 10° C. and reacted for 0.5 hours. Then, the reaction solution was added dropwise to 280 mL of ethyl acetate cooled to 10°C. Then, the mixture is stirred while maintaining the temperature for 0.5 hours. The crystals were filtered and washed with 50 mL of ethyl acetate. The filtered crystals are charged with nitrogen at room temperature for about 2 hours to remove the solvent. Thereafter, it was dried under reduced pressure at 40° C. for 40 hours to obtain an off-white solid cefmetazole sodium (Cefmetazole sodium, yield: 93.5%).

Claims (5)

Dissolving Cefmetazole acid in an organic solvent, reacting by adding an organic sodium salt, and performing crystallization of the product after the reaction using a crystallization solvent,
The organic solvent is selected from the group consisting of acetone, acetonitrile (ACN), dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran (THF), methanol and ethanol,
The organosodium salt is sodium 2-ethyl hexanoate,
The crystallization solvent is ethyl acetate or pentane, characterized in that, Cefmetazole sodium (Cefmetazole sodium) production method. delete The method of claim 1,
A method for preparing cefmetazole sodium), characterized in that 1.0 to 1.5 equivalents of an organic sodium salt are used based on 1 equivalent of Cefmetazole acid. delete The method of claim 1,
The reaction temperature is a method for producing cefmetazole sodium, characterized in that 0 to 20 ℃.