KR20040033568A - METHOD FOR PRODUCING 7α-METHOXYCEPHALOSPORIN DERIVATIVE SODIUM SALT 7-HYDRATE - Google Patents

Abstract

PURPOSE: A method for producing 7α-methoxycephalosporin derivative sodium salt 7-hydrate is provided, thereby conducting the method at low or room temperature, minimizing formation of coloring materials and impurities, as well as the amount of water and organic solvent used, and separating and reusing the organic solvent. CONSTITUTION: A method for producing 7α-methoxycephalosporin derivative sodium salt 7-hydrate comprises the steps of: dissolving 7α-methoxycephalosporin derivative sodium salt or hydrates thereof in a basic solution of pH 9 to 13; adding acid into the solution to regulate pH to 5.0 to 9.0 to crystallize 7α-methoxycephalosporin derivative sodium salt; and adding a crystallizing agent into the solution to separate 7α -methoxycephalosporin derivative sodium salt 7-hydrate, wherein the 7α -methoxycephalosporin derivative sodium salt 7-hydrate is represented by the formula(1), in which R1 is heterocyclic ring or -S-heterocyclic ring; R2 is hydrogen, carboxyl or -COOR4; R4 is lower alkyl, dialkylamino-lower alkyl or YCHOR5; R5 is lower alkyl, lower acyl or lower alkoxycarbonyl; Y is hydrogen or lower alkyl; R3 is hydrogen, carbamoyl(-CONH2) or lower acyl; A and B is independently C1 to C5 linear or branched chain alkylene; and x is 0 or 1.

Description

Method for producing 7α-methoxycephalosporin derivative sodium salt 7-hydrate {Method for producing 7α-methoxycephalosporin derivative sodium salt 7-hydrate}

The present invention relates to a method for preparing a 7α-methoxycephalosporin derivative sodium salt heptahydrate, and more particularly, to hydrate a crude 7α-methoxycephalosporin derivative sodium salt to stabilize 7α-methoxycepharose. Palosporin derivative sodium salt heptahydrate.

7α-methoxycephalosporin derivative is an antimicrobial substance that exhibits broad antimicrobial spectrum against various strains such as gram-positive bacteria, gram-negative bacteria except anaerobes, anaerobes, and the method of preparation thereof is US Patent 4,357,331 and the like are known. The 7α-methoxycephalosporin derivative is excellent in antimicrobial activity, but has a disadvantage in that it is colored and has low stability, particularly high temperature stability, and is not suitable as a liquid formulation. Accordingly, U.S. Patent No. 4,555,404 discloses a method of converting 7α-methoxycephalosporin to 7α-methoxycephalosporin hexahydrate to improve stability while maintaining the activity of 7α-methoxycephalosporin. The method disclosed in U.S. Patent No. 4,555,404 adds rough primary crystals of the amorphous 7α-methoxycephalosporin derivative to sterile water, warms it to a temperature of 40 to 50 ° C to dissolve the crystals, and then adds alcohols to 7α. -Crystallize methoxy cephalosporin- heptahydrate. However, such amorphous compounds are colored and have low stability, so the method is not suitable for mass production. In addition, since the 7α-methoxycephalosporin derivative has low solubility in water, a large amount of water, usually 10 times or more by weight ratio, is required, and a large amount of organic solvent is required in the subsequent recrystallization process, and in general, 40 Since it must be dissolved by heating to 50 to 50 ℃, there is a problem that the reactant is colored or impurities are generated in the hot dissolution process.

Accordingly, an object of the present invention is to provide a method for preparing a sodium salt hexahydrate of 7α-methoxycephalosporin derivative which can minimize the amount of water and organic solvent in the process of dissolving and recrystallizing crude 7α-methoxycephalosporin. will be.

Another object of the present invention is to improve the yield of the 7α-methoxycephalosporin derivative sodium salt heptahydrate by minimizing the coloration of impurities and the generation of impurities, 7α-methoxycephalo which can stably perform industrial mass production It is to provide a method for producing a sporin derivative sodium salt heptahydrate.

Still another object of the present invention is to provide a method for preparing an environmentally friendly 7α-methoxycephalosporin derivative sodium salt heptahydrate which can be recovered and reused using an organic solvent separated from water in the recrystallization process. .

In order to achieve the above object, the present invention comprises the steps of dissolving the 7α- methoxy cephalosporin derivative sodium salt in a basic aqueous solution of pH 9 to 13; Adding an acid to adjust the pH of the solution to 5 to 9.0 to crystallize the 7α-methoxycephalosporin derivative sodium salt; And adding a crystallization solvent to the solution to precipitate the 7α-methoxycephalosporin derivative sodium salt hydrate.

Here, the basic aqueous solution includes a base such as triethylamine, diethylamine, sodium acetate, sodium 2-ethylhexanoic acid salt, ammonia water, sodium carbonate, sodium hydroxide, and the like, and the acid is acetic acid, 2-ethylhexanoic acid, formic acid. , Tartaric acid, lactic acid, hydrochloric acid, sulfuric acid, citric acid and the like, the crystallization solvent is a hydrophobic organic solvent selected from ethyl acetate, methyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl cellosolve, ethyl cellosolve, etc. It is preferable.

Hereinafter, the present invention will be described in detail.

The present invention dissolves a rough primary crystal of 7α-methoxycephalosporin derivative sodium salt or a hydrate thereof in an aqueous solution containing a base, and adjusts the pH of the solution to weak alkali by adding an acid. A method of sterilizing is provided by adding a hydrophobic organic solvent to precipitate the 7α-methoxycephalosporin derivative sodium salt heptahydrate.

7α-methoxycephalosporin derivative sodium salt according to the present invention 7α-methoxycephalosporin derivative sodium salt used to prepare the hexahydrate has the structure of Formula 1 below.

Wherein R ₁ is a heterocyclic ring or -S-heterocyclic ring, R ₂ is hydrogen, a carboxyl group, or -COOR ₄ , wherein R ₄ is a lower alkyl group, a dialkylamino-loweralkyl group or R ₅ is a lower alkyl group, a lower acyl group or a lower alkoxycarbonyl group, Y represents hydrogen or a lower alkyl group, and R ₃ represents hydrogen, a carbamoyl group (-CONH ₂ ) or a lower acyl group. And A and B each independently represent a linear or branched chain alkylene group having 1 to 5 carbon atoms, and x is 0 or 1. Lower alkyl group herein means an alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

In addition, a preferable example of the 7α-methoxycephalosporin derivative sodium salt is 7β- (2D-2-amino-2-carboxy-ethylthioacetamino) -7α-methoxy-3- (1) having the structure of Formula 2 below. -Methyl-1H-tetrazol-5-yl) -thiomethyl-3-cepem-4-carboxylic acid sodium salt.

In order to prepare the 7α-methoxycephalosporin derivative sodium salt heptahydrate according to the present invention, first, in the basic solution of pH 9 to 13, preferably pH 9.5 to 12.5, more preferably pH 10.0 to 11.5, The 7α-methoxycephalosporin derivative sodium salt or its hydrate is dissolved to a concentration of 2 to 70% by weight, preferably 15 to 30% by weight. At this time, when the pH of the solution is less than 9, there is a problem that the solubility of the compound is lowered and the yield is lowered. When the pH of the solution is higher than 12.5, a by-product is formed and there is a fear of coloring. In addition, when the amount of the sodium salt of 7α-methoxycephalosporin derivative dissolved in the basic solution is less than 2% by weight, the yield of the target product is lowered, and since many solvents are used more than necessary, it is not environmentally and economically desirable, and 70% by weight. When it exceeds%, there is a possibility that the 7α-methoxycephalosporin derivative sodium salt remains without being dissolved in the basic solution.

Examples of the base for preparing the basic solution include, but are not limited to, organic bases such as triethylamine, diethylamine, sodium acetate, and 2-ethylhexanoic acid sodium salt, ammonia water, sodium carbonate (Na ₂ CO ₃ ), sodium hydroxide (NaOH Inorganic bases such as) may be used alone or in combination of two or more thereof. In addition, the 7α-methoxycephalosporin derivative sodium salt may be dissolved in a basic solution of which pH is adjusted. First, the 7α-methoxycephalosporin derivative sodium salt is added, and then an appropriate base is added to the pH of the total solution. Can be adjusted, and they can be added simultaneously. By using the basic solution in this way, the solubility of the 7α-methoxycephalosporin derivative sodium salt in water can be increased, and the dissolution temperature can be lowered. At this time, a suitable dissolution temperature is -20-30 degreeC, More preferably, it is 0-20 degreeC. As such, when the solubility of the 7α-methoxycephalosporin derivative sodium salt is increased, it can be dissolved using a small amount of water, and the amount of hydrophobic crystallized organic solvent such as ethyl acetate can be minimized and the yield can be improved in the subsequent crystallization process. have. It is also possible to dissolve the low temperature or room temperature 7α-methoxycephalosporin derivative sodium salt, so that the reaction can be carried out mildly and economically.

As such, after dissolving the 7α-methoxycephalosporin derivative sodium salt in the basic solution, the acid is added to adjust the pH of the solution to 5.0 to 9.0, preferably 7.5 to 8.5, thereby adjusting the 7α-methoxycephalosporin derivative sodium salt. Crystallize. In this case, when the pH of the solution is less than 5.0, the color of the solution may be poor, and when it exceeds 9.0, the 7α-methoxycephalosporin derivative sodium salt may not be sufficiently crystallized. Thus, as the acid for adjusting the pH of the solution, non-limiting examples of weak acids such as acetic acid, 2-ethylhexanoic acid, formic acid, tartaric acid, lactic acid, hydrochloric acid, sulfuric acid, citric acid, or the like can be used.

The pH of the solution is adjusted to be weakly alkaline, and then crystallized by adding a crystallization solvent to crystallize the 7α-methoxycephalosporin derivative sodium salt heptahydrate. As the crystallization solvent, a hydrophobic organic solvent may be used. Specifically, esters such as ethyl acetate, methyl acetate, n-butyl acetate, ketones such as methyl isobutyl ketone, alcoholic properties such as methyl cellosolve and ethyl cellosolve Ether organic solvents may be used alone or in combination. At this time, if necessary, the solution may be filtered to remove impurities before adding the crystallization solvent. After adding such a crystallization solvent and stirring at about 5 ° C. for about 3 hours, 7α-methoxycephalosporin derivative sodium salt hydrate in a white crystal state, mainly 7α-methoxycephalosporin derivative sodium salt heptahydrate, is precipitated. Filtration, washing and drying in the usual manner yields the final product.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited by the following examples.

Example 1

7β- (2D-2-amino-2-carboxy-ethylthioacetamino) -7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cepem-4- 10 g of sodium carboxylate salt hexahydrate was added to 40 ml of sterile water, cooled to 0-5 ° C., and then slowly added dropwise 2.1 ml of triethylamine to adjust the pH of the solution to 12 to dissolve the sodium salt. Next, the pH of the solution was adjusted to 8.0 by addition of acetic acid, followed by filtration. 20 ml of ethyl acetate and 1 ml of methyl cellosolve solution in which 3 g of 2-ethylhexanoic acid sodium was dissolved were added to the filtrate. Stir slowly for 3 hours. The resulting crystals were filtered off, washed with acetone and dried to obtain 9.3 g of white crystals.

Example 2

7β- (2D-2-amino-2-carboxy-ethylthioacetamino) -7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cepem-4- 10 g of sodium carbonate salt was added to 40 ml of sterile water, and sodium carbonate was added at 20 ° C. to adjust the pH of the solution to 11.8. Next, acetic acid was added to maintain the pH of the solution at 8.5, followed by filtration. Then, 20 ml of ethyl acetate and 1 ml of methyl cellosolve mixed solvent were added to the filtrate, and the mixture was slowly stirred at 5 ° C. for 3 hours. The resulting crystals were filtered off, washed with acetone and dried to obtain 9.2 g of white crystals.

Example 3

7β- (2D-2-amino-2-carboxy-ethylthioacetamino) -7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cepem-4- 10 g of sodium carbonate salt was added to 40 ml of sterile water, and sodium carbonate was added at 20 ° C. to adjust the pH of the solution to 11.8. Next, acetic acid was added to maintain the pH of the solution at 8.5, followed by filtration. Then, 30 ml of methyl cellosolve was added to the filtrate, and the mixture was slowly stirred at 5 ° C. for 3 hours. The resulting crystals were filtered off, washed with acetone and dried to obtain 8.1 g of white crystals.

Example 4

7β- (2D-2-amino-2-carboxy-ethylthioacetamino) -7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cepem-4- 10 g of sodium carbonate salt was added to 40 ml of sterile water, and sodium carbonate was added at 20 ° C. to adjust the pH of the solution to 11.8. Next, acetic acid was added to maintain the pH of the solution at 8.5, followed by filtration. 20 ml of ethyl acetate was added to the filtrate and stirred slowly at 5 ° C. for 3 hours. The resulting crystals were filtered off, washed with acetone and dried to obtain 5.1 g of white crystals.

As described above, the method for preparing a 7α-methoxycephalosporin derivative hydrate according to the present invention increases the solubility of the 7α-methoxycephalosporin derivative sodium salt in water using a base and then adjusts the pH to weak alkalinity. By crystallization, the manufacturing process is performed at low temperature or room temperature, and it is possible to minimize the coloring and impurity generation generated during heating. In addition, the method for preparing a 7α-methoxycephalosporin derivative hydrate according to the present invention can minimize the amount of water and an organic solvent, and since the hydrophobic organic solvent is used as a crystallization solvent, the organic solvent can be separated and reused after recrystallization. Economical, eco-friendly, mass production is possible.

Claims (6)

dissolving a 7α-methoxycephalosporin derivative sodium salt or a hydrate thereof in a basic aqueous solution having a pH of 9 to 13; Adding an acid to adjust the pH of the solution to 5.0 to 9.0 to crystallize the 7α-methoxycephalosporin derivative sodium salt; And By adding a crystallization solvent to the solution of 7α- methoxy cephalosporin 7α- quote ticker methoxy cephalosporin derivative production method of the sodium salt heptahydrate to derivatives comprising the step of precipitating the sodium salt hydrate. The method of claim 1, wherein the 7α-methoxycephalosporin derivative sodium salt has a chemical formula of 7α-methoxycephalosporin derivative sodium salt hydrate. Wherein R ₁ is a heterocyclic ring or -S-heterocyclic ring, R ₂ is hydrogen, a carboxyl group, or -COOR ₄ , wherein R ₄ is a lower alkyl group, a dialkylamino-loweralkyl group or R ₅ is a lower alkyl group, a lower acyl group or a lower alkoxycarbonyl group, Y represents hydrogen or a lower alkyl group, and R ₃ represents hydrogen, a carbamoyl group (-CONH ₂ ) or a lower acyl group. And A and B each independently represent a linear or branched chain alkylene group having 1 to 5 carbon atoms, and x is 0 or 1. The method of claim 1, wherein the 7α-methoxycephalosporin derivative sodium salt has a chemical formula of 7α-methoxycephalosporin derivative sodium salt hydrate. The method of claim 1, wherein the basic aqueous solution comprises a base selected from the group consisting of triethylamine, diethylamine, sodium acetate, sodium 2-ethylhexanoic acid, aqueous ammonia, sodium carbonate, sodium hydroxide and mixtures thereof. Method for producing phosphorus 7α-methoxycephalosporin derivative sodium salt hydrate. The 7α-methoxycephalosporin according to claim 1, wherein the acid comprises an acid selected from the group consisting of acetic acid, 2-ethylhexanoic acid, formic acid, tartaric acid, lactic acid, hydrochloric acid, sulfuric acid, citric acid and mixtures thereof. Method for preparing derivative sodium salt hydrate. The method of claim 1, wherein the crystallization solvent comprises a hydrophobic organic solvent selected from the group consisting of ethyl acetate, methyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl cellosolve, ethyl cellosolve and mixtures thereof Method for producing a 7α-methoxycephalosporin derivative sodium salt hydrate.