KR100399195B1 - Process for preparing cefuroxime axetil of the amorphous form - Google Patents

Abstract

The present invention comprises the steps of dissolving cefuroxime axetil in a polar organic solvent, and adding an aqueous solution containing an inorganic salt while passing carbon dioxide (CO ₂ ) gas to precipitate the amorphous cefuroxime axetyl, amorphous A method for preparing cefuroxime axetyl. According to the present invention, it is possible to prepare a stable amorphous cefuroxime axetyl with high purity and high yield when the oral administration in a simple facility and easy process.

Description

Process for preparing cefuroxime axetil of the amorphous form

The present invention relates to a novel process for preparing a compound of Formula 1 (common name: cefuroxime axetil), and more particularly, through a carbon dioxide (CO ₂ ) gas through a solvent system containing cefuroxime axetyl. The present invention relates to a method for preparing high purity amorphous cefuroxime axetyl in high yield by adding an aqueous solution containing an inorganic salt to precipitate amorphous cepuroxime axetyl.

Cefuroxime axetyl is a useful antibiotic characterized by having a very broad antimicrobial spectrum against gram positive and negative bacteria. This feature is enhanced by the high stability to β-lactamase produced by the series of Gram-positive and negative bacteria possessed by this compound. This compound is widely used as an antibiotic having high resistance in mammals and having high absorption in the gastrointestinal tract after oral administration. It is known that cefuroxime axetyl has an amorphous state in terms of bioavailability and chemical storage stability when administered orally. In addition, cefuroxime axetyl is in the form of a mixture containing about 1: 1 of R and S isomers containing asymmetric carbon atoms in the molecule, and it is reported that such isomer mixture has an excellent effect when it is amorphous ( British Patent No. 2,127,401, US Patent No. 4,562,181, Korean Patent Publication Nos. 91-46 and European Patent No. 107,276). Therefore, amorphous cefuroxime axetyl having an isomer ratio of R and S forms of about 1: 1 is now commercially available.

Several attempts have been made to make cefuroxime axetyl. For example, British Patent Nos. 1,571,683 and US Pat. No. 4,267,320 describe a process for preparing cefuroxime acetyl by reacting an alkali metal salt of cefuroxime of formula (2) with 1-haloethyl acetate of formula (3):

Wherein M represents an alkali metal and X represents a halogen.

According to the above methods, cefuroxime axetyl is obtained in which the crystalline form or the crystalline form and the amorphous form are mixed. Meanwhile, British Patent No. 2,145,409 and Korean Patent Publication No. 91-8377 disclose a process for preparing crystalline cefuroxime axetyl.

In order to prepare such a crystalline form or a mixture of crystalline form and amorphous cepuroxime acetil with amorphous cepuroxime axetyl, a special manufacturing process is required. For example, in British Patent No. 2,127,401, US Patent No. 4,562,181, Korean Patent Publication Nos. 91-46 and European Patent No. 107,276, spray drying, roller drying, solvent precipitation, Methods for preparing crystalline cefuroxime axetyl into amorphous cefuroxime axetyl by precipitation or freeze drying or the like are disclosed. Among these, the spray drying method and the roller drying method which are rapid solvent removal methods which deposit a cefuroxime axetyl by vaporizing and removing a solvent from the liquid solution containing cefuroxime axetyl rapidly are the most preferable methods. Nevertheless, the spray drying method and the roller drying method require unsatisfactory mechanical equipment and operation, which increases the manufacturing cost, and involves a very complicated and inconvenient process such as removing the product from the roller when the product is recovered. There is this. In addition, the solvent precipitation method is a method of dropping an amorphous cefuroxime acetyl by dropwise addition of a liquid solution of cefuroxime acetyl to a stirring liquid solvent having a different polarity, but the yield is not constant, and is used to prepare a cefuroxime acetyl solution. There is a disadvantage in that the solvent is heated or boiled to dissolve, an excessive amount of organic solvent, or a non-polar organic solvent that is difficult to handle is used. The freeze-drying method, like spray drying and roller drying, requires expensive mechanical equipment. There is a disadvantage in that it is impossible to remove impurities contained in the starting material. In addition, these methods are disadvantageous for industrial scale mass production, requiring high speed agitation of 600-800 rpm to produce amorphous cefuroxime axetyl.

In addition, Korean Patent Publication No. 99-187959 discloses a method for preparing a low-melting amorphous cefuroxime acetyl. In this patent, a solid solution such as dimethyl sulfoxide, dioxane and t-butanol is added to a solid medium such as crystalline or crystalline and amorphous mixtures to prepare a solution in a molten state in which the cefuroxime axetyl is uniformly contained. Cooling the solution to a melting point or lower to prepare a solid medium containing cefuroxime acetil uniformly, and then adding water at a melting point or lower to the solid medium to stir to form a precipitate to recover the precipitate. Disclosed is a method for producing a low melting amorphous amorphous cefuroxime acetyl having a melting point of 94 to 96 ° C. However, according to this method, in the step of freezing a low melting solvent containing cefuroxime axetyl, it is impossible to obtain a complete amorphous cefuroxime axetyl in a state where some solid medium is mixed in a liquid state and is not frozen uniformly. Sepuroxime axetyl in which the crystalline forms are mixed is obtained. Thus, the method has the disadvantage of requiring a special process to ensure uniform freezing during industrial scale mass production.

As described above, although various methods have been developed to prepare amorphous cefuroxime axetyl from crystalline form or a mixture of crystalline form and amorphous form, it has been developed to provide high purity with simpler equipment and easier process. There is still a need to develop new methods for producing amorphous cepuroxime axetyl in high yields.

The inventors have carried out ongoing research to develop a new method for producing high purity amorphous cefuroxime axetyl with high yield with simple equipment and easy process. As a result, the foamed cefuroxime acetyl obtained by the reaction of the alkali metal salt of cepuroxime with 1-haloethyl acetate was dissolved in a polar organic solvent without crystallization, and then the inorganic material was stirred under low temperature at room temperature while passing carbon dioxide gas therethrough. By adding an aqueous solution containing a salt to precipitate amorphous cefuroxime axetyl, it was confirmed that the above object can be achieved, and the present invention has been completed.

Accordingly, an object of the present invention is to provide a simple facility and easy by adding an aqueous solution containing an inorganic salt while passing carbon dioxide gas through a solvent system of crystalline form or a mixture of crystalline form and amorphous form while passing carbon dioxide gas. The process provides a method for producing high purity amorphous cefuroxime axetyl in high yield.

The present invention comprises the steps of dissolving cefuroxime acetil in a polar organic solvent, and adding an aqueous solution containing an inorganic salt while passing carbon dioxide gas to precipitate the amorphous cefuroxime acetil, Relates to a method of manufacture:

[Formula 1]

In the process of the invention, the cefuroxime axetyl may be a foamed cefuroxime axetyl prepared by reacting the alkali metal salt of cefuroxime of formula (2) with 1-haloethyl acetate of formula (3):

[Formula 2]

[Formula 3]

Wherein M represents an alkali metal and X represents a halogen.

The polar organic solvent used in the process according to the invention is preferably selected from the group consisting of dimethylacetamide, dimethylformamide, dimethylsulfoxide and mixtures thereof, wherein the ratio of polar organic solvent to cefuroxime axetyl is 1 It is preferable that they are 1: 1: 2 (v / w). In addition, the inorganic salt used in the method of the present invention is preferably selected from the group consisting of sodium carbonate, sodium hydrogen carbonate and potassium carbonate, wherein the concentration of the aqueous solution containing the inorganic salt is preferably 0.1 to 2%. . In the process of the invention, the step is preferably carried out at a temperature of 0-40 ° C., more preferably 15-30 ° C., and the passage rate of carbon dioxide gas is preferably 5-25 L / min, more preferably Is 10-20 L / min. In addition, the step is preferably carried out while stirring at a speed of 50 to 350 rpm, more preferably 150 to 250 rpm.

Hereinafter, the present invention will be described in detail.

The present invention relates to a process for the preparation of cefuroxime axetyl of formula (1) in amorphous form. The cefuroxime axetyl of formula (1) is, for example, 1-haloethyl acetate of formula (3), starting with the alkali metal salt of cefuroxime of formula (2), in particular cefuroxime sodium, as disclosed in British Patent No. 1,571,683. Prepared in the form of a foam by reaction with 1-bromoethyl acetate. Subsequently, the cefuroxime acetyl was dissolved in a polar organic solvent without crystallization, and an aqueous solution containing an inorganic salt was added thereto under slow stirring at room temperature while passing carbon dioxide gas into the solution to precipitate the amorphous cefuroxime axetyl and separated it. And, by drying, high purity amorphous cefuroxime axetyl can be produced in high yield.

The polar organic solvent used in the present invention may be a conventional polar organic solvent, preferably dimethylacetamide, dimethylformamide, dimethyl sulfoxide or mixtures thereof. The concentration of cefuroxime axetyl dissolved in these polar organic solvents may vary depending on necessity, but the organic solvent that dissolves the foamed cefuroxime axetyl is used in a small amount sufficient to dissolve the foamed cefuroxime axetyl. It is preferable to use, for example, it can be used in the ratio of 1: 1-1: 2 (v / w) with respect to foamy cefuroxime acetyl.

The inorganic salt used in the present invention may be a conventional inorganic salt, for example sodium carbonate, sodium hydrogen carbonate and potassium carbonate and the like can be used. Moreover, although the density | concentration of the aqueous solution containing the said inorganic salt changes with kinds of inorganic salt, 0.1 to 2% is preferable normally.

In the production method according to the present invention, unlike the conventional production method, it is not necessary to boil the reaction solution, and preferably, the reaction is performed at 0 to 40 ° C, more preferably 15 to 30 ° C, and most preferably at room temperature. Further, carbon dioxide gas is passed through the reaction solution at a rate of preferably 5 to 25 L / min, more preferably 10 to 20 L / min, most preferably 15 L / min. As described above, the production method according to the present invention does not require high speed (600 to 800 rpm) agitation unlike the conventional production method by using carbon dioxide gas, and even under stirring at 50 to 350 rpm, particularly 150 to 250 rpm. A uniform amorphous cefuroxime acetyl can be prepared without agitation.

In the aqueous solution containing the inorganic salt used in the present invention, water is preferably used in a 10 to 40 volume ratio (v / v) with respect to the organic solvent, and 10 minutes to 2 hours after the addition of the aqueous solution containing the inorganic salt. More preferably, stirring is performed for 30 minutes to 1 hour. In addition, the pH of the solution containing amorphous cefuroxime axetyl in the manufacturing process is preferably 5 to 9, more preferably 6 to 8.

Even under the same conditions as in the present invention, when only water is used instead of an aqueous solution containing an inorganic salt, a non-uniform amorphous cefuroximexetyl may be prepared, and an inorganic salt may be used when carbon dioxide gas is not passed into the solution. Agglomeration may occur when adding or not containing an aqueous solution to cefuroxime axetyl dissolved in a polar organic solvent.

The present invention is explained in more detail by the following examples, but the present invention is not limited in any way by these.

Preparation of Cefuroxime Axetyl in Foam

[Production example]

The foamed cefuroxime axetyl was prepared according to the preparation methods disclosed in British Patent No. 1,571,683 and US Patent No. 4,267,320. That is, 40 g of cefuroxime sodium was added to 220 ml of dimethylacetamide, cooled to 0 ° C., and 25 g of (R, S) -1-bromoethyl acetate was added and stirred at 0 to 1 ° C. for 90 minutes. 1.0 g of potassium carbonate was added thereto, followed by stirring at 0 to 3 ° C for 2 hours. The reaction solution was added to a mixed solution of 400 ml of ethyl acetate and 400 ml of 3% sodium bicarbonate, stirred for 1 hour, and the organic layer was separated. The organic layer was washed sequentially with 200 mL of 1 N hydrochloric acid and 20% brine, and 4 g of activated carbon was added thereto, followed by stirring for 30 minutes. The organic layer was washed with ethyl acetate and distilled under reduced pressure to obtain a foamed cefuroxime acetyl.

Preparation of Amorphous Sepuroxime Axetyl

Example 1

The foamed cefuroxime acetyl prepared in Preparation Example was completely dissolved in 60 ml of dimethylacetamide at room temperature, and then stirred at 200 rpm to supply carbon dioxide gas in an amount of 15 liters per minute to generate bubbles. To this was added a solution in which 3.5 g of sodium carbonate was completely dissolved in 1.6 L of water, followed by stirring for 1 hour. Thereafter, the reaction mixture was filtered under reduced pressure, washed with 200 ml of water, and then vacuum dried at 40 to 45 ° C. for 48 hours to obtain 42.22 g of amorphous cefuroxime acetil as a target product.

Yield: 92.3% (total yield of Preparation Example 1)

HPLC analysis:

Amorphous Sepuroxime Axetyl: 98.1%

Δ ² isomer: 0.11%

Ratio of R isomer / S isomer (HPLC): 1.04 / 1

Water Content (Karl Filscher): 1.0%

Melting Point: 95 ~ 98 ℃

NMR (DMSO-d ₆ , ppm): δ 1.5 (d, 3H), 2.0 (d, 3H), 3.4 to 3.6 (m, 2H), 3.9 (s, 3H), 4.5 to 4.8 (m, 2H), 5.2 (m, 1H), 6.5 to 6.7 (m, 4H), 6.8 to 7.0 (m, 1H), 7.8 (m, 1H), 9.7 (d, 1H)

IR (KBr, cm ⁻¹ ): 3480 to 3210 (NH, NH ₂ complex), 1782 (β-lactam), 1760 (acetate), 1720 (4-ester group), 1720 and 1594 (carbamate), 1676 and 1534 (7-amido)

Example 2

The foamed cefuroxime acetyl prepared in Preparation Example was completely dissolved in 60 ml of dimethylformamide at room temperature, and then stirred at 200 rpm to supply carbon dioxide gas in an amount of 15 L per minute to generate bubbles. Here, a solution in which 2.7 g of sodium hydrogen carbonate was completely dissolved in 1.6 L of water was added at room temperature, followed by stirring for 1 hour. Thereafter, the reaction mixture was filtered under reduced pressure, washed with 200 ml of water, and then vacuum dried at 40 to 45 ° C. for 48 hours to obtain 42.97 g of amorphous cefuroxime acetil as a target product.

Yield: 93.9% (total yield of Production Example and Example 2)

HPLC analysis:

Amorphous Sepuroxime Axetyl: 98.1%

Δ ² isomer: 0.12%

Ratio of R isomer / S isomer (HPLC): 1.03 / 1

Water Content (Karl Filscher): 1.1%

Melting Point: 94 ~ 97 ℃

NMR (DMSO-d ₆ , ppm): δ 1.5 (d, 3H), 2.0 (d, 3H), 3.4 to 3.6 (m, 2H), 3.9 (s, 3H), 4.5 to 4.8 (m, 2H), 5.2 (m, 1H), 6.5 to 6.7 (m, 4H), 6.8 to 7.0 (m, 1H), 7.8 (m, 1H), 9.7 (d, 1H)

IR (KBr, cm ⁻¹ ): 3480 to 3210 (NH, NH ₂ complex), 1782 (β-lactam), 1760 (acetate), 1720 (4-ester group), 1720 and 1594 (carbamate), 1676 and 1534 (7-amido)

Example 3

The foamed cefuroxime axetyl prepared in the above preparation was completely dissolved in 60 ml of dimethyl sulfoxide at room temperature, and stirred at 200 rpm to supply carbon dioxide gas in an amount of 15 L per minute to generate bubbles. A solution in which 4.6 g of potassium carbonate was completely dissolved in 1.6 L of water was added thereto at room temperature, followed by stirring for 1 hour. Thereafter, the reaction mixture was filtered under reduced pressure, washed with 200 ml of water, and then vacuum dried at 40 to 45 ° C. for 48 hours to obtain 42.38 g of amorphous cepuroxime acetil as the target product.

Yield: 92.6% (total yield of Preparation Example 3)

HPLC analysis:

Amorphous Sepuroxime Axetyl: 98.5%

Δ ² isomer: 0.11%

Ratio of R isomer / S isomer (HPLC): 1.04 / 1

Water Content (Karl Filscher): 1.0%

Melting Point: 94 ~ 97 ℃

NMR (DMSO-d ₆ , ppm): δ 1.5 (d, 3H), 2.0 (d, 3H), 3.4 to 3.6 (m, 2H), 3.9 (s, 3H), 4.5 to 4.8 (m, 2H), 5.2 (m, 1H), 6.5 to 6.7 (m, 4H), 6.8 to 7.0 (m, 1H), 7.8 (m, 1H), 9.7 (d, 1H)

IR (KBr, cm ⁻¹ ): 3480 to 3210 (NH, NH ₂ complex), 1782 (β-lactam), 1760 (acetate), 1720 (4-ester group), 1720 and 1594 (carbamate), 1676 and 1534 (7-amido)

Comparative Example 1

According to the method described in Example 22 of Korean Patent Publication No. 91-46, amorphous Sepuroxime Axetyl was prepared as follows.

Cold water was fed in an amount of 750 L per minute into a 5 L plastic beaker equipped with a horizontal opening just below the staging. While the water supplied was further stirred using a paddle stirrer (600 rpm), a stream of nitrogen was supplied in an amount of 12 L per minute to generate bubbles. A crystalline mixture of cefuroxime axetyl R and S isomers (200 g) dissolved in a heated (45 ° C.) mixture of acetone (600 mL) and water (66 mL) was fixed over a period of 13 minutes into a vortex of water using a peristaltic pump. Added at speed. Precipitated amorphous cefuroxime axetyl was collected by flowing through a horizontal opening. The amorphous cefuroxime axetyl product was immediately recovered and dried in vacuo at 55 ° C. to give 170 g (yield: 85%). X-ray crystallography showed that the product was substantially amorphous containing small amounts of crystals.

Solvent Content (GLC): <0.01 m / m

Impurity Content (HPLC): 1.8%

R / S Isomer Ratio: 1.14 / 1

Comparative Example 2

Using cefuroxime sodium as starting material, amorphous cefuroxime axetyl was prepared according to the solvent precipitation method as follows.

A slurry of cefuroxime sodium (20 g) in dimethylacetamide (100 mL) was cooled to 14 ° C and (R, S) -1-bromoethyl acetate (10 mL) was added. The mixture was stirred at 14 ° C. for 45 minutes before anhydrous potassium carbonate (0.5 g) was added. The mixture was further stirred for 45 minutes before ethyl acetate (200 mL) and 3% sodium bicarbonate solution (200 mL) were added. The mixture was stirred at ambient temperature for 1 hour and separated into two layers. The aqueous layer was washed with ethyl acetate (100 mL) and then the organic layer was washed sequentially with 1 M hydrochloric acid (100 mL) and 20% sodium chloride solution (30 mL). The combined organic layers were stirred with activated carbon (2 g) for 30 minutes and then filtered. The filtrate was concentrated in vacuo to 176 mL and water (1.9 mL) was added to the concentrate, which was added to 60-80 ° C. petroleum (1.76 L) stirred over 15 minutes. The precipitated product was filtered off and washed with a mixture of petroleum (105 mL) and ethyl acetate (12 mL) followed by petroleum (118 mL). Vacuum drying at 40 ° C. yielded 17.9 g (yield: 78.27%) of cefuroxime axetyl. The infrared spectrum (new sol) was of a typical amorphous material.

Solvent Content: 1.6% Ethyl Acetate, 1.5% Petroleum

Impurity Content (HPLC): 4.1% m / m

R / S Isomer Ratio: 1.06 / 1

As described above, in Comparative Example 1, amorphous cepuroxime axetyl with purity of 98.2% was obtained in 85% yield from crystalline cepuroxime axetyl, and in Comparative Example 2, amorphous cepuroxime acetyl with purity of 95.9% was purified from cefuroxime sodium. While each was obtained in a yield of%, in the examples of the present invention, all of the amorphous cefuroxime axetyl of purity exceeding 98% from the cefuroxime sodium were obtained in the yield of 92 to 94%. Thus, by using the method of the present invention, not only can the amorphous high purity amorphous cefuroxime axetyl be produced in high yield, but the method of the present invention was found to be much simpler and easier than the conventional method.

According to the present invention, it is possible to prepare an amorphous cefuroxime axetyl with high purity and high yield with excellent dissolution rate in vivo upon oral administration with simple equipment and easy process.

Claims (12)

Dissolving cefuroxime axetil in a polar organic solvent and adding an aqueous solution containing an inorganic salt while passing carbon dioxide (CO ₂ ) gas to precipitate the amorphous cefuroxime axetyl, wherein the amorphous of Formula 1 Method for preparing cefuroxime axetyl: [Formula 1] The process according to claim 1, wherein the cefuroxime axetyl is foamed cefuroxime axetyl prepared by reacting an alkali metal salt of cefuroxime of formula (2) with 1-haloethyl acetate of formula (3). [Formula 2] [Formula 3] Wherein M represents an alkali metal and X represents a halogen. The method of claim 1 wherein the polar organic solvent is selected from the group consisting of dimethylacetamide, dimethylformamide, dimethylsulfoxide and mixtures thereof. The method according to claim 3, wherein the ratio of the polar organic solvent to cefuroxime axetyl is 1: 1 to 1: 2 (v / w). The method of claim 1 wherein the inorganic salt is selected from the group consisting of sodium carbonate, sodium hydrogen carbonate and potassium carbonate. The method according to claim 5, wherein the concentration of the aqueous solution containing the inorganic salt is 0.1 to 2%. The method of claim 1 wherein said step is performed at a temperature of 0-40 ° C. 8. The process according to claim 7, wherein said step is carried out at a temperature of from 15 to 30 ° C. A process according to claim 1 wherein the rate of passage of carbon dioxide gas is 5-25 l / min. 10. The process of claim 9 wherein the rate of passage of carbon dioxide gas is 10-20 L / min. The method of claim 1 wherein said step is carried out with stirring at a speed of 50-350 rpm. The method of claim 11, wherein said step is carried out with stirring at a speed of 150-250 rpm.