KR20000013423A - Synthesis of amorphous cephroxim acetyl - Google Patents

Abstract

PURPOSE: A synthetic method is provided which omits a crystallization stage by addition of side reaction inhibitors. CONSTITUTION: Cefuroxime sodium is esterified using the side reaction inhibitors such as transition metal, alkali metal halide, zinc chloride, zinc bromide, zinc iodide, sodium iodide, followed by dispersion in a solvent such as water, hexane, cyclohexane or isopropyl ether to give 1-acetoxyethyl(6R, 7R)-3-carbamoyloxymethyl-7-£(z)-2-(fur-2- yl)-2-methoxy-iminoacetamido|cefu-3-em-4-carboxylate. For example, 40ml of dimethyl acetamide, 10g of Cefuroxime sodium and 5g zinc chloride are stirred at 10 degree C for 30 minutes, followed by addition of 3.6ml of ethyl bromoacetate at 10 degree C for 2 hours. A separated organic fraction is dispersed in 900ml of isopropyl ether to give the title compounds.

Description

Synthesis of Amorphous Sepuroxime Axetyl

The present invention relates to cefuroxime acetyl (1-acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacet Amido] sef-3-em-4-carboxylate) was added to the synthesis reaction to minimize the formation of side reactants, thereby minimizing the formation of side reactants, followed by high purity amorphous cefu directly without crystallization from the reaction solution. A novel process for preparing Roxime Axetyl.

Cepuroxime axetyl is an antibiotic for oral administration that shows useful physiological activity against a wide range of Gram-positive and Gram-negative microorganisms. This antibiotic is orally administered and then rapidly absorbed in the intestinal tract and is easily deesterified by esterases in the blood to exhibit intrinsic antibiotic action by favoring cepuroxime. Sepuroxime released in the body has high stability against beta-lactamase, a substance that causes microbial antibiotic resistance by producing microorganisms and breaking down beta-lactam antibiotics. Is keeping.

Cefuroxime axetyl is known to be crystalline and amorphous in its properties. Generally, oral administration has a better effect than amorphous to facilitate disintegration and absorption of the preparation in the intestinal tract after administration. It is widely known to represent.

Sepuroxime axetyl is described in Korean Patent Publication No. 83-1543 and British Patent 1353049 for its synthesis method. In order to synthesize cefuroxime acetil according to these methods, basically, first, disperse or dissolve cefuroxime sodium in a suitable inert solvent, and then react with this solution by adding 1-bromoethyl acetate to the resulting cefuroxime acetyl. It is known to separate and purify using a suitable method.

In order to prepare the cefuroxime acetil in the amorphous state, first, the cefuroxime acetil is synthesized, and then the cefuroxime acetyl in the impure solution obtained by removing the remaining by-products and the solvent of the reaction, which is used in the reaction, is prepared. It can be easily obtained by dispersing directly in a second solvent having low solubility with respect to axetyl. However, the cepuroxime acetil obtained in this way is substantially amorphous, but since some impurities are not removed in the manufacturing process, the actual purity of the prepared cepuroxime axetyl is difficult to accept for medical use. Dropped to a degree.

Therefore, the substantially high purity amorphous amorphous cepuroxime axetyl is described first in the Republic of Korea Patent Publication No. 91-8377 and Republic of Korea Patent Publication No. 91-47, sepuroxime axetyl synthesized by a chemical reaction first high purity It is known to obtain amorphous cepuroxime axetyl by an appropriate method using a crystalline cefuroxime axetyl thus obtained after purification through crystalline cefuroxime axetyl. At this time, as a method of obtaining amorphous cefuroxime axetyl from crystalline cefuroxime axetyl, a rapid solvent removal method, a solvent precipitation method, a freeze drying method, a spray drying method and a roller drying method are known. The substantially amorphous cepuroxime axetyl thus obtained is known to contain less than 3% impurities by weight, and other residual solvents are known to comprise less than 6% by weight, preferably less than 2% by weight. Representative impurities present at this time are the corresponding delta 2- and anti-isomers of cefuroxime axetyl, and unesterified cefuroxime.

However, in this method, it is a fundamental disadvantage to unnecessarily separate crystalline cefuroxime acetyl in order to prepare amorphous cefuroxime axetyl. This process is a necessary purification step because there are a lot of side reactions generated in the reaction mixture when synthesizing cefuroxime axetyl, and it is not easy to remove them economically easily.

As described in Korean Patent Publication No. 83-1543, cefuroximexetyl was synthesized in a conventional manner, and a part of the synthetic reaction stock solution at that time was analyzed by high-performance liquid chromatography, which corresponds to the equivalent of cefuroxime axetyl. It is known that delta2-isomers and E-isomers together form at least 2-3%, and at least 10%, respectively (exemplified in US Pat. No. 5498787).

In this regard, U. S. Patent No. 5498787 already describes a method for reducing the amount of delta2-isomers produced together in the synthesis of cefuroxime axetyl. According to this technique, at the time of preparing cefuroxime acetyl, at least 30% to 40% or more of quaternary ammonium salts, particularly preferably monobutyl sulfate of sabutylammonium, are converted to the molecular weight ratio of cefuroxime sodium as a raw material. It has been described that the addition of to can significantly reduce the production of delta2-isomers. The disadvantage of this technique is that it is not only a relatively expensive amount, but also a relatively inexpensive material because of the high molecular weight of the monohydrosulfate of tetrabutylammonium used to achieve the desired results. This is a relatively economical technology because it is reflected in the manufacturing cost of cefuroxime axetyl as it is. Another drawback of this technique is that the sabutylammonium salt is particularly a substance with high surface activity, which causes a great deal of difficulty in the process of separating and purifying cefuroxime axetyl.

Therefore, the inventors have invented a new method for the preparation of cefuroxime axetyl, which is simpler and more economical, directly from the reaction solution. According to this method, it is possible to prepare an amorphous cefuroxime axetyl by eliminating the step of crystallization in order to remove the reaction by-product from the synthetic reaction solution.

The key to this new technology is to minimize the occurrence of unwanted side reaction products generated during the synthesis of cefuroxime axetyl. In other words, by adding an appropriate amount of side reaction inhibitor to the reactants during the synthesis reaction of cefuroxime axetyl to suppress the generation of side reactions, thus, crystalline cefuroxime axetyl is prepared first as in the conventional method, and then amorphous cefuroxime axetyl is prepared. It is possible to prepare cefuroxime axetyl in an amorphous form directly after the reaction without the cumbersome process.

The new technique devised by the researchers adds a certain amount of salts of certain metals to the reaction system as side reaction inhibitors that minimize side reaction products. At this time, as a suitable metal salt, a salt of a transition metal such as copper, iron, zinc, or an alkali acid of an alkali metal may be used. In particular, salts such as hydrochloric acid, hydrobromic acid, or hydroiodic acid of zinc, and hydroiodic acid salts of sodium show particularly preferable results. When using these salts, cefuroxime acetyl can be prepared by adding cefuroxime sodium and the metal salt in a constant ratio to a suitable solvent such as dimethylacetamide and dissolving it, and then adding an appropriate amount of an esterification reagent. The amount of the metal salt added at this time can be used from 5% to 100% by weight with respect to cefuroxime sodium. Preferably, the metal salt may be used in a weight ratio of 20% to 60% with respect to cefuroxime sodium. The reaction can usually be carried out conveniently in the range of -10 ° C to 50 ° C, preferably in the range of 10 ° C to 30 ° C. In fact, when synthesizing cefuroxime axetyl using this technology, the reaction solution is taken and analyzed by high-performance liquid chromatography to confirm that delta2-isomer is produced at 0.1% or less. However, the comparative experiments show that when synaproximexetyl is synthesized in a conventional manner, delta2-isomers are generated in amounts of 2 to 3%, and as much as 10% (see US Pat. No. 5498787).

After completion of the reaction, the cefuroxime acetyl can be separated from the reaction mixture using a mixture of sodium bicarbonate water and a suitable organic solvent. The suitable organic solvent that can be used at this time should be one that can be easily separated because the solubility of cefuroxime axetyl is large and does not mix with water, preferably ethyl acetate, methyl acetate, methyl chloride and the like can be used. The organic solution containing separated cefuroxime axetyl is pure enough to be used to prepare amorphous cefuroxime axetyl as it is after drying, bleaching, properly concentrating and removing the solvent.

In order to prepare amorphous cefuroxime axetyl using this concentrated solution, various methods such as dispersion precipitation in an insoluble solvent, spray drying, rapid solvent removal, and freeze drying, which are commonly used, are prepared. have. At this time, if necessary, the solvent may be changed to another solvent which is more suitable for the production method.

For example, in the case where it is desired to prepare amorphous cefuroxime axetyl directly using solvent precipitation, the solution of cefuroxime axetyl obtained after the reaction and purification carried out according to the technique of the present invention is dispersed in an excess of insoluble solvent. The resulting amorphous solids can then be easily obtained amorphous by filtration and drying. Suitable insoluble solvents that may be used at this time include, but are not limited to, isopropyl ether, petroleum ether, water, and hexane.

The amorphous cefuroxime axetyl obtained by this technique has a sufficient purity for medical use after proper drying to remove residual solvents and the results of X-ray diffraction and microscopic examination are substantially amorphous. Indicates. Substantially amorphous cefuroxime axetyl also exhibits a distinct melting point from the crystalline form.

Comparative Example 1 and the examples of the present invention described below are sufficient to show the superiority of this new manufacturing method. However, the scope of the present invention is not limited thereto.

Comparative Example 1 (Reaction by the method of Korean Patent Publication No. 83-1543)

Sepuroxime sodium (10 g) was added to dimethylacetamide (55 mL) at 0 ° C, ethyl bromoacetate (6.25 g) was added, followed by stirring at the same temperature. After stirring for 90 minutes at 1 ° C., anhydrous potassium carbonate (0.25 g) was added and stirring continued.

After a total of 2 hours of reaction, the reaction mixture was poured into a mixture of saturated sodium bicarbonate (50 mL), saturated brine (50 mL) and ethyl acetate (100 mL), stirred vigorously for 45 minutes, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (50 ml) to separate the organic layer, and the organic layers thus obtained were combined. The resulting organic solution was washed with a mixture of 2N hydrochloric acid (40 mL) and saturated brine (40 mL), followed by successively washing with 3% sodium bicarbonate (60 mL) and saturated brine (60 mL). The organic solution was dried over anhydrous magnesium sulfate, activated carbon (2 g) was added thereto, decolorized for 30 minutes, and filtered through celite. The resulting clear colorless solution was distilled under reduced pressure, concentrated to 125 g, and dispersed in isopropyl ether (900 mL) with vigorous stirring. The obtained solid was filtered quickly and the residual solvent was removed for 2 days under high vacuum at 50 ° C. 8.44 g (74.0%) of white, amorphous cepuroxime axetyl was obtained.

Purity of cefuroxime axetyl: impurity delta2-isomer 3.10%, anti-isomer 0.43%.

Isomer ratio of Sepuroxime Axetyl: (1: 1.03)

Example 1

Cefuroxime sodium (10 g) and zinc chloride (5 g) were added to dimethylacetamide (40 ml), and the mixture was stirred at 10 ° C for 30 minutes. Ethyl bromoacetate (3.6 ml) was added and then stirred for another 2 hours at the same temperature. The reaction mixture was poured into a mixture of saturated sodium bicarbonate (50 mL), saturated brine (50 mL) and ethyl acetate (100 mL), stirred vigorously for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (50 mL) to separate the organic layer, and the organic layers thus obtained were combined. The resulting organic solution was washed with a mixture of 2N hydrochloric acid (40 mL) and saturated brine (40 mL), followed by successively washing with 3% sodium bicarbonate (60 mL) and saturated brine (60 mL). The organic solution was dried over anhydrous magnesium sulfate, activated carbon (2 g) was added thereto, decolorized for 30 minutes and filtered through celite. The resulting clear colorless solution was distilled under reduced pressure, concentrated to 125 g, and dispersed in isopropyl ether (900 mL) with vigorous stirring. The solid obtained was filtered quickly and the residual solvent was removed for 2 days under high vacuum at 40 ° C. 9.69 g (85%) of white, amorphous cepuroxime axetyl was obtained. The cefuroxime axetyl produced by this method can be seen to be substantially amorphous by X-ray diffraction analysis and microscopy.

NMR (CDCl ₃ , ppm) 7.51 (1H) 7.39 (1H) 7.12 (0.5H) 6.99 (0.5H) 6.89 (1H) 6.48 (1H) 5.96 (1H) 5.13 ~ 4.79 (6H) 4.09 (3H) 3.66 ~ 3.42 (2H) 2.11 (3H) 1.55 (3H)

Purity of Sepuroxime Axetyl: 98.5% (weight ratio, HPLC)

Impurities: Delta 2-isomer 0.1%, Anti-isomer 0.15%

Isomer ratio of Sepuroxime Axetyl: (1: 1.03)

Residual Solvent Content: 0.5%

Melting Point: 95 ~ 97 ℃

Example 2

Cefuroxime sodium (10 g) and zinc iodide (5 g) were added to dimethylacetamide (40 mL), and the mixture was stirred at 10 ° C for 30 minutes. Ethyl bromoacetate (3.6 ml) was added and then stirred for another 2 hours at the same temperature. The reaction mixture was poured into a mixture of saturated sodium bicarbonate (50 mL), saturated brine (50 mL) and ethyl acetate (100 mL), stirred vigorously for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (50 mL) to separate the organic layer, and the organic layers thus obtained were combined. The obtained organic solution was washed with a mixed solution of 2N hydrochloric acid (40 ml) and saturated brine (40 ml), followed by successively washing with 3% sodium bicarbonate (60 ml) and saturated brine (60 ml). The organic solution was dried over anhydrous magnesium sulfate, activated carbon (2 g) was added thereto, decolorized for 30 minutes and filtered through celite. The resulting clear colorless solution was distilled under reduced pressure, concentrated to 125 g, and dispersed in vigorous stirring with normal hexane (900 mL). The obtained solid was filtered quickly and the residual solvent was removed for 2 days by 40 degreeC hot air. 10.03 g (88%) of white, amorphous cepuroxime axetyl was obtained. The cefuroxime axetyl produced by this method can be seen to be substantially amorphous by X-ray diffraction analysis and microscopy.

Purity of Sepuroxime Axetyl: 98.5% (weight ratio, HPLC)

Impurities: Delta 2-isomer 0.1%, Anti-isomer 0.2%

Isomer ratio of Sepuroxime Axetyl: (1: 1.03)

Residual Solvent Content: 0.5%

Melting Point: 95 ~ 97 ℃

Example 3

The same procedure as in Example 2 was carried out, but amorphous was prepared using cyclohexane instead of normal hexane. 9.92 g (87%) of white amorphous cefuroxime axetyl was obtained.

Purity of Sepuroxime Axetyl: 98.8% (weight ratio, HPLC)

Impurities: Delta 2-isomer 0.1%, Anti-isomer 0.2%

Isomer ratio of Sepuroxime Axetyl: (1: 1.03)

Residual Solvent Content: 0.5%

Melting Point: 94 ~ 96 ℃

Example 4

Cefuroxime sodium (10 g), anhydrous magnesium sulfate (5 g) and sodium iodide (5 g) were added to dimethylacetamide (40 mL), and the mixture was stirred at 10 ° C for 30 minutes. Ethyl bromoacetate (3.6 mL) was added and further stirred at the same temperature for 3 hours. The reaction mixture was poured into a mixture of saturated sodium bicarbonate (50 mL), saturated brine (50 mL) and ethyl acetate (100 mL), stirred vigorously for 30 minutes, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (50 ml) to separate the organic layer, and the organic layers thus obtained were combined. The resulting organic solution was washed with a mixture of 2N hydrochloric acid (40 mL) and saturated brine (40 mL), followed by successively washing with 3% sodium bicarbonate (60 mL) and saturated brine (60 mL). The organic solution was dried over anhydrous magnesium sulfate, activated carbon (2 g) was added thereto, decolorized for 30 minutes and filtered through celite. The clear, colorless solution obtained was distilled under reduced pressure, and the residue was dissolved in acetone (45 mL) and dispersed in distilled water (500 mL) with vigorous stirring. The obtained solid was quickly filtered, dehydrated and dried for 2 days at 40 ° C. 9.46 g (83%) of white, amorphous cepuroxime axetyl was obtained.

Purity of Sepuroxime Axetyl: 98.8% (weight ratio, HPLC)

Impurities: Delta 2-isomer 0.1%, Anti-isomer 0.1%

Isomer ratio of Sepuroxime Axetyl: (1: 1.09)

Melting Point: 95 ~ 97 ℃

Moisture Content: 1.4%

Part of the reaction solution (0.1 mL) was taken at a certain time while the reaction was carried out according to the method of Comparative Example 1, and immediately analyzed by high performance liquid chromatography. In addition, the sample was taken in the same manner and the analysis was carried out under the same conditions while the reaction was carried out according to the method of Example 1. The amount of delta 2-isomer compound produced as a result of analysis is shown in Table 1 as%.

Time response 30 minutes 45 minutes 60 minutes 90 minutes 120 minutes Comparative Example 1 0.86 0.95 1.00 1.70 2.30 Example 1 0.008 0.04 0.06 0.07 0.09

Amorphous cefuroxime axetyl obtained directly after carrying out the reaction according to Comparative Example 1 has a large amount of impurities and is not suitable for use in medicine as it is. However, as shown in Table 1, what is obtained according to the embodiment of the present invention is a high purity amorphous cefuroxime acetyl, so it can be used for medical purposes as it is.

Claims (3)

In preparing cefuroxime axetyl by esterifying cefuroxime sodium, an amorphous cefuroxime accessory is prepared by dispersing the product in a second solvent without using a crystallization process, using a halide salt of a transition metal or an alkali metal as a side reaction inhibitor. How to make teal. The method of claim 1, wherein zinc chloride, zinc bromide, zinc iodide or sodium iodide is used as a side reaction inhibitor. The method of claim 1 wherein the second solvent is water, hexane, cyclohexane or isopropyl ether.