KR20010011909A - Method for producing crystalline cefuroxime axetil - Google Patents

Abstract

PURPOSE: A method for producing crystalline Cefuroxime axe til ester is provided for mass-producing effectively and safely high purity crystalline cefuroxime axetil ester in higher yield. CONSTITUTION: The crystalline cefuroxime axetil ester having about 1:1 of R:S isomer ratio, is produced from the reaction solution containing cefuroxime axetil ester by using a first solvent selected from acetic acid ethyl, acetic acid methyl or isopropanol alcohol and a second solvent of cyclohexene, in which the first solvent is used firstly to crystalize cefuroxime axetil ester then the second solvent is used or the first solvent and the second solvent are used together to crystallize cefuroxime axetil ester, in a ratio of the first solvent to second solvent of 1:1 to 1:3, preferably 1:1.8 to 1:2.5, and the crystallization is performed at 5 to 35deg.C.

Description

Method for producing crystalline cefuroxime axetyl ester {Method for producing crystalline cefuroxime axetil}

The present invention relates to an improved process for the preparation of high purity crystalline cefuroxime axetyl esters, in particular using a specific crystallization solvent to produce high purity crystalline cefuroxime axetyl esters having an R: S isomer ratio of about 1: 1. It relates to a manufacturing method.

Sepuroxime 1-acetoxy ethyl ester represented by the following general formula (1) (1-acetoxyethyl (6R, 7R) -3-carbamoyloxymethyl-7-[(Z) -2- (fur-2) -Yl) -2-methoxyiminoacetamido] sef-3-m-4-carboxylic acid) ("cefuroxime axetyl") has a broad spectrum of antibacterial activity against gram negative and gram positive microorganisms. Have In particular, since it is very stable against β-lactamase produced by gram-negative microorganisms, antimicrobial activity is increased and resistance in mammals is widely used as an antibiotic. This compound is also an antibiotic that is well absorbed in the gastrointestinal tract after oral administration and is very potent, for example described in US Pat. No. 4,267,320 and UK Pat. No. 2,145,409.

(I)

The cefuroxime axetyl ester of the general formula (1) has an asymmetric carbon atom in the first position so that it exists in the form of isomers of R and S or mixtures thereof, while the ratio of isomers of R and S is about 1: 1. The importance of the crystallization method of cefuroxime axetyl ester has been highlighted because of the benefit of the case. This is because it is not easy to obtain R and S isomers by determining the isomer ratio of 1: 1. The crystalline form of cefuroxime axetyl ester having an isomer ratio of R and S of about 1: 1 has a high bioavailability when administered orally, and an amorphous form of cefu that has more suitable properties than the crystalline form of material for commercial use. It is a useful material as a starting material for the preparation of roxime axetyl ester. Therefore, a product having a high ratio of isomeric ratio of R and S of about 1: 1 is required.

On the other hand, a number of patents have been reported on the method for preparing cefuroxime axetyl ester. For example, US Pat. No. 4,267,320 uses a mixed solvent of isopropyl ether in a process for crystallization after completion of the reaction to form the cefuroxime axetyl ester, which method comprises a 1: 1 mixture of R: S isomers. Although it can be obtained, there is a disadvantage that there is a risk of explosion in mass production due to the low flash point of the solvent used.

British Patent No. 2,146,409 provides a method of using ethyl acetate and isopropyl ether solvent system in the preparation of cefuroxime axetyl ester, according to which the impurities Δ2-isomer and E-isomer are 0.5-0.7%, respectively. There are disadvantages involved.

Korean Patent Publication No. 91-8377 also discloses a process for preparing crystalline cefuroxime axetyl. Particularly, cefuroxime axetyl prepared by a conventional general preparation method (UK Patent No. 1,571,683) is dissolved in a suitable solvent and crystallized. It discloses a method for separating it. Solvents disclosed as suitable solvents in this invention are ethers, ethers that can be mixed with hydrocarbons, halogenated hydrocarbons that can be mixed with hydrocarbons, ketones mixed with water, amides mixed with water, or alcohols that can be mixed with water. According to this method, however, the impurities Δ2-isomers and E-isomers are contained in an amount of 0.1-0.5% and 0.6-0.7%, respectively.

In addition, Korean Patent Publication No. 98-082654 discloses a method for preparing crystalline cefuroxime axetyl, and Korean Patent Publication No. 98-082654 discloses the preparation of cefuroxime axetyl under isopropyl alcohol and normal hexane. A method for preparing cefuroxime axetyl in mixed solvents is disclosed.

Therefore, it has been desired to provide a new method for crystallization of cefuroxime axetyl ester which does not have the above disadvantages.

The present invention provides a process for the safe production of high purity cefuroxime axetyl ester crystals in an isomer ratio of about 1: 1.

According to the method of the present invention, cefuroxime axetyl is obtained in a ratio of about 1: 1 from the cefuroxime axetyl solution obtained by reacting cefuroxime acid with 1-bromo ethyl acetate and potassium carbonate in a dimethylacetamide solvent. For example, a method of crystallizing at an R: S isomer ratio of about 0.9 to 1.1: 1 ratio is provided.

According to the present invention, in the process for producing the cefuroxime acetyl ester crystals from the reaction solution containing the cefuroxime acetyl ester, a primary solvent selected from ethyl acetate, methyl acetate or isopropanol alcohol as the crystallization solvent; A process for the preparation of cefuroxime axetyl ester crystals, which is used in combination with a secondary solvent of cyclohexene, is provided.

In the process of the present invention, the cefuroxime axetyl solution prepared as above is crystallized with one solvent ('primary solvent') selected from methyl acetate, ethyl acetate or alcohol, and then simultaneously or simultaneously cyclohexene ('2 Primary solvent '), which allows the crystalline cefuroxime acetyl ester having a high purity and an isomer ratio of R: S of about 1: 1 to be obtained in high yield. The primary solvent and the secondary solvent may be added to the reaction solution sequentially in this order, or may be added as a mixed solvent from the beginning.

In the case of dissolving and recrystallizing the cefuroxime crystals, a primary solvent is added to crystallize, followed by addition of a secondary solvent to complete the crystallization. The reaction solution containing cefuroxime axetyl may be washed with an acidic aqueous solution and a basic solution, and then the purified cefuroxime axetyl solution may be concentrated to a degree that does not affect crystallization.

After the cefuroxime axetyl crystal is completely formed by crystallization with a secondary solvent, the purity of the target object can be improved by washing the crystal using a mixed solvent of a primary solvent and a secondary solvent.

The ratio of the primary solvent to the secondary solvent used in the crystallization step is not particularly limited so long as it does not affect the ratio of the R and S isomers, but it is about 1: 1 to 1: 3 by volume, preferably about 1: 1.8 to 1 It can be selected in the range of volume ratio of: 2.5. If the ratio of the secondary solvent is low, the ratio of R to S is out of the desired range, and if the ratio of the secondary solvent is high, there is a problem that impurities are increased. If a predetermined amount of the primary solvent is already present in the reaction liquid before the crystallization step with the primary solvent, an appropriate amount of the primary solvent is added to the reaction liquid to determine the volume of the total primary solvent present in the reaction liquid. The proportion of the volume of the binary solvent can be adjusted within the scope of the present invention.

In the method of the present invention, the temperature at the time of crystallization is not limited as long as it does not affect the crystallization, but can be suitably selected in the range of 5 to 35 ° C.

Hereinafter, the configuration and operation of the present invention will be described in detail with reference to Examples, but the present invention is not limited only to these Examples.

Comparative Example 1

Cefuroxime acid acetyl was synthesized in a similar manner to Example 1 of US Pat. No. 4,267,320. 4.88 g of potassium carbonate and 25 g of cefuroxime acid were stirred in 100 ml of dimethylacetamide, and the mixture was cooled to 5-10 C with 14.81 g of 1-bromo ethyl acetate solution. After the reaction solution was further reacted for 4 hours, a mixed solution of 250 ml of ethyl acetate and 250 ml of 3% aqueous sodium bicarbonate solution was poured and stirred for 1 hour. The organic layer was washed with 125 ml of 1N hydrochloric acid solution and then with 35 ml of 20% sodium chloride and 2% sodium bicarbonate solution. The organic layer was again decolorized with 2.5 g of activated carbon, filtered, and washed with 100 ml of ethyl acetate. The filtrate was concentrated under reduced pressure at 35 ° C., evaporated to 187 g, and crystallized by stirring at room temperature for 1 hour. 312 ml of diisopropyl ether was added dropwise thereto for 40 minutes to complete crystallization. The resulting crystals were filtered, washed with a mixed solution of ethyl acetate and diisopropyl ether, and then dried at 35 ° C. to obtain 24.5 g of crystalline cefuroxime acetyl.

¹ H-NMR (DMSO-d ₆ , 300mHz): 1.53 (1d, 3H), 2.07 (s, 3H), 3.57 (br, s, 2H), 3.97 (s, 3H), 4.83 (br, s, 2H ), 5.85 (Abq, 1H), 6.20 (br, s, 2H), 67.47 ~ 6.8 (m, 2H), 6.90 ~ 7.20 (q, 1H), 7.60 (br, s, 1H), 9.63 (d, 1H )

Isomer Ratio (HPLC): 0.52 (Isomer A / (Isomer A + Isomer B))

Purity (HPLC): 98%

Δ2-isomer: 0.05%, E-isomer: 0.05%

Yield: 81.5%

Example 1

After cooling 9.77 g of potassium carbonate and 50 g of cefuroxime to 200 ml of dimethylacetamide, the mixture was cooled to 5 to -10 ° C and 29.6 g of 1-bromo ethyl acetate solution was added thereto. After the reaction solution was further reacted for 4 hours, a mixed solution of 500 ml of ethyl acetate and 500 ml of 3% sodium bicarbonate aqueous solution was poured and stirred for 1 hour. The layers were separated and the organic layer was washed with 250 ml of 1N hydrochloric acid solution and then with 20% sodium chloride and 2% sodium bicarbonate solution. The organic layer was again decolorized with 5 g of activated carbon, filtered and washed with 200 ml of ethyl acetate. The decolored solution was concentrated under reduced pressure to concentrate the concentrate to 374 g, and crystallized by stirring at room temperature for 1 hour. 624 ml of cyclohexene was added thereto for 30 minutes to complete crystallization. The resulting crystals were filtered and washed with a mixed solvent of ethyl acetate and cyclohexene and dried at 35 ° C. to obtain 49.5 g of crystalline cefuroxime acetyl.

¹ H-NMR (DMSO-d ₆ , 300mHz): 1.53 (1d, 3H), 2.07 (s, 3H), 3.57 (br, s, 2H), 3.97 (s, 3H), 4.83 (br, s, 2H ), 5.85 (Abq, 1H), 6.20 (br, s, 2H), 67.47 ~ 6.8 (m, 2H), 6.90 ~ 7.20 (q, 1H), 7.60 (br, s, 1H), 9.63 (d, 1H )

Isomer Ratio (HPLC): 0.52 (Isomer A / (Isomer A + Isomer B))

Δ2-isomer: 0.03% or less, E-isomer: 0.03% or less

Purity (HPLC): 99%

Yield: 82.3%

Example 2

The cefuroxime acetyl solution prepared in the same manner as in Example 1 was concentrated under reduced pressure and evaporated to 60 g, and 320 ml of methyl acetate was added thereto, followed by crystallization by stirring at room temperature for 1 hour. 624 ml of cyclohexene was added dropwise thereto for 30 minutes to complete crystallization. The resulting crystals were filtered off, washed with a mixed solution of methyl acetate and cyclohexene, and then dried at 35 ° C. to obtain 48.2 g of crystalline cefuroxime acetyl.

Isomer Ratio (HPLC): 0.515 (Isomer A / (Isomer A + Isomer B))

Purity (HPLC): 99%

Δ2-isomer: 0.03% or less, E-isomer: 0.03% or less

Yield: 80.1%

Example 3

The cefuroxime axetyl solution prepared in the same manner as in Example 1 was concentrated under reduced pressure and evaporated to 60 g, and 320 ml of isopropyl alcohol was added thereto and stirred at room temperature for 1 hour to crystallize. 624 ml of cyclohexene was added dropwise thereto for 30 minutes to complete crystallization. The resulting crystals were filtered off, washed with a mixture of isopropyl alcohol and cyclohexene, and then dried at 35 ° C. to obtain 49.4 g of crystalline cefuroxime acetyl.

Isomer Ratio (HPLC): 0.518 (Isomer A / (Isomer A + Isomer B))

Purity (HPLC): 99%

Δ2-isomer: 0.04% or less, E-isomer: 0.04% or less

Yield: 82.1%

As described above, the method of the present invention has the advantage of industrially and safely obtaining high purity and high yield of crystalline cefuroxime acetyl ester by using a specific crystallization solvent, and thus is very useful for the antibiotic pharmaceutical industry.

Claims (6)

In the process for producing the cefuroxime 1-acetoxyethyl ester crystals from the reaction solution containing the cefuroxime 1-acetoxyethyl ester, one primary selected from ethyl acetate, methyl acetate or isopropyl alcohol as a crystallization solvent A process for producing cefuroxime 1-acetoxyethyl ester crystals comprising using a solvent together with a secondary solvent of cyclohexene. The method according to claim 1, wherein the crystallization is carried out with a primary solvent, followed by crystallization with a secondary solvent. The method according to claim 1, wherein the crystallization is carried out using a mixed solvent of a primary solvent and a secondary solvent. The method of claim 1, wherein the ratio of the primary solvent to the secondary solvent is in the range of 1: 1 to 1: 3 volume ratio. The method of claim 4, wherein the ratio of the primary solvent to the secondary solvent is in the range of 1: 1.8 to 1: 2.5 by volume. The production method according to claim 1, wherein the crystallization is performed at a temperature of 5 to 35 deg.