KR100378731B1 - Method for producing crystalline cefuroxime axetil ester - Google Patents

Abstract

The present invention provides a process for producing the cefuroxime 1-acetoxyethyl ester crystal from the reaction solution containing the cefuroxime 1-acetoxyethyl ester such that the ratio of the R: S isomer is 0.98: 1.02. In the method of the present invention, the use of one primary solvent selected from ethyl acetate, methyl acetate or isopropyl alcohol and one secondary solvent selected from hexenes or heptene as a crystallization solvent is used. It features. By this method, cefuroxime 1-acetoxy ethyl ester can be safely mass-produced in high yield and high purity.

Description

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

FIELD OF THE INVENTION The present invention relates to an improved process for preparing high purity crystalline cefuroxime acetyl esters, wherein high purity of crystalline cefuroxime axetyl esters having a R: S isomer ratio of about 1: 1 is achieved using certain crystallization solvents. It's about how to do it.

The compound represented by the following formula (1) is cefuroxime 1-acetoxyethyl ester having a very broad antimicrobial activity spectrum for gram negative and gram positive microorganisms, especially for β-lactase produced by gram negative microorganisms. As it is stable, it is widely used as an antibiotic because of its increased antibacterial resistance and excellent resistance in mammals. In addition, the compound is a highly effective antibiotic that is well absorbed in the gastrointestinal tract after oral administration, and known technologies for this compound include US Pat. No. 4,627,320 and UK Pat. No. 2,145,409.

... (I)

The process for preparing the cefuroxime acetyl ester of formula (1) in crystalline form is of great importance. The reason is that by having an asymmetric carbon atom in the first position of the cefuroxime axetyl ester represented by the formula (1), it exists in the form of an isomer of R and S or a mixture thereof. In general, although the ratio of the isomer ratio of R and S is about 1: 1, it is not easy to obtain a crystal with an isomer ratio of 1: 1. In addition, the crystalline form of Formula (1) is an amorphous form of the crystalline cefuroxime axetyl ester of Formula (1), which has a high bioavailability when administered orally and has properties that are more suitable than commercially available forms of substance for use. As a useful starting material for the preparation of the form, a product with high purity and an isomer 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, UK Pat. No. 2,146,409, UK Pat. No. 1,571,683, Korean Patent Publication No. 91-8377, Korean Patent Publication No. 1998-082654, and the like, prepare a method for producing cefuroxime acetyl ester in various mixed solvent systems. Although the method described in these patents contains a considerable amount of Δ2-isomer and E-isomer as impurities, the ratio of R and S isomers is about 49 to 51 to 48 to 52. have. Therefore, there is a need to provide a new method of crystallization of a pureer cefuroxime acetyl ester having a ratio of 50 to 50 with an isomer ratio of R and S without having 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 present invention, the cefuroxime axetyl solution from the cefuroxime axetyl solution obtained by reacting cefuroxime acid with 1-bromo ethyl acetate and potassium carbonate in a dimethylacetamide solvent at a ratio of about 1: 1, for example 0.98 A method of crystallizing with an R: S isomer ratio of 1: 1 to 1.02: 1 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, one primary solvent selected from ethyl acetate, methyl acetate or isopropyl alcohol as the crystallization solvent There is provided a process for producing cefuroxime axetyl ester crystals, which is used in combination with one kind of secondary solvent selected from hexene or heptene.

In the process of the present invention, the cefuroxime axetyl solution prepared as described above is crystallized with a solvent (primary solvent) selected from methyl acetate, ethyl acetate or isopropyl alcohol, and simultaneously or at the same time selected from hexene or heptene. It is characterized by crystallization with a solvent (secondary solvent), thereby making it possible to obtain crystalline cefuroxime axetyl ester having a high purity and an isomer ratio of R: S of about 1: 1.

As the primary and secondary solvents, ethyl acetate and hexene, methyl acetate and hexene, ethyl acetate and heptene, methyl acetate and heptene or isopropyl alcohol and hexene, isopropyl alcohol and heptene solvent system may be used, respectively. Use ethyl acetate and hexene, methyl acetate and hexene or isopropyl alcohol and hexene solvent. The primary solvent and the secondary solvent may be sequentially added to the reaction solution, or may be added as a mixed solvent from the beginning.

Hexene or heptene used as the secondary solvent in the method of the present invention has one double bond in the molecule, and the position of the double bond may be any one, two or three positions.

The reaction solution containing cefuroxime axetyl may be washed with an acidic aqueous solution and a basic aqueous 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 is not particularly limited as long as it does not affect the ratio of the R and S isomers, but the ratio of the volume ratio of about 1: 1 to 1: 3, preferably about 1: 1.8 to 1: 2.5 Can be selected in a range.

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 preferably can be selected in the range of 5 ~ 35 ℃.

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

As shown in US Pat. No. 4,267,320, 200 ml of dimethylacetamide was cooled to 5-10 DEG C while stirring 9.77 g of potassium carbonate and 50 g of cefuroxime acid, and 29.6 g of 1-bromo ethyl acetate 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 organic layer was washed with 250 ml of 1N hydrochloric acid solution, followed by 20% sodium chloride and 2% sodium bicarbonate solution. The organic layer was further decolorized with 5 g of activated carbon, filtered and washed with 200 ml of ethyl acetate. The decolored solution is concentrated to 374 g and crystallized by stirring at room temperature for 1 hour. 624 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 49.0 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: 0.15%, E-isomer: 0.15%

Yield: 81.67%

Example 1

To 200 ml of dimethylacetamide, 9.77 g of potassium carbonate and 50 g of cefuroxime were cooled to 5-10 DEG C while stirring, and 29.6 g of 1-bromo ethyl acetate 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 further decolorized with 5 g of activated carbon, filtered and washed with 200 ml of ethyl acetate. The decolorized solution was concentrated under reduced pressure to 374 g, and crystallized by stirring at room temperature for 1 hour. 624 ml of hexene was added thereto for 30 minutes to complete crystallization. The resulting crystals were filtered, washed with a mixture of ethyl acetate and hexene, and then dried at 35 ° C. to obtain 50.5 g of crystalline cefuroxime axetyl.

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): 0.503 (Isomer A / (Isomer A + Isomer B))

Δ2-isomer: 0.1% or less, E-isomer: 0.1% or less

Purity (HPLC): 99.3%

Yield: 83.96%

Example 2

The cefuroxime acetyl solution prepared in the same manner as in Example 1 was concentrated under reduced pressure 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 hexene was added dropwise thereto for 30 minutes to complete crystallization. The resulting crystals were filtered, washed with a mixed solution of methyl acetate and hexene, and then dried at 35 ° C. to obtain 49.5 g of crystalline cefuroxime acetyl.

Isomer Ratio (HPLC): 0.501 (Isomer A / (Isomer A + Isomer B))

Purity (HPLC): 99.4%

Δ2-isomer: 0.1% or less, E-isomer: 0.1% or less

Yield: 82.3%

Example 3

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

Isomer Ratio (HPLC): 0.505 (Isomer A / (Isomer A + Isomer B))

Purity (HPLC): 99%

Δ2-isomer: 0.1% or less, E-isomer: 0.1% or less

Yield: 82.13%

Example 4

The ceproximexetyl solution prepared in the same manner as in Example 1 was concentrated under reduced pressure to 374 g, and then crystallized by stirring at room temperature for 1 hour. To this was added 624 ml of heptene for 30 minutes to complete crystallization. The resulting crystals were filtered, washed with a mixture of ethyl acetate and heptene, and then dried at 35 ° C. to obtain 50.5 g of crystalline cefuroxime axetyl.

Isomer Ratio (HPLC): 0.505 (Isomer A / (Isomer A + Isomer B))

Δ2-isomer: 0.1% or less, E-isomer: 0.1% or less

Purity (HPLC): 99.3%

Yield: 83.96%

As described above, the method of the present invention has the advantage of obtaining industrially safe high purity and high yield of crystalline cefuroxime acetyl ester by using a specific crystallization solvent, and thus obtained high purity crystalline cefuroxime acetil Esters can be usefully used as antibiotics.

Claims (5)

In the method for producing cefuroxime 1-acetoxyethyl ester crystals from a reaction solution containing 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 characterized by using a solvent together with a secondary solvent selected from linear or branched hexenes or heptenes except 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 of claim 1 or 2, 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 3, wherein the ratio of primary solvent to secondary solvent is in the range of 1: 1.8 to 1: 2.5 volume ratio. The method according to claim 1, wherein the crystallization is carried out at a temperature of 5 to 35 ° C.