KR20010036798A - Method for producing crystalline cefuroxime axetil - Google Patents

Abstract

PURPOSE: Provided is a method for safely mass-producing high purity crystalline cefuroxime axetil ester. CONSTITUTION: The crystalline cefuroxime axetil ester is produced by using both the first crystallizing solvents which are one or more solvent selected from acetic acid ethyl, acetic acid methyl or isopropyl alcohol and the second crystallizing solvents which are one or more solvent selected from hexenes or heptenes from a solution containing crystalline cefuroxime axetil ester, optionally by first crystallizing using the first crystallizing solvents and by second crystallizing using the second crystallizing solvents, in which the volume ratio of the first and second crystallizing solvents is 1:1 to 1:3 and the crystallization temperature is 5 to 35 deg. C.

Description

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

FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of high purity crystalline cefuroxime axetyl esters, wherein a specific crystallization solvent is used to prepare high purity crystalline cefuroxime axetyl esters having an R: S isomer ratio of 1: 1. It's about how.

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, and particularly for β-lactamase produced by gram negative microorganisms. As it is stable, its antibacterial properties are increased and its resistance in mammals is widely used as an antibiotic. In addition, this compound is an antibiotic that is well absorbed in the gastrointestinal tract after oral administration and is very effective. US Pat. No. 4,627,320 and UK Pat. No. 2,145,409 are known.

(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 above 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 upon oral administration and has properties that are more suitable than commercially available forms of substance. Since it is useful as a starting material for preparing a product, a product having 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, etc. Although the methods described in these patents have a significant amount of Δ2-isomers and E-isomers as impurities, the ratio of R and S isomers is about 49 to 51 to 48 to 52. . Therefore, it is required 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 method for safely preparing high purity cefuroxime axetyl ester crystals in an isomer ratio of 1: 1.

According to the 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 with an R: S isomer ratio of 0.98: 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 characterized in that it uses together with one kind of secondary solvent selected from hexene or heptene.

The process of the present invention comprises crystallizing the cefuroxime axetyl solution prepared as above with a selected solvent (primary solvent) in methyl acetate, ethyl acetate or alcohol, and at the same time one solvent selected from hexene or hexene ( Crystallization with a secondary solvent), thereby making it possible to obtain crystalline cefuroxime acetyl ester having a high purity and an isomer ratio of R: S of about 1: 1 with high purity and high purity.

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

The 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 of 1, 2 or 3 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

To 200 ml of dimethylacetamide as shown in US Pat. No. 4,267,320, 9.77 g of potassium carbonate and 50 g of cefuroxime acid 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% aqueous sodium bicarbonate 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% aqueous sodium bicarbonate 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 decolorized solution was concentrated under reduced pressure to 374 g, and crystallized by stirring at room temperature for 1 hour. To this was added 624 ml of hexene for 30 minutes to complete the crystallization. The resulting crystals were filtered and washed with a mixed solution of ethyl acetate and hexene and dried at 35 ° C. to obtain 50.5 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): 0.503 (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 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 off, 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 60g, and 320ml 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 374g, and crystallized by stirring at room temperature for 1 hour. 624 ml of heptene was added thereto for 30 minutes to complete crystallization. The resulting crystals were filtered and washed with a mixed solution of ethyl acetate and heptene and dried at 35 ° C. to obtain 50.5 g of crystalline cefuroxime acetyl.

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 the obtained high purity crystalline cepuroxime acetyl ester Can be usefully used as an antibiotic.

Claims (5)

A method for producing cefuroxime 1-acetoxyethyl ester crystals from a reaction solution containing cefuroxime 1-acetoxyethyl ester, wherein the one 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 secondary solvent and one secondary solvent selected from hexenes or heptenes together. 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.