PL171244B1 - Method of separating r and s isomers of 1-acetoxyethyl cefuroxime ester - Google Patents

Abstract

1. The method of separating R and S isomers of 1-acetoxyethyl cefuroxime ester - Characterized in that: The ester is dissolved in ethyl acetate or acetone or their mixture. Then, the solution - possibly, after decolouration with activated coal - is condensed until the solution reaches the concentration of 25-75 percent. Then, 0.5 parts by volume of ethyl alcohol or n-propyl or isopropyl alcohol, or their mixture are added to 3 parts by volume of the formerly condensed solution of the ester in ethyl acetate or acetone or their mixture. The components are mixed or filtered. The filtrate is mixed with 1 to 5 parts by volume of water, with respect to the volume of the formerly added ethyl alcohol or n-propyl alcohol or isopropyl alcohol or their mixture. The liquid is mixed and the obtained precipitate of S isomer is filtered, rinsed with an alcohol appropriate for the process or alcohol mixture or with a mixture of the alcohol and water. Then, it is dried. The filtrate is condensed and mixed and the precipitate of R isomer is filtered, rinsed with water or a mixture of water with the alcohol used in the discussed process. Then, it is dried. The precipitate of R isomer may also be suspended in ethyl acetate, filtered, or dissolved in ethyl acetate and - possibly, after decolouration with activated coal - the filtrate is condensed until dry, or it is gradually condensed and left to crystallize. Then, it is filtered, rinsed with ethyl acetate and dried.

Description

The present invention relates to a new method of separating the R and S isomers of cefuroxime 1-acetoxyethyl ester (i.e. (6R, 7R) -3-carbamoyloxymethyl acid-7 - [(Z) -2- (furyl-2) -2 -methoxyiminacetamide-4-cephem-3-carboxylic-4, which is a second generation cephalosporin, is now widely used to combat infections caused by both Gram positive and Gram negative bacteria.

This compound belongs to the group of in vivo cleavable esters which, after oral administration, are easily absorbed from the gastrointestinal tract, and under the influence of esterases, they are rapidly hydrolyzed to the corresponding free acids, thanks to which high levels of the parent antibiotic are obtained both in the blood and in organs.

Cleavable esters are used in cases where a given antibiotic in the form of salt or free acid is poorly absorbed after oral administration, while the introduction of an ester group increases the absorption from the gastrointestinal tract many times.

The 1-acetoxyethyl ester of cefuroxime, due to the presence of an asymmetric carbon atom in the ester group, may exist in the form of a mixture of R and S isomers. Such a mixture, in a ratio of 0.9: 1 to 1.1: 1, is currently used in the preparation of pharmaceutical forms such as tablets or syrup making powder.

According to British Patent No. 1571683, said mixture can be separated into the individual isomers by crystallizing a concentrated from about 30 to -70% methanolic solution of cefuroxime 1-acetoxyethyl ester at 0 ° C for at least 18 hours. The S-isomer is obtained in a yield of 60-70%. After recrystallization from methanol, the mentioned isomer is obtained in a yield of 75% and a purity of -90%. The overall yield of the S-isomer based on 100% yield isomer content in the starting ester mixture is 45-52%.

According to the above-mentioned patent, the filtrate, after separating the S-isomer, is concentrated to dryness, heated with ethyl acetate at its boiling point, cooled and then filtered and the filtrate is concentrated to obtain the R-isomer with a purity of about 80% and a yield of 24%.

Said data show that according to the above process both isomers are obtained in low yield, while the R-isomer of relatively low purity

Another method of separating the R and S isomers of the discussed cefuroxime 1-acetoxyethyl ester, known from US Patent No. 5,063,224, consists in heating their mixture in methyl alcohol at 50-60 ° C, cooling it to 24-30 ° C and filtering the S-isomer. the filtrate is isolated by direct evaporation or after dilution with organic solvents or water. The S-isomer is obtained with a yield of 86.6 - 118%, the latter value indicating a high content of impurities. The R isomer is obtained with a yield of about 72%, with a purity of 85-93%.

During the research, it was unexpectedly found that the separation of the R and S isomers can be performed by fractional crystallization of cefuroxime 1-acetoxyethyl ester from a mixture of solvents such as: ethyl acetate, acetone or their mixture, ethyl, n-propyl, isopropyl alcohol or their mixture, and water. Separation of individual isomers is carried out by mixing, gradual evaporation of the initial solvent mixture, which causes a change in its composition, and then further mixing and filtering of the separated precipitate.

The volume ratios of the individual components of the mixture during the isolation of the isomers depend on the type of alcohol used. For example, when using a mixture of ethyl acetate, ethyl alcohol and water, the approximate volume ratio for isolating the S isomer is about 6:11:22, while for isolating the R isomer about 1: 4:66. On the other hand, when using isopropyl alcohol under the given conditions, the volume ratio is -6: 9: 22 and 1: 4: 15, respectively. Due to the optimally selected volume ratios of the mentioned solvents, high yield of 80-90% and> 90% purity of both isomers is obtained.

According to the invention the method for separation of the R and S acid 1-acetoxyethyl _of acid _{for which} f _uro ksymu lies in the fact that the ester was dissolved in ethyl acetate or acetone or in the city _are understated _n and _e, and the resulting solution optionally after decolorizing carbon Connectors active Zage _{s t} o give a 25-75% concentration of the solution, to which was then added to ethyl alcohol, l _u b n-propyl or isopropyl, or a mixture thereof in a volume of from 0.5 to 3, often _are unk _in the volume previously concentrated solution of the ester in ethyl acetate, acetone or I _can and _n and _n and _e, and then stirred and optionally filtered and to the filtrate was added dropwise from 1 to 5 volumes of water _relative to the volume previously added ethyl alcohol, or n-propyl or isopropyl or their mixtures, and then the resulting precipitate of the S-isomer is filtered, washed with the alcohol used in the process or with their mixture or with a mixture of the alcohol and water mentioned, and then dried, while the filtrate is concentrated, stirred and divided precipitate the R-isomer is filtered, washed with water or a mixture of water and of alcohol employed _{and the} nego _in the process, are then dried or separated precipitate the R-isomer is suspended in ethyl acetate, filtered, or dissolved in ethyl acetate and possible decolorization with carbon active, the filtrate is concentrated to dryness or is gradually concentrated and left to crystallize, then filtered, washed with ethyl acetate and dried.

The method according to the invention can separate the mixture of R and S isomers with any ratio of isomers, preferably from 0.9: 1 to 1.1: 1. In the discussed separation, the volume ratio of ethyl acetate, acetone or their mixture to the aforementioned alcohol or mixture of alcohols and water when isolating the S isomer, it ranges from 1: 0.5: 0.5 to 1: 4: 9, while when isolating the R isomer, it ranges from 1: 3: 6 to 1: 5:30. The process of separation of isomers according to the invention is carried out at a temperature of 5 to 40 ° C, preferably 15-25 ° C, for 0.5 to 10 hours, preferably 3 to 6 hours.

The individual isomers are obtained with a yield of 80-90% and a purity> 90%.

Compared to the known method described in Great Britain Patent _Nos. 1,571,683 and US Pat. No. 5,063,224, the method according to the invention has a number of advantages, such as:

_the possibility of separating the mixture of R and S isomers into individual isomers containing from 5 to 95% of a given isomer, shorter reaction time, higher process efficiency when isolating both the S and R isomer, and at the same time high purity of the R isomer of> 90%, the possibility of obtaining both crystalline and amorphous forms of S and R isomers, the possibility of regeneration of the solvents used for the discussed process, which significantly reduces the costs of the process.

The following examples illustrate the invention without, however, limiting its scope.

Example 1 10 g of 1-acetoxyethyl ester of cefuroxime, which mieszamną R and S isomers in the ratio 1: 1, dissolved in 110 cm ³ of acetone is stirred with 1 g of activated charcoal and filtered. The filtrate was concentrated to a volume of about 40 cm ^3, was added 60 c _m ^{3 of} ethanol and stirred. 120 cm ^{3 of} water were then added dropwise to the suspension obtained at room temperature and over 1.5 hours, and stirred for 1 hour.

The precipitate formed, after filtration, washed twice with a mixture of ethyl alcohol and water, _these it in a volume ratio of 1: 2 and dried at 40 - 45 ^o C.

4.3 g of solid S-isomer, 86% of yield in the conversion _of sc on how much _of this isomer in the starting ester 1-acetoksyetylowym. Prepared in the above food _are crib compound contains:

94.4% - the S-isomer

4.2% - the R isomer

1.3% - ethyl alcohol

0.3% - water

The filtrate and washings were gradually concentrated in vacuo to a volume _{of about} 110 _cm ³ , stirred for 1 hour at room temperature, and then the separated precipitate was filtered, washed twice with a mixture of water and ethanol in a volume ratio of _m 4 _: 1 and dried. The resulting solid was suspended in ethyl acetate, stirred and filtered off and the filtrate decolorized with activated charcoal the solvent is evaporated and dried under oz P _{y c} k _at 40 - 45 ^o C.

The obtained 3.9 g of the precipitate of the R isomer containing:

91.8% - isomer R.

5.6% - S isomens

1.1% - ethyl acetate

0.6% - water

Yield of the R isomer - 78%.

The Publishing Department of the Polish Patent Office of the Republic of Poland Circulation 90 copies

Price PLN 2.00

Claims (5)

Patent claims The method of separating the R and S isomers of 1-acetoxyethyl ester of cefuroxime, characterized in that the ester is dissolved in ethyl acetate or acetone or in a mixture thereof, and then the obtained solution, optionally after decolorization with active carbon, is concentrated to obtain a concentration of 25-75% solution, then ethyl, or n-propyl or isopropyl alcohol or their mixture is added in a volume ranging from 0.5 to 3 in relation to the volume of the previously concentrated solution of the ester in ethyl acetate, acetone or their mixture, then stirred, optionally filtered, and 1 to 5 volumes of water are added to the filtrate in relation to the volume of previously added ethyl or n-propyl or isopropyl alcohol or their mixture, then the mixture is stirred and the resulting precipitate of the S isomer is filtered, washed with the alcohol used in the process or their mixture or a mixture of the mentioned alcohol and water, and then dried, while the filtrate is concentrated, stirred, and the separated precipitate of the R isomer is filtered, washed with water and or with a mixture of water and alcohol used in the process in question, and then either the precipitate of the R-isomer which has separated out is dried or suspended in ethyl acetate, filtered or dissolved in ethyl acetate and, after any decolorization with active charcoal, the filtrate is concentrated to dryness or gradually concentrated and left to crystallize, then filtered, washed with ethyl acetate and dried. 2. The method according to p. A process as claimed in claim 1, characterized in that the separation of cefuroxime 1-acetoxyethyl ester containing a mixture of R and S isomers with any ratio of isomers, preferably in a ratio of 0.9: 1 to 1.1: 1. 3. The method according to p. The process of claim 1, wherein the volume ratio of ethyl acetate, acetone or a mixture thereof to the aforementioned alcohol or mixture of alcohols and water during the isolation of the S-isomer is from 1: 0.5: 0.5 to 1: 4: 9. 4. The method according to p. The process of claim 1, characterized in that the volume ratio of ethyl acetate, acetone or a mixture thereof to the aforementioned alcohol or mixture of alcohols and water during the isolation of the R isomer is 1: 3: 6 to 1: 5:30. 5. The method according to p. The process of claim 1, characterized in that the reaction of the isomer resolution is carried out at a temperature of 5 to 40 ° C, preferably 15 to 25 ° C.