KR910008377B1 - Process for preparation of celphaslosporin - Google Patents

Abstract

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Description

Method for preparing cephalosporin

1 is the IR spectrum in Nujol of the crystalline cefuroxime axetyl isomer mixture.

The present invention relates to an improved method of making cephalosporins. In particular, the present invention relates to an improved process for preparing cefuroxime 1-acetoxyethyl ester (cefuroxime axetyl).

Compound (6R, 7R) -carbamoyloxymethyl-7-[(Z) -2- (fur-2-yl) -2-methoxyiminoacetamido] sef-3-m-4-carboxyl The mountain is called "Sepuroxim." This compound is a useful antibiotic with a broad spectrum of activity against Gram-positive and Gram-negative microorganisms, which is highly stable against β-lactamase produced by Gram-negative microorganisms, thus enhancing the antibiotic properties of the compound. In addition, this compound has excellent resistance in mammals and is widely used as an antibiotic in clinical practice. Cefuroxime and its salts are mainly useful as antibiotics for injection, because they are poorly absorbed in the gastrointestinal tract and are present only in low concentrations in serum and urine after oral administration. Therefore, there is a need for a form of cefuroxime that can be absorbed in the gastrointestinal tract after oral administration.

The inventors have found that the appropriate esterification of the carboxyl group of cepuroxime improves the efficacy upon oral administration. Such suitable esterification groups allow the compound to be significantly absorbed from the gastrointestinal tract, which is hydrolyzed by enzymes present in serum and body tissue, for example, to produce antibiotically active mother acids. . To be effective for oral administration, the ester must be stable enough to reach the absorption site with little or no degradation of the ester, must be sufficiently absorbed upon reaching the appropriate absorption site, and the systemic ester can be released to the parent acid in a short time. It should be very sensitive to hydrolysis by agents. British Patent Specification No. 1,571,683 describes and patents many cefuroxime esters having the properties of antibiotics which are very effective upon oral administration.

We find that cefuroxime axetyl is of particular interest in the present invention, among the esters described in British Patent Specification No. 1,571,683. This product possesses an asymmetric carbon atom in the first position of the 1-acetoxyethyl group and therefore may exist in the form of R and S isomers or mixtures thereof. The process for the preparation of the esters exemplified in British Patent No. 1,571,683 produces this material in a relatively impure amorphous or crystalline form. Moreover, crystalline materials produced by the methods described herein generally contain more of one of these isomers, despite the benefit of administering when the ratio of the R or S isomer is about 1: 1. . Thus crystalline products are not ideal for administration.

The present invention improves the process for the preparation of cepuroxime axetyl to enable this compound to be obtained in high purity crystalline form and in high yield. Such products are useful in terms of high purity active compounds and are therefore more suitable for biological administration, and in particular, are surprisingly high bioavailability in oral administration and have high purity amorphous properties that are more suitable than crystalline materials for commercial use. Very useful as starting material for the preparation of the form cefuroxime axetyl. The preferred ratio of R: S isomers of amorphous cepuroxime axetyl having this property is about 1: 1, since the 1: 1 ratio of amorphous cepuroxime axetyl is effective to maximize solubility in aqueous media. The improved process of the invention can provide crystalline cefuroxime axetyl with an isomer ratio of about 1: 1.

Accordingly, the present invention provides a method for preparing high purity crystalline cefuroxime acetyl by crystallizing cefuroxime axetyl from a cefuroxime axetyl solution dissolved in an organic or aqueous solvent or a mixture thereof and then separating and drying the product. do.

The choice of crystallization solvent is important if the yield is to be maximized and the R: S isomer ratio is preferably in the range of about 1: 1, such as 0.9: 1 to 1.1: 1. We have found that different isomers of cefuroxime axetyl have different solubility and one of them dissolves better than the other. Since the solubility varies depending on the solvent, a solvent system which preferably guarantees an isomer ratio of about 1: 1 is considered in consideration of the actual quantitative recovery of the cefuroxime axetyl present before crystallization.

Solvent systems capable of crystallizing the product are optionally but preferably esters in mixed form (e.g. methyl acetate or ethyl acetate) with ethers (e.g. diisopropyl ether) or aliphatic or aromatic hydrocarbons (e.g. petroleum ether or toluene). ) Or halogenated hydrocarbons (e.g. methylene chloride), optionally but preferably alcohols (e.g. ethanol or isopropanol) mixed with water, such as industrially modified aqueous ethanol solutions, amides (e.g. dimethylformamide) mixed with water Or dimethylacetamide) or ketones (eg acetone).

The crystallization step is preferably carried out at room temperature, for example from about 10 to 30 ° C., in general the concentration of cefuroxime axetyl in the solution in which crystallization takes place evaporates the solvent, for example so that the solution is not too diluted or too concentrated. Or diluted. Crystallization may comprise forming cefuroxime axetyl, the last step (s) of the reaction. In this case the initial stage of crystallization can be carried out at a considerably high temperature, for example at up to about 65 ° C., but it is preferred to finally separate in the temperature range of 10 to 30 ° C. in order to maximize the yield and to obtain the product of suitable isomer ratio. Do.

The reaction to form cefuroxime axetyl is preferably carried out an ester reaction by the method described in British Patent Specification No. 1,571,683, using high purity sodium cefuroxime as starting material. Preferred reagents for the esterification reaction are brominated 1-acetoxyethyl and it is preferred that the reagents used are racemates in order to produce an R: S isomer ratio of about 1: 1 before recrystallization.

Preferred sodium cefuroxime starting materials are generally very pure. Such materials are for example (6R, 7R) -3-hydroxymethyl-7- [Z-2- (fur-2-yl) -2-methoxyiminoacetamido] -sef-3-m- 4-carboxylic acid and isocyanate chlorosulfonyl are reacted at an alkyl acetate solvent at a temperature of -25 ° C to + 10 ° C, followed by hydrolysis at + 10 ° C to + 30 ° C in situ, followed by acetone or methyl acetate solvent. It can be obtained by adding sodium 2-ethylhexanoate in water and crystallizing it. Such materials generally have a purity of at least 90% mass / mass (m / m).

The cefuroxime axetyl produced according to the present invention has an R: S isomer ratio of about 1: 1 molar ratio and generally has a purity of 95% m / m or more (not corrected for residual solvent).

In very pure crystalline form, the cepuroxime axetyl produced by the present invention is a novel form of material, which also constitutes another aspect of the present invention. This material sample has an IR spectrum in the newsol as shown in the accompanying drawings.

The following Preparation Examples and Examples are not intended to limit the invention but merely to illustrate the invention.

The R and S isomers of cefuroxime 1-acetoxyethyl ester are conveniently represented by the letters A and B, respectively, which are used to denote each isomer in British Patent No. 1,571,683. The A and B isomers were not identified. Isomer ratios described in the following examples are expressed as A: B.

Preparation Example 1

[Sodium cefuroxime]

Chlorosulfonyl isocyanate (226 mL) was added to a solution of triethylamine (10 mL) in methyl acetate (3.8 L). The resulting clear solution was cooled to −15 ° C. and (6R, 7R) -3-hydroxymethyl-7- [Z-2- (fur-2-) in methyl acetate (2.3 L) precooled to −15 ° C. I) -2-methoxyiminoacetamido] sef-3-m-4-carboxylic acid (763 g) suspension was added to the clear cooling solution over 10 minutes. The remaining solid was washed with methyl acetate (700 mL). The mixture was stirred at -5 [deg.] C. for 30 minutes, giving a clear solution after 10 minutes of stirring. Water (1.2 L) at 18 ° C. was quickly added to the reaction mixture, the temperature was raised to 10 ° C. and then slowly raised to 17 ° C. The mixture was stirred at 15 ° C. for 60 minutes to give a thick white suspension. To this was added methyl acetate (3.6 L), followed by constant addition of aqueous sodium hydroxide solution (288 g in 5.2 L water). Thus, a clear two-phase mixture of pH 2.35 was obtained. The layers were separated and the upper layer, ie the organic layer, was washed with aqueous sodium chloride solution (600 g in 2 liters of water). The two aqueous layers were subsequently washed with methyl acetate (2 L). The organic layers were combined, stirred with Norit SX Plus charcoal (76 g) for 30 minutes, filtered through a Hyflo supercel bed and washed with methyl acetate (1.5 L). The combined filtrate and washings were stirred at 20 ° C., while a 2-ethylhexanoate (338 g) solution in a mixture of methyl acetate (2 L) and water (40 mL) was added to the stirred solution over 20 minutes to give a white pH of 5.5. A suspension was obtained. The suspension was stirred for 10 minutes, filtered, and the filter cake was washed with methyl acetate (5 × 1 L), suction dried and dried for 24 hours at 30 ° C. in vacuo to give sodium cefuroxime (851.9 g).

; HPLC에 의한 불순도 2.0%; 분석치(HPLC) 92% m/m; 수분함량[칼 피셔(Karl Fisher)법] 2.8% m/m; 용매(GLC) 0.5% m/m.

; 2.0% impurity by HPLC; Assay (HPLC) 92% m / m; Moisture content (Karl Fisher method) 2.8% m / m; Solvent (GLC) 0.5% m / m.

Example 1

[Sepuroxime Axetyl]

²이성체임)을 분리하고, 1M 염산(100㎖) 및 2% 중탄산나트륨을 함유하는 20% 염화나트륨 수용액(30㎖)으로 세척하였다. 3개의 수성상 모두를 계속해서 아세트산에틸(100㎖)로 세척하였다. 한데 모은 유기 추출물을 목탄(Norit SX Plus:2g)과 함께 30분 동안 교반하고, 아세트산에틸(2×25㎖)로 세척된 규조토 베드를 통하여 여과하였다. 한데 모은 여액 및 세척액을 진공 중에서 150g으로 증발시키고, 결정화가 잘 이루어질 때까지 상온에서 1시간 동안 교반하였다. 여기에 디이소프로필 에테르(250㎖)를 45분에 걸쳐 가하여 결정화를 완결하고, 추가로 1시간 동안 교반을 계속하였다. 생성물을 여과하여 모으고 2 : 1 비율의 디이소프로필 에테르/아세트산에틸(150㎖)로 세척한 후, 50℃, 진공 중에서 2-3일 동안 건조시켜서, 제1도에서 보여주는 바와 같은 뉴졸(Nujol) 중에서의 IR스펙트럼을 갖는 결정성 세푸록심 악세틸(19.3g)을 얻었으며, 이것은 전형적인 결정성 이성체 혼합물에 해당하였다.Brominated (RS) -1-acetoxyethyl (12.5 g) was added to a mixture of stirred sodium cefuroxime (20 g) (prepared in a similar manner to preparation method 1) in dimethyl acetamide (110 mL) at 0 ° C. The mixture was stirred at + 1 ° C. for 90 minutes and potassium carbonate (0.5 g) was added thereto. If the reaction mixture was added to a rapidly stirred mixture of ethyl acetate (200 mL) and 3% aqueous sodium bicarbonate solution (200 mL) to decompose excess brominated 1-acetoxyethyl, stirring was further performed at 1 to 3 ° C. Continued for more time. After 1 hour organic layer (HPLC results, 1.5%

² isomer) and washed with 20% aqueous sodium chloride solution (30 mL) containing 1M hydrochloric acid (100 mL) and 2% sodium bicarbonate. All three aqueous phases were subsequently washed with ethyl acetate (100 mL). The combined organic extracts were stirred with charcoal (Norit SX Plus: 2 g) for 30 minutes and filtered through a diatomaceous earth bed washed with ethyl acetate (2 x 25 mL). The combined filtrate and washings were evaporated to 150 g in vacuo and stirred for 1 hour at room temperature until crystallization was successful. Diisopropyl ether (250 mL) was added thereto over 45 minutes to complete crystallization, and stirring was continued for an additional hour. The product was collected by filtration and washed with a 2: 1 ratio of diisopropyl ether / ethyl acetate (150 mL) and then dried for 2 to 3 days at 50 ° C. in vacuo to give Nuzol as shown in FIG. Crystalline cefuroxime axetyl (19.3 g) with an IR spectrum in the middle was obtained, corresponding to a typical crystalline isomeric mixture.

²이성체 0.3% m/m 및 E-이성체 0.6% m/m을 함유하여 1.8%; 이성체비(HPLC) 1.09 : 1; [α]_D(디옥산 중에서 1%) +37˚:

389; HPLC에 의한 분석치 99%m/m(보정되지 않은 것임).Solvent content (GLC) 0.2% m / m; Impurity by HPLC

² 1.8% containing 0.3% m / m of isomer and 0.6% m / m of E-isomer; Isomer ratio (HPLC) 1.09: 1; [α] _D (1% in dioxane) + 37 °:

389; HPLC analysis 99% m / m (not calibrated).

Example 2

[Sepuroxime Axetyl]

²이성체임을 확인)을 1M 염산(100㎖) 및 2% 중탄산나트륨을 함유하는 20% 염화나트륨 수용액(30㎖)으로 세척하였다. 모든 수성상을 아세트산에틸(100㎖)로 계속 세척하였다. 한데 모은 유기 추출물을 목탄(Norit SX Plus:2g)과 함께 30분 동안 교반하고, 아세트산(2×25㎖)로 세척된 규조토 베드를 통하여 여과하였다. 한데 모은 여액 및 세척액을 120g까지 증발시킨 후, 이 농축물을 20분 동안 교반하여 결정화할수 있도록 하였다. 여기에 공업용 변성 에탄올(120㎖)를 신속히 가하고, 이어서 15분에 걸쳐 증류수(240㎖)를 가하였다.생성된 슬러리를 진공 중에서 310g으로 농축시키고, 45분 동안 상온에서 교반하였다. 생성물을 수득하고 증류수(200㎖)로 세척하고, 50℃, 진공 중에서 67시간 동안 건조시켜 결정성 세푸록심 악세틸(20.01g)을 얻었다. 용매 함량(GLC) 0.2% m/m; 불순도(HPLC) 1.5% m/m(

²이성체 0.5% m/m 및 E-이성체 0.6% m/m을 함유); 이성체비 1.01 : 1 [α]_D(디옥산 중에서 1%)+40˚:

388; HPLC에 의한 분석치 98% m/m(보정하지 않은 것임).A stirred suspension of sodium cefuroxime (20 g) in dimethylacetamide (110 mL) was cooled to 15 ° C. and brominated (RS) -1-acetoxyethyl (12.5 g) was added thereto. It was stirred for 45 minutes at the same temperature and potassium carbonate (0.5 g) was added thereto. The mixture was further stirred at 15 ° C. for 45 minutes, and then poured into a quick stirring mixture with ethyl acetate (200 mL) and 3% aqueous sodium bicarbonate solution (20 mL). After 1 hour the layers were separated and the organic phase (1.6% by HPLC)

² isomer) was washed with 20% aqueous sodium chloride solution (30 mL) containing 1M hydrochloric acid (100 mL) and 2% sodium bicarbonate. All aqueous phases were washed continuously with ethyl acetate (100 mL). The combined organic extracts were stirred with charcoal (Norit SX Plus: 2 g) for 30 minutes and filtered through a diatomaceous earth bed washed with acetic acid (2 × 25 mL). The combined filtrate and washings were evaporated to 120 g and then the concentrate was stirred for 20 minutes to allow crystallization. To this was added industrially modified ethanol (120 mL) quickly, followed by distilled water (240 mL) over 15 minutes. The resulting slurry was concentrated to 310 g in vacuo and stirred at room temperature for 45 minutes. The product was obtained, washed with distilled water (200 mL) and dried in vacuo at 50 ° C. for 67 hours to give crystalline cefuroxime axetyl (20.01 g). Solvent content (GLC) 0.2% m / m; Impurity (HPLC) 1.5% m / m (

² containing 0.5% m / m of isomer and 0.6% m / m of E-isomer); Isomer ratio 1.01: 1 [α] _D (1% in dioxane) + 40 °:

388; HPLC analysis 98% m / m (not calibrated).

Example 3

[Sepuroxime Axetyl]

²＜0.1% m/m ; 수분(칼 피셔법) 0.4% m/m.Sodium cefuroxime (20 g) was stirred with dimethylacetamide (100 ml) at about 25 ° C. for 15 minutes, the mixture was cooled to 15 ° C. and brominated (RS) -1-acetoxyethyl (9.8 ml) Was added. While the mixture was stirred for an additional 90 minutes at 14-16 ° C. (medium), 60 mesh potassium carbonate (0.5 g) was added. The reddish brown mixture was then diluted with ethyl acetate (200 ml) and 3% aqueous sodium bicarbonate solution (200 ml) and stirred at room temperature (about 25 ° C.) for 1 hour. The layers were then separated and the aqueous layer was re-extracted with ethyl acetate (200 ml) and discarded (α 0.21 ° / dm). The organic solution was washed continuously with 1M hydrochloric acid (100 ml) and 20% sodium chloride (30 ml) containing 2% sodium bicarbonate, pooled and treated with Norit SX Plus charcoal (2 g) for 25 minutes. Charcoal was removed by filtration with a standard super pad, the filter paper washed with ethyl acetate (50 mL), and the combined filtrates were evaporated to 120 g in vacuo. The residual solution was seeded and stirred at 22 ° C. for 1 hour and toluene (250 mL) was added to the stirred slurry over 30 minutes, and the mixture was further stirred for 30 minutes. The suspension was then evaporated to 182 g in the perforations, cooled to about 25 ° C. and stirred for 30 minutes. The product was collected, washed with toluene (100 mL), suction dried for 15 minutes, and then dried overnight in vacuo at 45 ° C. to give crystalline cefuroxime axetyl (19.8 g). 0.9% solvent by GLC (0.7% ethyl acetate; 0.15% toluene); Impurity 0.9% by HPLC; HPLC analysis 100%; Isomer ratio 1.03: 1,

² <0.1% m / m; Moisture (Karl Fischer method) 0.4% m / m.

Example 4

[Sepuroxime Axetyl]

²이성체 및 안티 이성체); 이성체비 0.98 : 1.An washed, evaporated (up to about 125 g) ethyl acetate solution of cefuroxime axetyl (prepared similar to the method described in Example 1) was stirred at room temperature until crystallization was successful. Light petroleum ether (boiling point 100-120 ° C .; 188 ml) was added dropwise thereto for 1 hour, and then the suspension was further stirred at room temperature for 2 hours. Crystalline precipitates were collected by filtration, which was light petroleum ether (boiling point 100-120 ° C.); The mixture was washed with a 2: 1 mixture (75 ml) of ethyl acetate and dried overnight at 40 ° C. in vacuo to give the title compound (19.2 g). Water (Carl Fischer method) 0.4% m / m; Solvent (GLC) 0.4% m / m; Analysis by HPLC 100% m / m; Impurity of 1.1% m / m by HPLC (0.1% and 0.6% m / m, respectively)

² isomers and anti isomers); Isomer ratio 0.98: 1.

Example 5

[Sepuroxime Axetyl]

²이성체 및 안티 이성체); 이성체비 1.05 : 1; HLPC에 의한 분석치 96% m/m.The washed and concentrated (up to about 125 g) cefuroxime axetyl solution (prepared in Example 1) in ethyl acetate was stirred at 33 ° C. for 1 hour until crystallization was successful. After the suspension was left at room temperature overnight, IMS (62.5 ml) was added over 5 minutes under stirring, followed by addition of light petroleum ether (boiling point 100-120 ° C .; 250 ml) over 1 hour. After stirring the crystalline suspension for another 1.5 hours, crystals were obtained, and light petroleum ether (boiling points 100 to 120); It was washed with a 2: 1 mixture of ethyl acetate (75 ml) and dried overnight at 45 ° C. in vacuo to yield 19.2 g of the title compound. Water (Carl Fischer method) 0.2% m / m; Solvent (GLC) 0.8% m / m: impurity 0.8% m / m by HPLC (0.1% m / m and 0.7% m / m respectively)

² isomers and anti isomers); Isomer ratio 1.05: 1; Analysis by HLPC 96% m / m.

Example 6

[Sepuroxime Acetyl]

²이성체를 함유하는, 세척되고 목탄으로 처리된 아세트산에틸 중의 세푸록심 악세틸 농축물(약 100g)(실시예 1에 기술된 방법과 유사하게 제조됨)을 시드시켜, 결정화가 잘 이루어질 때까지 30분간 교반하였다. 여기에 이소프로판올(100ml)을 30분에 걸쳐 적가하고, 이어서 50분에 걸쳐 증류수(170ml)를 적가하였다. 생성된 슬러리를 진공 중에서 250g으로 농축시키고, 1시간에 걸쳐 12℃로 냉각하였다. 결정성 생성물을 여과하여 모으고, 증류수(100ml)중의 20% 이소프로판을 빙냉 용액으로 세척하여, 40℃, 진공 중에서 2-3일간 건조시켰다. 표제 화합물 20.1g을 얻었다. 수분(칼 피셔법) 0.4% m/m; 용매(GLC) 0.03% m/m; HPLC에 의한 불순도 1.5% (각각 0.4% m/m 및 약 0.6% m/m의

²이성체 및 안티 이성체); 이성체비 1.05 : 1.About 2%

Seeds of cefuroxime axetyl concentrate (ca. 100 g) (prepared analogously to the method described in Example 1) in washed and charcoal treated ethyl acetate containing ² isomers until 30 Stirred for a minute. Isopropanol (100 ml) was added dropwise over 30 minutes, followed by dropwise distilled water (170 ml) over 50 minutes. The resulting slurry was concentrated to 250 g in vacuo and cooled to 12 ° C. over 1 hour. The crystalline product was collected by filtration, 20% isopropane in distilled water (100 ml) was washed with an ice cold solution and dried for 2 days in 40 ° C. in vacuo. 20.1 g of the title compound were obtained. Water (Carl Fischer method) 0.4% m / m; Solvent (GLC) 0.03% m / m; Impurity 1.5% (0.4% m / m and about 0.6% m / m, respectively) by HPLC

² isomers and anti isomers); Isomer ratio 1.05: 1.

Claims (4)

Ester or halogenated hydrocarbons which may be mixed with ethers or aliphatic or aromatic hydrocarbons; Ketones or amides in admixture with water; Or high purity crystalline cefu characterized by crystallizing the cefuroxime 1-acetoxyethyl ester in a solution of cefuroxime 1-acetoxyethyl ester in a solvent consisting of an alcohol which can be mixed with water and separating the dried product. Process for the preparation of roxime 1-acetoxyethyl ester. The method of claim 1, wherein the cefuroxime 1-acetoxyethyl ester is crystallized at an R: S isomer ratio of about 1: 1. The process according to claim 1 or 2, wherein the solvent is selected from methyl or ethyl acetate which can be mixed with diisopropyl ether, petroleum ether or toluene. The process according to claim 1 or 2, wherein at least the second half of the crystallization step is carried out at 10 to 30 ° C.

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