WO2002016372A1

WO2002016372A1 - New method for preparation of amorphous cefuroxime axetil

Info

Publication number: WO2002016372A1
Application number: PCT/KR2001/001432
Authority: WO
Inventors: Tae-Seop Hwang; Chan-Yong Ahn
Original assignee: Choongwae Pharma Corporation
Priority date: 2000-08-24
Filing date: 2001-08-24
Publication date: 2002-02-28
Also published as: KR20020016052A; AU2001282638A1

Abstract

Disclosed is a method for preparation of amorphous cefuroxime axetil. The amorphous cefuroxime axetil can be prepared by (a) obtaining a reaction mixture by reacting sodium cefuroxima with (R, S)-1-acetoxylethylbromide at -10 °C to 0 °C in the presence of at least crown ether catalyst; (b) extracting the resulting mixture with an suitable organic solvent, and then concentrating the obtained organic layer; (c) dissolving the obtained residue into an water-soluble organic acid; and (d) dropping the obtained solution in cooling water. The method of present invention can effectively provide amorphous cefuroxime axetil with high purity and yield and is easily handled.

Description

NEW METHOD FOR PREPERATION OF AMORPHOUS CEFUROXIME AXETIL

FIELD OF THE INVENTION

The present invention relates to a method for preparation of amorphous cefuroxime axetil with high yield and purity by solvent precipitation.

BACKGROUND OF THE INVENTION

Cefuroxime axetil is a 1-acetoxyethyl- ( 6R, 7R) -3- carbamoyloxy-7- [ (Z) -2- (fur-2-yl) -2-methyoxyiminoacetimido] cef-3-em-4-carboxylate, a cephalosporin antibiotic with a broad spectrum of activity against gram-positive and gram- negative microorganisms. Cefuroxime axetil is classified as a member of the second-generation cephalosporin for oral administration and exists in two-different forms of crystalline and amorphous. U.S. Pat. No. 4,820,833 discloses that amorphous form of cefuroxime axetil has a higher rate of dissolution and absorption as well as more excellent properties with a respect to chemical stability and pharmacokinetics than the crystalline form.

Cefuroxime axetil has a stereochemical structure with an asymmetric carbon atom and exists as R and S diastereomers . Cefuroxime axetil is marketed as a mixture of R- and S-isomers in a 1:0.9 ~ 1:1.2 ratio approximately. Both EP Pat. No. 107,276 and KR Pat. No. 42,097 disclose that the above-mentioned mixture has more superior solubility as compared with each diastereomer .

GB. Pat. No.1,571, 683 (Glaxo Co.) and KR Pat. No. 91-46 provide a method for preparing amorphous cefuroxime axetil by crystalline cefuroxime ester. It embodies the invention by claiming that preferable organic solvents include ketones, alcohols, acetonitrile, tetrahydrofuran, dioxane, esters and chlorinated solvents and a homogeneous mixture of at least two such solvents. The above invention also discloses a method for preparation of amorphous cefuroxime axetil, which comprises dissolving cefuroxime axetil in above-mentioned solvents, and carrying out the obtained mixture via rapid solvent removal or solvent precipitation. In addition, the invention also discloses a method for preparation of amorphous cefuroxime axetil by spray drying, roller drying and freeze-drying. However, KR Pat. No. 187,959, with the exception of solvent precipitation among the above-mentioned methods, presents numerous limitations with respect to cost e fectiveness and mass production since the methods require costly special facilities and know-how. US Patent No. 5,847,118

Solvent precipitation

Cry ¹stalline Cefuroxime Axetil A „ —pro -ti —c so ;l —ven ;t — or : fo —rm :i —c ac →id/H₂0 Amorphous Cefuroxime Axetil

Meanwhile, US Pat. No. 5,847,118 (Canada, APOTEX Co.) relates to a method for preparing amorphous cefuroxime axetil which comprises dissolving crystalline cefuroxime axetil in aprotic solvent such as dimethylsulfoxide and N, N-dimethylformamide, or formic acid and adding water to the mixture. However, the described method is not advantageous with respect to filtration in that because the mixture becomes more turbid as the amount of the aprotic solvent added to water is increased. In contrast, when formic acid is used as an alternative, it leads to de-esterification, thereby isolating cefuroxime as a by-product from the mixture in amounts of 5-7 wt% and exposing its strong toxicity. Therefore, the invention is not suitable for large-scale production.

Solvent precipitation

Cefuroxime : Na -Residue Amorphous : KR No.214,709

H₂0 Cefuroxime Axetil

+

CH₃ 0

A X Dispersion method Amorphous

^'Residue organic solvent mix. > Cefuroxime Axetil ; KR No.187,959

Inhibitor

/Transition metal or alkali metal halide

Besides, we, inventors of the present invention, tried to develop a new method for preparing amorphous cefuroxime axetil without any crystallization. In relation to this concept, inventors of the present invention have already filed applications of KR Pat .Nos .214, 709 and 187,959. KR

Pat. No.214,709 provides a method for preparing amorphous cefuroxime axetil which comprises preparing cefuroxime axetil (as is known in GB Pat. No. 1,571,683), concentrating and adding water to the obtained residue. In preferred embodiments, there still remains many problems, for example, it requires high speed of at least 500 rpm for inhibiting coagulation and also impurities cannot be removed because water is used as the sole solidification solvent.

Also, KR Pat .No.187, 959 relates to a method for preparing amorphous cefuroxime axetil, in particular, which comprises dispersing a residue of cefuroxime axetil dissolved in organic solvent, without crystallization, to another organic solvent. While this invention can give dramatically to prevent for formation of a byproduct such as Δ 3-isomer, by means of employing a halogenated acid salt with transition metal or alkali metal as an inhibitor of byproduct, also results in cost increase for facility investment because it requires highly vehement conditions of dispersing and stirring which appears not suitable for industrialization .

SUMMARY OF THE INVENTION

Accordingly, the present invention is directed to a method for preparing amorphous cefuroxime axetil that substantially obviates the above-mentioned problems due to accommodation and cost and is suitable for industrialization. More specifically, an object of the present invention is to provide a method for preparing amorphous cefuroxime axetil which does not require rapid solvent removal, spray drying, roller drying or freeze drying of prior art, and thereby incurring no necessity of special facilities.

The present invention provides a method for preparing amorphous cefuroxime axetil comprising reacting cefuroxime sodium with (R, S) -1-acetoxyethylbromide in the presence of crown ether, dissolving the obtained residue in aqueous organic acid and carrying out solvent precipitation.

The present invention is further illustrated by the following examples, none of which should be construed as limiting the scope of this invention any way.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for preparing amorphous cefuroxime axetil, comprising the steps of: a) obtaining a reaction mixture by reacting cefuroxime sodium with (R,S)-1- acetoxylethylbromide in the presence of crown ether catalyst; b) extracting the reaction mixture with a suitable organic solvent, followed by concentration of said extract; c) dissolving the obtained residue into an water- soluble organic acid; and d) dropping the obtained mixture into cold water of 0

to 4 ^°C.

Cefuroxime : Na inhibitor ^ Residue ^ent P^rec|P'^tatl0tV Amorphous ⁺ Crown ether acetic acid/distilled water Cefuroxime Axetil

_CH, ₀ catalyst / -10 °C 4'C

A X

Below, a detailed description will be given in a stepwise fashion of the method for preparing according to present invention. In the first step, the reaction mixture is obtained by reacting cefuroxime sodium with (R, S) -1-acetoxyethylbromide in the presence of crown ether catalyst.

The present inventors, in order to inhibit byproduct such as Δ 3-isomer and concurrently increase reactivity, carried out the first step at a low temperature of -10 to 0 ^°C in the presence of crown ether catalyst such as 18- crown-6, 15-crown-5 and 12-crown-4. The used crown ether is a mixture of 1,4-dioxane and DMF of polar solvent in an approximately 4:3 ratio, (as described by S. Mobashery et al . ) , thereby enabling it possible to exhaustedly inhibit the formation of a byproduct such as 3-isomer. However, when the above condition was applied to the present invention, the reaction was not totally completed because of there was a decrease in reactivity while it had inhibited the formation of byproduct .

Through many lines of studies conducted, the present inventors, crown ethers catalyst, ring ester like 1,4- dioxane, with strong interaction with alkali metal and high reactivity, confirmed that it can greatly increase reactivity while decreasing the formation of a byproduct considerably.

On the basis of this result, the present invention provides a high yield cefuroxime axetil by dissolving cefuroxime sodium and crown ether catalyst in highly polar solvent such as DMF, and rapidly adding at least 1 equivalent (R, S) -1-acetoxyethylbromide at a low temperature of -10 to 0 ^°C. Crown ether catalyst is preferably used in the amount of about 1 to 3 mol% relative to the cefuroxime axetil .

Suitable for reaction temperature is -10 to 0 ^°C much below than 10 to 20 °C , as known in this art.

According to the present invention, there are four major byproducts: Δ 3-isomer of formula I; (E) -isomer of formula II; unreacted cefuroxime of formula HI; and inevitable impurity of formula IV. The structure of the byproduct is represented by as follows and defines by

European parmacopoeia supplment 200.512-513.

In accordance with the present invention, it is found that the byproduct directly taken an effect on temperature, time and amount of reagents for esterification, thereby, the more temperature or time increases, the more contents the byproduct except cefuroxime increase. Therefore, to estimate reactivity and degree of formation of byproduct, the present invention was performed by high performance

liquid chromatography . As a result, Δ 3-isomer and (E)- isomer in amounts of below 0.5% and 0.3%, respectively, was measured in the present invention, while 3-isomer and (E) - isomer in amounts of about 1.5-2% and at least 0.6%, respectively, was determined in KR Pat No.91-46 as known. After the completion of the reaction, the obtained reaction mixture is extracted with organic solvent, and followed by concentration under reduced pressure.

In a preferred embodiment, using a mixture of IN HC1 solution and suitable solvents separates cefuroxime axetil among the reaction mixture. Suitable solvents have both high solubility to cefuroxime and dissolubility to water, preferably, ethylacetate, methylacetate or dichloromethane .

The separated organic layer is washed with 3% Na₂C0₃(aq) and 20% NaCl solution, dried over and then concentrated under reduced pressure.

Next, amorphous cefuroxime axetil of the present invention is obtained by dissolving the obtained residue into water-soluble organic acid and dropping the mixture

into cold water of 0 to 4 ^°C . In preferred embodiments, the obtained residue is dissolved in water-insoluble organic acid without crystallization, consequently, the mixture is slowly added

to cold water of 0 to 4 "C for 0.5-1 hr with mechanical 'stirring 200-500 rpm. Suitable as water-soluble organic acid includes acetic acid, in an amount of 3-10 fold relative to that of cefuroxime sodium. The content of cold water is preferably in an amount of 5-15 fold relative to water-soluble organic acid. Thereafter, cefuroxime axetil with high purity is obtained by subsequently washing with water, cyclohexane or hexane and suitable drying. It is found that the obtained cefuroxime axetil afford amorphous structure as examined by IR, X-ray diffraction, and microscope. The amorphous cefuroxime axetil of the present invention is at least 98% highly pure as examined by HPLC, shows an acceptable ratio of the R and S diastereomers, 1:0.9 - 1:1.1.

The invention will be more fully understood by the following examples, which illustrate the present invention, but are not to be considered limiting to the scope of the invention .

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiments of the invention and together with the description serve to explain the principle of the invention. In the drawings: FIG.l is an IR spectrum of amorphous cefuroxime axetil in the present invention;

FIG.2 is an X-ray spectrum of crystalline cefuroxime axetil in the prior art;

FIG.3 is an X-ray spectrum of amorphous cefuroxime axetil in the present invention.

EXAMPLE 1

Cefuroxime sodium (20 g) and 18-crown-6 (0.2 g, 1.6 mol%) were dissolved in dimethylacetamide (110 mL) at room temperature. The mixture was cooled to -20 ^°C and rapidly added dropwise (R, S) -1-acetoxyacetyl bromide (10 mL) . The mixture was stirred at -10 ^°C for 1.5 hr, added anhydrous K₂C0₃ (0.5 g) and then stirred at the same temperature for 1 hr . The completion of the reaction, the reaction mixture was poured into ethylacetate (200 mL) and 1N-HC1 (200 mL) , stirred at room temperature for another 1 hr and then separated with aqueous/organic layer. The solution obtained by extracting the aqueous layer with ethylacetate (100 mL) was combined with the organic layer, consequently, the mixture was washed with 3% aqueous sodium carbonate monohydrate solution (100 mL) and 20% aqueous sodium chloride solution (100 mL) , repeatedly. The mixture was dried over activated carbon (2 g) and anhydrous MgS0₄ (10 g) with stirring at room temperature for 0.5 hr, was filtered and then was concentrated under reduced pressure. The obtained residue was dissolved in acetic acid (160 mL) , was

slowly added to cold water of below 4 ^°C for 0.5 hr with stirring 250 rpm, and then stirred another 0.5 hr . After the completion of stirring, white powdery solid product was filtered, washed with cold water (500 mL) and cyclohexane

(300 mL) , and then dried to yield white amorphous cefuroxime axetil (20.6 g) at 40 ^°C for 24 hr in vacuo .

HPLC analysis

CD condition (ref : US Parmacopoeia vol. 24, pp. 356) column : 4.6 mmx25 cm, packing L13 (Phenomenex) UV : 278 nm

column temperature : 30 ^°C speed rate of moving phase : 1.5 ml/min

(2) contents of impurities (total : 2.1 %) Δ 3-isomer : 0.4% (E)-isomer : 0/4% cefuroxime : 0.3%

1760 (acetamide) , 1720(4-ester group), 1720 and

1592

(carbamoyl) , 1676 and 1534 (7-amido) XRD (Schmadzu DX-1 powerdiffractometer) : see the fig.3

Cu Ka : 40 KV, 300 mA, scanning rate : 15.0/min (As can be seen from the fig. 3, a spectrum of cefuroxime axetil in the present invention shows a typically amorphous pattern (halo) .

EXAMPLE 2

White amorphous cefuroxime axetil (21.1 g) was prepared as the same manner in example 1, except that 18-crown-5 (1.0 g, 8.4 mol%) was used as a catalyst. φ condition : as defined example 1

(2) contents of impurities (total : 2.1%)

Δ 3-isomer : 0.3%

(E) -isomer : 0.3% cefuroxime : 0.2%

(3) ratio of diastereomers (R isomer:S isomer = 1:1.05)

EXAMPLE 3

White amorphous cefuroxime axetil (21.1 g) was prepared as the same manner in example 1, except that 15-crown-5 (1.0 g, 8.4 mol%) was used as a catalyst. φ condition : as defined example 1

(2) 2. contents of impurities (total : 1.9%) Δ 3-isomer : 0 . 4%

(E) -isomer : 0.3% cefuroxime : 0.1%

ratio of diastereomers (R isomer :S isomer = 1:1.07

EXAMPLE 4

White amorphous cefuroxime axetil (20.1 g) was prepared as the same manner in example 1, except that the reaction

was carried out at 0 ^°C . φ condition : as defined example 1

Δ 3-isomer : 0.6%

(E) -isomer : 0.4% cefuroxime : 0.4% (3) ratio of diastereomers (R isomer:S isomer = 1:1.05)

COMPARATIVE EXAMPLE 1 (KR Patent No.91-46, example 25)

A slurry of cefuroxime sodium dissolved in

dimethylacetamide (100 mL) was cooled to 14 ^°C and was added (R, S) -1-acetoxyethylbromide (10 mL) . The reaction mixture

was stirred at 14 ^°C for 45 min., was added with anhydrous K₂C0₃ (0.5 g) , and then was further stirred for 45 min. After the completion of the reaction, a resulting mixture was added ethylacetate (200 mL) and Na₂C0₃ (200 mL) solution. Both^' the solution obtained by extracting the aqueous layer with ethylacetate (100 mL) and the organic layer were washed with 1 M HC1 (100 mL) and 20% aqueous NaCl solution (30 mL) , repeatedly, and then were combined. Consequently, the mixture was dried over charcoal (2 g) and then was concentrated under reduced pressure up to 176 mL . The obtained residue in H₂0 (1.9 mL) was poured into petroleum

ether (1.76 L) at 60-80 ^°C for 15 minutes with stirring.

The produced solid was filtered, washed with a mixture of petroleum ether (105 mL) and ethylacetate (12 mL) , petroleum ether (118 mL) , systematically, and then dried to yield

white amorphous cefuroxime axetil (17.5 g) at 40 ^°C for 24 hr in vacuo . φ IR-spectrum (Newsol) : a spectrum of cefuroxime axetil in the present invention shows a typically amorphous pattern.) (2) contents of impurities : 4.1%

(H) ratio of diastereomers (R isomer :S isomer = 1:1.06)

REFERENCE EXAMPLE 1

Crystalline cefuroxime axetil (20 g) as described in KR Patent No. 83-1543, was dissolved in acetic acid (160 mL) .

The mixture was added dropwise to cold water (1 L, below

4 ^°C ) for 0.5 hr with stirring at 250 rpm, and further stirred for 0.5 hr. The resulting mixture was filtered, washed with cold water (500 mL) and cyclohexane (300 mL) , and then dried to yield white amorphous cefuroxime axetil

(19.1 g) at 40 ^°C for 24 hr in vacuo . φ condition : as defined example 1

(2) contents of impurities (total : 2.2%)

Δ 3-isomer : 0.6% (E) -isomer : 0.5% cefuroxime : 0.3%

(3) ratio of diastereomers (R isomer :S isomer = 1:1.03)

As comparison with prior art such as spray drying, roller drying and freeze-drying, in employing solvent precipitation in this invention, does not necessitate for expensive accommodations. Also, the method for preparing of the present invention can be easily handled because it enables to eliminate crystallization, as well as has high purity product by means of using aqueous organic acid and cold water as solvents. Further, though this invention employs simple work-up and low speed-rate for stirring, it allows to obtain amorphous cefuroxime axetil with high purity and yield, thus being suitable for large-scale production .

The forgoing embodiments are merely exemplary and are not to be construed as limiting the present invention. The present teachings can be readily applied to other types of apparatuses. The description of the present invention is intended to be illustrative, and not to limit the scope of the claims. Many alternatives, modifications, and variations will be apparent to those skilled in the art.

Claims

What is claimed is :

1. A method for preparing amorphous cefuroxime axetil, comprising the steps of: a) obtaining a reaction mixture by reacting cefuroxime sodium with (R, S) -1-acetoxylethylbromide in the presence of crown ether catalyst; b) extracting the reaction mixture with a suitable organic solvent, followed by concentration of said extract; c) dissolving the obtained residue into a water- soluble organic acid; and d) dropping the obtained mixture into a cold water of

0 to 4 ^°C.

2. The method according to claim 1, wherein the crown ether catalyst is selected from the group consisting of 18-crown-6, 15-crown-5 and 12-crown-4.

3. The method according to claim 2, wherein the content of the crown ether catalyst is 1 to 3 mol% relative to the cefuroxime sodium.

4. The method according to claim 1, wherein the reaction in step a) is carried out at a low

temperature of -10 to 0 ^°C to inhibit the formation of a byproduct .

5. The method according to claim 1, wherein the water- soluble organic acid in the step c) is acetic acid.