JPS6075484A - Manufacture of crystalline cefuroxime accetyl - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to improved cephalosporins or cephalosporins. More specifically, the present invention provides cefuroxime 1-
Acetoxyethyl ester (cefuroxime acetil)
Concerning improvements in the manufacture of.

(6B,,7R) -5-Carbamoyloximethyl-7-[(powder-2-(flu-2-yl)-2-methoxyiminoacetamide)] Cef-3-M-4-carboxylic acid is officially recognized as “cefuroxime”. It has a given name.

This compound is a valuable antibiotic characterized by its high broad-spectrum activity against Durham-positive and Gram-negative microorganisms. This property is enhanced by the highly sieving stability of this compound towards β-lactamases produced by a wide range of Gram-negative bacteria. It is well tolerated in sentinel mammals and is widely used as an antibiotic in clinical practice. Cefuroxime and its salts are primarily valued as injectable antibiotics.

This is because they are poorly absorbed from the intestinal tract and are therefore present in low concentrations in the serum and urine after oral administration. Therefore, a need exists for a form of cefuroxime that can be absorbed from the intestinal tract after oral administration.

The inventors have discovered that appropriate esterification of the carboxyl group of cefuroxime improves its efficacy upon oral administration. The presence of such a suitable esterifying group results in significant absorption of the compound from the intestinal tract. In this case, the esterification functional group is hydrolyzed, for example by enzymes present in serum or body tissues, to form the antibiotically active native acid. To be effective upon oral administration, the ester must be stable enough to reach the site of absorption without significant degradation, and must be sufficiently absorbed when it reaches the appropriate site. It should not be hydrolyzed sufficiently by total esterase to release the original acid in a short time after absorption of the ester. British patent number 1
No. 571,683 discloses a number of cefuroxime esters as having properties that make them of significant value as orally administrable antibiotics.

Among the esters described in GB 1,571,683 we have found cefuroxime axetil to be of particular interest. This 5- product has an asymmetric carbon atom in the 1-position in the 1-acetogyethyl group and can therefore exist in the form of R and S isomers or mixtures thereof. British Patent No. 157
The process for preparing the esters, as exemplified in No. 1683, produces materials in either relatively impure amorphous form or in the form of crystalline material. Furthermore, the crystalline material produced by the method described in Specification 1 generally contains a large amount of either the R isomer or the S isomer.

However, for dosing, a 1:1 ratio is advantageous. This crystalline product is therefore not ideally suited for administration.

The inventors have now succeeded in developing a method by which cefuroxime axetil can be obtained in highly pure crystalline form and in iA[J. Such products are not only useful in that they are highly purified forms of the active compound and therefore more suitable for biological administration, but also in particular highly purified forms. Cefuroxime axetil in pure, substantially sterile (amorphous) form, which unexpectedly has high biological activity when administered orally and is better suited for artistic use than the crystalline material. It is also highly useful as a starting material for the production of Amorphous cefuroxime axetil having these properties preferably has an R:S isomer ratio of bold line 1:1. This is because it has been found to be valuable in maximizing the solubility of the amorphous product in aqueous media.

This method developed by the present inventors can provide crystalline cefuroxime axetil having the isomer ratio shown in the bold line.

Accordingly, the present invention provides highly pure crystalline cefuroxime axetil, which involves crystallizing cefuroxime axetil from its solution in an organic or aqueous solvent or a mixture thereof, isolating and drying the product. It provides a method for manufacturing with high yield.

In order to maximize the yield and achieve the desired R isomer ratio of the product in the bold line 1:1, e.g. in the range 0.9:1 to 1:11, the choice of crystallization solvent is essential. Something was discovered. We found that different cefuroxime axetyl isomers have different solubility. One of them is always more soluble than the other. Solubility levels vary depending on the solvent. It is therefore desirable that the solvent thread be chosen to enable substantially routine recovery of the cefuroxime axetil present prior to crystallization, thereby ensuring an isomer ratio of about 1:1. .

The solvent systems in which the product can be crystallized are preferably esters such as methyl acetate or ethyl acetate, or halogenated hydrocarbons such as methylene chloride (optionally but preferably ethers such as diisopropyl ether or aliphatic or aromatic hydrocarbons such as petroleum ether or toluene), alcohols such as ethanol or improno-7nol (which may optionally be prepared but preferably mixed with water, such as an aqueous industrial methyl liquor); or amides such as dimethylformamide or dimethylacetamide or ketones such as acetone, which may be mixed with water.

The crystallization step is preferably performed at room temperature, e.g. about 10' to 50C.
The concentration of cefuroxime axetil in the solutions carried out and causing their crystallization is generally adjusted to be neither too dilute nor too concentrated, for example by evaporation or dilution of the solvent. Crystallization may constitute the final step in the reaction to produce cefuroxime axetil.

In such a case, the first stage of crystallization is e.g.
It can be carried out at very high temperatures at even temperatures. However, a temperature range of 10 DEG to 30 DEG is preferred for the final isolation in order to maximize yield and produce a suitable isomer ratio in the product.

The reaction in which cefuroxime axetil is formed is preferably described in British Patent No. 1,571,687! The esterification reaction is carried out as described in the above specification and using high purity sodium cefuroxime starting material. A preferred reagent for the esterification pool is 1-acetoxyethyl bromide, and such a reagent is racemic in order to produce an R isomer ratio of 1:1 prior to recrystallization. This is clearly preferred.

10- Preferred sodium cefuroxime starting materials are generally highly pure themselves. Such substances are inter alia T -25 to +10' in alkyl acetates as solvents.
+7) (6R,7R)-3-hydroxymethyl-7-[IZ-2-(flu-2-yl)-
2-methoxyiminoacetamide]7fu 6-emu 4
- by reaction with carboxylic acid tochlorosulfonyl isocyanate, then hydrolysis in situ at temperatures of 10 to +30°C and crystallization after addition of sodium 2-ethylhexanoate in acetone or methyl acetate as solvent. You can get it. Such materials generally have a purity water rate of 90 m/rn or higher.

Cefrogisim axetil produced by the method of the invention has a H:s isomer molar ratio of approximately 1:1, which is 95% m/m (uncorrected for residual solvent). The purity is above.

In its highly pure crystalline form, cefuroxime axetil, which can be produced by the process of the invention, is a novel form of substance and this constitutes another feature of the invention. A sample of this material has an R spectrum in Nujol as shown in the accompanying drawings.

The invention will now be illustrated by the following non-limiting examples.

Individual R of Cefuroxime 1-acetoxyethyl ester
and S isomers are designated by the letters A and B for convenience.

These letters are used in GB 1,571,683 to refer to the respective isomers. Isomer A
The identification of and B is not marked. The isomer ratios given in the examples below are expressed as A:B.

All temperatures are given in °C.

Reference Example Sodium cefrogisim chlorosulfonylisocyanate (226 m) was added to a solution of triethylamine (10 ml) in methyl acetate (5,8 t). The resulting 6-light solution was cooled to -15° and methyl acetate (2,5 t) pre-cooled to -15°.
(6R,7R)-5-hydroxymethyl-7-[Z
-2-(Flu-2-yl)-2-notoxyiminoheptamide]7fu-3-emu-4-carboxylic acid (763F)
suspension was added over 10 minutes. The remaining solids were washed with methyl acetate (70M). This mixture was heated at -5° for 3
Stirred for 0 minutes. A clear molten oil was obtained after 10 minutes. 18°
of water (1.2 t) was quickly added to the reaction mixture. Humidity quickly rises to 10° and then gradually to 17°
It rose to The mixture was stirred at 15° for 60 minutes to give a thick white suspension. Methyl acetate (3,6t) was added followed by a constant rate of addition of a solution of sodium hydroxide (22El) in water 13- (5,2t). This gave a clear two-phase mixture with a pH of 2.35 at 26°. The layers were separated and the upper organic layer was dissolved in sodium chloride (600F) in water (2t).
) solution. The two aqueous layers were combined with methyl acetate (2
t).

The organic layers were combined, stirred for 30 minutes with Norlt, SX Plus Charcoal C76t), and washed with methyl acetate C1.5T).
It was filtered through a bed of 7F and 5uppercel.

The lachrymal fluid and wash solution were combined and stirred 20'. Meanwhile, a solution of sodium 2-ethylhexanoate (338t) in a mixture of methyl acetate (2t) and water (40+7t) was added over 20 minutes to form a white suspension with a pH of 5.5. The suspension was stirred for a total of 10 minutes, filtered and the mass washed with methyl acetate (5 x 14), sucked dry, and dried for 24 hours under a 30' tube for 24 hours. Kissim (
851,9t) was given. [α几−−60°((!
0.5.0.1 M, pH 4,5 buffer),'
max (R20) 273nm (Fi14587), H
Impurities due to PLC2. [11. Assay (HPLC)
) 92% m/m, water content, It (Karl Fischer) 2.8% m//]]1, solvent (glc) 0.5
%n'v'm.

Example 1 Cefuroxime axetyl (R8)-1-acetoxyethyl bromide (12,52
) was added at OC to a stirred mixture of cefuroxime sodium (209) (prepared in a similar manner as in Reference Example 1) in dimethylacetamide (110+m). The mixture was stirred at +1° for 90 minutes and then potassium carbonate (0,!
M) was added. Stirring was continued for a further 2 hours at 1-6°C.

The reaction mixture was then added to a rapidly stirred mixture of ethyl acetate (200v) and aqueous IJ carbonate (200ml) to destroy any excess 1-acetoxyethyl bromide. After 1 hour, the organic layer (15% Δ2 isomer, by TPLC) was separated and treated with 1M hydrochloric acid (100 d
) and aqueous 20% sodium chloride ('30 ml) containing 2% sodium bicarbonate. All three aqueous phases were washed in series with ethyl acetate (100++g). The combined organic extracts were stirred for 30 minutes with whole charcoal (Frit SX Plus, 2v) and diluted with ethyl acetate (2X2
5++d) Filtered through a washed bed of diatomaceous earth. The combined oki liquor and wash liquor were evaporated under vacuum to give 1507 and stirred for 1 hour at ambient temperature until crystallization was well established. Diisopropyl ether (250 m7) was added over a total of 45 minutes to complete crystallization and stirring continued for a further 1 hour. The product was collected in bulk, washed with diisopropyl ether/ethyl acetate (2M) (150d) and dried at 50°C under vacuum over the weekend to yield crystalline cefuroxime axetil (19,39). It has an infrared-edge absorption spectrum (see accompanying drawing) typical of crystalline isomer mixtures in Nujol.

Solvent-containing i (()LC) 0.2% m/m, HPL
Impurity due to C: 1.8. This is 0.3% m of Δ2 isomer
1m, containing 0.6% rrv'rn of the Ri-isomer.

Isomer ratio (HPLC) 1.09 + 1° [αID
(1% in dioxane) +37°, E1% (2781 tweed, MeOH) 389, assay by HPLC 99% TV/m (uncorrected).

Example 2 A stirred suspension of cefuroxime sodium (20?) in cefuroxime axetyl dimethylacetamide (110) was cooled to 15° and (RB)-1-acetoxyethyl bromide (12
゜5ri) was added. Stirring at this temperature was continued for 45 minutes and potassium carbonate (0.5 f') was added. After further stirring this mixture for 45 minutes at 15°C, it was diluted with ethyl acetate (2
00 m) and aqueous -1,'/- 3 g of bicarbonate) IJum (200 m) were poured into a rapidly stirring mixture. After 1 hour, the layers were separated and the organic phase (HPLC showed 1.6% Δ2 isomer)
was washed with aqueous 20% sodium chloride containing 1M hydrochloric acid (100g) and 2% sodium bicarbonate. All aqueous phases were washed successively with ethyl acetate (100m). Combined organic extract! Stir with charcoal (Nori) SX Plus, 2t) for 10 minutes, and add ethyl acetate (2X2!1m).
The mixture was filtered through a bed of diatomaceous earth washed with chlorine. After evaporating the combined filtrate and washing liquid to 1202 ml, this concentrated liquid was
Stirred for 0 min to ensure crystallization.

Industrial methyl spirit (120 tnl) was added quickly followed by distilled water (240 m/liter) over 15 minutes.

The resulting slurry was concentrated under vacuum to 310f and stirred at ambient temperature for 45 minutes. Harvest the product and add distilled water (2
oooy) and dried at 50° C. for 67 hours under vacuum to give crystalline cefuroxime axetil (20,01)). Solvent content (GLC)
0.21Jm/m, impurities (HPLC) 1.5%r
ry'm 0 This is △2 isomer 0,5% m/m and E
The isomer is 0.6% m/m. Isomer ratio 1.01=
1, [α]D (1% in dioxane) +40°, 81%
(278nm methanol) 688°IqpLC assay +; s1m/m (no correction).

Example 6 Cefuroxime axetil Cefuroxime sodium (2Or)'e was stirred with dimethylacetamide (10M) for 15 minutes at about 25°, the mixture was cooled to 15°, and (R8)-1-acetogyethyl Bromide (9,8mg) f7) II
I got it. The mixture was stirred for a further 90 minutes at 14-16°,
60 mesh potassium carbonate ([1,59)i was added during this period. This reddish-brown mixture was then mixed with ethyl acetate (
200 m/liter and 6% aqueous sodium bicarbonate (20
0 mg) and stirred at room temperature (approximately 25°C) for 1 hour. The layers were then separated and the aqueous jVi was re-extracted in ethyl acetate and discarded (α, 021°/dm).

The organic solution was sequentially diluted with 1M hydrochloric acid (100 m/) and then 2%
20% sodium chloride containing sodium carbonate water (
Washed with 30 + +7 ml and then combined and treated with Norit Sx Plus Charcoal (2f) for 25 minutes.

The charcoal was passed through a standard supercell bed, washed with ethyl acetate (50 m/s), and the combined F solution was evaporated under vacuum to 120 v
And so. Seed crystals were added to the remaining solution and stirred for 1 hour at 22°C, at which time toluene (25M) was poured into the stirred slurry over 60 minutes, and the mixture was stirred for 60 minutes.The suspension was then evacuated under vacuum. Re-evaporated down to 1821, cooled to about 25' and stirred for 30 minutes. The product was harvested, washed with toluene (100d),
Suction dry for minutes and then drying in vacuo at 45° overnight to produce crystalline cefuroxime axetil (19,8&). Solvent 0.9% (EtAa O
,7q6. ) Luene 0.15% [. Impurity by HPLC @ 0.996.

100% HPLC attachment. Isomer ratio 1.031゜m2
<0.1% m7'm, moisture (Karl Fischer method) 0
．． 4% rry'm.

Example 4 Cefuroxime Axetil A washed and evaporated (approximately 125 f) ethyl acetate solution of Cefuroxime Axetil obtained from a reaction similar to that described in Example 1 was stirred at ambient temperature until crystallization was well established. . Light petroleum ether (b, p, 100-120°,
188 mt) was added dropwise over a period of 1 hour, after which the S suspension was stirred for an additional 2 hours at room temperature. Crystalline precipitate p by total filtration
collected, light petroleum ether (b, p, 100-120°)
Washing with a 2:1 /21-ethyl acetate mixture (75 Wtt) and drying in vacuo at 40 DEG overnight yielded the title compound (19,21). Moisture (Karl Fischer method) 0.4% m/m. Solvent (glc) 0.4%Vm
.

100% m/m O) by HPLC (PIC
Impurity due to O 1.1%rn/m (0.1%m/m)
m and 0.6 cm/m were the Δ2 and anti isomers, respectively), and the isomer ratio was 0.981.

Example 5 Cefuroxime Axetil A washed and concentrated solution of cefuroxime axetil in ethyl acetate prepared as in Example 1 (ca.
It was stirred with After storing this suspension at room temperature overnight, ys (62,5 mg) was added over 5 minutes with stirring, followed by light petroleum ether (b, p, i) over the next hour.
oo~120°, 250m) was added. After stirring this crystalline U suspension for an additional 1.522-h, it was harvested and light petroleum ether (b,p
, 100-120°)/ethyl acetate (21) mixture qll
Wash the tie with tJ (75ml) (-L tea night 45
Drying in vacuo at .degree. C. produced the title compound 1922. Moisture (Karl Fischer method) 0.2% m/m o
Solvent (glc) o, 8% m7m o) IPLC! Nyoru impurities o, B% m/m (of which 0.1% m/m and (J, 7% m/m were Δ2 and anti-isomers, respectively).

The isomer ratio was 1.051. HPLC assay is 9
It was 6%ψ.

Example 6 Seeds were planted in a washed and charcoal-treated concentrate (approximately 100 f) of cefuroxime axetil in ethyl acetate containing about 2% Δ2 isomer and obtained as in example 1. and stirred for 30 minutes until crystallization was well established. Improper tool (100 m/l) was sieved for 30 min, distilled water (170 m/l) was then added over 50 min. The resulting slurry was reduced under vacuum to 250 g" and Cooled to 12°. The crystalline product was collected by filtration and incubated at 20°C in distilled water (100mA).
Displacement washing was performed with a water-cooled solution of multi-inzolopanol and then dried in vacuo at 40' over the weekend. The title compound 2D, 1f was obtained. Moisture (Karl Fischer method)
0.4% m/m, solvent (glc) 0.05% m/m
Impurities by OHPLC: 1.5% m/m (0.
4% m/m and approximately 0.6% Ill/m were the Δ2 and anti-isomers, respectively).

The isomer ratio was 1.051.

[Brief explanation of the drawing]

The attached drawing is the spectral curve of cefuroxime axetil obtained by the method of the present invention. Patent Applicant: Gluckts Group Ltd. Continued from page 1 [Phase] Inventor: John Peter Turnpul0 Inventor: John Φ Francis Orton 361 Greenford Road, Greenford, Middlesex, United Kingdom Patskingham, United Kingdom 82 Fulmer Drive, Gerrards Cross, Shire

Claims (1)

Claims: 1) High purity crystalline cefwaxime comprising: 1) crystallizing cefurexime 1-acetoxyethyl ester from a solution in an organic or aqueous solvent or mixtures thereof, isolating and drying the product; A method for producing 1-acetoxyethyl ester. 2) Ceflexime 1-acetoxyethyl ester is approximately 1
2. A method according to claim 1, wherein the R2S isomer ratio is crystallized at an R2S isomer ratio of: 3) Claim 1 wherein the solvent includes an ester
The method described in Section 2 or Section 2. 4) wherein the solvent comprises an ester or a halogenated hydrocarbon, optionally in a mixture with a diether or an aliphatic or aromatic hydrocarbon, or a ketone or amide in a mixture with water; Method. 5) A method according to claim 1 or 2, wherein the solvent includes alcohol in a mixture with water. 6) A process according to claim 4, wherein the solvent is selected from methyl acetate or ethyl acetate optionally mixed with p-diisopropyl ether, petroleum ether or toluene. 7) A method according to any one of the preceding claims, wherein at least the subsequent part of the crystallization step is carried out at a temperature of 10 to 30<0>C. 8) A method substantially as described in connection with the Examples. 9) Crystalline cefwaxime 1-acetoxyethyl ester having a purity level of at least 95 w/w. 10) Crystalline cefuroxime 1-acetoxyethyl ester with an R spectrum in Nujol as shown in the accompanying drawings.