Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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Improvements in or relating to cephalosporins
This invention relates to improvements in
or relating to cephalosporins. More particularly
it relates to improvements in the manufacture of
cefuroxime l-acetoxyethyl ester (cefuroxime axetill.
The compound (6R,7R)-3-carbamoyloxymethyl-
7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-
3-em-4-carboxylic acid has the approved name "cefuroxime".
10 This compound is a valuable antibiotic characterised
by high broad spectrum activity agains~ gram-positive
and gram-negative microorganisms, this property
being enhanced by the very high stability of the
compound to ~-lactamases produced by a range of
gram-negative microorganisms. It is well tolerated
in the mammalian body and is used widely as an
antibiotic in clinical practice. Cefuroxime and
its salts are principally of value as injectable
antibiotics since they are poorly absorbed from
the gastro-intestinal tract and are therefore present
in sera and urine only in low concentrations after
oral administration. There has therefore been
a need for a form of cefuroxime which is capable
of being absorbed from the gastro-intestinal tract
following oral administration.
We have found that appropriate esterification
of the carboxyl group of cefuroxime improves the
effectiveness on oral administration. The presence
of such an appropriate esterifying group results
in significant absorption of the compound from
the gastro-intestinal tract, whereupon the esterifying
group is hydrolysed by enzymes present in, for
example, serum and body tissues to yield the anti-
biotically active parent acid. To be effective
upon oral administration the ester must be stable
enough to reach the site of absorption without
significant degradation, must be sufficiently absorbed
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upon reaching the appropriate site, and must be
sufficiently susceptible to hydrolysis by systemic
esterases for the parent acid to be liberated within
a short time of the ester being absorbed. British
5 Patent Specification No. 1571683 discloses and
claims a number of esters of cefuroxime as ha~7ing
properties rendering them of significant potential
value as orally administrable antibiotics.
Of the esters described in ~3ritish Patent
10 Specification No. 1571683, we have found cefuroxime
axetil to be of particular interest. This product
possesses an asymmetric carbon atom at the l-position
of the l-acetoxyethyl group and can therefore exist
in the form of R and S isomers or mixtures thereof.
15 The processes for the preparation of the above
ester exemplified in British Patent Specification
No. 1571683 produce the material either in relatively
impure amorphous form or in the form of a crystal-
line material. Furthermore, the crystalline material
20 produced by the methods described in this specification
generally contains a predominance of either the
R or the S isomer whereas an approximately 1:1
ratio is advantageous for administration. The
crystalline product is not therefore ideally suited
25 to administration.
We have now been able to develop a process
whereby cefuroxime axetil may be obtained in highly
pure crystalline form and in high yield. Such
a product is not only useful from the point of
30 view of being a highly pure form of the active
compound and hence more suitable for biological
administration but, more particularly, is also
highly useful as a starting material for the preparation
of a highly pure, substantially amorphous form
35 of cefuroxime axetil, which form we have surprisingly
found has high bioavailability upon oral administration
and a better balance of properties for commercial
use than the crystalline material. The amorphous
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cefuroxime axeti] which has these properties is desirably and
approximately l:l ratio of R to S isomers since this has been
found to be of value in maximising the solubility in aqueous media
of the amorphous product, and the process we have developed can
provide crystalline cefuroxime axetil having this approximate
ratio of isomers.
Accordingly, we provide a process for the preparation
of highly pure crystalline cefuroxime l-acetoxyethyl ester which
comprises crystallizing cefuroxime l-acetoxyethyl ester from a
solution thereof wherein the solvent is an ester or a halogenated
hydrocarbon, optionally in admixture with an ether, an aliphatic or
aromatic hydrocarbon or an alcohol, said alcohol op-tionally in
admixture with water or an aliphatic or aromatic hydrocarbon; or
wherein the solvent is an amide or ketone in admixture with water,
isolating and drying the product.
The choice of crystallisation solvent has been found
important if the yield is to be maximised and the R to S isomer
ratio of the product is to be, as is desirable, approximately l:l,
for example i.n the range 0.9:1 to l.l:l. We have found the
different isomers of cefuroxime axetil to have different solu-
bilities, one of them being consistently more soluble than the
other. The levels of solubi].ity vary according to the solvent,
and so a solvent system will desirably be chosen which allows a
practically quantitative recovery of the ceEuroxime axetil that is
present prior to crystallization, thereby assuring an approxi-
mately l:1 ratio of isomers.
The solvent system from which the product may be
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crystallized will be selected from an ester, for example methyl
or ethyl acetate, or a halogenated hydrocarbon such as methylene
chloride, optionally but preferably in admixture with an ether,
for example diisopropyl ether or an aliphatic or aromatic hydro-
carbon, for example petroleum ether or toluene; or an alcohol, for
example ethanol or isopropanol, optionally but preferably in ad-
mixture with water r such as in aqueous industrial methylated
spirit; or an amide,
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such as dimethylformamide or dimethylacetamide,
or ketone, such as acetone, in admixture with
water.
The crystallisation step will desirably be
carried out at ambient temperature, for example
at from about 10 to 30C and the concentration
of the cefuroxime axetil in the solution from which
crystallisation will occur will generally be adjusted
e.g. by evaporation of solvent or by dilution so
as to be neither too dilute nor too concentrated
respectively. The crystallisation may comprise
the last stage or stages of a reaction in which
the cefuroxime axetil is formed. In such a case,
the initial stage of crystallisation may occur
at quite a high temperature, e.g. up to about 65C,
but in order to maximise the yield and obtain a
suitable ratio of isomers in the product, a temper-
ature range of from 10 to 30 is preferred for
the final isolation.
The reaction in which the cefuroxime axetil
is formed will preferably be an esterification
reaction carried out in the manner described in
British Patent Specification No. 1,571,683 and
using a highly pure sodium cefuroxime starting
material. A preferred reagent for the esterification
is l-acetoxyethyl bromide and in order to produce
an approximately 1:1 ratio of R and S isomers prior
to recrystallisation, it is clearly preferred that
such a reagent be racemic.
The preferred sodium cefuroxime starting
material will generally be itself highly pure.
Such a material may be obtained inter alia, by
reaction of (6R,7R)-3-hydroxymethyl-7-[Z-2-(fur-
2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic
acid with chlorosulphonyl isocyanate in an alkyl
acetate as solvent at a temperature of from -25
to +10C, followed by hydrolysis in situ at a temper-
ature of +10 to +30C an~ crysta1lisation eollowing
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addition of sodium 2-ethylhexanoate in acetone
or methyl acetate as solvent. Such a material
will generally have a purity ]evel of 90% mass/mass
(m/m) or greater.
The cefuroxime axetil produced by the process
of this inven~ion has an R to S isomer mole ratio
of approximately 1.1, and is generally not less
than 95% m/m pure (uncorrected for residual solvents).
In its highly pure, crystalline form the
cefuroxime axetil which may be produced by the
process of this invention is a novel form of matter
and constitutes a further aspect of this invention.
A sample of this material has the IR spectrum in
Nujol*shown in the accompanying drawing.
The invention will now be illustrated by
the following non-limiting Preparation and Examples.
The individua] R and S isomers of cefuroxime
l-acetoxyethyl ester are denoted for convenience
by the letters A and B, these letters being used
to denote the respective isomers as in British
Patent No. 1571683. The identities of isomers
A and B have not been assigned. The isomer ratios
given in the following Examples are expressed as
A:B. All temperatures are given in C.
PreParation 1
odium Cefuroxime
Chlorosulphonyl isocyanate (226 ml) was added
to a solution of triethylamine (10 ml) in methyl
acetate (3.8 1). The resulting clear solution
was cooled to -lS and a suspension of (6R,7R)-
3-hydroxymethyl-7-[Z-2-(fUr-2-yl)-2-methoxyiminoacet-
amido]ceph-3-em-4-carboxylic acid (763g) in methyl
acetate (2.3 1), pre-cooled to -15, was added
over 10 minutes. The residual solid was rinsed
in with methyl acetate (700 ml). The mixture was
stirred at -5 for 30 minutes, a clear solution
being obtained after 10 minutes~ Water (1.2 1)
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at 18 was added rapidly to the reaction mixture,
the temperature rising quickly to 10 and then
slowly to 17. The mixture was stirred for 60
minutes at 15 to give a thick, white suspension.
Methyl acetate ~3.6 1) was added followed by a
steady addition of a solution of sodium hydroxide
(288 g) in water (5.2 1). This gave a clear two-
phase mixture at 26 with a p~ of 2.35. The layers
were separated and the upper, organic layer was
washed with a solution of sodium chloride (600
g) in water (2 1). The two aqueous layers were
washed sequentially with methyl acetate--(2 1).
The organic layers were bulked, stirred with Norit
S~ Plus charcoal (76 g) for 30 minutes and filtered
through a bed of Hyflo*Supercel, the bed being
washed with methyl acetate (1.5 1). The filtrate
and wash were combined and stirred at 20 whilst
a solution of sodium 2-ethylhexanoate (338 g) in
a mixture of methyl acetate (2 1) and water (40
ml) was added over 20 minutes to give a white suspension
with a pH of 5.5. The suspension was stirred for
10 minutes and filtered, and the cake was washed
with methyl acetate (5 x 1 1), sucked dry, and
dried at 30 in vacuo for 24 hours to give sodium
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cefuroxime (851.9 g); [~]DO+ 60, (c0.5; O.lM pH
~.5 buffer); ~max (H20) 273 nm (ElCm 387); impurities
by HPLC 2.0%. Assay (HPLC) 92% m/m; Water content
(Karl Fisher) 2.8~ m/m; Solvents (g.l.c.) 0.5% m/m.
Example 1
Cefuroxime Axetil
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(RS)-l-Acetoxyethylbromide (]2.5 g) was added
to a stirred mixture of sodium cefuroxime (20 g)
(prepared by a method similar to that in Preparation
1) in dimethyl acetamide (110 ml) at 0C. The
mixture was stirred at +1 for 90 minutes and potassium
carbonate (0.5 g) was added. Stirring was continued
for a further 2 hours at 1-3 when the reaction
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mixture was added to a xapidly stirred mixture of ethyl acetate
(200 ml) and aqueous 3% sodium bicarbonate (200 ml) to destroy any
excess l-acetoxy-ethyl bromide. After l hour the organic layer
(1.5% ~2 isomer by HPLC) was separated, washed with M hydro-
chloric acid (100 ml) and aqueous 20% sodium chloride containing
2% sodium bicarbonate (30 ml). All three aqueous phases were
sequentially washed with ethyl acetate (100 ml). The combined
organic extracts were stirred for 30 minutes with charcoal (Norit
SX Plus; 2g), filtered thxough a kieselgiihr bed which was washed
with ethyl acetate (2 x 25 ml). The combined filtrate and washes
were evaporated in _cuo to 150 g and stirred at ambient tempera-
ture for 1 hour until the crystallisation was well established .
Di-isopropyl ether (250 ml) was added over 45 minutes to complete
the crystallisation and stirring was continued for the additional
1 hour. The product was collected by flltration, washed with 2:1
di-isopropyl ether/ethyl acetate (150 ml) and dried for a weekend
in vacuo at 50 to give crystalline cefuroxime axetil (19.3 g)
with an infra-red spectrum in Nujol as shown in the Figure in the
accompanying drawing which is typical of a mixture of crystalline
isomers. The spectrum has the following absorption bands:
vrnax (Nujol) 3500, 3420, 3356, 3308, 3282, 3218, 1778, ]770
(shoulder), 1748, 1708, 1650, 1622, 16:L0, 1526, l332, :1300, 1220,
1102, 1074, 1054, 1040, 1010, 940, 884, 860, 818, 776 and 748 cml.
Solvent content (GLC) 0.2 m/m. Impurities by HPLC
1.8% including ~ isomer 0.3% m/m; E-isomer 0.6% m/m. Isomer
ratio (HPLC) 1.09:1 [~]D (1% in dioxan) + 37; ElCm (278 mm, MeOH)
389. Assay by HPLC 99% m/m (uncorrected).
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Example 2
Cefuroxime Axetil
A stirred suspension of sodium cefuroxime (20 g) in
dimethylacetamide (110 mL ) was cooled to 15 and (RS)-l-acetoxy-
ethyl bromide (12.5 g) was added. Stirring at the foregoing
temperature was continued for 45 minutes and potassium carbonate
(0.5 g) was added. After stirring the mixture for an additional
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45 minutes at 15~ it was poured into a rapidly stirred
mixture of ethyl acetate (200 ml) and aqueous 3~
sodium bicarbonate (200 ml). After 1 hour the layers
were separated and the organic phase (EIPLC showed
1.6% ~2isomer) was washed with M hydrochloric acid
(100 ml) and aqueous 20% sodium chloride containing
2~ sodium bicarbonate (30 ml). All the aqueous phases
were sequentially washed with ethyl acetate (100
ml). The combined organic extracts were stirred
for 30 minutes with charcoal (Norit SX Plus~ 2 g),
filtered through a bed of kiesielgUhr which was washed
with ethyl acetate (2 x 25 ml). After evàporating
the combined filtrate and washes to 120 g the concentrate
was stirred for 20 minutes to enable crytallisation
to become established. Industri~al methylated spirit
(120 ml) was added rapidly followed over 15 minutes
by distilled water (240 ml). The resultant slurry
was concentrated in vacuo to 310 g and stirred at
ambient temperature for 45 minutes. The product
was harveste~, washed with distilled water (200 ml)
and dried for 67 hours in vacuo at 50 to give crystalline
cefuroxime axetil. (20.01 g). Solvent content (GLC)
0.2~ m/m; impurities (HPLC) 1.5% m/m including ~
isomer 0.5% m/m and E-isomer 0.6% m/m; isomer ratio
25 1.01:1; [a]Dtl% in dioxan) +40; ElCm (278 nm, methanol)
388; Assay by HPLC 98% m/m (uncorrected).
Example 3
Cefuroxime Axetil
Sodium cefuroxime (20 g) was stirred with dimethyl-
acetamide (100 ml) at ca 25 for 15 minutes, the
mixture was cooled to 15 and (RS)-1-acetoxyethyl
bromide (9.8 ml) was added. The mixture was stirred
for a further 90 minutes at 14-16, adding 60-mesh
potassium carbonate (0.5 g) halfway through this
period. The red-brown mixture was then diluted with
ethyl acetate (200 ml) and 3% aqueous sodium hydrogen
carbonate (200 ml) and stirred for an hour at ambient
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temperature (ca 25)~ The layers were then separated
and the aqueous layer was re-extracted with ethyl
acetate (200 ml) and discarded (~, 0.21/dm). The
organic solutions were washed sequentially with M
hydrochloric acid (100 ml), then 20% sodium chloride
(30 ml) containing 2% sodium hydrogen carbonate and
were then combined and treated with Norit SX Plus
charcoal (2 g) for 25 minutes. The charcoal was
filtered off through a Standard Supercel*pad, the
filter was washed with ethyl ac~tate (50 ml), and
the combined filtrates were evaporated in vacuo to
120 g. The residual solution was seeded, stirred
at 22 for 1 hour when toluene (250 ml was run into
the stirred slurry over 30 minutes, and the mixture
stirred for a further 30 minutes. The suspension
was then re-evaporated in vacuo to 182 g, cooled
to ca 25 and stirred for 30 minutes. The product
was harvested, washed with toluene (100 ml), suction- -
dri-ed for 15 minutes, then dried in vacuo at 45
overnight to give crystalline cefuroxime axetil (19~8 g).
Solvents by GLC, 0.9% ~EtAc 0.7~; toluene 0.15~);
impurities by HPLC, 0.9%, HPLC assay 100%, isomer
ratio 1.03~ 0.1% m/m. Water (by Karl Fischer)
0.4% m/m.
Example 4
Cefuroxime Axetil
The washed and evaporated (ca 125 g) ethyl acetate
solution of cefuroxime axetil obtained from a similar
reaction to that described in Example 1 was stirred
at ambient temperature until crystallisation was
well established. Light petroleum ether (b.p. 100-
120; 188 ml) was added dropwise during 1 hour after
which the suspension was stirred at ambient temperature
for a further 2 hours. The crystalline precipitate
was collected by filtration, displacement washed
with 2:1 light petroleum ether tb.p. 100-120) -
ethyl acetate mixture (75 ml) and dried overnight
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at 40 ln vacuo to give the title compound, (19.2 g)~
Water (Karl Fischer) 0.4% m/m, solvents (glc) 0.4~ m/m.
Assay by HPLC 100% m/m. Impurities by HPLC 1.1% m/m
(of which 0.1% and 0.6% m/m were ~2 and anti isomer
respectively); the isomer ratio was 0.98:1.
Example 5
Cefuroxime Axetil
A washed and concentrated (ca 125 g) solution
of the required cefuroxime acetil in ethyl acetate
as prepared in Example 1 was stirred for 1 hour at
33 until crystallisation was well established.
After storing the suspension overnight at ambient
temperature IMS (62.5 ml) was added over 5 minutes
with stirring followed, over the next 1 hour by light
petroleum ether (b.p. 100-120; 250 ml). After stirring
the crystalline suspension for a further 1.5 hours
it was harvestea, displacement washed with 2:1 light
petroleum ether (b.p. 100-120 - ethyl acetate mixture
(75 ml) and dried overnight in vacuo at 45 to give
the title compound, 19.2 g. Water ~Karl Fischer)
0.2% m/m; solvents (glc) 0.8% m/m. ImpuritieS by
HPLC 0.8~ m/m (of which 0.1% m/m and 0.7% m/m were
~2 and anti isomers respectively); isomer ratio was
1.05: lo Assay by HPLC 96% m/m.
Example _
Cefuroxime Axetil
A washed and charcoaled concentrate (ca 100 g)
of cefuroxime axetil in ethyl acetate, containing
ca 2~ ~2 isomer, obtained similarly to that in Example
1 was seeded and stirred for 30 minutes until crystal-
lisation was well established. Isopropanol (100 ml)
was added dropwise over 30 minutes followed over
50 minutes by distilled water (170 ml). The resultant
slurry was concentrated _ vacuo to 250 g and cooled_
to 12 over a period of 1 hour. The crystalline
product was collected by filtration, displacement
washed with an ice-cold solution of 20% isopropanol
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in distilled water (100 ml) and dried for a week-
end in vacuo at 40. The title compound amounted
to 20.1 g. Water (Karl Fischer) 0.4% m/m, solvents
(glc) 0.03% m/m. Impurities by HPLC 1.5% (of which
0.4% m/m and ca 0.6% m/m were ~2 and anti isomers
respectively~; isomer ratio 1~05:1.
