Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
loa3~6s
This invention is concerned with improvements in
or relating to cephalosporin antibiotics. More
particularly the invention is concerned with esters of
(6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-~-
methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (i.e.
the syn isomer), which has the approved name "cefuroxime".
Cefuroxime, as disclosed in British Patent No.
1,453,049 is a valuable broad spectrum antibiotic
characterised by high activity against a wide range of
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. Additionally the compound is
stable in the body owing to its resistance to the action
of mammalian esterases, and gives high serum levels
following parenteral administration (e.g. in the form of
the sodium salt) to human and animal subjects, while
exhibiting low serum binding.
Cefuroxime and its salts, for example alkali metal
salts such as the sodlum salts, are principally of value
as injectable antibiotics since they are poorly absorbed
from the gastro-intestinal tract and are therefore present
-- 2 --
1093068
in sera and urine only in low concentrations after oral
administration. We have accordingly conducted extensive
studies into the result of administering various
derivatives of cefuroxime by the oral route, since the
development of derivatives which are absorbed from the
gastro-intestinal tract and are converted in the body
sera to the parent antibiotic following oral administration
would extend still further the valuable therapeutic
potential of cefuroxime.
It is known from the literature pertaining to
~-lactam antibiotics that the absorption from the gastro-
intestinal tract following oral administration of certain
penicillin and cephalosporin antibiotics can be improved
(compared with the parent antibiotic) by converting the
lS free 3-carboxy group in the case of penicillin compounds,
or the free 4-carboxy group in the case of cephalosporin
compounds, to particular esterified carboxy groups.
Thus, for example, Penicillin G may be converted into its
acetoxymethyl ester to provide a compound having improved
absorption from the gastro-intestinal tract after oral
administration compared with Penicillin G itself.
It is believed that the presence of an appropriate
esterifying group enhances absorption of the parent
1093{)68
antibiotic ~rom the gastro-intestinal tract, the
esterifying group being hydrolysed after absorption by
enzymes present in, for example, serum and body tissues
to yield the antibiotically-active parent acid. It
will be appreciated that the precise nature of the
esterifying group is critical since it is necessary
that the ester should be sufficiently stable to allow
the ester to reach the site of absorption without under-
going significant degradation, e.g. in the stomach, while
on the other hand the ester must be sufficiently
susceptible for conversion to the antibiotic-
ally active parent acid within a short time
of the ester being absorbed.
Moreover, the extent to which the particular ester
lS group enhances the oral absorption of the ~-lactam
antibiotic is random and unpredictable and depends upon the
nature of the parent acid selected. For example, an esterifying
group which has been found to be efective in improving
the usefulness of a penicillin antibiotic does not
necessarily convey similar advantages to an antibiotic
of the cephalosporin series, and inconsistencies are
noted within each of these particular series of ~-lactam
- 4 -
1093068
antibiotics.
We have now surprisingly found that cefuroxime may
be esterified at the 4-carboxy group with certain
esterifying groups (as defined below) to provide
compounds which have a high level of a~sorption from the
gastro-intestinal tract and which break down readily after
absorption to yield the parent antibiotic.
The new cefuroxime esters of our invention may be
represented by the formula
~ ~ (I)
N N ~ CH2ØCO.NH2
OCH3
CO.O.CH.O.CO.OR
R2
(wherein Rl is an alkyl group containing 1 to 6 carbon
atoms, R2 is hydrogen or an alkyl group containing 1 to
6 carbon atoms, and the asterisk denotes an asymmetric
carbon atom when R is other than hydrogen). These
esters possess properties which render the compounds of
significant potential value as orally administrable
antibiotics. Individual diastereoisomers, as well as
mixtures thereof, are embraced by the invention.
~W3~68
The esters (I) possess reasonable stability as
evidenced by the fact that they exhibit low antibacterial
activity in vitro compared to cefuroxime (this indicates
that a high proportion of ester remains unchanged through-
out the in vitro tests and so confirms the stability ofthe esters). The esters are, on the other hand,
extremely susceptible to esterase hydrolysis leading to
formation of cefuroxime, as evidenced for example by
in vitro tests employing esterases derived from rat
__ .
liver, human liver or human serum.
In vivo testing in rats confirms that oral
administration of the esters (I~ leads to significantly
greater absorption of cefuroxime, as evidenced by higher
serum levels and increased urinary recovery, than does
oral administration of cefuroxime itself.
Compounds of formula (I) wherein Rl represents a
Cl 3 alkyl group and R2 represents a hydrogen atom or
a methyl group have been shown to provide particularly
good absorption of cefuroxime, as evidenced by animal
tests, examples of such compounds including:-
methoxycarbonyloxymethyl (6R,7R)-3-carbamoyloxy-
methyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-
3-em-4-carboxylate;
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1093068
l-(ethoxycarbonyloxy)-ethyl (6R,7R)-3-carbamoyl-
oxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido~-
ceph-3-em-4-carboxylate; and
l-(methoxycarbonyloxy)-ethyl (6R,7R)-3-carbamoyl-
ox~ethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]-
ceph-3-em-4-carboxylate.
The esters of formula (I)may be used for treating
a variety of diseases caused by pathogenic bacteria in
human beings and animals, such as respiratory tract and
urinary tract lnfections.
The compounds (I) may be prepared in conventional
manner, for example by reacting cefuroxime, a salt
thereof (e.g. an alkali metal salt such as the sodium or
potassi~m salt or an onium salt, e.g. an ammonium salt
for example a quaternary ammonium salt) or a corresponding
l-oxide, with a haloester of formula
*
X.CH.O.CO.OR ~II)
R2
(where Rl, R2 and the asterisk have the above-defined
meanings and X is halogen such as chlorine, bromine or
iodine) and, where a l-oxide is formed, reducing the
resulting product, e.g. by treatment with acetyl chloride
~093068
and potassium iodide, to produce the desired compound of
:formula I. The reaction is conveniently effected in
solution in an inert organic solvent (e.g. an N,N-di-
substituted amide such as N,N-dimethylformamide or N,N-
dimethylacetamide, a ketone such as acetone, a sulphoxidesuc.h as dimethylsulphoxide, a nitrile such as acetonitrile,
or hexamethylphosphoric triamide) at a temperature in the
range -50 to ~150C, e g -10 to +500C, conveniently
between 0C and room temperature When a cefuroxime salt,
for example, the potassium salt, is employed as starting
material and the reaction is effected in a nitrile solvent,
a crown ether such as 18-crown-6 may, if desired, be
employed When cefuroxime acid is employed as start-
ing material it may be advantageous to effect the reac-
tion in the presence of a base, e g. a weak inorganicbase such as sodium carbonate or potassium carbonate; it
is convenient to add the base to the cefuroxime-contain-
in~ reaction system prior to addition of the haloester
(II) The use of potassium carbonate as base in con
junction with a compound (II~ in which X is bromlne or iodine
has been found advantageous in that under these conditions
the formation of a ceph-2-em ester product is kept to a
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~093068
minimum. It is convenient to employ substantially
equivalent amounts of cefuroxime and base, e.g. about
0 5 moles of a diacidic base such as potassium carbonate
per mole of cefuroxime. The haloester (II) is conven-
S iently employed in slight excess, e g. in an amount of1-1.5 moles per mole of cefuroxime.
The course of the reaction may readily be monitored
by t.l.c., since the process involves conversion of a
polar acid or salt starting material to a neutral ester
product.
The esters (I) may also be prepared by acylation of
a compound of formula:-
S
H2N
o ~, ~ CH20CONH2
CO.O.CHO.CO.OR
l2
(wherein R1 and R are as hereinbefore defined) or an
acid addition salt or N-silyl derivative thereof, using
an acylating agent corresponding to (Z)-2-(fur-2-yl)-2-
methoxyiminoacetic acid, for example, an acid halide,
acid anhydride or carbodiimide, for example, in the
manner disclosed in British Patent No. 1,453,049.
_ 9 _
93068
The above-described starting materials of formula
(III) mAy be prep~red in conventional manner, for ex~mple,
~sing the techniques described in U.S, Patent Specification
No, 3j905,963 and British Patent Specific~tions Nos. 1,041,985
and 1,350,772.
Alternatively, the esters of formula (I) may be
prepared by in situ carbamoylation of a compound of
formula:-
CONH - ~/ S ~ (IV)
N ~ CH2H
OCH - -* - - 1
3 CO.O.CHO.CO.OR
(wherein Rl and R are as hereinbefore defined), by con-
ventional means, for example, in the manner disclosed in
British Patent No. 1,453~049. Carbamoylation may be
effected for example using an appropriate isocyanate or
cyanic acid.
The above-described starting materials of formula
(IV) may be prepared in situ by the esterification of the
corresponding 4-carboxylic acid, or a salt thereof (e.g.
an alkali metal salt such as the sodium or potassium salt)
with a haloester of formula II, as described above except
that a temperature in the range -100C to -~150C, con-
veniently between -70C to 0C, is preferably employed.
- 10 -
1~93~)6~
If the desired ester product is significantly con-
taminated by the corresponding ceph-2-em isomer the pro-
duct may be oxidised (e.g, by treatment with a peracid
such as metaperiodic acid, peracetic acid,monoperphthalic
S acid or m-chloroperbenzoic acid or with t-butyl hypo-
chlorite in the presence of a weak base such aspyridine)
to give the ceph-3-em l-oxide ester, which may then be
reduced (e,g. by treatment with acetyl chloride and
potassium iodide) to yield substantially pure ceph-3-em
ester.
The individual disstereoisomers may be isolated
from the isomeric mixture by crystallisation.
The esters of formula I may be formulated as com-
positions for oral administration in conventional manner,
with the aid of any necessary pharmaceutic ~ carriers or
excipients, The compositions are conveniently prepared
as tablets, capsules or sachets, advantageously in unit
dose form, and may contain conventional excipients such
as binding agents, fillers, lubricants, disintegrants
and wetting agents. Tablets may be coated in conventional
manner, Alternatively, the compositions may be for~ulated
as liquid preparations e,g, suspensions or emulsions, which
may contain edible oils, e,g, peanut oil, The active
- 11 -
~09306~il
compounds may further be formulated in rectal compositions
such as suppositories or retention enemas.
The compositions may contain from 0 1% upwards,
e.g. 0.1-99%, conveniently from 10-60% of the active
ingredient (I), depending on the method of administration.
Compositions in dosage unit form conveniently contain 50-
500 mg of the active ingredient (calculated as cefuroxime).
Doses employed for adult human treatment will typically
be in the range 500-5000mg per day,
e g. 1500mg per day, (calculated as cefuroxime), although
the precise dose will depend on, inter alia, the frequency
of administration
The following Examples illustrate the invention.
All temperatures are quoted in C. Melting points were
determined in a Mettler apparatus and take the form (M )
where x is the raté of heating (in C per minute) and y
is the insertion temperature
The N,N dimethylformamide employed was dried by passage
through acidic alumina.
Organic solutions were dried over anhydrous
magnesium sulphate.
- 12 -
1093068
T.l.c. plates were developed in chloroform: methanol:
formic acid (45:8:1) and the compounds located under U.V.
light at 254 nm and by exposure to iodine vapour, or by
spraying with ninhydrin and heating to 120.
Preparation 1
Iodomethyl methyl carbonate
A solution of chloromethyl methyl carbonate (7.07 g,
56.75 mmole) in acetone (5 ml) was treated with a
solution of sodium iodide (8.51 g, 56.75 mmole) in
acetone (30 ml). The resultant suspension was stirred at
22 for 2 /4 hours after which it was evaporated in vacuo
to a solid. This solid was partitioned between ether
(75 ml) and water (75 ml). The aqueous phase was extracted
with more ether (2 x 75 ml) and the combined organic
extracts were washed successively with water (3 x 75 ml),
aqueous sodium metabisulphite (50 ml) and saturated brine
(100 ml). The solution was dried and evaporated in _acuo
to give the title ester (6.45 g),
Preparation 2
(R,S)-l-Chloroethyl chloroformate
Ethyl chloroformate (100 ml) was treated with
chlorine at room temperature for 5 hours .~nd the reaction
~093068
mixture was allowed to stand for 5 days. Distillation of
the mixture at atmospheric pressure afforded the title
ester (71.8 g) b.p. 120 to 130.
Preparation 3
(R,S)-l-Chloroethyl methyl carbonate
(R,S)-l-Chloroethyl chloroformate (10.0 g, 70 mmole)
and methanol (25 ml) were stirred together for 1 hour;
initially the reaction was exothermic but the reaction
mixture cooled down to ca 20. The excess methanol was
removed in vacuo to give the title compound (11.37 g).
Preparation 4
(R,S)-l-Chloroethyl isopropyl carbonate
(R,S)-l-Chloroethyl chloroformate (10.14 g, 71 mmole)
was refluxed with propan-2-ol (35 mol) for 30 minutes and
triethylamine (8 drops) was added, and refluxing was
continued for 20 minutes. The solution rapidly darkened
and it was distilled to give two fractions:-
(i) Fraction l;b.p. 80 to 90/760 mm (30 ml)
(ii) Fraction 2;b.p. 60 to 70/15 mm (5.93 g),
which was the title_ester.
- 14 -
~0930t~8
Example 1
Methoxycarbonyloxymeth~l (6R,7R)-3-carbamoyloxymethyl-7-
[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-
carboxylate
Iodomethyl methyl carbonate (0.93 g, 4.3 mmole) in
N,N-dimethylformamide (3 ml) was added to a solution of
potassium (6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-
yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate
(1.00 g, 2.2 mmole) in N,N-dimethylformamide (10 ml) and
the solution was stirred at 22 for 45 minutes (t.l.c.
indicated essentially complete reaction after 30 minutes).
The above solution was partitioned between ethyl
acetate (80 ml) and 2-N-hydrochloric acid (80 ml) and the
aqueous phase was re-extracted with ethyl acetate
(2 x 100 ml). The combined organic extracts were
successively washed with water (100 ml), 3% aqueous
sodium bicarbonate solution (2 x i5 ml), water (75 ml),
aqueous sodium metabisulphite (50 ml), water (50 ml),
2-N-hydrochloric acid (4 x 50 ml), water (50 ml) and
saturated brine (50 ml). The solution was dried and
evaporated in vacuo to a foam (1,19 g). This foam was
triturated with anhydrous ether (S0 ml); the solid obtained
was filtered off and washed with anhydrous ether (2 x 20 ml)
1093068
and dried in vacuo to give the title ester (0.93 g),
-
m.P. (M80) 100, C~]D + 41 (C 0. ~1, DMSO).
Example 2
(R and S)-1-(Ethoxycarbony~oxy)-ethyl (6R,7R)-3-carbamoyl-
oxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]
ceph-3-em-4-carboxylate
(a) (R,S)-l-Iodoethyl ethyl carbonate
A solution of (R,S)-l-chloroethyl ethyl carbonate
(13.14 g, 86.4 mmole) and sodium iodide (14.8 g, 99 mmole)
in acetone (100 ml) was refluxed for 35 minutes. The
acetone was removed _ vacuo and the residue was partitioned
between ether (150 ml) and water (150 ml). The organic
phase was separated and washed successively with water,
aqueous sodîum metabisulphite solution, water (3 times)
and saturated brine and dried. The ether was removed in
vacuo to give the title ester.
(b) (R and S)-l-(EthoxYcarbonyloxy)-ethYl (6R,7R)-3-
carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-
iminoacetamido]-ceph-3-em-4-carboxylate and its
isomer
The product from (a) was immediately dissolved in
N,N-dimethylformamide (20 ml) and was added to a solution
- 16 -
1093068
of potassium (6R,7R)-3-carbamoyloxymethyl-7~[(Z)-2-(fur-2-
yl)-2-methoxyiminoacetamido]ceph-3 em-4-carboxylate
(8.58 g, 18.5 mmole) in N,N-dimethylformamide (50 ml).
The reaction mixture was stirred at 25 for 1 hour and
was then partitioned between ethyl acetate (150 ml) and
2-N-hydrochloric acid (200 ml), The aqueous layer was
extracted with further ethyl acetate (3 x 100 ml) and the
combined organic extracts were washed successively with
water (2 x 200 ml), 3% aqueous sodium bicarbonate solution
(200 ml), water (3 x 200 ml) and saturated brine (200 ml)
and dried and the solvent was removed in vacuo to give a
glass (5.64 g). Trituration of this glass with ether
gave the ~ e~ (5.51 g) as a gel [this contained
ca 20% of a2 isomer],
(c) (R and S~ (Ethoxycarbony~oxy~-ethYl_(lS,6R,7R)-3
carbamoYloxymethyl-7-[(Z)-2-~fur-2-vl)-2-methoxy-
_minoacetamido]ceph-3-em-4-carboxylate, l-Oxide
A solution of the product from (b) (1,985 g,
3,65 mmole) in dry dichloromethane (40 ml) was treated
with a solution of m-chloroperbenzoic acid (0,8 g, 465 mmole)
in dichloromethane (40 ml) to give an immediata gelatinous
precipitate, The reaction mixture was stirred at 21 for
~093068
45 minutes and the solvent was removed in vacuo to give
a solid. Trituration of this solid with ether (2 x 100 ml)
gave the title ester sulphoxide (1.47 g) which decomposed
without melting at ca 200; ~max (EtOH) 275.5 nm
(El cm
(d) (R and S)-l-(EthoxycarbonyloxY)-ethyl (6R,7R)-3-
carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-
iminoacetamido]ceph-3-em-4-carboxylate
A solution of the product from (c) (1.18 g,
2.12 mmole) in N,N-dimethylformamide (20 mi) was cooled
to -10 and treated with potassium iodide (1.38 g, 8.3
mmole) followed by acetyl chloride (0.31 ml, 0.34 g,
4.35 mmole). The reaction mixture was stirred at -10
for 30 minutes and then allowed to warm up over the next
~5 minutes by which time t.l.c. indicated disappearance
of sulphoxide starting material.
The reaction mixture was partitioned between ethyl
acetate (80 ml) and 2-N-hydrochloric acid (80 ml) and the
aqueous solution was extracted with further ethyl acetate
(80 ml). The combined organi~ extracts were successively
washed with sodium metabisulphite solution~ water and
saturated brine and then dried and the solvent was removed
- 18 -
~aO93U6lS
in vacuo to give a froth (1.35 g) which~ on trituration
with ether (30 ml) afforded the title ester ~1.00 g)
m-p. (M80) 103, [a]D +12.8 (c 1.09, DMS0).
Example 3
~R and S)-l-(Methoxycarbonyloxy)-ethyl (6R,7R)-carbamoyl-
oxymethyl-7-~(Z)-2-(fur-2-yl)-2-methox~__inoacetamido]-
ceph-3-em-4-carboxylate
(A), (R and S)-l-(Methoxycarbonyloxy)-ethyl (lS,6R~7R)-3-
carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyimino~cetamido]
ceph-3-em-4-carboxylate~-l-oxide
Method (i)
(a) (R and S)-l-(MethoxYcarbonYloxy)-ethYl ~ 3-
carbamoyloxymethYl-7-[(Z)-2-(fur-2-yl)-2-methoxy-
iminoacetamido]ceph-3-em-4-carboxylate and its
Isomer
A solution of (R,S)-l-chloroethyl methyl carbonate
(11.37 g) in acetone (10 ml) was treated with a solution
of sodium iodide (~7.0 g, 113 mmole) in acetone (50 ml).
A precipitate formed immediately and after stirring for
5 minutes the mixture was evaporated in vacuo to dryness,
The residue was partitioned between ether (150 ml) and
water (100 ml) and the aqueous phase was re-extracted with
ether (3 x 50 ml).
The combined organic extracts were successively
25 washed with water (100 ml), sodium metabisulphite solution
(75 ml), water (75 ml) and saturated brine (70 ml) and were
dried and evaporated in vacuo to dryness to give (R,S)-l-
- 19 -
1~93068
iodoethyl methyl carbonate (5.5 g) as a solid.
A solution of (R,S)-l-iodoethyl methyl carbonate
(5.50 g, 24 mmol) in N,N-dimethylformamide (5 ml) was
added to a solution of potassium (6R,7R)-3-carbamoyloxy-
methyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-
em-4-carboxylate (4.0 g, 8.6 mmole) in N,N-dimethyl-
formamide (15 ml). The reaction mixture was stirred at
22 for 4 hours and was then allowed to stand overnight.
The mixture was then partitioned between ethyl
acetate (75 ml) and 2-N-hydrochloric acid (75 ml).
The aqueous phase was extracted with further ethyl
acetate (3 x 50 ml) and the combined organic extracts
were successively washed with water (50 ml), aqueous
sodium bicarbonate solution (3%, 2 x 50 ml), water
(2 x 50 ml) and saturated brine (50 ml) and dried and
evaporated _ vacuo to dryness. Trituration of the
residue (3.8 g) with di-isopropyl ether (100 ml) aforded
a solid which was filtered off and dried in vacuo to give
the title ester (2.7 g), m.p~ (M36 )~ 70 (decomp), [a]2
. . O
; 20 +183 (c 0,84, DMSO), ~max (EtOH) 281 nm (El cm 278) with
an inflection at 260 nm (El%Cm 219),
.
- 20 -
.
1093068
(b) (R and S)-l-(Methoxycarbonyloxy)-ethyl (lS~6R,7R)-3-
carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-
iminoacetamido]ce~3-em-4-carboxylate, l-Oxide
A solution of the product from (a) (2.59 g, 4.92 mmol)
in dichloromethane (20 ml) was treated with m-chloroper-
benzoic acid (1.06 g, 6.14 mmole). The reaction mixture
was stirred for 1 hour at 21 and then diluted with
anhydrous ether (20 ml). The resultant solid was filtered
off and washed with ether and dried in vacuo to give the
0 title ester sulphoxide.
The filtrate was evaporated to dryness and the
residue was triturated with anhydrous ether (100 ml) and
the resultant solid processed in a similar manner to that
described above to give a further crop of title ester
sulphoxide. The two batches of sulphoxide ester were
combined to give 2.26 g of product, m.p. (M140) 165,
[a]D +44 7 (c 0.91, DMSO).
- 21 -
10S~3~)68
Method (ii)
a) Potassium (lS,6R,7R)-3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-
yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate? l-oxide
A solution of potassium acetate (0.216 g, 2.2 mmole)
5 in ethanol (15 ml) was added to a solution of (lS,6R,7X)-3-
carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacet-
amido]ceph-3-em-4-carboxylic acid, l-oxide (0.88 g, 2 mmole)
in dry N,N-dimethylformamide (15 ml) and more ethanol (10 ml)
was added.
The resultant suspension was cooled and the solid
filtered off and dried ~o give the title salt as a DMF
solvate (0.946 g, 86~/o), ~m x (pH 6 buffer), 263 nm
(El/ 312) with an inflectlon at 280 nm (El cm 278).
b) (R and S)-l-(Methoxycarborlyloxy)-ethvl(lS.6R,7R)-3-carbamoyl-
oxymethyl-7-[,(Z~-2-(fur-~yl)-2-methoxyiminoaceta do]ceph-
3-em-4-carbox~late~-oxide
(R,S)-l-Chloroethylmethyl carbonate (1.07 g, 7.7 mmole)
in N,N-dlmethylformamide (5 ml) was added to a heated (40)
suspension of potassium (lS,6R,7R)-3-carbamoyloxymethyl-7-
[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-
carboxylate, l-oxide, N,N-dimethylformamide solvate (2 76 g,
- 22 -
~0~3~)68
5 mmole) in dry N,N-dimethylformamide (45 ml). Af~er 21~4
hours the reaction mixture was poured into 2N-hydrochloric
acid (100 ml) and ethyl acetate (100 ml). The aqueous
layer and solid were extracted with ethyl acetate
(2 x 100 ml) and the organic solutions were combined and
washed successively with 2N-hydrochloric acid (3 x 100 ml),
water (100 ml), saturated aqueous sodium bicarbonate
(2 x 100 ml), water (100 ml) and saturated brine (2 x 100 ml).
The solution was treated with charcoal then dried
(magnesium sulphate) and evaporated to a yellow solid
(0.64 g). Trituration of this material with ether gave
the titl sulphoxide ester (0.06 g), [a]D + 40 (c 0.58
in DMS0), ~max (CHC13) 277.5 nm (El cm 289).
109306~
(B) (R and S)-l-(Methoxycarbonyloxy)-ethyl (6R,7R)-3-
carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl ? -2-methoxy-
iminoacetamido]ceph-3-em-4-carboxylate
A cooled solution of (R and S)-l-(methoxycarbonyloxy)-
ethyl (lS,6R 7 7R)-3-carbamoyloxymethyl-7-C(Z)-2-(fur-2-yl)-
2-methoxyiminoacetamido] ceph-3-em-4-carboxylate, l-oxide
(2.12 g, 3.9 mmole) in N,N-dimethylformamide (10 ml) was
treated successively with potassium iodide (2.59 g, 15.6
mmole) and acetyl chlorid~ (0.55 ml) and the mixture was
stirred at ca 4 for 1 hour and was then partitioned
between ethyl acetate (60 ml) and 2-N hydrochloric acid
(60 ml). The aqueous phase was extracted with ethyl
acetate (3 x 40 ml) and the combined organic extracts
were successively washed with water (40 ml), aqueous
sodium bicarbonate solution (3%, 40 ml), water (40 ml),
aqueous sodium metabisulphite (50 ml), water (40 ml) and
saturated brine (50 ml). The organic solution was dried
and evaporated to dryness in vacuo.
Trituration of the residue (2.1 g) with di-isoprow 1
ether (50 ml) afforded a solid which was filtered off,
washed with further di-isopropyl ether and dried in vacuo.
This solid (1.99 g) was stirred with anhydrous
ether (20 ml) for 2 hours and successively filtered,
washed with more ether, filtered off and dried in acuo
- 24 -
~09;~068
Ito give the title ester (1.6 g) m.R. (M3 ) 121 (decomp),
[~]D + 11.8 (c 0.91, DMS0).
Example 4
(R and S)-l-(Isopropoxycarbonyloxy)-ethyl (6R.7R)-3-
Carbamoyloxymethyl-7-c(Z)-2-(fur-2-yl)-2-methoxyimin
acetamido]ceph-3-em-4-carboxylate
(a) (R and S)-l-(Isopropoxycarbonyloxy)-ethyl-(6R,7R)-3-
carbamoyloxymethY1-7-[(Z)-2-(fur-2-yl)-2-methoxy-
minoacetamidoJceph-3-em-4-carboxylate and its
~ isomer
A solution o (R,S)-l-chloroethyl isopropyl carbonate
(1.0 g, 6 mmole) in acetone (5 ml) was stirred with a
solution of sodium iodide (1.50 g, lQ mmole) in acetone
(20 ml) for 4 hours.
The mixture was then evaporated to dryness in vacuo
and the residue was added to a solution of potassium
(6R,7R)-3-carb~moyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-
iminoacetamido]ceph-3-em-4-carboxylate (2.50 g, 5.4-mmole)
in N,N-dimethylformamide (20 ml) which was stirred for 2
hours, Further portions of (R,S)-l-chloroethyl isopropyl
carbonate (1,0 g, 1.0 g and 1.5 g; 6, 6 and 9 mmole) were
added after 0, 16 and 22 hours and the reaction mixture
- 25 -
lO~;~V6~
was stirred for a further 16 hours by which time reaction
1was essentially complete (by t.l.c.). The reaction
mixture was partitioned between ethyl acetate (70 ml)
and 2-_ hydrochloric acid (80 ml). The aqueous phase was
extracted with ethyl acetate (3 x 40 ml) and the combined
organic extracts were successively washed with water
(2 x 50 ml), aqueous sodium bicarbonate solution (50 ml),
water (50 ml) and saturated brine (50 ml) and dried and
evaporated in vacuo to dryness. Trituration of the
residue with di-isopropyl ether (50 ml) afforded a
mixture of the two title esters. This mixture possessed
the following physical properties: ~max (EtOH) 277.5 nm
(ElCm 303)
(b) (R and S2-1-(IsopropoxycarbonYlo~-ethyl (lS.6R,7R~-
3-carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-
iminoacetamido]ceph-3-em-4-carboxylate, l-oxide
A solution of the product from (a) (1.90 g, 3.43 mmole)
in dichloromethane (20 ml) was treated with m-chloroper-
benzoic acid (0.74 g, 4,3 mmole).
The mixture was stirred at 22 for 1 hour and was
then evaporated in vacuo to dryness, Trituration of the
residue with anhydrous ether (80 ml) afforded a solid which
was filtered off, washed (with anhydrous ether~ and dried
- 26 -
~9;~068
in vacuo to give the title ester sulphoxide (1.50 g) m.p.
(M140) 176 (decomp), [a]D + 55.4 (c 1.0, DMS0)
(c) (R and S)-l-(Isopropoxycarbonyloxy)-ethyl-~6R,7R)-3-
carbamoyloxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxy-
iminoacetamido]ceph-3-em-4-carboxylate
A cooled (ca 4) solution of the product from (b)
(1.37 g, 2.4 mmole) in N,N-dimethylformamide (20 ml) was
treated with potassium iodide (1.60 g, 9.64 mmole) and
acetyl chloride (0.34 ml) and the reaction mixture was
stirred at 4 for 1 hour.
The mixture was then partitioned between ethyl
acetate (70 ml) and 2-N hydrochloric acid (80 ml).
The aqueous phase was extracted with ethyl acetate
(3 x 50 ml) and the combined organic extracts were
successively washed with water (2 x 50 ml), aqueous sodium
metabisulphite solution (50 ml), water (50 ml) and saturated
brine (50 ml) and dried and evaporated to dryness in vacuo.
The resultant residue was triturated with anhydrous ether
(100 ml), filtered off and dried in vacuo to give the
title ester (0.86 g), m.p (Mgo) 109 (decomp), [a]D + 18.2
(c 1.0, DMS0),
- 27 -
1o~068
~9959~99l~aggg~les
A. Powder for Oral Suspension (in sachet)
Composition per sachet
(R and S)-l-(Methoxycarbonyloxy)-
S ethyl(6R,7R)-3- equivalent to 250 mg
carbamoyloxymethyl-7-[(Z)-2-(fur-2- cefuroxime
yl)-2-methoxyiminoacetamido]ceph-3-em-
4-carboxylate (mille~ (product of
Example 3)
Sodium Carboxymethyl Cellulose90 mg
(low viscosity)
Sunset Yellow FCF 5 mg
Spray-dried Orange Flavour 150 mg
Caster Sugar 2.2 g
The product of Example 3 is milled (using a fluid
energy mill) and blended intimately with the Sodium
Carboxymethyl Cellulose and the flavouring and colouring
agents. This blend is then further blended with the
Caster Sugar, adding the latter in two stages. The required
weight is transferred to a paper/aluminium/polythene sachet
and sealed by heat. The contents of each sachet are
intended for constitution in about 15 mls of water,
shortly before administration.
- 28 -
1~9306~
B. Product of Example 3, micronised
(250 mg acid) 338.4 mg
Sodium Starch Glycolate 8.0 mg
Magnesium Stearate 2.0 mg
Microcrystalline Cellulose 51.6 mg
Total Weight 400.0 mg
Method
The ingredients are mixed in ascending order of
weights and the mixture compressed on a F3 single punch
machine using 13/32" normal concave punch to produce the
required tablet.
_ ~9 _
