Note: Descriptions are shown in the official language in which they were submitted.
~'7~3J ~3
The present invention is concerned wi-th novel cephalo-
sporin derivatives, namely a cephalosporin derivative of the
formula
H H
- ~ H3C
CH20N = C - CONH ~ S ~ N ~ I
1 N ~ ~ N ~ CH2 - S ~ N
H2N COOH
as well as readily hydrolysable esters and salts of this compound
and hydrates of the compound of formula I or of esters and salts
thereof, when prepared by the process described hereinafter,
wherein the esters and salts are pharmaceutically acceptable.
As readily hydrolysable esters of the compound of
formula I there are to be understood the compound of formula I in
which the carboxy group is present in the form of a readily
hydrolysable ester group. Examples of such esters, which can be
of the conventional type, are the lower alkanoyloxyalkyl ester
(e.g. the acetoxymethyl, pivaloyloxymethyl, l-acetoxyethyl and
l-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters
(e.g. the methoxycarbonyloxymethyl, l-ethoxycarbonyloxyethyl and
l-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e.g. the
phthalidyl
~$
; - 2 - ~ ~'77~Z3
and thiophthalidyl ester), the lower alko~ymethyl esters
(e.g. the methoxymethyl ester) and the lower alXanoylamino-
methyl esters (e.g. the acetamidomethyl ester). Other
esters (e.g. the benzyl and cyanomethyl esters) can also be
used.
Examples or salts of the compound of formula I-are
alkali metal salts such as the sodium and potassium salt,
the ammonium salt, alkaline earth metal salts such as the
calcium salt, salts with organic bases such as salts wlth
amines (e.g. salts with N-ethyl-piperidine, procaine,
dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines
or dialkyi~mines) as well as salts with amino acids such
as, for example, salts with arginine or lysine.
The compound o~ formula I also forms addition salts
with organic or inorganic acids. Examples of such salts
are hydrohalides (e.g. hydrochlorides, hydrobromides and
hydroiodides) as well as other mineral acid salts such as
sulphates, nitrates, phosphates and the like, alkylsulphonates
and monoarylsulphonates such as ethanesulphonates, toluene-
sulphonates, ben2enesulphonates and the like and also other
organic acid salts such as acetates, tartrates, maleates,
citrates, benzoates, salicylates, ascorbates and the like.
The compound of formula I as well as its salts and
readily hydrol~sable esters can be hydrated. The hydration
~' - 3 -
can be effected in ~he course of the manufacturing process
or can occur gradually as a result of the hygroscopic
properties of an initlally anhydrous product.
The products in accordance with the in~ention can
be present in the syn-isomeric form
N~--CONH~
OCH~
or in the anti-isomeric form
/
CH30
or as mixtures of these two forms. The syn-isomeric form
: 10 or mixtures in which the syn-isomeric form predominates is/
are preferred.
The compound of formula I, i.e.
(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-methoxy-
imino]acetamido~-3-[[(2,5-dihydro-2-me~hyl-5-oxo-as-
-triazin-3-yl)thio~methyl]-8-oxo-5-~hia-1-azabicyclo[~.2.0~-
:
,t~78~3
oct-2-ene-2-carboxylic acid, is preferred, as are its salts
and the corresponding hydrates, the salts be.ing pharmaceutic-
ally acceptable.
The abo~e cephaLosporin derivatives are manufac-tured
in accord2nce with the i~vention by
(a) cleaving off the protecting group R, and, if desired,
also a carboxy protecting group which may be present, in a
compound of the general formula
H H
CH30N==~ CO~H I ~ N ~ q
N ~ ~ ~ C~2 S ~ N ~ 0
RHN S
COOH
in ~hich R represents a cleavable
protecting group and the carboxy
group can be present in protected
form,
or
(b) reacting a halide of the general rormula
1~ H
C H3 0 N=~--C O ~I H ~ 3 ~ N~'~
C o d~-~H~
2Y
C~O~
- 5 - ~ ~r~8'~3
in which ~- represents a halogen atom
and the carboxy group can be present
in protected form,
with thiourea,
or
tc) for the manufacture of a readily hydrolysable ester of
the carboxylic acid of formula I, subjecting this to a
corresponding esterification,
or
(d) for the manufacture of salts or hydrates of tne compound
of formula I or hydrates of these salts, converting the
compound OI formula I into a salt or hydrate or into a
hydrate of said salt.
If desired, the carboxy group present in the starti~g
materials of formulae II and III can be protected; for
example, by esterification to form a readily cleavable
ester such as a silyl ester (e.g. the trimethylsilyl ester).
The readily hydrolysable esters mentioned above also come
into consideration. The carboxy group can also be protected
by salt forma~ion with an inorganic or tertiary organic
base such as triethylamine. Possible R-protec~ing groups
are, for example, protecting groups which are cleavable by
acid hydrolysis such as, for example, tert butoxycarbonyl or
trityl, or protecting groups which are cLeavable by basic
2i nydrolysis such as, for example, trifluoroacetyl. Pre-erred
- 6 ~ 7~23
R-protecting groups are chloroacetyl, bromoacetyl and
iodoacetyl, especially chloroacetyl. The last-mentioned
protecting groups can be cleaved off by treatment with
thiourea.
S The starting materials of formula II can be prepared,
for example, by N-acylating the corresponding 7-amino
compound, namely by reacting a compound of the formula
H H
H2N ~ f CHz - S ~ ~ ~ IV
COOH
in which the carboxy group and/or
the amino group can be present in
protected form,
with an acid of the general formula
CH30N---v COOH V
11 ,~
RHN \S
- 7 ~ 77~23
in which R has the significance given
above,
or with a reactive functional derivative of this acid and,
if desired, cleaving off a carboxy protecting group which
may be present.
If desired, the carboxy group present in the 7-amino
compound of formula IV can be protected in the manner
mentioned above for the starting material of formula II
to be prepared. The amino group of the compound of formula
IV can be protected, for example by a silyl protecting
group such as trimethylsilyl.
As reactive functional derivatives of acids of formula
V there come into consideration, for example, halides
(i-e. chloridesr bromides and fluorides), azides, anhydrides,
especially mixed anhydrides with strong acids, reactive
esters (e.g. N-hydroxysuccinimide esters) and amides (e.g.
imidazolides).
The reaction of the 7-amino compound of formula IV
20 with an acid of formula V or a reactive functional
derivative thereof can be carried out in a manner known per
se. Thus, for example, a free acid of formula V can be
condensed with one of the aforementioned esters corresponding
to formula IV by means of a carbodiimide such as d cyclo-
~ 8 ~ 77~3
hexylcarbodiimide in an inert solvent such as ethyl acetate,acetonitrile, dioxan, chloroform, methylene chloride, kenzene
or dimethylformamide and subsequently the ester group can
be cleaved off. Oxazolium salts (e.g~ N-ethyl~5-phenyl-
-isoxazolium-3'-sulphonate) can also be used as the
condensation agent in place of carbodiimides.
According to another embodiment, a salt of an acid of
formula IV (e.g. a trialkylammonium salt such as the
triethylammonium salt) is reacted with a reactive functional
derivative of an acid of formula V as mentioned above in an
inert solvent (e.g. one of the solvents named above).
.
According to a further embodiment, an acid halide,
preferably the chloride, of an acid of formula V is reacted
with the amine of formula IV. The reaction is preferably
carried out in the presence of an acid-binding agent,
for example, in the presence of aqueous alkali, preferably
sodium hydroxide, or in the presence of an alkali metal
carbonate such as potassium carbonate or in the presence of
a lower alkylated amine such as triethylamine. As the
solvent there is preferably used water, optionally in
admixture with an inert organic solvent such as tetrahydro-
furan or dioxan. The reaction can also be carried out in an
aprotic organic solvent such as, for example, dimethyl-
formamide, dimethyl sulphoxide or hexamethylphosphoric acid
- g ~ 7823
triamide. When a silylated startins material of formula IV
is used, the reaction is carried out in an anhydrous medium.
The reaction of the 7-amino compound of formula IV
with an acid of formula V or a reactive functional derivative
thereof can conveniently be carried out at temperatures
between about -40C and room temperature, for example
at about 0-10C.
Starting materials of ~ormula II wherein R is not
monohalogenated (as in bromo-, chloro andi.cdoacetyl) can also
be prepared by thiolation, namely by reacting a compound of
the general formula
H H
CH30N '`--CONH--~S~
~CH2--Z VI
FF~I N S
CO~H
in which R is as R but cannot be mono-
halogenated, z represents a leaving
lS yroup and the carboxy group can
be protected by salt formation with
an inorganic or tertiary organic
base,
with a thiol of the formula
- 10 ~L~778~:3
H3C ~
~ N VII
and, if desired, cleaving off a carb~xy protecting group
which may be present.
As the leaving group Z in a compound of formula VI
there come into consideration, for example, halogens (e.g.
chlorine, bromine or iodine), acyloxy groups ~e.g. lower
alkanoyloxy groups such as acetoxy), lower alkylsulphonyloxy
or arylsulphonyloxy groups such as me~yloxy or tosyloxy, or
the azido group.
The reaction of a compollnd of formula VI with the
thiol of formula VII can be carried out in a manner known
per se; for example, at a temperature between about 40C
and 80C, conveniently at about 60C, preferably in wa.er or
in a buffer solution with a pH of about 6 to 7, preferably 6.5.
77~'23
~ he carboxy group of the resulting compound of rormula
II can subsequently be protected if desired (e.g. by salt
formation or esterification).
The thiol of formula VII is in tautomeric equilibrium
with the corresponding thione. Its preparation is
described in Example 1.
In accordance with variant (a) of the process in
accoxdance with the invention, the amino protecting group
R in a starting material of formula II is cleaved off.
Protecting groups which are cleavable by acid hydrolysis are
preferably removed with the aid of a lower alkanecarboxylic
acid which may be halogenated. In particular, formic acid
or trifluoroacetic acid is used. This cleavage is generally
carried out at room temperature, although it can be carried
out at a slightly higher or slightly lower temperature,
for example, a temperature in the range of aboùt 0C to
~40C. Protecting groups which axe cleavable under alkaline
conditions are generally hydrolysed with dilute aqueous
caustic alkali at 0C to 30C. The chloroacetyl, bromo-
acetyl and iodoacetyl protecting groups can be cleaved offby means of thiourea in acidic, neutral or alkaline medium
at about 0-30C. Hydrogenolytic cleavage (e.g. cleavage
of benzyl) is unsuitable in this case, since the oxime
function is reduced to the amino sroup during the hydrogen
olysis.
- 12 ~ 77~3
After carrying out process variant (a), a carbo~y
protecting group which may be present in the reaction product
can be cleaved off if desired. When the protecting group
is a silyl group (silyl ester), this group can be cleaved orf
especially readily by treating the reaction product with
water. Lower alXanoyloxyalkyl, alkoxycarbonyloxyalkyl,
lactonyl, alkoxymethyl and alkanoylaminomethyl esters are
preferably cleaved enzymatically with the aid of a suitable
esterase (at about 20-40C). When the carboxy group is
protected by salt formation (e.g. with triethylamine), then
the cleavage of this salt-forming protecting group can be
carried out by treatment with acid. The acid which can be
used for this purpose can be, for example, hydrochloric acid,
sulphuric acid, phosphoric acid or citric acid.
lS The carboxy protecting group can be cleaved off in the
same manner as just described also prior to the cleavage
of the protecting group R.
The halide of formula III used in accordance with
the invention can be prepared, for example, by reacting a
compound of fcrmula IV with a halogenated carboxylic acid
of the general formula
CH30N==~ CCOH
CO
I VIII
C H2Y
- 13 - ~1'77~23
in which Y represents a halogen atom,
or with a reactive derivative of this compound. The
halogenated carboxylic acid of formula VIII is used either
in free form in the presence o~ a condensation agent (e.g.
a N,N'-disubstituted carbodiimide such as N,N'-dicyclo-
hexylcarbodiimide or an azolide compound such as N,~'-
-carbonyldiimidazole or N,N'-thionyldiimidazole) or also in
the form of an acid halide such as th~ acid chloride or acid
bromide, in the form of an acid anhydride such an acid
anhydride with a carbonic acid monoester (e.g. with monomethyl
carbonate or monoisopropyl carbonate) or in the form of an
activated ester such as the p-nitrophenyl ester, 2,4-dinitro-
phenyl ester, N-hydroxysuccinimide ester or N-hydroxy-
phthalimide ester. The reaction is generally carried out in
an inert organic solvent, for example in a halogenated
hydrocarbon such as chloroform, dichloromethane or carbon
tetrachloride, in an ether (e.g. tetrahydrofuran or dioxan),
in dimethylformamide, dimethylacetamide, water or mixtures
thereof. The reaction temperature lies mainly in the range
of about -50C to +40C, preferably at about -10C to +10C.
The reaction of a halide of formula III with thiourea
in accordance with the invention, variant (b) of the process
in accordance with the invention, is preferably carried out
in an inert solvent such as, for example, in a lower alXanol
(e.g. ethanol), in a lower ketone such as acetone, in an
ether such as tetrahydrofuran or dioxan, in dimethylformamide,
7~:3
dimethylacetamide, in water or in mixtures tnexeo~. The
reaction temperature generally lies in the range of about
0C to 60C, preferably at room temperature. The chloride,
bromide, fluoride or iodide can be used as the halide of
formula III, the chloride or the bromide preferably being
used. The free acid of formula III or, if desired, a
salt thereof can be used, whereby the same salts as the
aforementioned salts of the compound of formula I come into
consideration.
In order to manufacture the readily hydrolysable esters
of the carboxylic acid of formula I in accordance with variant
(c), this is preferably reacted with the corresponding halide
preferably with the iodide, containing the ester group. The
reaction can be accelerated with the aid of a base, for
example, an alkali metal hydroxide or carbonate or an
organic amine such as triethylamine. The esterification i3
pre~erably carried out in an inert solvent such as dimethyl-
acetamide, hexamethylphosphoric acid triamide, dimethyl
sulphoxide or, preferably, dimethylformamide. The temperature
preferably lies in the range of about 0-40C.
The manufacture of the salts and hydrates or the
compound of formula I or the hydrates of these salts can
be carried out in a manner known per se; for example, by
reacting the carboxylic acid of formula I with an equivalent
amount of the desired base, conveniently in a solvent such as
- 15 -
water or in an organic solvent such as ethanol, methanol,
acetone etc. The temperature at which the salt for~ation
is carried out is not critical. It is generally carried
out at room temperature, but it can also be carried out at a
temperature slightly above or below room temperature (e.g.
in the range of 0C to ~50C).
The manufacture or the hydrates usually takes place
automatically in the course of the manufacturing process or
as a result of the hygroscopic properties of an initially
anhydrous product. ~or the controlled manufacture of a
hydrate, a completely or partially anhydrous product (carboxylic
acid of formula I or ester, ether or salt thereof) can be
exposed to a moist atmosphere (e.g. at about ~10C to ~40C).
The 7-amino compound of formula IV used above can be
prepared starting from a compound of the formula
H H
H2N~S~
C~z~~~ Z IX
COOH
in which Z represents a leaving group
and the carboxy group can be protected
by salt ~ormation ~ith an inorganic or
tertiary organic base,
~7823
- 16 -
with the thiol of formula VII. The reaction can be carried
out under the same conditions as those which have been
, described for the reaction of the starting materials of
formulae VI and VII. On th~ other hand, the compounds of
formula VI can be prepared starting from a compound of
formula IX and an acid of formula V or a reactive functional
derivative thereof under the same conditions as have been
described for the reaction of the compounds of formulae IV
and V.
The carboxy group and/or the amino group of the
resulting compound of formula,IV can subsequently be
protected if desired; for example, by esterifying the
carboxy group or forming a salt thereon or by silylating
the amino groupO
A syn/anti mixture of a compound of formula I which
may be obtained,can be separated into the corresponding
syn- and anti-forms in the customary manner, for example by
recrystallisation or by chromatographical methods using a
suitable solvent or solvent mixture.
The compounds of formulae I and II as well as the
corresponding readily hydrolysable esters and salts or the
hydrates of these products have antibiotic, especially
bactericidal, activity. They possess a broad spectrum ot
` - 17 - ~ ~77~3
action against gram-positive bacteria (e.g. Staphylococci)
and against gram-negative bacteria such as, for example,
Haemophilus influenzae and Neisseria gonorrhoeae, as ~ell
as against various ~-lactamase-forming gram-negative
organisms such as Escherichia coli, Serratia marcescens,
Pseudomonas aeruginosa, Proteus mirabilis and Proteus
vulgaris.
The compounds of formulae I and II as well as the
corresponding readily hydrolysable ester~ and salts or the
hydrates of these products can be used for the treatment
and prophylaxis of infectious diseases. A daily dosage of
about 0.1 g to about 2 g comes into consideration for adults.
The parenteral administration of the compounds provided by
the invention is especially preferred.
In order to demonstrate the antimicrobial activity
of the aforementioned products (6R,7R)-7 [2-(2-amino-5-
-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-dihydro-
-2-methyl-5-oxo-as-triazin-3~yl)thio]methyl]-8-oxo-5-thia-
-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt
was tested for its activity in vitro a~ainst various pathogenic
organisms. The corresponding minimum inhibitory concentrations
(MIC; ~g/ml) are compiled hereinafter:
- - 18 - ~ ~77~3
Pathogenic organism MIC
.. ... ~ _
Escherichia coli *) 0.04
Serratia marcescens *) 0.16
Enterobacter cloacae *) 2.5
Proteus mirabilis *) 0.04
Proteus vulgaris *) 0.02
Pseudomonas aeruginosa
strain 1*) 40
strain 2*) 40
Haemophilus influenzae 0.02
Neisseria gonorrhoeae 0.02
Staphylococcus aureus 2.5
*) ~-lactamase-forming strain
Toxicity
.... _ _ .__ _ _ ,
Test substance
_.._ . _.
oo, mg/ks i . v 1000
s.c. >5000
p.o. >5000
- 1 9 ~ 3
The products provided Dy the invention can be used as
medicaments, for example, in the form of pharmaceutical
preparations which contain them in admixture with a pharma-
ceutical, organic or inorganic inert carrier materiaL which
is suitable for enteral of parenteral administration such
as, for example, water, gelatin, gum arabic, lactose, starch,
magnesium stearate, talc, vegetable oils, polyalkylene
glycols, Vaseline etc. The pharmaceutical preparations can
be made up in solid form (e.g. as tablets, dragées,
suppositories or capsules) or in liquid form (e.g. as
solutions, suspensions or emulsions). If necessary, th~y
can be sterilised and/or can contain adjuvants such as
preserving, stabilising, wetting or emulsifying agents, salts
for varying the osmotic pressure, anaesthetics or buffers.
They can also contain still other therapeutically valuable
substances. The compound of ormula I and its salts of
hydrates are preferably administered parenterally and for
this purpose are preferably prepared as lyophilisates or dry
powders for dilution with customary agents such as water or
isotonic sodium chloride solution. The readily hydrolysable
esters of the compound of formula I and their salts or
hydrates also come into consideration for enteral administration.
- 20 - ~ ~77~3
In the following Examples, which illustrate the
present invention, all temperatures are degrees Centigrade.
Example 1
(6R,7R)-7-[2-(2-Amino-4-thia201yl)-2-[(Z)-methoxyimino]-
s acetamido]-3-[[(2,5 dihydro-2-methyl-5-oxo-as-triazin-3-
- l)~thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-
Y . .__
-2-carboxylic acid sodium salt
61 g of (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-
-2-[(Z)-methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methyl-
-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic a~id are treated in 1.5 1
of water with 30.4 g of thiourea and, while gassing with
nitrogen and stirring, held for 20 hours at a pH-value of
7.0 with lN sodium hydroxide via an autotitrator. The pH-
-value is adjusted to 3.75 by the dropwise addition of
lN hydrochloric acid while stirring. The separated
precipitate is filtered off under suction and rejected. Now,
the filtrate is adjusted to a pH-value of 3.0 with lN hydro-
chloric acid while stirring, the precipitate is flltered off
under suction, washed with water, ethanol and petroleum ether
and dried. The crude product obtained is suspended in 90
ml of acetone/water ~1:1), treated w1th 45 ml of a 2N
solution of sodi~m 2-ethylcaproa.e in athyl acetate, stirred
- 21 ~ 778Z3
until completa solution has occurred and thereafter
precipitated by dropwise addition into 800 ml of acetone
while stirring. The sodium salt is filtered off under suction,
washed with acetone, ether and petroleum ether and dried.
For further purification, the substance is dissolved in 800
ml of methanol while stirring and filtered off from a small
amount of undissolved substance. The filtrate is treated with
active charcoal, filtered, evaporated to ca 400 ml in vacuo and
filtered off from a small amount of precipitated substance.
The filtrate is treated dropwise with 1.6 1 of ethyl acetate
to bring about precipitation, and the precipitate is
filtered off under suction, washed with ethyl acetate, ether
and petroleum ether and dried. There is obtained (6R,7R)-7-
-~2-(2-amino-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]-3-
-[[(2,5-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-
-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylic acid
sodium salt; m.p. from 192 (slow decomposition), [a]25
-135 (c = 1 in water).
The (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-2-[(Z)-
-methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methyl-5-oxo-
-as-triazin-3-yl(thio]methyl]-8-oxo-S-thia-l-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid used as the starting
material can be prepared as follows:
- 22 ~ 7~3
2-Meth l-S-oxo-3-thioxo-2,3,4,5-as-triazine
_ Y
34 g of 2-methyl-thiosemicarbazide are introducea
portionwise into a solution of 80.8 g of glyoxylic acid
hydrate in 450 ml of dimethylformamide. The suspension is
stirred at 80 for 45 minutes. The reaction mixture is
cooled, treated with 2~5 1 of water and the suspension is
stirred at 0 for 1 hour. After filtration under suction,
washing with water and drying, there is obtained the 2-
-methyl-thiosemicarbazone of glyoxylic acid, m.p. 204-205
(decomposition). This substance is introduced while
stirring into a solution of 74 g o~ sodium carbonate in
700 ml of water and thereafter heated at 9S-98 for 3
hours while stirring. The solution is cooled to 5 and
adjusted to a pH-value of 2 with stirring and dropwise
addition of concentrated hydrochloric acid. After suction
filtration, washing with ice/water and drying, there is
obtained 2-methyl-5-oxo-3-thioxo-2,3,4,5-as-triazine, m.p.
221-222.
(6R,7R)-7~Amino-3-[[(2,5-dihydro-2-methyl-5-o~o-as-triazin-
-3-yl)thio]met ~ ~5-thia-1-azabicyclo[4.2.0~oct-2-
-ene-2-carboxylic acid
27.2 g o~ 7-amino-cephalosporanic acid are treated
in 200 ml of water while s-tirring first of all portionwise
with 23.1 g or sodium hydrogen carbonate and thereafter
- 23 - ~ ~77823
with 21.5 g of 2-methyl-5-oxo-3-thioxo-2,3,4,5-as-triazir.e.
subsequently, the mixture is heated at 60 for 5 hours
while gassing with nitrogen. The solution is cooled to 5,
adjusted to a pH-value of 3.5 with concentrated hydrochloric
acid, the precipitated substance is filtered off, washed with
water and stirred twice with 230 ml of methanol each time,
filtered off, washed with methanol and ether and dried in
vacuo. There is obtained (6R,7R)-7~amino-3-[[(2,5-dihydro-
-2-methyl-5-o~o-as-triaxin-3-yl)thio]methyl]-8-oxo-5-
-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, m.p.
from 195 (decomposltion), which is further reacted without
additional purification.
(6R,7R)-7-[2-(Chloroacetamido-4-thiazol~l)-2-[(Z)-methoxy-
imino]acetamido-3-C[(2,5-dihydro-2-methyl-5-oxo-as-triazin-
-3-yl)thio]methyl]-8-oxo-5-thia-l-a7abicyclo[4.2.0]oct-2-
-ene-2-carboxylic acid
63 ml of N,N'-dimethylformamide are added dropwise
to a suspension, cooled to -20, of 34.5 g of phosphorus
pentachloride in 500 ml of dichloromethane, the mi~ture is
stirred at -15 for 10 minutes, thereafter cooled to -25,
treated with 46 g of 2-(2-chloroacetamido-4-thiazolyl)-2-
-methoxyimino-acetic acid (s~yn form) and stirred at -15
for 45 minutes. The solution is cooled to -30 and mi~ed
with 50 g of ice, whereby the temperature rises to -1~.
- 2~ 778~3
The mixture is stixred at -15 for 10 minutes and then the
dichloromethane solution is separated. It is cooled to -15
and used immediately for the following acylation.
Meanwhile, 61 g of (6R,7R)-7-amino-3-[[2,5-dihydro-
-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-
-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid are
dissolved in ~00 ml of water at a pH-value of 7. 8 via an
autotitrator by the dropwise addition of 2N sodium hydroxide
while stirring and cooled to 0. At this temperature there
is added dropwise within 45 minutes the above (cooled to -15)
dichloromethane solution of the acid chloride and a pH-value
or 7.8-8.0 is maintained by the simultaneous dropwise addition
of 2N sodium hydroxide via an autotitrator. The mixt~re is
subsequently stirred for a further 30 minutes at 5 and for
1 hour at 20. The solution is treated with 500 ml of n-butanol
and 500 ml of dichloromethane, whereafter it is adjusted to
a pH-value of 7 with citric acid, stirred for 5 minutes at
this pH-value and subsequently filtered in vacuo. The
or~anic phase is separated, washed three times with 200 ml of
water each time, treated with active charcoal, filtered off
and evaporated in vacuo at 55 to ca 200 ml. The suspension
obtained is cooled to 20 and filtered in ~acuo. There is
obtained a first fraction o~ solid (6R,7R)-7-~2-(chloro-
acetamido-4-thiazolyl)-2-[(Z)-methoxyimino]-acetamido]-3-
-[[(2,5-dihydro-2-methyl-5~oxo-as-triazin-3-yl)thio]methyl]-
-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
_ ~5 _ ~ ~77~3
The mother liquor is evaporated to 100 ml in vacuo, mixed
with 100 ml of ether and yields, after suction ~iltration,
a second fraction of the mentioned acid. Both fractions are
dissolved together in 2 1 of acetone while stirring within
15 minutes and insolubles are filtered of~. 300 ml of
butyl acetate are added to the filtrate and the acetone is
distilled off in vacuo until the substance crystallises.
There is obtained (6R,7R)-7-[2-(chloroacetamido-4-thiazolyl)-
-2-C(Z)-methoxyimino]-acetamido]-3-[[(2,5-dihydro-2-methyl-
-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-aza~icyclo-
[4.2.0]oct-2-ene-2-carboxylic acid, m.p. from 173
(decomposition), ~25 = -238.7~ (c = 1 in dimethylformamide).
The product is uniform in accordance with thin-layer
chromatography in the system n-propanolJacetic acid/~ater
55:15:30 and is further reacted without addi.ional
purification.
Example_2
Meth~lene (6R,7R)-7-[2-(2-amino-4-thiazolyl)-2~[(Z~-
-methoxyimino]acetamido]-3-[[(2,5-dihydro-2-methvl-5-oxo-
-as-triazin-3-yl)thio]methyli-8-oxo-5-thia-1-azabicyc~o-
[4.2.0]oct-2-ene-2-carboxylate pivalate
8 g of (6R,tR)-7-[2-(2-amino-4-thiazolyl)-2-[(Z)-
-methoxyimino]ace.amido]-3-[[(2,5-dihydro-2-me~nyl-5-oxo-
~ - 26 - ~ ~77~3
-as-triazin-3-yl)thio]methyl]-8-oxo-S-thia l-azabicyclo-
[4.2.0]oct-2-ene-2-carboxylic acid sodium salt are
dissoLved in 80 ml of dimethylformamide, cooled to 0,
treated with 6 g of pivaloyloxymethyl iodide and stirred
at 0 for 30 minutes. The solution is precipitated in
ice/water, the precipitate is filtered of~ in vacuo,
dissolved in ethyl acetate with the addition of some methanol,
washed with sodium hydrogen carbonate solution and sodium
chloride solution, dried with magnesium sulphate and
evaporated in vacuo until crystallisation begins. The
crystallisation is completed by the addition of a mixture
of ether/petroleum ether 1:1. The substance is filtered
off and subsequently chromatographed over silica gel with
benzene/methanol 4:1. The uniform fractions are combined,
evaporated in vacuo and finally crystallised from chloroform/
ether. There is obtained methylene (6R,7R)-7-[2-(2-amino-
-4-thiazolyl)-2-[(Z)-methoxyimino]acetamido]~3-[[(2,5~
-dihydro-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-
-5-thia-1-azabicyclo[4.2.0]oct-2-ane-2-carboxylate pivalate.
M.p. 149 (decomposition), [a]25 = -173 (c = 1 in dimethyl-
formamide).
Example 3
Preparation of dry am~poules for intramuscular
administration:
~ ` \
- 27 ~ 8~
A lyophilisate of 1 g of the active substance is
prepared in the customary manner and ~illed into an ampoule.
Prior to the administration, the lyophilisate is treated
with 2.5 ml of a 2~ aqueous lidocaine hydrochloride solution.
