Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
12~098~
- 1 - 23189-5448F
This is a divisional application of Serial Number
505,254 filed March 26, 1986 which in turn is a divisional
application of Serial Number 415,708 filed November 17, 1982.
The invention relates to the preparation of certain
cephalosporins.
Cephalosporins of the general formula
CO-NH ~ ( I
C02H
in which Rl denotes an alkyl or aryl radical, are mentioned in
German Offenlegungschrift 30 37 997, published on May 5, 1982.
These compounds have a broad antibacterial activity both against
Gram-negative and also against Gram-positive bacteria.
According to the process mentioned in this publication,
the compounds of the formula (I) are prepared according to the
following reaction scheme:
~1 R -CHO Hal H2~ C NH
~C02Et ~ C2Et 2 ~ H2N~ 3~, C02Et
(II) ( III ) ~1 (IV) LLL~Rl
Alkali
I) ~ coupling
(V) '~
1240~8~
- 2 - 23189-544BF
However, this process leads only to unsatisfactory
yields of compounds of the formula (I) in which Rl denotes an
alkyl radical. Thus, for example, for the case in which Rl
denotes an isopropyl radical, on reaction of the compound of
formula (III) with thiourea, in addition to the desired compound
of formula (IV), the products of the following formulae
N ~\~ 2 t --~\N~I~ C02Et
(VI) (VII)
are obtained a~ by far the largest fraction, due to deconjugation
of the double bond and to Michael addition.
Furthermore, when Rl denotes an alkyl radical, when the
processes described in the application mentioned (with for
example, hydroxybenzotriazole/DCC) are used for the coupling of
the acids of formula (V) to the 7-aminocephalosporanic acids to
give the products of the formula (I), isomerisation of the double
bond to give the products of the formula:
i
2N ~ ~ CO-NH ~ ~ (VIII)
C02H
1~40385
- 3 - 23189-5448F
occurs to a large extent. However, the compounds of the formula
(VIII) generally show only aout 1/10 of the biological activity of
the compounds of the formula (I).
A process for the preparation of the compounds of the
formula (I) has now been found, which proceeds via new inter-
mediate products, and which does not have the abovementioned dis-
advantages.
According to the present invention, there is provided
a process for the production of a compound of the general
formula:
/~
2 ~ ~_ ~ C0-~H ~ S
l o ~ ~ X (I)
co2
(in which
Rl represents an alkyl or cycloalkyl radical, each of which
may have 1 to 5 substituents selected from the group consisting of
(Cl-C6) alkyl, (Cl-C6) O-alkyl, (Cl-C6) S-alkyl, (Cl-C6) N-alkyl,
(Cl-C6) alkyloxycarbonyl or optionally substituted phenyl; or Rl
represents an aryl or heterocyclic radical, each of which may have
1 to 5 substituents, wherein the substituents of the aryl and
heterocyclic radicals and the above mentioned phenyl are selected
from the group consisting of (Cl-C6) alkyl, (Cl-C~) O-alkyl,
(Cl-C6) S-alkyl, alkyloxycarbonyl, halogen or phenyl, and
~24Q98~
_ 4 - 23189-5448F
X represents hydrogen, (Cl-C4) alkyl, halogen (Cl-c4) alkoxy,
hydroxymethyl, formyloxymethyl, [(Cl-C4) alkyl]-carbonyloxymethyl,
aminocarbonyloxymethyl, pyridiniummethyl, 4-carbamoylpyridinium~
methyl or heterocyclythiomethyl radical wherein heterocyclyl
represents a radical of the formula:
~N ' -~S ~ R or ~ S
R6 H
(in which
R6 denotes hydrogen, methyl, 2-dimethylaminoethyl, carboxy-
methyl or sulphomethyl and,
R7 denotes hydrogen or methyl),
which process comprises:
coupling a compound of the general formula
R -NH ~\ ~ Co-o-So2-R5
ll (XVI)
~Rl
(in which
Rl is as defined above,
~2~0~
- 5 - 23189-5448F
R2 denotes Co2R3 or hydrogen,
R3 denotes an alkyl, cycloalkyl, alkenyl or cycloalkenyl
radical, each of which may have 1 to 5 substituents
selected from the group consisting of (Cl-C4) alkyl,
(Cl-C4) 0-alkyl, halogen, C--N, tri-[(Cl-Cs) alkyl]-silyl
and optionally substituted phenyl, or denote an aryl or
heterocyclyl radical, each of which may have 1 to 5 sub-
stituents, wherein the substituents of the aryl and
heterocyclic radicals and the above mentioned phenyl are
(Cl-C4) alkyl, (Cl-C4) O-alkyl, (Cl-C4) S-alkyl, alkyloxy-
carbonyl, halogen, phenyl, nitro or C--N, there being at
least one carbon atom separating heteroatoms as sub-
stituents of the radicals and double bonds in the alkenyl
and cycloalkenyl radicals from the oxycarbonyl group, and
R5 denotes an alkyl, alkenyl, cycloalkyl, cycloalkenyl,
carbocyclic or heterocyclic aryl or heterocyclyl radical
each of which may have 1 to 3 substituents selected from
the group consisting of halogen, alkyl, aryl, O-alkyl,
S-alkyl, CN, alkoxycarbonyl or nitro), with a cephalo-
sporanic acid of the general formula:
`r~ 1
~ N ~ (XVII)
O I X
C02H
(in which
X is as defined above), and then splitting off the protectivegroup R2 except when R2 is hydrogen.
lZ40~15
- 6 - 23189-5448F
A preferred overall process for producing the compound
of formula (I) starting from an easily available material may be
described as follows:
a) a compound of the general fo~mula
2 ~ ~ ~ Co2R4 (IX)
tin which
R4 denotes an alkyl, cycloalkyl, alkenyl, or cycloalkenyl
radical, each of which may have 1 to 5 substituents
selected from the group consisting of (C1-C4) alkyl,
(Cl-C4) O-alkyl, halogen, C-N, tri[(Cl-Cs) alkyl]-silyl
and optionally substituted phenyl; or denote an aryl or
heterocyclyl radical, each of which may have 1 to 5
substituents, wherein the substituents of the aryl and
heterocyclic radicals and the above mentioned phenyl are
(Cl-C4) alkyl, (Cl-C4) O-alkyl, (Cl-C4) S-alkyl,
alkyloxycarbonyl, halogen, phenyl, nitro or C-~, there
being at least one carbon atom separating hetero-atoms as
substituents of the radicals and double bonds in the
alkenyl and cycloalkenyl radicals from the oxycarbonyl
group),
is reacted with a pyrocarbonic acid ester of the general formula
R3-o-Co-o-Co-o-R3 (IXa)
(in which R3 can be the same or different from R4 and has the
meaning given to R4),
b) the product of the general formula
12409~
~ 7 ~ 23189-5448F
2 S ~
N ~ N ~ C02R (X)
oo
in which R3
R2 denotes Co~R3, and
R3 and R4 have the meanings given above, thus obtained
is initially reacted with a suitable base and then with an
aldehyde of the general formula Rl-CHO (in which Rl has the
meaning given above), to give a compound of the general formula
R -NH ~ \ ~ C02R (XI)
R -O-CO-O R
(in which
Rl, R2, R3 and R4 have the meanings given above), which
c) is then treated with a base to give a compound of the general
formula
R2-NH ~ Co2R4
R (XII)
~09~35
- 8 - 23189-5448F
(in which
R1, R2 and R4 have the meanings given above~,
d) the Z-acid of the general formula
R -NH --~\N ~ CO H
2 (XIII)
R
(in which
Rl and R2 have t~e meanings given above, or R2 may be
hydrogen) is then obtained from the compound o~ formula
(XII) by separation of the Z and E isomers and subsequent
saponification or by selective saponification, and
e) the Z-acid of formula (XIII) is then reacted with a compound
of the general formula
Z-So2-R5
(in which
Z denotes a chlorine or bromine atom or -o-So2-R5 , and
R5 denotes an optionally substituted alkyl, alkenyl,
cycloalkyl, cycloalkenyl, aryl or heterocyclyl radical),
to give a compound of the general formula
I
R -NH ~ ~ 5
\~ / CO-O-S02-R
I ~ Rl (XVI)
~24Q9~3~
23189--5448F
(in which
Rl, R2 and R5 have the meanings given above), which
f) is then coupled with a cephalosporanic acid of the general
formula
2 ~ S
/J J7~\x
C02H (XVII)
(in which
X has the meaning given above),
and
g) the protective group R2 is then split off unless, R2 is
hydrogen.
The preferred overall process including the reaction
according to the present invention forthe production of compounds
of formula (I) may be summarized in the following reaction
scheme:
R2HN ~ ~ 4 (R -O-CO)20 2 S ~ 1 Base
C=O
R 3
( IX ) (X)
124~
- 10 - 23189-5448F
2 ~ ~ 4 Base_ ~ R NH ~ ~ o R4 'flcation >
R O~C-O R
(XI) (XII)
3~ 1 + ~ ~ ~ Co2H
(XIII) (XIV)
1. Silylation Separation
(XIV) > (XIII) + (XIV) (XIII)
2. Base _ .
~LZ40~8~:;
~ 23189-5448F
1. Base
(XIII) R2 NH ~ ~ 5
2. XSo2R5 N~ ~ CO-O-S02-R
(XV) (XVI)
base
(XVI ) + H2N ~ ~ R2_NH~ 1
~O~X
C02H
(XVII) (XVIII) (I)
Further details of the reaction steps for the production
of compounds of formula (I) are given later in -the specification.
Particularly preferred compounds of formula (X) are those
in which,
R2 denotes 0-CO-C(CH3)3,
R3 denotes C(CH3)3 and
R4 denotes optionally substituted alkyl radical with 1 to 15
I 10 carbon atoms, an optionally substituted alkenyl radical
with 3 to 15 carbon atoms, an optionally substituted cyclo-
alkyl radical with 3 to 10 carbon atoms, an optionally
substituted cycloalkenyl radical with 5 to 10 carbon atoms,
an optionally substituted aryl radical with 1 to 3 rings or
an optionally substituted heterocyclyl radical
124Q985
- 12 - 23189-5448F
with 1 to 3 rings, which can contain up to 5 hetero atoms
selected from nitrogen, sulphur and oxygen.
Especially preferred compounds of formula (X) are those
in which
R2 denotes a tert.-butoxycarbonyl radical,
R3 denotes a tert.-butyl radical, and
R4 denotes a methyl, ethyl, tert. butyl ~r trimethylsilyl
ethyl radical.
The alkyl, alkenyl, cycloalkyl and cycloalkenyl,
radicals mentioned can be substituted by alkyl radicals
. ~
~2~
- 13 - 23189-5448F
with 1 to 4 carbon atoms, O~alkyl radicals with 1 to 4 carbon
atoms, halogen (preferably chlorine3, optionally substituted
phenyl radicals, C-N and tri-(Cl to C5 alkyl)-silyl,
All the aryl and heterocyclyl radicals, including the
phenyl radicals mentioned, can be substituted by alkyl, O-alkyl,
S-alkyl, alkyloxycarbonyl, halogen and phenyl radicals, it being
possible for all alkyl radicals to have 1 to 4 carbon atoms, and
by nitro and C-N.
When the radicals R3 and/or R4 are substituted, prefer-
ably by the abovementioned substituents, they can carry 1 to 5,
preferably 1 or 2, substituents.
It is particularly advantageous for the process when R2
denotes a protective group which is stable to base and removable
in acid, such as tert.-butoxy-carbonyl, and when R4 denotes a
radical which is saponifiable by base, such as methyl or ethyl.
The compounds of the formula (IX) used in the process
according to the invention for the production of compounds of
formula (X) are known in themselves (see, for example, E. Campaine
and T.P. Selby, J. Heterocycl. Chem. 17 (1980)).
Particularly suitable solvents for the production of
compounds of formula (X) are aprotic polar solvents such as aceto-
nitrile, dimethylformamide, hexamethylphosphoric acid triamide or
dimethyl sulphoxide, particularly the latter two. The reaction
takes place particularly advantageously at room temperature or at
lower temperatures, for example, between 10 and -50C, the compon-
ents generally being allowed to react with oneanother for 1 to 7
days. The pyrocarbonic acid ester of formula (IXa) is generally
employed in 2 to 2.5 mol-equivalents.
- 14 - 12~0985 23189-5448F
Other solvents~ higher temperatures or acylation catalysts,
such as 4-dimethylaminopyridine, strongly fa~our the formation of
the undesired products of the formula.
R2 S
~ ~ ~ CO2R (XIX)
o
In the process according to the invention for the prep-
aration of the novel compounds of the formula (XI), generally
the compound of the fGrmula (X) is treated with 1 to 1.1 equivalents
of a base in a solvent for the reactants at a low temperature, and
then 1 to 1.2 equivalents of an aldehyde of the formula Rl-CHO is
added.
Solvents which may be used for this reaction are, for
example, dimethylformamide, diethyl ether, tetrahydrofuran or
toluene - preferably tetrahydrofuran - and bases which may be
used are alcoholates, hydrides, amides or organometallics -
preferably potassium tert.-butylate, lithium diisopropylamide
and butyllithium. To carry out the reaction, the base is generally
added, at -50 to -80C, to a solution of the compound of formula
(X), and then the aldehyde is added at -50 to -60C, and the
mixture is stirred at -50 to -60C for about 12 hours. To isolate
the product of the formula (XI), the mixture may be neutralised
and worked up.
Preferred compounds of the formula (XI) are those in
which R2 to R4 have the meanings given above, and Rl denotes an
optionally substituted alkyl radical with 1 to 15 carbon atoms,
an optionally substituted cycloalkyl radical with 3 to 10 carbon
12~0~85
- 15 - 23189-5448F
atoms, an optionally substituted carbocyclic or heterocyclic arvl
radical with 1 or 2 rings or an optionally substituted hetero-
cyclic radical with 1 to 3 rings, which can contain up to 5 hetero-
atoms selected from nitrogen, sulphur and oxygen atoms.
Suitable substituentsfor alkyl and cycloalkyl are alkyl
radicals with 1 to 6 carbon atoms, O-alkyl radicals with 1 to 6
carbon atoms, S-alkyl radicals with 1 to 6 carbon atoms, N-alkyl
radicals with 1 to 6 carbon atoms, alkyloxycarbonyl radicals with
1 to 6 carbon atoms and optionally substituted phenyl radicals.
All the aryl and heterocyclyl radicals, including the
phenyl radicals mentioned, can be substituted by alkyl, O-alkyl,
S-alkyl, alkyloxycarbonyl, halogen, preferably chlorine, and
phenyl radicals, it being possible for all the alkyl radicals to
carry 1 to 6 carbon atoms.
If Rl represents a substituted (preferably by the above-
mentioned substituents) radical, 1 to 5, preferably 1 or 2,
substituents are preferred.
It is particularly preferred that Rl denotes an alkyl
radical with 1 to 10 carbon atoms or a cycloalkyl radical with 3
to 10 carbon atoms, which, in each case, can be substituted by 1
or 2 alkyl radicals with 1 to 6 carbon atoms and/or 1 or 2 phenyl
radicals.
It is unnecessary to isolate the compounds of the formula
(XI) on carrying out the process according to the invention for
the preparation of the compounds of the formula (I). On the con-
trary, it is advantageous to convert the former directly into the
compounds of the formula (XII) in situ. For this purpose, it is
generally sufficient to allow the mixture after addition of the
~; ~2~(~9~
- 16 - 23189-5448E
aldehyde Rl-CHO to warm to xoom temperature and to stir it over-
night at room temperature. If the elimination reaction of the
compound of formula (XI) to give the compound of formula (XII) is
not then complete, 1 to 1.2 equivalents of a base (such as a
hydride, an alcoholate or an amide - particularly potassium
tert.-butylate) is added and the mixture stirred at room tempera-
ture for about 10 hours.
If, on the other hand, the compounds of the formula (XI)
had been previously isolated, for the preparation of the compounds
of the formula (XII), 1.1 to 2.2 equivalents of a base are added
to a solution of the compounds of the formula (XI) in a suitable
solvent. The solvent and the base used can be those mentioned for
the reaction of the compound of formula (X3 to give the compound
of formula (XI), preferably tetrahydrofuran and potassium
tert.-butylate.
The compounds of the formula (XII) are obtained as
mixtures of E/Z isomers, which, for example, may be separated by
recrystallisation or by column chromatograph-y on silica gel.
Rl, R and R4 in the compounds of the formula (XII) have
the same meaning as in the compounds of the formula (XI).
For the preparation of the Z-carboxylic acids of the
formula (XIII), the Z-esters, which can be obtained by separation
of the mixture of the E/Z isomers of the esters of the formula
(XII), can be sapo~fied. However, it is more favourable for
carrying out the process for the preparation of the compounds of
the formula (I) to saponify selectively the mixture of E/Z isomers
of the esters of the formula (XII) in such a manner that the
E-esters are first converted, under mild conditions, into the
X
~24098~
- 17 - 23189-5448F
E-carboxylic acids of the formula (XIV) ! and separated out and
then the remaining Z=esters, in which the ester group is more
sterically shielded, are saponified under more drastic conditions
to give the Z-carboxylic acids of the formula (XIII).
The mild conditions for saponification~ which lead to the
E-carboxylic acids (XIV), are, for example, ethanol/2 N sodium
hydroxide solution/room temperature/24 hours. It is advantageous
to carry out the saponification in such a manner that, after con-
version of the compounds of the formula (XI~ into the compounds
of the formula (XII), 2 N sodium hydroxide solution is directly
added to the reaction mixture and this is stirred at room tempera-
ture or with slight heating until the E~esters are saponified.
Thereafter, the Z-esters are removed from the mixture by extraction
under alkaline conditions and they are saponified under more
drastic conditions.
More drastic conditions for saponification are, for
example, ethanol/2 N sodium hydroxide solution/24 hours reflux -
possibly even more concentrated sodium hydroxide solution or
higher-boiling solvents, for example dioxane.
The desired Z-carboxylic acids of the formula (XIII) and
the E carboxylic acids of the formula (XIV) are obtained in this
manner. The latter may be converted back, after conversion into
the silyl esters, for example, with bistrimethylsilylacetamide,
in a suitable solvent, for example, diethyl ether or tetrahydro-
furan, with a base, such as potassium tert.-butylate and subsequent
hydrolysis with dilute acid into a mixture of the E-carboxylic
acids of the formula (XIV) and the Z-carboxylic acids of the
formula (XIII).
~1
~24~985
- 18 - 23189-5448F
The Z-carboxylic acids of the formula (XIII) may be
isolated in pure form from this mixture o~ E/Z isomers ! for
example by crystallisation or by separation on an ion exchanger~
Separation with the aid of ion exchangers is simple, since the
Z-carboxylic acids of the formula (XIII) have a much higher
acidity than the E-carboxylic acids of the formula (XIV). Thus,
the E-carboxylic acids of the formula (XIV) are eluted just with
methanol from weakly basic ion exchangers, whilst, in contrast,
the Z-carboxylic acids of the formula (XIII) are only eluted
after addition of electrolytes, for example, 2 N sodium hydroxide
solution. Weakly basic ion exchangers are to be understood as
including those ion exchangers in solid or liquid 40rm which
contain tertiary amino groups, for example Lewatit MP 62.
Rl and R2 in the compounds of the formula (XIII) and (XIV)
have the same meaning as in the compounds of the formula (XII).
In addition, R2 can be a hydrogen atom, if, before saponification,
R2 in the compounds of the formula (XII) was a protective group
saponifiable by alkali (such as a methyloxycarbonyl group). How-
ever, it is more advantageous for carrying out the process for the
preparation of the compounds of the formula (I) if R2 is a pro-
tective group which is stable under the conditions of saponifica-
tion, preferably tert.-butyloxycarbonyl.
A large number of methods, which in the last analysis are
derived from peptide chemistry, are known in cephalosporin chemis-
try for coupling carboxylic acids to 7-aminocephalosporanic acids.
However, these methods fail on attempting to form the amide bond
between the Z-carboxylic acids of the formula (XIII) and the ceph-
* Trade Mark
124098~
= 19 -- 23189-5448F
alosporanic acids of the formula (XVII), ox they only lead to very
poor yields, particularly when R is an alkyl radical. The reasons
for this are to be found in the large steric hindrance of the
carboxyl group in the carboxylic acids of the formula (XIII) by the
radical Rl and in the pronounced tendency of the radical Rl to
isomerise into the E-form after activation of the carboxyl function,
for example, conversion into the acid chloride. Then, after re-
action with the 7-aminocephalosporanic acids of the formula (XVII),
the desired compounds of the formula (XVIII) are not obtained, but
rather the compounds of the formula
R -NH ~ ~ CO-NH ~ ~ (XXI)
C02H
or mixtures of the two.
It has now been found that the Z-carboxylic acids of the
formula (XIII) can be activated in a simple, mild and inexpensive
manner and without the abovementioned disadvantages by converting
them into the mixed anhydrides of the formula (XVI) at low temper-
atures.
As indicated previously, these compounds of the formula
I (XVI) are new and form a further subject of the present invention.
In these compounds R5, when an optionally substituted
alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or hetero-
cyclyl radical, can be substituted by a substituent
selected from halogen, alkyl, aryl, O-alkyl, S-alkyl, CN,
alkoxycarbonyl and nitro.
',~i
09~5
- 20 - 23189-5448F
Especially preferred compounds of formula (X~I) are
those, in which
R5 denotes an alkyl radical with 1 to 10 carbon atoms,
which is optionally substituted by fluorine, chlorine,
CN, phenyl, alkyloxycarbonyl, alkyloxy or alkyl (it
being preferred for the alkyl groups of these substituents
to carry 1 to 4 carbon atoms); or denotes a phenyl
radical, which is optionally substituted by fluorine,
chlorine, bromine, CN, alkyl, alkyloxy, alkylthio and
alkyloxycarbonyl (it being preferred for the alkyl groups
of these substituents to carry 1 to 4 carbon atoms), and
nitro, trifluoromethyl and phenyl.
When R5 is substituted, there are preferably 1 to 3 sub-
stituents, preferably those mentioned, present.
In very particularly preferred compounds of formula (XVI)
R represents a methyl or p-tolyl radical.
This type of mixed anhydrides of the formula (XVI) is
preferably prepared by dissolving the caroxylic acid of formula
(XIII) and a suitable amine in equimolar amounts in a suitable
solvent and allowing them to react with 1 to 1.05 equivalents of
a sulphonic acid derivative of the formula (XV).
Suitable solvents here are any of the solvents which are
stable under the reaction conditions (such as diethyl ether,
tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloro-
form or dimethylformamide).
Suitable amines are tertiary amines (such as triethyl-
amine or tributylamine) and also sterically hindered secondary
amines (such as diisopropylamine).
~.,"i,
~409~35
- 21 - 23189~5448F
The reactions can be carried out at ~ temperature between
-80C and room temperature. low temperatures preventin~ isomerisa-
tion of the su~stituents on the double bond. The reactions are
advantageously carried out at -20 to -50C with a duration of
reaction of 10 minutes to 6 hours.
The compounds of the formula (XVI) can be isolated by
using, for example, tetrahydrofuran as the solvent and triethyl-
amine as the base, filtering off under suction the triethylamine
hydrochloride formed and distillina off the solvent in vacuo.
However, it is more advantageous to react the solutions of the
compounds of the formula (XVI) obtained directly with the cephalo-
sporanic acids of the formula (XVII). For this purpose, the
ce~halos~oranic acids of the formula (XVII) are dissolved in a
suitable solvent with 2 to 4 equivalents of an amine, the solution
is pre-cooled to the desired subsequent reaction temperature and
this solution at this temperature is added to the solution of the
compound of the formula (XVI) described above. In order to prevent
isomerisation of the radical Rl in the reaction products of the
formula (XVIII), the reaction is advantageously carried out at -60
to -30C and the mixture is allowed to reach room temperature
overnight.
I The amines and solvents mentioned for the preparation of
the compounds of the formula (XVI) can be used to dissolve the
cephalosporanic acids of the formula (XVII). If solutions with
satisfactory concentrations of the cephalosporanic acids of the
formula (XVII) cannot be obtained in this manner, it is obviously
also possible to employ the readily soluble esters of the compounds
of the formula (XVII), which are sufficiently well-known from
,
~l~24()98~
- 22 - 23189-5448F
cephalosporin chemistry (such as silyl, tert.-butyl or diphenyl-
methyl esters).
After work-up, the compounds of the formula (XVIII) are
obtained, in which Rl and R2 exhibit the meanings mentioned for the
compounds of the formula (XVI) and X represents a group suitable
as a cephalosporin substituent for example denotes hydrogen, Cl to
C4 alkyl, halogen, Cl to C4 alkoxy, hydroxymethyl, formyloxymethyl,
(Cl to C4 alkyl)-carbonyloxymethyl, aminocarbonyloxymethyl, pyri-
diniummethyl, 4-carbamoylpyridiniummethyl or heterocyclylthiomethyl
("heterocyclyl" preferably representing a radical of the formula
\\N ~ R7 ~ ~N
N N S S
16 H
in which
R6 denotes hydrogen, methyL, 2-dimethylaminoethyl,
carboxymethyl or sulphomethyl and R7 denotes hydrogen
or methyl).
Preferred compounds of formula (XVIII) are those,
in which
X denotes hydrogen, chlorine, methoxy, hydroxymethyl,
acetyloxymethyl, aminocarbonyloxymethyl, pyridiniummethyl
N--N N N
N--N
CH2 S--~N/N , CH2S ~N,N or CH -S ~ ~
¦ I ~ CH3 Me .
CH3 CH2 CH2 N - CH
~LZ~og8~
- 22a - 23189-5448F
The compound of the formula (Il~ in which Rl and X exhibit
the meaning mentioned for the compounds of the formula (XVIII), is
obtained from the compounds of the formula (XVIII) after splitting
off the protective group R2. As already mentioned for the com-
pounds of the formula (X), it is extremely advantageous for the
complete reaction sequence for the preparation of the compounds of
the formula (I) to be carried out directly from the compounds of
the formula (X) if R is a protective group stable in base which
may be selectively split off, such as tert.-butyloxycarbonyl (split
off with trifluoroacetic acid).
The process according to the present invention and the
production of compounds according to the invention are illustrated
by the following Examples.
Example 1
Ethyl 2-tert.-butoxycarbonylimino-3-tert.-butoxycarbonyl-4-
thiazolin-4-ylacetate
-
186 g (1 mol) of ethyl 2-aminothiazol-4-ylacetate, 300 ml
of dimethyl sulphoxide and 500 g (2.3 mol) of 98~ di-tert.-butyl
pyrocarbonate are stirred at room temperature for 7 days. Then 3.5
1 of ice-water are added with ice cooling at max. 20C, the mixture
is stirred for 30 minutes, the precipitate is filtered off under
suction, is washed with 2 1 of water and is taken up in 2 1 of
methylene chloride. The water is separated off, the methylene
chloride phase is dried over Na2SO4 and concentrated on a rotary
evaporator. The oil obtained is taken up immediately (before
crystallisation starts) for crystallisationin 21 ofpetroleum ether.
Yield 302 g (78~), melting point 90C.
~J
~LZ~09~3S
_ 23 _ 23189-5448F
Exam~le 2
Methyl 2-tert.-butoxycarbonylimlno-3-tert.-butoxycarbonyl-
4-thiazo~in-4-ylacetate
is prepared from methyl 2-aminothiazol-4-yl acetate in
analogy to Example 1.
Yield 67%, melting point 67-69C.
Exam~le 3
Ethyl 2-ethoxycarbonylimino-3-ethoxycarbonyl-4-thiazolin-
4-ylacetate
is prepared from ethyl 2-aminothiazol-4-ylacetate and
diethyl pyrocarbonate in analogy to Example 1.
Yield 71%, melting point 102C.
Exam~le 4
Tert.-butyl 2-ter-t -buto~Jcarbonylimino-3-tert.-butoxycar-
bonyl-4-thiazolin-4-ylaceta~e
_ ~ .
157 g (0.5 mol) of tert.-butyl 2-aminothiazol-
4-ylacetate, 150 ml of dimethyl sulphoxide and 260 g
(1.2 mols) of g8% di-tert.-butyl pyrocarbonate were
reacted in analogy to Example 1.
Yield 620~.
Exam~le ~
Trimethylsilylethyl 2-aminothiazol-4-ylacetate
11.2 g (15.8 ml, 0.1 mol) of trimethylsilyl-
ethanol, 100 mg of 4-dimethylaminopyridine and 11.4 g of
dicyclohexylcarbodiimide are added at room temperature
to 7.9 g (0.05 mol) of 2-aminothiazol-4-ylacetic acid in
50 ml o~ acetonitrile and the mixture is stirred for 2
days. The precipitated urea is then filtered off
under suction, washed with ether, the washings are con-
centrated on a rotary evaporator and the residue is takenup in ether and the ethereal solution is washed with 0.5
N hydrochloric acid and with NaHC03 solution, dried over
MgS04 and concentrated on a rotary evaporator. After
concentration of the solution and addition of petroleum
Le A 21 370
~ , , . - .
' - ~
~24C~98~
- 24 - 23189-5448F
ether, the desired ester crystallises out.
Yield 2.8 g.
Exam~le o
Trimethylsilylethyl 2-tert.-butyloxycarbonylimino-
3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetate
is prepared frorn trimethylsilyl 2-aminothiazol-
4-ylacetate in analogy to Example 1.
Yield 50%.
Exam~le 7
Ethyl 1-(2-tert.-`outoxycarbonylaminothiazol-4-yl)-
2-tert.-butoxycarbonyloxypropanecarboxylate
11.2 g (0.03 mol) of ethyl 2-tert.-butoxycarb-
onylimino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylace-
tate weredissolved in 80 ml of anhydrous tetrahydrofuran,
and, under nitrogen at -50 to -60C, 20 ml (0.032 mol)
of a 15% strength solutlon of n-butyllithium in n-hexane
wasadded, followed by 1.91 ml (0.034 mol) of acetalde-
hyde. The mixture is stirred at -50 to -60C for 2
hours, then 30 ml of a 10% strength solution of citric
acid in water is added and the mixture is allowed to
warm to room temperature. To work up, the tetrahydro-
furan is distilled off at room temperature in vacuo, the
residue is extracted with methylene chloride, the organic
extract is dried over Na2S04 and the solvent is distilled
off. 10.8 g of an oil is obtained which, according to
NMR, is a mixture of diastereorers (TLC: cyclohexane/
ether 1:1).
Exam~le 8
Ethyl 1-(2-tert.-butoxycarbOnylaminothiazol-4-yl)-l(E,Z)-
propenecarboxylate
me mixture is prepared as indicated in Example 7.However, after addition of the acetaldehyde, it is
allowed to warm to room temperature, is then stirred
overnight and is only then worked up as indicated in
Le A 21 370
~Z~098~
_ 2 ~ _ 23189-5448F
Example 7. 9.2 g of an oil is obtained which, accord-
ing to NMR and TLC (cyclohexane/ether 1:1, Z isomer runs
higher) is an approximately 1:1 mixture of E/Z isomers.
The two compounds can be separated on silica gel 60
5 (mobile phase cyclohexane/ether 1:1).
Z isomer:
H-NMR (250 MHz, CDC13): ~ = 10.5 (bs; lH, NH), 6.95
(s; lH, S~CH), 6.88 (q; J=
7 Hz, lH, CH-CH3), 4.35 (q;
J=7 Hz, 2H, CH-CH3), 2.04 (d,
J=7 Hz, 3H, CH-CH3), 1.50 (s;
9H, C(CH3)3), 1.36 (t; J=7 Hz,
3H, CH2-CH3).
E isomer:
1H-N~R (250 MHz, CDC13): o = 10.5 (bs; lH, NH), 7.22
(q; J=7 Hz, lH, CH-CH3), 6.94
(s; lH, S-CH), 4.19 (q; J=7
Hz, 2H, CH2 -CH3), 1.95 (d;
J=7 Hz, 3H, CH-CH3), 1.52 (s;
9H, C(CH3)3), 1.22 (t; J=7 Hz,
3H, CH2-CH3).
Exam~le_9
Ethyl 2-(2-tert.-butoxycarbonylaminothiazol-4-yl)-
2(E,Z)-benzylideneacetate
3.86 G (0.Ol mol) of ethyl 2-tert.-butoxycarbonyl-
imino-3-tert~-butoxycarbonyl-4-thiazolin-4-ylacetate in
40 ml of anhydrous tetrahydrofuran are cooled down to
-50, 2.8 g (0.024 mol) of potassium tert.-butylate are
added, the mixture is stirred until solution is complete
3o and 1.11 ml (0.012 mol) of benzaldehyde is added. The
mixture is allowed to warm to room temperature and is
stirred overnight
To worl~ up, about 12 ml of 2 N HCl areadded with
cooling in ice and monitoring the pH, until a pH of 4-5
is reached, the tetrahydrofuran and then the tert.-
Le A 21 370
,
lZ40985
~ 23189-5448F
"
butanol are removed in vacuo and the residue is extrac~ed
with methylene chloride. After drying over Na2S04,
the methylene chloride is removed in vacuo. 3.1 g of
an oil is obtained, which, according to Nl~R and TLC
(cyclohe~ane/ether 1:1), is an approximately 1:1 mixture
of E/Z isomers.
Exam~le 10
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-1-(Z)-pro-
penecarbo~ylic acid
.
0.145 mol (5~ g) of ethyl 2-tert.-butoxycarbonyl-
imino-3-tert.-butoxycarbonyl-4-thiazolin-4-ylacetate
and 40C ml of anhydrous tetrahydrofuran are initially intro-
duced under nitrogen and, at -~0 to -50C, 0.16 mol of
n-butyllithium in hexane (15% strength, 100 ml) is added
dropwise. Then 9.55 ml (0.17 mol) of acetaldehyde is
immediately added, the mixture is stirred for 10 minutes
at -60C and then overnight at room temperature.
Then 250 ml of 2 N sodium hydroxide solution is
added and the two-phase mixture is vigorously stirred at
room temperature for 24 hours. The tetrahydrofuran
is then distilled off at room temperature in vacuo and
the alkaline phase is extracted twice with 100 ml of
methylene chloride each time. After acidification of
the aqueous phase to pH 2-3 and extraction, the 1-(2-tert.-
butoxycarbonylaminothiazol-4-yl)-l(E)-propenecarboxylic
acid is obtained (21.0 g, 51%, melting point = 195C
(from acetonitrile)).
The methylene chloride phase is concentrated in
vacuo, the residue is taken up in 250 ml of ethanol,
this is treated with 250 ml of 2 N sodium hydroxide solu-
tion and heated at 60 C for 24 hours.
After removal of the ethanol by distillation,
the alkaline phase is extracted o~ce with 100 ml of
methylene chloride, the extract is discarded, the alkaline
phase is acidified to pH 2-3 and the desired 1-(2-tert.-
Le A 21 370
...... . . .. .
lZ~0985
- - 27 - 23189-5448F
butoxycarbonylaminothiazol-4-y~-l(z)-propenecarboxylic
acid is extracted with methylene chloride (8.3 g, 20%,
melting point = 183C (from acetonitrile)).
Exam~le 11
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butene-
carboxylic acid
_ _ _ _ . _
Preparation in analogy to ~Yample 10 with pro-
panal instead of acetaldehyde (yield 17/o~ mel~ing point
172C from acetonitrile).
Exam~le 12
1-(2-tert.-butoxycarbonylaminothiazol-4-yl~-l(Z)-pentene-
carboxylic acid
_ _ . _ _
Preparation in analogy to Example 10 with buta-
nal instead of acetaldehyde (melting point l62-3C,
from acetonitrile).
Exam~le 13
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-hexene-
carboxylic acid
Preparation in analogy to Example 10 with penta-
nal instead of acetaldehyde (melting point 158C, from
acetonitrile).
Exam~le 14
1-(2-ter~.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-~eptene-
carboxylic acid
Preparation iIl analogy to Example 10 with hexa-
nal instead of acetaldehyde (melting point 130-1C, from
acetonitrile).
Exam~le 15
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl~-l(Z)-octene-
carboxylic acid
. _
- Preparation in analogy to Example 10 with hepta-
nal instead of acetaldehyde (melting point 164C, from
acetonitrile).
~e A 21 370
12~985i
- 2$ - 23189-5448F
Ex_mPle 16
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-methyl-
l(Z)-butenecarboxylic acid
Preparation in analogy to Example 10 with iso-
butyraldehyde instead of acetaldehyde (melting point
169-71C, from acetonitrile)~
- Example 17
. _ .
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-4-methyl-
l(Z)-pentenecarboxylic acid
Preparation in analogy to Example 10 ~ h iso-
valeraldehyde instead of acetaldehyde (melting point
173C, from acetonitrile).
Exam~le 18
2-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-3-cyclohexyl-
(Z)-acrylic acid
Preparation in analogy to Example 10 with cyclo-
hexylaldehyde instead of acetaldehyde (melting point
~ 210C, from acetonitrile).
Example 19
1-(2-tert.-Butoxycarbonylaminothiazo1-4-yl)-4-phenyl-
l(Z)-butenecarboxylic acid
Preparation in analogy to Example 10 with dihydro-
cinnamaldehydeinsteadof acetaldehyde (melting point
174C, from acetonitrile).
Example 20
1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-
carboxylic acid
., ~
0.4~ mol (122 g) of 1-(2-tert.-butoxycarbonyl-
aminothiazol-4-yl)-l(E)-propenecarboxylic acid in 800 ml
of anhydrous tetrahydrofuran is treated with 0.52 mol
(129 ml) of bistrimethylsilylacetamide and the mixture
is stirred at room temperature for 1 hour. It is then
cooled down to -60C, 1.74 mols (200 g) of potassium
Le A 21 370
~2~85
- 23189-5448F
- 2 9 -
tert.-butylate (98%) is added, the m~c~ure is allowed to
warm to room temperature and is stirred at room tempera-
ture overnighi.
To wor~ up, 100 ml of water is added ~hile cool-
ing in ice, the pH is adjusted to 6-8 wi~h about 900 ml
of 2 N HCl, the tetrahydrofuran is removed in vacuo, the
pH is adjusted to 2-3 and the mixture is extracted 3
times with 300 ml of methylene chloriàe. The extract
is dried, concentrated on a rotary evaporator and the
residue is dissolved in 700 ml of methanol. The
methanolic solution is run ~hrough a column (2.5 x 80 cm;
400 ml) containing ~eakl~ basic ion exchan~er Lewatit
MP 62, at a rate of about 10 ml/.~inute, the column is
washed ~ith 2 1 of methanol and eluted ~ith 1 1 of
me-thanol/2 N sodium hydroxide solution 10:1. m e elu-
ate is concentrated, acidified io pH 2-3 with 2 N HCl and
extracted with methylene chloride. After drying over
Na2S04 and distilling off the methylene chloride, 50 g
(41%) of the desired Z-propenecarboxylic acid is
obtained. The E-propenecarboxylic acid which did not
isomerise is recovered from the column by evaporating the
methanolic washings.
Exam~le_21
1-(2-tert.-Butoxycarbonylaminothiazol-4-Yl)-l(Z)-pentene-
carboxylic acid
-
By isomerisation of the corresponding E-pentene-
carboxylic acid in analogy to Example 20
Yield 45%.
Example 22
1-(2-tert~-Butoxycarbonylaminothia7ol-4-yl)-l(z)-propene
carbo~ylic methanesulphonic anhydride
. _
0.005 mol (1.42 g) of 1-(2-tert.-outoxycarbonyl-
aminot~iazol-4-yl)-l(Z)-propenecarbo~Jlic acid and 0.0055
mol (0.76 ml) of triethylamine are dissolved in 10 ml of
anhydrous tetrahydrofuran and cooled down to -50C.
Le A 21 ~70
~24Q98~:i
3 2 3 1 8 9--5 4 48F
Then 0.0051 mol (0.40 ml) of methanesulphonyl chloride
are added and the mixture is stirred at -40 to -50C for
5 hours. Then the triethylamine hydrochloride is
filtered off under suction with exclusion of H20 and the
tetrahydrofuran is distilled off in vacuo at -10C.
m e mixed anhydride is obtained as an oil which readily
isomerises into the E form on warming (NMR).
Exam~le 23
l-(Z-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-butene-
carboxylic p-toluenesulphonic anhydride
Preparation in analo~y to Example 22 from the
appropriate Z-butenecarbo~flic acid and p-toluenesul-
phonyl chloride at -20 to -~0C.
Exam~le 24
_ _ _
7-[1-(2-tert.-~utoxycarbonylaminothiazol-4-yl)-l(Z)-pr
penecarboxamido]-3-aceto~ymethyl-3-cephem-4-carboxylic
acid
.... . . .
0.005 mol (1.42 g) of 1-(2-tert.-butoxycarbonyl-
aminothiazol-4-yl)-l(Z)-propenecarboxylic acid and 0.0055
mol (0.76 ml) of triethylamine are dissolved ln 20 ml of
anhydrous methylene chloride, the mixture is cooled down
to -50C, 0.0051 mol (0.40 ml) of methanesulphonyl chlor-
ide is added and the mixture is stirred at -50 to -40C
for 5 hours.
Then a solution of 0.00~ mol (1.63 g) of 3-acet-
oxymethyl-7-amino-3-cephem-4-carboxylic acid and 0.013 mol
(1.80 ml) of triethylamine in 20 ml of anhydrous methyl-
ene chloride, which has been previously cooled to -50C,
is added and the mixture is allowed to warm to room
temperature over 12 hours.
To work up, the mixture is washed twice with 10 ml
of H20 each time, the methylene chloride phase is covered
with 40 ml of H20 and acidified, with stirring and cooling
in ice, to pH 2-3 with 1 N HCl. The organic phase is
separated off, the H20 phase is extracted 2 times with
Le A 21 370
. . .
1240~t~5
..
- 31 _ 23189-5448F
20 ml of methylene chloride each time the combined
methylene chloride phases are washed l~ith saturated
NaCl solution dried over Na2S04 and concentrated in
vacuo on a rotary evaporator. The desired cep~a o-
sporin is obtained a~mos~ auant tatively.
Exam~le 25
7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-
propenecarboxamido]-3-(1-methyl-1 H-tetrazol-5~yl)thio-
methyl-3-cephem-4-carboxylic acid
Preparation is carried out in analogy to Example
24 from 1-(2-tert.-butox-ycarbonylaminothiazol-4-yl)-
l(Z)-propenecarboxyllc acid and 7-amino-3-(1-methyl-1 H-
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid.
Yield 92%.
Exam~le 26
7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-
butenecarboxyamido]-3-aceto~ymethyl-3-cephem-4-carboxylic
acid
Preparation in analogy to Example 24 ~rom
1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-1-(Z)-butene-
carboxylic acid and 3-acetox~methyl-7-amino-3-cephem-
4-carboxylic acid.
Exam~le 27
7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-
butenecarboxamido]-3-(1-methyl-1 H-tetrazol-5-yl)thio-
methyl-3-cephem-4-carbox-ylic acid
. _ _ . . .
Preparation in analogy to Example 24 ~om 1-(2-tert.-
butoxycarbonylaminothiazol-4-yl)-l(Z)-butenecarboxylic
acid and 7-amino~3-(1-methyl-1 H-tetrazol-5-yl)thio-
methyl-3-cephem-4-carboxylic acid.
Yield 88%,
Exam~le 28
- 7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-
l(Z)-heptenecarboxamido]-3-aCetoxymethyl-3-cephem-4-car-
boxylic acid
Le A 21 370
,
. ~ ., .
~ 3.2~0985
- 32 - 23189-5448F
Prepara~ion in analogy to Example 2k from
1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-heptene-
carboxylic acid and 3-acetoxymethyl-7-amino-3-cephem-
4-carboxylic acid.
Yield 90%.
Exam~le 29
7-[1~(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-hep-
tenecarboxamido~-3-(1-methyl-1 ~-tetrazol-5-yl)-thio-
methyl-3-cephem-4-carbox-ylic acid
Preparation in analogy to Example 24 from 1-(2-
tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-heptene-
carboxylic acid and 7-amino-3-(1-meth~Jl~ e~a~ol-~-yl)
thiomethyl-3-cephem-4-carboxylic acid.
Yield 85%.
Exam~le 30
7-[1-(2-tert,-Butoxycarbonylaminothiazol-4-yl)-3-methyl-
l(Z)-butenecarboxamido]-3-acetoxymethyl-3-cephem-4-car-
boxylic acid
Preparation in analo~y to Example 24 from
1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-3-methyl_l(z)_
butenecarboxylic acid and 3-acetoxymethyl-7-amino-3-ceph-
em-4-carboxylic acid.
Yield 93%,
Example 31
7-[1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-4-phenyl-
l(Z)-butenecarboxamido]-3-acetoxymethyl-3-cephem-4-car-
boxylic acid
-
Preparation in analogy to Example 24 from
1-(2-tert.-butoxycarbonylaminothiazol-4-Yl)-4-~henyl-l(Z)-
butenecarboxylic acid ~d ~-acetoxymethyl-7-amino-3-cephem
4-carboxylic acid. Yield 95%.
ExamPle 32
7-C1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-
propenecarboxamido]-3-methyl-3-cephem-4-carboxylic
acid
Le A 21 370
.
~240985
23189-5448F
- 33 -
Preparation in analogy to Example 24 from 1-(2-
tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-
carboxylic acid and 7-amino-3-methyl-3-cephem-k-carboxylic
acid. Unlike Example 24, the 7-amino-3-methyl-3-ceph-
em-4-carboxylic acid is dissolved in methylene chloride
with the equimolar amount of diisopropylamine ins~ead of
with triethylamine.
Yield 88%.
Exam~le 33
7-~1-(2-tert.-Butoxycarbonylaminothiazol-4-yl)-l(Z)-
propenecarboxamido]-3-aminocarbonyloxymethyl-3-cephem-
4-carboxylic acid
Preparation in analogy to Example 24 from
1-(2-tert.-butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-
carboxylic acid and 7-amino-3-aminocarbonyloxymethyl-
3-cephem-4-carbox~Jlic acid. Unlike Example 24, the
7-amino-3-aminocarbonylo~methyl-3-cephem-4-carboxylic
acid is not dissolved in methylene chloride with tri-
ethylamine, but in anhydrous dimethylformamide with the
equimolar amount of diisopropylamine, and the solution
obtained is added to the mixed carboxylic sulphonic
anhydride in methylene chloride.
Towork up, themixtureis evaporated at 0C in
vacuo, the residue is taken up in water, extracted with
methylene chloride, the aaueous phase is covered with
ethyl acetate and acidified to pH 2-3. The product
separates out as an oil bet~een the phases.
I Exam~le 34
Diphenylmethyl 7-~1-(2-tert.-butoxycarbonylaminothiazol-
4-yl)-l(Z)-propenecarboxamido]-3-cephem-4-carboxylate
... . _ . _
Preparation in analogy to Example 24 from
1-(2-tert -butoxycarbonylaminothiazol-4-yl)-l(Z)-propene-
carboxylic acid and diphenylmethyl 7-amino~3-cephem-
4-carboxylate.
Yield 93%.
Le A 21 370
.
12~)985
3~ 23189-5448F
Examle 35
7-[1-(2-Aminothiazol-4-yl)-l(Z)-propenecarboxamido~-
3-acetoxymethyl-3-cephem-4-carboxylic acid
10 ml of trifluoroacetic acid is added to the
BOC-protected cephalosporin from Example 24, and the mix-
ture is stirred at room temperature for 30 minutes.
m e trifluoroacetic acid is then removed at room tem~era-
ture in vacuo, the residue is treated with 20 ml of
methanol/H20 10:1 and then with 10% strength NaHC03
solution, until a clear solution at pH 6-7 is obtained.
The pH is then slowly adjusted to 3 ~ vr ' ~ 51,
the methanol is slowly removed in vacuo and, if neces-
sary, the pH is adjusted again to 3. The precipitated
product is filtered off under suction. Yield 700,6.
Exam~les 36-44
The cephalosporins from the Examples 25 to 34
are unblocked in analogy to Example ~5. Yields are
between 50 and 90%.
Le A 21 370
