Note: Descriptions are shown in the official language in which they were submitted.
35~
_ 2 -
One oP the greatest difficulties when manufacturing
cephalosporins and penicillins lies in finding conditions
which are as gentle as possible for the coupling of the
cephem or penam body with an acid component at the 7- or,
respectively, 6-amino group. For example, slight rises
in the temperature during the reaction, or alkaline or acid
reaction media result in a rapid degradation of the ~-lactam
or effect profound changes in the acid component to be
coupled.
The prior necessary activation of the acid component
is also freguently associated with not inconsiderable
stresses on the molecule, and for this reason it is fre-
quently neces~ary to make even greater efforts to find
optimum, gentle reaction conditions: thus, German Offen-
legungsschrift 2,265,235 indicates a specific process by
means of which 2-alkoximinoaryl-acetic acids are converted
to the acid chlorides without the undesired isomerization of
the syn- to the anti-alkoximino compound, which proceeds
very easily in acids, taking place.
Because of their instability, the active intermediate
stages can also present problems.
Thus, in German Offenlegungsschrift 2,540,37~, a
process for the manu~acture of cefazolin is described in
which tetrazolylacetic acid is converted to the acid chloride,
which, because of its low stability, is appropriately
immediately reacted in situ. In a case of this type,
control over the extent of activation is made more difficult.
: :
: , . ~:, ,
~ : ,
: , , . ,: :
~63
-- 3 --
s As is generally krlown from peptide chemistry, but
! especially from the investigations on the preparation of,
for example, ampicillin (Doyle et al. J Chem. Soc. 1962,
0), cephaloglycin (Kurita et al. J. Antibiot. 19, 243
(1966), Spencer et al. 3. Med. (,hem. 9, 746 (1966)), or
I cephalexin (Ryan et al~ J. Med. Chem. 12, 310 (1969)), the
¦ problem o~ racemi~ation at the ~-C atom always arises when
linklng the activated and N-prot;ected phenylglycine with the
! corresponding ~-lactam (in this context compare Flynn,
l 10 Cephalosporins and Penicillins, Academic Press, New York,
¦ 1972, page ~6).
In the abovementioned cases, and also in many other
cases, efforts must be made to obtain highly reactive inter-
mediate stages, such as acid anhydrides or acid chlorides,
for activation. Under certain circumstances, it is
therefore necessary to protect any reactive groups which may
be present in the acid molecule before activating the said
molecule, in order to excIùde undesired intra- or inter-
molecular adverse reaction.
The activation of a number of 2-aminothiazolylacetic
acids and the subsequent coupling thereof with 7-amino-
cephem derivatives is described in German Offenlegungsschrift
2,556,736, the 2-amino group being blocked by easily detach-
able protective groups, using processes which in some cases
are involved, prior to the activation and being set free
agaîn only after coupling has taken place. Considerable
losses arise with this process.
~
.
'"' ~ ' : ~ '
" ' ' ~ ~' ' . :,
,
. .
6~5~ '
,
In French Patent Specification 7,601,~3~, a process E
is described which links 2-tritylaminothiazolylacetic acid
derivatives with 7-aminocephalosporanic acid and subsequently
detaches the protective group, as tritylcarbinol, under acid
conditions.
The introduction of such prot0ctive groups, and the
detaching thereof after the coupling reaction has ended, is
generally associated with not inconsiderable substance losses
(see above), further stress on the acylating component and
on the acylation product and also a not inconsiderable
expenditure of time and effort.
In many cases it is also necessary to bring the
product into which the protective group is converted on
detaching, after isolation of the said product, into a form
in which it can be used again as a protective group reagent
and thus can be fed back into the process.
However, detaching of the protective group is fre-
quently associated with the irreversible loss thereof.
The purity of the desired substance in general
suffers so greatly during the manipulations carried out to
introduce and detach any protective groups that increased
efforts have to be made to purify the product.
It has now been found that the difficulties des-
cribed can be avoided, and cephalosporins and penicillins
can be obtained in high yield and purity by acylation of 6_
amino-penam and 7-amino-cephem derivatives, by converting the
acyla~ing component to an active derivative using an option-
. , ............................... .'
' '
35~3
; - 5 -
ally substituted l-hydroxybenzotriazole and then reacting
! the said derivative with a 6-amino-penam or 7-amino-cephem
derivative.
The invention relates espeeially to a process for
the acylation of 6-amino-penam and 7-amino-eephem deriva-
tives, which eomprises using, as the acylating component, a
carboxylic acid of the formula I
Rl
R - C - CO2H
R3
in which Rl represents alkyl having 1 to 4 carbon atoms, an
optionally substituted, saturated or mono- or poly-
unsaturated carbocyelie ring, optionally substituted aryl or
lS aralkyl or optionally substituted heteroaryl or heteroaryl-
thio and R and R3, whiCh ean be identieal or different,
represent hydrogen, alkyl having 1 - 4 C atoms in the
optionally substituted aeyloxy having 1 - 4 C atoms in the
acyl part, optionally substituted alkoxy having 1 - 4 C
atoms in the alkyl part, optionally substituted alkylamino,
; optionally substituted acylamino, alkoxycarbonyl having 1 -
4 C atoms in the alkyl part, sulfoxy or aminosulfonyl, or
together ean be oxygen or, espeeially, a group of the
formula VIII
= N - X VIII
in which X preferably has the syn configuration and repres-
ents hydroxyl, optionally substituted, saturated or unsatu-
rated alkoxy, optionally substituted aryloxy or optionally
substituted aeyloxy, reaeting this with a l-hydroxybenzo-
~iazole of the general formula II
:: - ' , ~ . . : :
: . : ' , :
-. ,, ' , . . . .. .
-" ' '' . '' ' ~
.. . . : .
~ ~63s~
: 6
: R
R
7 /~\ N
R OH
` in which R6, R7, R~ and R9, whic:h can be identical or
different, can represent hydrog~n, optionally ~ubstituted
alkyl having 1 - ~ C atoms, optionally substituted alkoxy
having 1 - ~ C atom~, halogeng cyano, nitro~ aminocarboxy,
alkylaminocarboxy having 1 - 4 alkyl C atoms, aminosulfonyl,
alkylaminosulfonyl having 1 - 4 alkyl C atoms or dialkyl-
;~ aminosulfonyl having 1 - ~ C atoms per alkyl group, in the
presence of a dehydrating agent, especially of a carbodi-
imide, to give an sctivated derivative of the formula XI a
or XI b
R
R~ ~1 XI a
R6 o - CO - C - R3
.,' R2
CO-ClR
R~ ' R2 XI b
R7~\N D
~3
,
, .
~ `
. , :. .
. . . . . , ~ .
~ 3
! - 7 -
or a mixture thereof, isolating this product if desired and
subsequently reacting it with a 6-amino-penam dérivative of the
formula III
()n
Y-NH ,~ ~Cc~3 I I I
N -- ~
O COOA
in which n can represent O, 1 or 2 and A can denote hydro-
gen, a cation or an ester group and Y represent~ hydrogen or
a trialkylsilyl group, or wlth a 7-amino-cephem derivative
of the formula IV ()n
y-N~ ~ s ~ IV
N ~
C02A
15 in which n, A and Y are as defined above and B represents
chlorine, bromine, hydroxyl, methoxy or a group of the
formula IX
- CH2-B' IX
in which B' can denote hydrogen, hydroxyl, optionally sub-
stituted acyloxy having 1 - 4 C atoms, optionally substitu-
ted acylthio having 1 - 4 C atoms, optionally substituted
aminocarbonyloxy, l-pyridinium or S-Hetj in which Het
represents an optionally substituted, 5-membered or 6-
membered heterocyclic ring, which optionally can also be
fused to a carbocyclic or heterocyclic ring, to giv8 a com-
pound of the formula V
.
.
.
3S~
Rl ( I)n
R2 _ C - CONH V
R O ~02A
or a compound of the formula VI
.~ Rl (I~n
R2 _ C - CONH--I~ S'~ VI
5R3 ~ N ~ B
~: C02A
in which formulae Rl, R , R3, A~ B and n can have the mean-
ings defined.
Compounds which can be used for the reaction accord-
ing to the invention are in particular those in which thesubstituents have tna following meanings.
R can represent alkyl having 1 4 carbon atoms,
preferably methyl or ethyl, an optionally substituted,
saturated or mono- or poly-unsaturated, 5-membered to 7-
; 15 membered carbocyclic ring, such as cycloalkyl, preferably
cyclohexyl, cycloalkenyl, preferably cyclohexenyl, or cyclo-
alkadienyl, preferably cyclohexadienyl, otpionally sub-
stituted aryl, preferably phenyl or m-methylsulfonylamido_
phenyl, optionally substituted aralkyl, preferably benzyl,
optionally substituted 5-membered to 6-membered heteroaryl,
which can contain, as hetero-atoms, nitrogen, sulfur or
s~
_ 9 _
oxygen, such as, for exampl~, 2-pyridon-1-yl, 4-pyridon-1-
yl, 3,5-dichloro-4-pyridon-1-yl, 2-thienyl or l-tetrazolyl,
but preferably a 2-furyl or a thiazolyl Or the formula YII
R4 ~f R5 VII
in which R4 preferably represents amino or represents option-
ally substituted acylamino, such as, in particular, formamido,
acetamido, chloroacetamido, bromoacetamido, trifluoroacet-
amido, phenoxyacetamido, (5-methyl-1,3,4-thiazol-2-yl)-thio-
acetamido or (5-amino 1,3,~-thiadiazol-2-yl)-thioacetamido,
optionally substituted alkyl- or dialkyl-amino having 1 - 4
C atoms per alkyl group, such as, preferably, methylamino,
dimethylamino and ethylamino, optionally substituted
alkenylamino having 2 - 4 C atoms, such as, preferably,
allylamino, or hydroxyl, alkoxy having 1 to 4 C atoms, such
as, preferably, methoxy, ethoxy or propoxy, acyloxy, such as,
preferably, ~ormyloxy, acetoxy or propionyloxy, halogen,
such as, preferably, chlorine or bromine, or alkylthio, such
as, preferably, methylthio, ethylthio, propylthio or butyl-
thio, and R preferably represents hydrogen or represents
halogen, such as, preferably, fluorine, chlorine or bromine,
cyano, thiocyano, hyd~oxyl, alkoxycarbonyl having 1 - 4 C
atoms in the slkyl radical, such as, preferably, methoxy- c
carbonyl or ethoxycarbonyl, acyloxy, such as, preferably,
formyloxy, acetoxy or propionyloxy, acylthio, such as,
preferably, acetylthio, alkoxy, such as, preferably, methoxy,
ethoxy or propoxy, or alkylthio, such as, preferably, methyl-
: thio or ethylthio, or Rl can represent an optionally sub-
~._
. ~,, ~.
:
.
~lg~635B
,. -- 10 --
stituted heteroarylthio radical, such as, preferably, 2-
methyl-1,3,4-thiadiazol-5-yl-thlo or 2_amino-1,3,4-thla-
diazol-5-yl-thio .
R and R , which can be identical or different, can
` 5 denote hydrogen, alkyl having 1 - 4 C atoms, preferably
-- methyl, or hydroxyl, optionally substituted acyloxy having
`~ 1 to ~ C atoms in the acyl part, such as, for example,
; formyloxy, acetoxy or propionyloxy, optionally substituted
alkoxy having 1 to ~ C atoms in the alkyl part, such as, for
example, methoxy, ethoxy or propoxy, optionally subst~tuted
alkylamino, such as, preferably, tert.-butylamino or tert.-
amylamino, benzylamino, p-methoxybenzylamino, benzhydryl-
amino, tritylamino, phenylethylamino, optionally substitu~
ted acylamino, such as, for example, formamido, acetylamino,
~- 15 chloroacetylamino, bromoacetylamino, benzoylamino, tert.-
butoxycarbonylamino, 2,2,2_trichloroethoxycarbonylamino, ~-
hydroxy-1,5-naphthyridine-3-carbonylamino, 3-hydroxy-pyrida-
zine-4-carbonylamino, imidazolidin-2-on-1-yl-carbonylamino,
(3-methyl-sulfonyl-imidazolidin-2-on-1-yl)-carbonylamino,
(4-ethyl-piperazin-~,3-dion-1-yl)-carbonylamino, or alkoxy-
carbonyl having 1 to 4 C atoms in the alkyl part~ such as,
for example, methoxycarbonyl or ethoxycarbonyl, or sulfoxy
or aminosulfonyl, or together denote oxygen or, preferably,
a group of the formula VIII
: 25 : = N - X VIII
in which X preferably has the syn configuration and prefer-
ably represents hydroxyl or represents optionally substitu-
ted, saturated or unsaturated alkoxy, such as, preferably,
"'
, )
, .. ,, ~
,.~ . ...
'
635~
11
methoxy, ethoxy, propoxy or butoxy, benzyloxy, p-chloro-
! benzyloxy, triphenylmethoxy, aminocarbonylmethoxy, tert.-
butoxycarbonylmethoxy, methoxycarbonylmekhoxy, ethoxy-
carbonylmethoxy, cyanomethoxy, allyloxy or bromoallyloxy,
or optionally substituted aryloxy, such as, preferably,
phenoxy, or optionally substituted acyloxy having 1 to 4 C
atoms, such as, preferably, acetoxy, chloroacetoxy or bromo-
acetoxy.
6 7 ~ 9
R , R , R and R can be identical or different and
~enote hydrogen, optionally substituted alkyl having 1 - 4
C atoms, preferably methyl or ethyl, which can carry, as
substituents, in particular halogen, preferably fluorine or
chlorine, or cyano, or optionally substituted alkoxy having
1 - 4 C atoms, preferably methoxy or ethoxy, which in par-
ticular can be substituted by halogen, such as fluorine or
chlorine, or halogen, such asl for example, bromine, chlorine
or ~luorine, cyano9 nitro, aminocarboxy, alkylaminocarboxy
having 1 - 4 alkyl C atoms, such as, preferably,` methylamino-
carboxy or ethylaminocarboxy, aminosulfonyl, alkylamino-
sulfonyl having 1 - 4 alkyl C atoms, preferably methylamino-
- sulfonyl, or dialkylaminosul~onyl having 1 - 4 alkyl C
atoms per alkyl group, preferably dimethylaminosulfonyl or
diethylam~nosulfonyl.
Particularly preferred compounds of the formula VI
are: l-hydroxybenzotriazole, 1-hydroxy-4-methyl-benzo-
triazole, l-hydroxy-5-methyl-benzotriazole, 1-hydroxy_6_
methyl-benzotriazole, l-hydroxy-5,6-dimethyl-benzotriazole,
1-hydroxy-5-methoxy-benzotriazole, 1-hydroxy-6-methoxy-
b~nzotriazole, l-hydroxy-6-trifluoromethyl-benzotriazole, 5-
., ~ ..
~, .
.
,
'
- 12 _
chloro-l-hydroxy-benzotriazole, 5,S-dichloro-l-hydroxy_
benzotriazole, 6-bromo_l_hydroxy_benzotriazole, ~ 7 5,6~7_
tetrachloro-l-hydroxy-benzotria~ole, 6-chloro-1-hydroxy-5_
methyl-benzotriazole, 6-chloro-1-hydroxy-5-~sopropyl-benzo-
triazole, 4-chloro-6-nitro-1-hydroxy-7-methyl-benzotriazole,
6-nitro-4-methyl-1-hydroxy-benzotriazole, 6_nitro-1-hydroxy-
benzotriazole, l-hydroxy-6-meth~yl-5-cyano-benzotriazole, 1-
hydroxy-benzotria~ole-carboxylic acid-~6) amide, l-hydroxy-
;~ 6-methylaminosulfonyl-benzotriazole, 1-hydroxy-6-amino-
sulfonyl-benzotriazole or 1-hydroxy-6_diethylaminosulfonyl-
benzotriazole.
A can represen~ hydrogen, a metal cation, for
example an alkali metal cation or alkaline earth metal
cation, especially sodium,potassium or calcium, a cation
of an organic base, such as, for example, a trialkyl-
ammonium ion, preferably tr~methyl-ammonium, triethyl-
ammonium or tri-n-butyl-ammonium, or an ester group, prefer-
ably an easily removable ester group, such as, in particular,
methyl, benzyl, benzhydryl, pivaloyloxymethyl, 2,2,2-tri-
chloroethyl, tert.-butyl or trimethylsilyl.
B can represent, in particular, chlorine, bromine,
. hydroxyl, methoxy or a group of the formula IX
-CH -B' IX
in which Br can denote hydrogen, hydroxyl, opttonally sub-
~ 25 stituted acyloxy having 1 - 4 C atoms, such as, preferably,
: acetoxy, optionally substituted acylthio having 1 - 4 C
,.
~ .
,
.
- 13 -
atom~, such as, preferably, acetylthio, optionally sub-
stituted aminocarbonyloxy, preferably unsubst~tuted amino-
carbonyloxy, l-pyridinium or -S-Het, in which Het can be an
optionally substituted 5-membered heterocycllc radical con-
taining nitrogen, sul~ur and/or oxygen, especially pyrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazo~yl,
isothiazolyl, thiadiazolyl, oxazolyl, lsoxazolyl or oxa-
diazolyl, which can also carry one or more substituents,
such as, for example, alkoxy having 1 to 4 C atoms, prefer-
lo ably methoxy or ethoxy, halogen, preferably chlorine, 5-
membered or 6-membered heteroaryl, especially furyl,
thienyl or pyridyl, amino or optionally substituted alkyl
having 1 - 4 C atoms, preferably methyl, in which the alkyl
substituent can be yet furthar substituted, preferably by
halogen, such as, ~or example, fluorine or chlorine,
hydroxyl, carboxyl, sulfonyl, aminocarbonyl or amino-
sulfonyl. Particularly preferred radical~ of this type
which may be mentioned are, for exampIe: l-methyltetrazolyl,
l-phenyltetrazolyl, l-hydroxyethyl-tetrazolyl, l-carboxy-
: 20 methyl-tetrazolyl, l-amino-carbonylmethyl-tetrazolyl, 1-
sulfonylmethyl-tetrazolyl, l-aminosulfonylmethyl-tetr3zolyl,
5-amino-1,3,4-triazolyl, 5-methyl-1,3,4-triazolyl, 5-tri-
fluoromethyl-1,3,~-triazolyl, 5-(2-thienyl)-1,3,~-triazolyl,
- 5_(2-furyl)-1,3,~_triazolyl9 5-trifluoromethyl-1-methyl-
1,3,~-triazolyl, 5-(2-thienyl)-1-methyl-1,3,4-triazolyl,
; l-carboxymethyl-1,39~-triazolyl, 1-carboxymethyl-5~methyl_1,3,4_
triazolyl, 5-methyl-1,3~4-thiadiazolyl, 5-amino-1,3,4-
thiadiazolyl, 5-methyl~1,3,4-thiadia~olyl, ~-methylthiazolyl, ~-
carboxymethyl-thiazolyl, 5-aminothiazolyl, 3-methyl-1,2,~-
thiadiazolyl, .~,5-dimethyl-hexazolyl or 4,5-dimethyl-thiazolyl.
', ~ .' .
'
;
~ ~ '
In the abovementioned radical -CH2-S-Het, Het can
also be an optionally substituted 6-membered heterocyclic
radical which contains one or more nitrogen atoms, optionally
together with sulfur or oxygen~ Examples which may be
mentioned are, in particular, pyridyl, pyrim~dinyl,
pyrazinyl and pyridazinyl, and these 6-membered hetero-
cyclic radicals can also carry one or more substituents,
such as, for example, alkyl having 1 - 4 C atoms, preferably
methyl, alkoxy having 1 - 4 C atoms, preferably methoxy or
ethoxy, halogen, such as, for example, chlorine or bromine,
amino, hydroxyl, mercapto, carboxyl or carboxymethyl.
Particularly preferred radicals which may be mentioned are,
for example, ~,6-diamino-pyrimidin-2-yl, 6-hydroxy-4-amino-
pyrimidin-2-yl, 4,5-diamino-6-hydroxy-pyrimidin-2-yl and 5-
carboxy-methyl-~-hydroxy-6-methyl-pyrimidin-2-yl.
The carbocyclic or hetarocyclic ring which can be
fused to the heterocyclic structure can be, in particular,
a benzo, furo, thieno or pyrido ring. A preferred
example of this which may be mentioned is 5,6-benzo-1,1
dioxo-1,~,~-thiadiazin-3-yl.
Y can represent hydrogen or a trialkylsilyl group,
especially trimethylsilyl.
The carbodiimides which can be used as the carbodi-
imide employed as the dehydrating agent for the reaction of
the acylating component with the hydroxybenzotriazole are
- the carbodiimides suitable for reactions of this type,
especially those of the general formula X
R - N = C = N - Rll X
.
~J6~5
5 -
in which R and R can have the following meaning.
R10 and R can be identical or dlfferent and represent
alkyl hav~ng 1 to 4 C atoms, such as; preferably, methyl,
ethyl, propyl, isopropyl or butyl, an optionally substituted
am~noalkyl having 1 to 4 C atoms per alkyl group, such as~
preferably, 3-dimethylamino-propyl, 3-triethylamino-propyl,
2-N-morpholino-ethyl or 2-pyrroJidino-ethyl, and also the
metho-iodides and metho-p-toluene-sulfonates thereof, or an
optionally substituted cycloalkyl radical, such as, prefer-
ably, cyclohexyl, or an optionally substituted aromatic
radical, such as, preferably, phenyl, p-chlorophenyl, p-
tolyl, m-chlorophenyl or m-tolyl.
The starting materials for the reaction according to
the invention are known from the literature or can be manu-
factured by processes known from the literature.
The reaction of the carboxylic acid of the formula I
with an optionally substituted l-hydroxy-benzotriazole of
the formula II can take place under variable experimental
conditions.
Thus, for example, it is possible to combine a mix-
ture of the carboxylic acid I, dissolved or suspended in a
suitable sol~ent, and an optionally substituted l-hydroxy-
benzotriazole II within a relatively wide temperature range
with a carbodiimide, dissol~ed in a suitable solvent or in
bulk.
The benzotriazole of the formula II can be employed
in approximately equivalent amounts, but preferably in an
' ' " ' ' .
- -. ~ :
- : .
~ :
- 16 -
excess of, for example, about 0.2 to 1 mole or more.
The progress of ~he reaction can be followed in a
manner which is in itself known, thus, for example, by thin
layer chromatography or high pressure liquid chromatography
or by nuclear magnetic resonance or infrared spectroscopy.
The activated carboxylic acids of the formula XI
can, if desired, be isolated by methods which in themselves
are generally known, such as extraction, precipitation or
fractional crystallization. In many cases, the reaction
solutions obtained from the manufacture of these acids can
also be reacted furtHer direct in the sense of the process
according to the invention, if necessary after removal of
the urea formed as the reaction product.
The activated carboxylic acids can be in two forms,
that of the "activated ester" of the general formula XI a
and that of the "activated amide" of the general formula
XI b, which in solution obviously are in equilibrium.
In the solid state, it is generally the l'activated
ester" of the general formula XI a which is present.
Depending on the substance, however, the "activated ester"
and the "activated amide" can also be isolated separately.
The isolation of the "activated ester" and of the
"activated amide" from the reaction medium and their separa-
tion can be carried out by methods which are in themselves
known and which are based, for example, on the differing
solubilities of the two products or on the differing
polarities or crystallinities of the two products:
~"' ~
5~
. . ~
- 17 -
Thus, for example, the activated ester of ~-syn-
methoximino~ 2-amino-thiazol-4-yl)-acetic acid can be
separated from the corresponding amide by fractlonal
precipitation from dimethylformamide solution by the addi-
s tion of water. Separation by chromatography, such as,for example, on silica gel, can also prove expedient.
If an amine, such as, for example, compounds of the
formula III or IV, is reacted w~th the "activated ester" of
the formula XI a or with the "activated amide" of the
formula XI b, the products obtained in both cases are iden-
-tical.
As a rule, however, neither the isolation of the
activated carboxylic acid nor separation into the "acti~ated
ester" and the "activated amide" is necessary for the pro-
cess according to the invention.
In the present text, therefore, an "activatedcarboxylic acid" is understood as meaning the product, in
the sense of the process according to;the invention, of the
reaction between a carboxylic acid of the formula I and an
: 20 optionally substituted l-hydroxy-ben~otria~ole of the formula
II~ independently of whether the said product is in one o~
the two pure forms - "activated ester" XI a or "activated
amide" XI b - or is a mixture of the two.
Suitable solvents are the solvents or solvent mix-
tures customary in penicillin and cephalosporin chemistry,such as, for example, dimethylformamide, dimethylacetamide,
diethyl ether, di-isopropyl ether, tetrahydro~uran, dioxane,
carbon tetrachloride, chloroform, methylene chloride, aceto-
,~
,
,' '' '
.. . : .
3~
nitrile, ethyl acetate, acetone or butanone.
Preferred solvents are dimethylformamide, tetra-
hydrofuran, methylene chloride, acetoni~rile and ethyl ace-
tate, and also mixtures thereof.
The only factor which must be taken into account is
that the solvent does not enter into reaction with the
reactanks, as is the case, for example, with solvents con-
taining hydroxyl groups, such as, for example, H20.
However, activations have already also successfully
been carried out employing acids which contained lower
alkanols~ such as methanol or ethanol, bonded in the form of
; adducts and/or contained an alcoholic hydroxyl group in the
: molecule.
In this case it is necessary merely to ensure that
no bases are present which result in a reaction, which is
undesired in the sense of the process according to the
invention, between the activated acid and the alcohol (in
this context compare Ikoh et al., Synthesis 1975, 456~.
The reaction temperature ~or the rsaction of the
carboxylic acid with the optionally substituted l-hydroxy-
ben~otr~a~ole is advantageously between about -20 and about
+60C, preferably from -10 to ~40 and especially between 0
and 25 C.
The reaction time is in general between about 10
minutes and about 24 hours and preferably in the range of 1
to 4 hours.
' ~.. ~i
,.~..,
- 19 -
The carbodiimides known from peptide chemistry and
from penicillin and cephalosporin chemistry, especially N,N'-
dicyclohexylcarbodiimide and N,N~-diisopropylcarbodiimide,
are particularly suitable for use as the carbodiimides which
are preferably employed as dehydrating agents.
The urea formed from the carbodiimide during the
activation can be separated off, particularly if it is
intended subsequently to isolate the activated carboxylic
acid. However, it is also possible, without disad~antage,
to dispense with the separation and to carry out the sub-
sequent reaction with the 6-amino-penam derivative or 7-
amino-cephem derivative in the presence of this urea.
The reaction of the activated carboxylic acid with
6-amino-penam or 7-amino-cephem derivatives can be carried
out under variable experimental conditions. Thus, for
example, it is possible to add the activated carboxylic acid
either in bulk or, after isolation thereof, as a solution or
suspension in a suitable solvent to a solution of the 6-
amino-penam or 7-amino-cephem derivative. However, it is
also possible to combine either the solution of the activa-
ted carboxylic acid which has been freed from the urea
formed from the carbodiimide or the solution of the activa-
ted carboxylic acid which still contains this urea with a
solution of the 6-amino-penam or 7-amino-cephem derivative.
Suitable sol~ents for the acylation reaction are,
above all, the solvents or solvent mixtures customary in
penicillin and cephalosporin chemistry.
Thus, t;he reaction can, for example, be carried out
L
j
.~c...~`
.''
3 5
-- 2 0
in amides, such as, preferably, dime~hylformamide or
dimethylacetamide, in ether~, such as, preferably, di-iso-
:
propyl ether, diethyl ether, tetrahydrofuran and dioxane,
in chlorinated hydrocarbons, such as, preferably, carbon
tetrachloride, chloroform and CH Cl , in nitriles, such as,
preferably, acetonitrile, in esters, such as, preferably,
ethyl acetate, or in ketones, such as, pre~erably, acetone
and butanone.
However, it is also poss~ble to use mixtures of
these solvents.
Particularly preferred solvents are dimethylform~
amide, tetrahydrofuran, methylene chloride, acetonitrile and
ethyl acetate, as well as mixtures thereof.
The finding that it is not necessary to take any
special meaSures in order to carry out the reaction under
completely anhydrous conditions was surprising. The
slight water content of the commercially available solvents
does not have an adverse effect on the reaction. The
presence of impurities o~ other solvents containing hydroxyl
groups, such as low-molecular alkanols, Por example methanol
or ethanol, also does not impair the reàction
If the reaction is to proceed well, lt is approp-
riate to employ the 6-amino-penam or 7-amino-cephem deriva-
tives in solution. An addition of organic bases,
especially of tertiary amines, such as, for example, tri-
` methylamine, triethylamine, tri-n-butylamine, N,N-dimethyl-
aniline or N-methylmorpholine, has proved suitable for
effecting dissolution of the derivatives in the above-
. .
.'', ~.
, . ~
,~ .
6~58
21 -
mentioned solvents and solvent mixtures. The bases are
generally added in at least stoichiometric amounts. An
"
excess of base of, for example, about 0.1 to about 2.0 and
especially 0.2 to 0.~ mole can be advantageous for the
: . .
reaction.
Esters Or 6-amino-penam and 7-amino-cephem acids can
also be employed in the reaction. Easily detachable
esters are preferably used, such as, for example, the benzyl,
methyl, pi~aloyloxymethyl, benzhydryl, 2,2,2_trichloroethyl
or tert.-butyl esters or a tri-alkylsilyl ester, especially
the trimethylsilyl ester. The advantage, above all of
the last-mentioned trialkylsilyl esters, such as, for
example, of the trimethylsilyl ester, lies in the fact that
it is detached easily, detaching frequently already taking
place during working up of the rsaction product.
In order to obtain high yields, the acti~ated car-
- boxylic acids are employed in at least stoichiometric
amounts. An excess of about 5 to 25% can prove approp-
riate.
The time taken for the reaction between the activa-
ted carboxylic acid and the 6-amino-penam or 7-amino-cephem
derivative is in general between about ~ hour and 25 hours,
preferably between 2 and 16 hours. a
The reaction can be carried out in a wide tempera-
ture range, for example between about -20 and +60C, but
appropriately a temperature of 40C should not be exceeded.
The reaction temperature is preferably between 0 and ~25C.
',
.
- `~ 7
s
''':
. .
, . ~ ~ ` ,
~1~635~
- 22 -
The compounds of th~ formulae V or VI can be iso-
lated from the reaction medium by method~ which are in them-
selves known and which depend on the solubilities of the
resulting compounds.
; 5 Thus, for example, the reaction products can be taken
up in water9 after evaporating off the organic solvent if
necessary, and, after appropriate purification operations,
such as, for example, filtering or centrifuging, precipitated
-~ by adding acids. In order to remove the hydroxybenzo-
triazole formed during the reaction, the product is approp-
riately stirred in a suitable solvent, such as, ~or example,
~ methanol, ethanol, propanol, butanol or acetone. I
; If desired, the hydroxybenzotriazole can also be
extracted at a pH between about 5.O and 3.5 from the aqueous
solution of the reaction product in a water-immiscible
organic solvent, for example ethyl acetate or methyl iso-
butyl ketone. The hydroxybenzotriazole employed in the
reaction is recovered by evaporating off the solvent.
Subsequent further acidification precipitates the
products of the formula Y or VI in the form of their free
acids.
They can be obtained by filtration,or, if desired,
extracted in water-immiscible organic solvents, such as, for
example, ethyl acetate or methyl isobutyl ketone.
The resulting products of the formula V or VI can be
obtained from the extracts, for example by evaporating off
the solvent and grinding with ether.
.
:
' ~ ' '
.. .. . . . .
3S~
2 3
Preparative separation by chromatography can also be
expedient.
Esters which are obtained from the reaction accord-
ing to the lnvention and in which the ester group has
protective group for the carboxyl group, such as, for
- example, p-methoxybenzyl, p-nitrobenzyl or tert.-butyl, can
be separated off from optionally substituted l-hydroxy-benzo-
triazole by conventional experilmental methods which depend
on the solubility, the crystallinity or the extractability
of the esters. If desired, they can then be converted to
the free carboxylic acids or to salts thereof in a manner
known from the literature.
; The process according to the invention is thus dis-
~inguished by the fact that it leads, under very mild reac-
tion conditions, to extremely reactive carboxylic acid
derivatives, and it is thus possible to convert both highly
sensitive carboxylic acids and also carboxylic acids which
- are difficult to activate because of steric or electronic
effects into highly reactive acylating reagents.
Thus, surprisingly, with some of the active carboxylic
acid derivatives manufactured by the process according to
the invention, for example with the reaction product of 1-
hydroxy-benzotriazoleand ~-(2-aminothiazol-~-yl)-~-syn-
methoximino-acetic acid, the transfer of the acyl component
to 6-amino-penam or 7-amino-cephem derivatives proceeds
successfully; this transfer does not take place whèn the
;.
carboxylic acid which has been activated with the N-hydroxy-
succinimide customary in cephalosporin chemistry and is in
~; the form of the N-acyloxysuccinimide, for example N-[~-(2-
, .............................. . .
,' ."`'1
. ~,.
. ~:
.
. .
: . ,
~63~
_ 24 -
amino-thiaæol-4-yl)~ syn-methoximino-acetoxy]-succinimide,
is used, even when more vigorous reaction condltions are
employed, such as a prolonged reaction time and ele~ated
temperature.
The finding tha~, when the activation is carried out
in the sense of the process according to the invention, an
amino protective group is not required in the case of those
amino-substituted carboxylic acids in which the amino group
has a PKS value of less than 6.o was also surprising: khe
lo abovementioned negative aspects of the use of a protective
group, such as additional synthesis steps, additional stress
on the molecule, the reduction in yield, the longer time
expended, the higher expenditure on purification and the
- reactivation of the protective group reagent are therefore
eliminated completely with the process according to the
invention.
; Hydroxyl groups are also surprisingly not attacked by
the carboxylic acids activated with optionally substituted
l-hydroxybenzotriazoles, although according to Mc Carthy et
al., J. Chem. Soc. Perkin II 1977, 224 the reactivity of the
~aid acids can be compared with that of anhydrides.
This also applies in the case of alcoholic hydroxyl
,~.
groups: It is, therefore, surprisingly also possible
successfully to activate, in the sense of the process
according to the invention, those carboxylic acids which con-
tain alkanols bonded in an adduct-type manner in the crystal
or which are otherwise contaminated with these alkanols.
French Patent Specification 7,601,~34 describes a
process in which ~-[2-tritylamino-thiazol-4-yl]-~-syn-
methoximino-acetic acid is converted to its symmetrical
.
~,~. J
;,~ ~.. .. ..
.' .: : , : ' .
~: , ~ . : - -
.
: ' - ' . . -: ' :
: :
:
. '
-: . :
-6;3~3
- 25 _
anhydride and coupled with 7-amlno-cephalosporanic acid
utilizing theoretically only at.most half of the carboxylic
acid employed.
Compared with this process, the process according to
the invention is distinguished, on the one hand, by the fact
that, as stated above, an amino protective group is not
required for the acid and, on the other hand; by the fact
that the unavoidable loss of ha:Lf of the carboxylic acid is
avoided.
The activated derivatives XI a and/or XI b obtained
from the reaction of optionally substituted l-hydroxybenzo-
triazoles of the formula II w~th a carboxylic acid of the
: formula I are very valuable for the syntheses of penicillins
. and cephalosporins because, as stated in de~ail above, they
are formed, inter alia, as highly reactive compounds under
very mild conditions, because their manufacture, handling
and reaction is extremely problem-free, because they react
with penicillins and cephalosporins in the des~red manner
under very mild conditlons and because they render a protec-
tive group superfluous in the case Or weakly basic aminogroups and in the case of hydroxyl groups.
The following Examples illustrate the invention,
without, however, restricting it thereto.
Example 1:
7~ s~n-Methoximino-~-(2-amino-thiazol-4-yl)-acetamido]__
cephalosporanic acid
Variant A
: lst Sta~e:
. ~
. .
" , ,. - : ' '
, . , - .
:
'. ' ' :
26
60.3 g of ~-(2-amino-thiazol-4-yl)-a~syn-methox-
imino-acetic acid are dl~solved in 540 ml of DMF, and 40.5 K
of hydroxybenzotriazole dis~olved in 240 ml of DMF are added.
61.~9 g of dicyclohexylcarbodiimide are added,
whilst stirring. After 2 hours, the dicyclohexylurea
which has precipitated out is filtered off and the filter
residue is washed with 20 ml of DMF. The filtrate is
cooled to 10C and 500 ml of H20 are added dropwise, whilst
stirring. The precipitate whic~h forms is filtered off,
washed with H20 and dried over P205 in vacuo:
This gives 77.1 g of a mixture of l-[~-syn-methox-
imino-~-(2-amino-thia~ol-~-yl)-acetoxy]-benzotriazole and
l-[~-syn-methoximino-~-(2-amino-thiazol-~-yl]-acetyl)-benzo-
triazole 3-oxide with a melting point of 145 - 147.
2nd Sta~e:
6~.o~ g of 7-aminoceph~losporanic acid are stirred
- up in 600 ml of methylene chlor~de and 75.75 g of triethyl-
amine are added. The mixture is stirred until a clear
solution is obtained and 79.5~ g of the mixture obtained in
stage 1, suspended in 600 ml of tetrahydrofuran, are added
in portions. The solution ls stirred overnight, after
which the acti~e ester has been converted.
The reaction solution is evapora~ed and the residue
is taken up in a mixture of 350 ml of formic acid (100%~ and
100 ml of H20. This solution is added slowly dropwise to
a solution of ~75 g of ammonium sulfate in 1,750 ml of H 0,
whilst stirring~
.
.'~
:
. . ~.
. . ' ' '
.
: `, ' ' ~
~ 6~S~3
_ 27 -
After stirring for 1 hour, the light granular preci-
pitate is filtered off, washed with H 0, dried and stirred in
500 ml of ethanol for ~ hour at 50 C and for 1 hour at room
temp~rature~ It is filtered off and washed a furkher twice
with, in each case, 50 ml of ethanol. After drying over
P2s, 7~- 5 g of the title compound result.
IR (KBr~: 1770 cm~~ lactam)
NMR (DMSO-d6~: S= 2.05 ppm (s, 3H, OCOCH3
= 3.~5 ppm (s) 3H, OCH ~
~ = 6.75 ppm (s, lH, thiazole-H)
Variant B:
1.0 g of ~-(2-amino-thiazol-4-yl)-a-syn-methoximino-
acetic acid are suspended in 25 ml of tetrahydrofuran and
0.676 g of hydroxybenzotriazole and then 1003 g of dicyclo-
hexylcarbodiimlde are added. The mixture is stirred for2 hours, the dicyclohexylurea formed is filtered off and a
solution of 1.36 g of 7-aminocephalosporanic acid and 1.5 g
of triethylamine in 25 ml of methylene chloride is added
dropwise at room temperature to the solution obtained after
filtering. The mixture is stirred for 16 hours at room
temperature, undissolved material is filtered o~f and the
filtrate is eYaporated. The residue is taken up in 25 ml
of water and the solution is three times extracted by shak-
ing with, in each case, 10 ml of ethyl acetate, at pH ~.5.
The aqueous phase is acidified to pH 2.5 with 2 N hydro-
chloric acid at O C. The acid solution is filtered and
the product is dried over P205 in vacuo and 1.07 g of 7-[~-
,
, ~ ~r.r,
~, ~~
~, ~ ` ' , ' `' ' .`
,
,
.
s~
- 2~ _
syn-methoximino~ ~(2-aminothiazo~ -yl)-acetam~do]-cepha
sporanic acid are obtained~ The NMR spectrum of this
product (recorded in DMSO_d6) is identical to that of the
compound prepared according to Example 1.
-! 5 Variant C
.
Sta~e 1
l-[~-syn-Methoximino-~-(2-amino-thia ~ tXYl-
benzotriazole and 3-~-syn-methoximino-~-(2-amino-thia ol-4-
i yl)-acetyl]-benzotriazole l-oxide
!
5,~ g of l-hydroxybenzotriazole, dissolved in ~0 ml
of dimethylformamide, and then ~.9 g Or solid N,N-dicyclo-
hexylcarbodiimide were added, at O , to ~.6 g of ~-syn-
methoximino-~-(2-amino-thiazol-4-yl)-acetic acid, dissolved
in ~0 ml o~ dimethylformamide. After stirring for 5 hours
in an ice bath, the dicyclohexylurea formed was filtered off.
60 ml of H20 were added droFwise, at 0C, to the
mother liquor. After 10 minutes, 7.14 g of l-[~-syn-
- methoximino-~-(2~amino-thiazol-4-yl)-acetoxy]-benzotriazole
were isolated.
Melting point: 153 - 155 (decomposition)
Rf: 0.5~ (chloroform/acetone = 2/3)
IR (~Br): 1~05 cm (ester)
NMR (DMSO-d6): ~ = 4.07 ppm (s, 3H, OCH )
~ = 7.23 ppm (s, lH, thiazole-H)
~ = 7.0 - ~.5 ppm (m, 7H, NH , benzo-H,
thiazole-H)
; After 40 minutes at O C, 3.9~ g of 3-[~-syn-methox-
imino-~-(2-amino-thiazol-~-yl¦-acetyl]-benzotriazole l-oxide
x 1~ H20 crystallized out from the mother liquor.
~ ...... .... .s, i~
.
` `' . , ` . : :
.
. . ,
, ~
.
635~
,~
- 29 _
3 Melting point: 151 - 1S3 (decomposition)
¦ Mixed melting point of the two products : 1~ - 149 (decom-
positionJ
Rf: 0.52 (chloroform/acetone = 2/3)
IR tXBr): 1725 cm (amide)
NMR (DMS0-d~ = 3.~7 ppm (s, 3H, OCH3)
= 7.15 ppm (s, lH, thiazole-H)
, ~ = 7.22 ppm (s, 2H, NH2)
~= 7.5 ~ ~.55 ppm (m, 4H, benzo-H)
~ = 3.25 ppm (s, 3H, H20) ~
, Sta~e ? a:
1~593 g of 1-[~-syn-methoximino-~-(2-amino-thiazol-
~-yl)-acetoxy]-benzotriazole, suspended in 20 ml of tetra-
hydrofuran, are added to a solution, which is stirred at
room temperature, of 1.365 g-of 7-amino-cephalosporanlc acid
and 1.515 g of triethylamine in 20 ml of methylene chloride.
After a short time, a clear solution forms and th~s is
stirred overnight at room temperature. After filtering,
~ the reaction solution is evaporated and the residue is taken
`~ 20 up in a-mixture of 7 ml of formic acid (100%) and 2 ml of
H 0.
- The solution is added slowly dropwise to a solution
of 17.5 g Or (NH4)2S0 in 35 ml of H20. The precipitate
- is filtered off and stirred in 30 ml of ethanol for ~ hour at
55 and for 1 hour at room temperature. The product
is filtered off and stirred in 30 ml of ethanol for ~ hour at
55 and for 1 hour at room temperature. The product is
filtered off and dried over P20s in vacuo. This gives
7-~-[~-syn-methoximino-~-t2-amino-thiazol-4-yl)-acetamido]-
,
.
:
.
58
-- 30
cephalosporanic acid, which according to thin layer chromato-
graphy and IR and NMR spectroscopy is identical to the pro-
duct obtained in Variant A.
Sta~e 2_b:
If 1.593 g of 3-[~-syn-methoximino-~-(2-amino-
thiazol-4-yl)-acetyl~-benzotriazole l-oxide are used in
stage 2 a of variant C, this likewise gives 7-~-[~-syn
methoximino-a-(2-amino-thiazol-4-yl)-acetamidoJ-cephalo-
sporanic acid, which according to thin layer chromatography
and IR and NMR spectroscopy is identical to the product
obtained from stage 2 a of variant C.
1 Example 2:
¦ 7-B-[~-syn-Ethoximino-~-(?-amino-thiazol-4-yl)-acetamido]
cephalosporanic acid
In accordance with Example lB, using 1.07 g of ~-(2-
amino-thiazol-4-yl)-~-syn-ethoximino-acetic acid. 0.9~ g
of the title compound is isolated.
Melting point: 125 - 135 (decomposition)
- IR (KBr): 1770 cm (~-lactam)
1720 cm~l (acetate)
NMR (DMS0-d6) ~ = 2.0 ppm (s, 3H, OCOCH3)
= 1.27 ppm (t, 3H, CCH3)
= 4.13 ppm (q, 2H, OCH2-~
~ = 6.~ ppm ~s, lH, thiazole-H)
E_ample 3:
7-~-[~-s~n-Propoximino-~-~2-amino-thiazol-4=~1)-acetamido]-
ce~halosporanic acid
In accordance with Example lB, using 1.15 g of ~-(2-
amino-thiazol-4-yl)-~-syn-propoximino-acetic acid. 0.~ g
~-,the title compound is isolated.
~:''
. '
.
;8
.,~.~
31 -
Melting polnt = 120 - 130 (decomposition)
IR (KBr): 1775 cm~l (~-lactam)
1720 cm 1 (acetate)
NMR (DMSO-d6): ~ = 1.23 ppm (t, 3H, CH3~
~ = 2.05 ppm (c;, 3H, COCH3)
= 4.00 ppm (t, 2H, O-CH2)
~= 6.70 ppm (s, lH, thiazole-H)
Example 4:
7-~-[ a-syn-I sopropoximino- a_ (2-amino-thiazol~ 1)-acet-
~o amido~-cephalo~poranic acid_
; In accordance with Example lB, using 1.15 g of a-(2-
amino-thiazol-~-yl)-~syn-isopropoximino-acekic acid.
1.03 g of the title compound are isolated.
Melting point: lgO - 190 tdecomposition)
IR (KBr): 1770 cm~l (~-lactam)
1725 cm~l ~acetate)
NMR (DMSO-d6): ~ = 1.2 ppm (d, 6H, CH(CH3)2)
- ~ = 2.0 ppm (s, 3H, CO ~ )
= 6-75 ppm (s, lH, thiazole-H)
Example 5:
7-~-~ a - sYn -n - But oximin o-a - ( 2 -am~ _ ~ e =
cephalosporanic acid
In accordance with Example lB, using 1.22 g Or a-(2~
amino-thiazol-~-yl)-a-syn-n-butoximino-acetic acid.
0.~2 g of the title compound is isolated.
Melting point: 250 (decompositi OR )
IR (KBr). 1770 cm~l (~-lactam)
1715 cm~l (acetate)
NMR (DMSO-d6): ~ = 007 - 1.~ ppm (m, 7H, CH2 - CH2 - I )
~ = 2.05 ppm Is, 3H, COCH~)
S = 6.75 ppm (s, lH, thiazole-H)
.__ .. _ .... .. ... . . . ... .. ~ ,,. __ _ .. _. .. . .. . . . ~
- 32 _
I Exam~e 6:
7-~ -s~n-Methoxim~no-~-(2-amino-thiazol-4-Yl)-acetamidol-
.
3-(2_amino~ -thiadiazol_~-yl_thiomethyl)-~_cephem-~-
_rboxylic acid
3.34 g of the mixture obtained in stage 1 of Example
lA are added to a solution of 3.55 g of 7-amino-3-(2-amino-
1,3,~-thiadiazol-5-yl-thiomethyl)-3-cephem-~-carboxylic acid
and 4.0 ml of triethylamine in 40 ml of dry methylene
chloride. After adding 30 ml of tetrahydrofuran, the
- 10 mixture is stirred overnight at room temperature. It is
e~aporated, the residue is taken up in 60 ml of H20, the
undissolved material is filtered off and the filtrate is
covered with a layer of ethyl acetate and acidified to pH
4.5 with 1 n HCl, with ice-cooling. The phases are
separated, a further extraction with ethyl acetate is carried
~- out at pH 4.5 and the aqueous phase is acidified to pH 2.5
in an ice bath.
After filtering off and drying over P205, 3.1 g of
the title compound are obtained.
Melting point: 190 - 200 (decomposition)
IR (KBr): 1760 cm (~-lactam)
NMR (DMSO-d6): ~ = 3.~ ppm (s, 3H, OCH3)
S= 5.7 ppm (q, lH, 7-CH)
S= 6.73 ppm (s, lH, thiazole H)
~= 7.4 ppm (broad signal, 2H, NH2)
Example 7:
7-~-[~-syn-Met;hoximino-~-(2-allylamino-thiazol-~ acet-
amido]-ceE~halosporanic acid
;
' ' ' : ' '
. ,., , :
.
- 33 -
1.6~ g (7 mmoles) of ~-syn-methoximino-~-(2-allyl-
! amino-thiazol-~-yl)-acetic acid are dissolved in 50 ml of
~ anhydrous tetrahydrofuran and O.95 g (7 mmoles) of hydroxy-
.,
benzotriazole is added. The mix~ure is warmed to 45C,
1.45 g (7 mmoles) of dicyclohexylcarbodiimide are added and
~-! the resulting mixture is stirred for 5 hours at this tem-
perature. After cooling, the dicyclohexylurea which has
.
precipitated out is filtered off. The solution of the
activated ester which is thus obtained is added dropwise at
room temperature to a solution of 1.91 g (7 ~oles) of 7-
- aminocephalosporanic acid and 3.36 ml of triethylamine in
30 ml of anhydrous methylene chloride. The mixture is
stirred overnight at room temperature, the undissolved
material is filtered off and the filtrate is evaporated to
dryness. The residue is dissolved in water and the solu-
tion is washed several times with ethyl acetate at pH 5~
` The pH is then adjusted to 2.9 with 1 N hydrochloric acid.
The product precipitates out and is filtered off, washed
well with water and dried over potassium hydroxide. This
gives 1.75 g of 7-~-[~-syn-methoximino-~-(2-allylamino-
thiazol-4-yl)-acetamido]-cephalosporanic acid~
` Melting point: 155 - 170 (decomposition~
IR (KBr): 1775 cm~l (~-lactam)
; 1730 cm (OCOCH3)
NMR (DMSO-d6): ~ = 2.05 ppm (s, 3H, OCO ~ )
= 3.~ ppm (s, 3H, OCH3)
~= b.~ ppm (s, lH, thiazole-H)
~'
., .
~ . . . ~ . .
., , -'' . ~
6;~8
- 34 -
¦ 7-~-[a-s~n-Methoximin~ 2_chloroacetamino thlazo1-~-yl)-
acetamido]-cephalosp ranic acid
~ . .
In accordance with Example 7, using 1.9~ g of a(2-
chloroacetylamino-thiazol-4-yl)-a-syn-methoximino-acetic acid.
2.4 g o~ the title compound are obtained.
- Melting point: 200 (decomposition)
IR (KBr): 1770 cm~l (~-lactam)
1725 cm (acetate)
NMR (DMSO-d6): ~ = 2.05 ppm (s, 3H, COCH3)
= 3.9 ppm (s, 3H, OCH3)
S = 4.~ ppm (s, 2H, COCH2 Cl)
~= 7.45 ppm (s, lH, thiazole H)
Example 9:
.' 15 7-~-[a-s~n-Methoximino-(2-(5-amino-1,3,4-thiadiazol-2_yl=
mercapto-acetamido)-thiazol-4-~l)-acetamido]-cephalosp-oranic
acid
' In accordance with ~xample 7, using 2.6 g of a-syn-
~ methoximino-[2-(5-amino-1,3,4-thiadiazol-2-yl-mercaptoacet-
- 2~ amido)-thiazol-4-yl]-acetic acid. 2.3 g of the title
compound are obtained.
Melting point: 250 (decomposition)
IR (KBr): 1770 cm (~-lactam)
NMR (DMSO-d6): ~ = 2.05 ppm (s~ 3N, COCH3)
~= 3.95 ppm (s, 3H, OCH3)
= 7.4 ppm (s, lH, thiazole-H)
3 = 7.2 ppm (broad 9i gnal, 2H, NH2)
Example 10:
7-~-ra-syn--Methoxi-m-i-n-o--(2--l5---m-ethy~ 4-thiadiazo-l--2-yl-
mercaptoacetamido)-thiazol-4-~1)-.acetamidol-cephalosporanic
~acid
~" ~ .
- . . ~ . .
.
. . .
., ' .
:
. . . .
3S~
.~
- 35
In accordance with Example 7, using 2.6 g of ~-syn-
methoximino-[2-(5-methyl-1~3,4-thiadiazol-2-yl-mercapto-
acetamido)-thiazol-4-yl]-acetic acid. 2.1 g of the t1tle
compound are obtained.
S Melting point: l90 ~ 200 (decomposition)
IR IKBr~: 1775 cm l ( ~-lactam)
NMR (DMSO-d6): ~ = 2.05 ppm (s, 3H, COCH3)
S= 2.7 ppm ~s, 3H, CH3)
~ = 3.95 ppm (s, 3H, OCH3)
~ = 7.3 ppm (s, lH, thiazole-H)
Example ll:
7-~i-[~-s~n-Methoximino-~-(2-amino-5-bromo-thiazol-~-yl)-acet-
amido~-cephalo ~_anic acid
750 mg of a-s~n-methoximino-~-(2-amino-5-bromo-
thiazol-4-yl)-acetic acid, containing ~ mole of ethanol, are
dissolved in 7 ml of DMF, 30 ml of carbon tetrachloride are
added and the mixture is e~aporated to 7 ml. 0.373 g of
hydroxybenzotriazole in 5 ml of DMF and then 0.5 g of di-
cyclohexylcarbodiimide are added at room temperature, whilst
stirring.
After stirring for 2 hours at room temperature, a
solution of 6~0 mg of 7-aminocephalosporanic acid and 750 mg
of triethylamine in 25 ml of methylene chloride is added to
the mixture and the resulting mixture is stirred for a
further 16 hours.
The dicyclohexylurea is filtered off, the methylene
chloride is evaporated off in vacuo and the residual solu-
tion is diluted with water to 70 mlO The pH ~s ad~usted
~i~
'`'`'```' .
~` - 36 _
~ to 7.5 with saturated NaHC03 solution and the result$ng solu-
i tion is extracted 3 times with 20 ml bf ethyl acetate and
filtered again and the pH is ad~usted to 2.0 with 2 N HCl at
~ 0C. After stirring for one hour in an ice bath7 750 mg
1 5 of 7-[~-syn-methoximino~ 2_amino-5-bromo-thiazol-~-ylJ-
! acetamido]-cephalosporanic acid can be filtered off.
Melting point = 140 - 150 (delomposition)
IR ~KBr): 1770 cm ( ~-lactam)
1720 cm 1 (acetate)
NMR: S = 2.0 ppm (s, 3H, OC0 ~ )
. I .
l ~ = 3.9 ppm 23~ Hz (s, 3H, =N - 0 ~ )
. ~ = 9.5 ppm (d, lH, - NH - C0 _ )
Example 12:
, 7- B -J~-syn-Methoximino-~-(2-amino-5-chloro-thiazol-~-yl)
15 acetamido]-cephalosporanic acid
1.42 g of ~-(2-amino-5-chloro-thiazol-~-yl3--syn-
methoximino-acetic acid, containing 1 mole of methanol, were
dlssol~ed in 20 ml of tetrahydrofuran, 30 ml of carbon tetra-
chloride were added and the mixture was evaporated to dry-
ness. The residue is dissolved in ? ml of.~tetrahydro-
furan and after adding 670 mg of hydroxybenzotriazole the
:-~ mixture is warmed to 50~. 1.03 g of dicyclohexylcarbo-
diimide are added, whilst stirring, and about 1 minute later
dicyclohexylurea starts to precipitate out.
. 25 A~ter stirring for ~ hours, the urea which has
. formed is filtered off and the mother liquor is added drop-
I wise to 1.36 g of 7-aminocephalosporanic acid and 2.0 ml of
' ' .
.
'
'
35 53
3 7
triethylamine, dissolved in 20 ml of methylene chloride.
The mixture is left to stand overnight at room temperature
and is evaporated to dryness, the residue is taken up in
30 ml of H20 and the solution is covered with a layer of
ethyl acetate and acidified to pH 4.5 with 2 N HCl, with
ice-cooling. The phases are separated, the extraction
with ethyl acetate i5 repeated and the aqueous phase is
acidified to pH 2.2 in an ice bath. After filtering off
and drying the product over P205, 0.9g g of 7-[~ syn-methox-
imino-~-(2-amino-~-chloro_thiazol_~-yl)_acetamido]_cephalo_
sporanic acid is obtained.
Melting point = 135 - 145 (decomposition)
IR ~KBr): 1770 cm (~-lactam)
1720 cm~l (acetate band)
NMR (DMSO-d6): S = 2.0 ppm (s, 3H, OCOCH3)
= 3.~5 ppm [231 Hz] (s, 3H, = NOCH3)
~ = 9.5 ppm (d~ lH, NHCO)
Example 13:
7-~ -syn-Methoximino-~-~2-amino-5-chloro-thiazol-4-yl)-
acetamido]-cephalosPoranic acid
1.42 g of ~-(2-amino-5-chloro-thiazol-4-yl)-~-syn-
methoximino-acetic acid~ containing 1 mole of methanol, are
dissolved in 20 ml of tetrahydrofuran and, after adding
670 mg of hydroxybenzotriazole, 1.03 g of dicyclohexylcarbo-
diimide are added, whilst stirring. Dicyclohexylurea
starts to precipitate out after about 3 minutes.
The further react~on and working up are carried out
' ' .
.
6~
. .
- 3~ -
as described in Example 12. This gi~es 1.2 g of the title
¦ compound, the physical constants of which, according to thin
layer chromatography and NMR and IR spectroscopy, are iden-
tical to those of the product obtained according to Example
12.
Example 14:
?~ yn-Methoximino-~-(2-amino-5-thioc~anato-thiazol-4-
yl)-acetamidol-cephalosporanic acid
645 mg of ~-(2_amino_5 thiocyanato-thiazol-4-yl)-
~-syn-methoximino-acetic acid are suspended in a mixture of
2 ml Or dimethylformamide and 15 ml of methylene chloride.
350 mg of hydroxybenzotriazole are added, the mixture is
heated to the reflux temperature and 500 mg of dicyclohexyl-
carbodiimide are now added. The reaction mixture is
stirred at room temperature for 1~ hours, the urea is
separated off by filtration and a solution of 6~o mg of 7-
aminocephalosporanlc acid and l.O g of triethylamine in
20 ml of methylene chloride is`added dropwise to the filtrate.
The mixture is stirred for 5 hours at room tempera-
ture, 20 ml of H20 are added, the phases are separated and
the organic layer is again extracted with 10 ml of H20.
The pH of the comblned aqueous phases is adjusted to 5 and
the solution is three times extracted by shaking with ethyl
acetate and then acidified to pH 2.3 with 2 N HCl. The
.
solution is extracted 3 times with ethyl acetate, the
organic phases are combined, a layer of 20 ml Or H20 is
introduced below these combined phases and the pH is ad~us-
ted to 7 with saturated NaHC0 solution.
~' .
. ' ,
~6~ ;3
~,
- 39 -
The aqueous phase is separated off and freeze-dried.
This gives 700 mg of 7-[~-syn-methoximlno-~-(2-amino-5-thio-
cyanato-thiazol-~-yl)-acetamido]-cephalosporanic acid.
Melting point = 210
IR (XBr): 1760 cm~l (~-lactam band)
NMR (DMS0-d6): ~ = 2.0 ppm (s, 3H, OCOCH3)
= 3.9 ppm [236 Hz] (s, 3HI = N0 ~ )
~ = 9.5 ppm (d, lH, -NHC0-)
Example 15:
10 7-~-[~-syn-M,ethoximino-~-~2-hydroxy-thiazol-4-yl~-acetamido]-
cephalosE~
1.01 g (5 mmoles) of ~-syn-methoximino-a-(2-hydr
thiazol-~-yl~-acetic acid are dissolved in 30 ml of tetra-
hydrofuran. 0.67~ g (5 mmoles) of hydroxybenzotriazole are
added to this solution, the resulting mixture is warmed to
about 40 C and 1.03 g (5 mmoles) of dicyclohexylcarbodiimide
are added. The mixture is stirred for 4 hours, the urea
which has formed is filtered orf and the clear yellow solu-
tion is added dropwise to 1.36 g (5 mmoles) of 7-amino-
cephalosporanic acid and 2.4 ml of triethylamine dissolvedin 25 ml of methylene chloride. The mixture is stirred
for 13 hours at room temperature, the undissolved material is
filtered off and the filtrate is evaporated. The residue
is taken up in water and washed at pH 5 with ethyl acetate.
The pH value is adjusted to 3 with 1 N hydrochloric acid and
the product is extracted with ethyl acetate. After
evaporating off the solvent, 1.22 g of crude product, which
still contains hydrox~zotriazole3 are obtained. For
';I f.
:lj,, ~j~ j
. .
. ' '
'
" ' ' ' '
o -
purification, the product is dissol~ed in 30 ml of acetone,
the undissolved mater~al is filtered of r and the filtrate is
concentrated to half its volume. This concentrate is
left to ~tand for several hours at ice-bath temperature and
the product which has crystall:ized out is then filtered orf
This gives o.6 g of 7-~-[~-syn-methoximino-a-(2-hydroxy-
thiazol-4-yl~-acetamido]-cephalosporanic acid.
Melting point = 15~ - 160 (decomposition~
IR (KBr): 1775 cm (~-lactam)
1725 cm (OCOCH3)
NMR (DMSO-d6): ~ - 2.05 ppm (s, 3H, OCO ~ )
; ~ - 3.9 ppm (s, 3H, OCH3)
= 6.53 ppm (s, lH, thiazole-H)
Example 16:
`:
~ _ ]_
cephalosporanic acid
Sta~e 1:
27.1 g of a-syn-ethoximino-a-(2-amino-thiazol-4-yl)-
acetic acid were dissolved in 145 ml~of DMF and, successively,
:.
12.1 g of l-hydroxy-benzotriazole and 1~.~ g of dicyclohexyl-
carbodiimide were added at room temperature.
After 2 hours, the urea was filtered off.
H20 was added to the filtrate, with ice-cooling and
; whilst stirring, until no further precipitate formed.
The precipitate was filtered off and dried. This gave
19.~ g of l_[a~ n_ethoximino-a-(2-amino-thiazol_4-yl)~
acetoxy]-benzotriazole. Melting point~ 120
` (decomposition)
Sta~e 2:
, ~ '
'.': 5~'l
:.
. . . .
.. . .
, . . ~
j35~
1~1
i 2.72 g of 7-aminocephalosporanic acid were made to
dissolve in 40 ml of methylene chloride with 3.5 ml of tri-
ethylamine, and 3 g of the ester obtained in Stage 1 were
added to the solution. A clear solution had formed after
10 minutes. This solution was stirred for a further 5-~
hours. After the dropwise addition of 25 ml of 1 N HCl,
the precipitate was filtered off and ground in alcohol.
After filtering off and dr~ing, it was possible to collect
1.9 g of the title compound, which according to th~n layer
chromatography and IR and NMR spectroscopy was identical to
the product obtained in Example 2.
Example 17:
7~ syn-Methoximino-~-(2-amino-5-c~loro-thiazol-4-yl)-
acetamido]-deacetoxyceE~halosporanic acid
26~ ~g of ~-syn-methoximino-~-(2-amino-5-chloro-
thiazol-4-yl)-acetic acid, containing 1 mole of methanol,
were dissolved in 10 ml of THF, and 135 mg of l-hydroxy-
benzotriazole and 216 mg of dicyclohexylurea were added.
After 1 hour the urea was filtered off. A solution of
214 mg of 7-amino-deacetoxycephalosporanic acid and 303 mg
of triethylamine in 10 ml of acetone~2 ml of H20 was added
to the mother liquor and the resulting mixture was stirred
overnight at room temperature. 30 ml of ethyl acetate
were added to the reaction solution and the solu~ion was
~ 25 acidified to pH 2.0, whilst stirring. The residue which
- remained after concentrating the ethyl acetate phase was
dissolved in 2.5 ml of ~0% formic acid and this solution was
.
. . . ' ' ~ :
.
' ~ . '
- 42 _
added dropwise to a solution of 5.25 g of ammonium sulfate
in 11.25 ml of H20, whilst stirring vigorously. It was
possible in this way to isolate 120 mg Or the title compound
in the form of the formate.
- 5 Melting point: ~ 200 (decomposition)
IR (KBr): 1760 cm 1 (~-lactam)
NM~ (DMSO_d6): ~ = 1.9~ ppm ~s, 3H, CH3)
= 3.~3 ppm [230 Hz] (S, 3H, OCH3, syn)
- ~= 9.43 ppm (d, lH, NHCO)
Exam~le lB:
7~ s~yn-Ethox-imino--a-(2-amino-5-chloro-thiazo~ acet
amido?-cephalosp-o-ranic acid
; In accordance with Example 12, using 1.25 g of a-syn-
ethoximino-a-(2-amino-5-chloro-thiazol-4-yl)-acetic acid.
1.45 g of the title compound are obtained.
Melting point: 140 - 150 (decomposition)
` IR (KBr): 1775 cm~l t~-lactam)
1725 cm (O-acetate)
NMR (DMSO-d6)- ~ = 1.25 ppm (t, 3H, OCH2 CH3)
. ~ 20 S= 2.0 ppm (s, 3H, OCOCH3)
~ = 4.1 ppm t251 Hz] (q, 2H, ~ CH3
; ~ = 9.7 ppm (d, lH, NHCO)
Example 19:
7-~-(a-syn-Ethoximino-~-(2-amino-s-chloro-thiazol-~-yl)
acetamidol-deacetoxy-cephalosporanic acid
1.~7 g of a-syn-ethoximino-~-(2_amino-5-chloro-
thiazol-4-yl)-acetic acid together with 1.35 g of l-hydroxy-
- benzotriazole were dissolved in 50 ml of THF at 50, and
2.06 g Or dicyclohexylGarbodiimide were added. After 1
hourJ the precipitate was filtered off and a solution of -
. - .
:
' : ' ' ,.
'
- ~3 -
2.14 g of 7~amino-deacetoxy-cephalosporanic acid and 3 g of
triethylamine in 50 ml of THF!10 ml of H O was added to the
filtrate. The mixture was stirred overnight. After
diluting with 60 ml of water, the organic solvents were
removed in vacuo. The residue was shaksn with twice
30 ml of ethyl acetate and the aqueous phase was then care-
fully acidified to pH 4.5. After extracting five tlmes
with, in each case, 30 ml of ethyl acetate, the solution was
further acidified to pH 2.5 and the product was filtered off
and dried.
This gave 1.1 g of the title compound.
Melting point: 130 (decomposition)
IR (KBr): 1775 cm-l ( ~-lactam)
NMR (DMSO-d6): ~ = 1.3 ppm ~tr. 3H, CH2CH3)
~ = 2.0 ppm (s, 3H, CH3)
= 3.3 ppm (broad, 2H, C-2-H)
3 = 4.10 ppm (q, 2H, N-O-CH2CH3, syn)
= 5.10 ppm (d, lH, C-6-H)
~ = 5.70 ppm (q, lH, C-7_H~
~ = 7.35 ppm (broad, 2H, NH2)
= 9.5 ppm (d, lH, CONH)
; Example 20:
7-[~-syn-Ethoxycarbonyl-methoximino~ 2-amino-5_chloro_
thiazol-4-yl)-acetamido~-cephalosporanic acid
2.75 g o~ ~-syn-ethoxycarbonylmethoximino-~-(2-
tritylamino-5-chloro-thiazol-4-yl)-acetic acid together with
0.675 g Or l-hydroxybenzotriazole were dissolved in 50 ml
of dry THF, and 1.0~ g of dicyclohexylcarbodiimide were
added. After stirring for one hour at room temperature,
~J
.. , . ... .. . ..... . . .
.. . .
.. . . . .
.
0.~3 g of dlcyclohexylurea was filtered off. A solution
of 1.36 g of 7-ACA and 1.52 g of triethylamine in 30 ml of
acetone/5 ml of H20 was added to the mother liquor, whilst
Il stirring. After stirring o~ernight, the solution was
I s concentrated, the concentrate was taken up in 50 ml of ethyl
acetate and the solution extracted with H20 at pH 1.~.
After evaporating the ethyl acetate phase, 4.4 g of a brown-
colored residue remained. This residue was stirred in
12 ml Or 75% HC02H for 1 hour at 50 and the solu-
tion was twice extracted with toluene and decolorized with
1 g of active charcoal. The light colored formic acid
solution was added dropwise to a stirred solution of 26 g of
(NH432 S04 in 56 ml of water. This gave 0.~ g of 7~
~ syn-ethoxycarbonyl-methoximino-~-(2-amino-5-chloro-thiazol-
; 15 4-yl)-acetamidol-cephalosporanic acid with a melting point
of 175 - 1~0 (decomposition)
IR (KBr): 1765 cm (~-lactam)
; 1725 cm (OCOCH3 and -C02C2Hs)
NMR (DMSO-d6~: ~ = 9.5 ppm (d, lH, CONH)
~ = 7.22 ppm (s, broad, NH2)
= 5.7 ppm ~q, 7-H)
~ = 5.1 ppm (d, 6-H)
S = ~.~2 ppm (A B, 2H, CH20)
~= 4.65 ppm [279 Hz syn]
! 25 (s, 2H, CH2 C02)
= 4.13 ppm ( q, 2H, OCH2 CH3)
= 3.5 ppm (d, 2, 2-H)
= 2.0 ppm (s, 3H, COCH3)
= 1.2 ppm (t, 3H, OCH2 ~ )
~i '
.. . ..... _ _ _ .... . _ _ . . .... . .. .
6;~5~
- ~5 -
Example 21:
7-[a -sYn-EthoxycarbonYl-me~hoximino-~12-amino-5-chloro-
` thiazol~ yl)-acetamido]-deacetoxAy---ce~halosporanic acid
;~ Analogously to Example 17, using 310 mg of ~-syn-
ethoxycarbonylmethoximino-~-(2-amino-5-chloro-thiazol-4-yl)-
acetic acid. In this way, 210 mg of the title compound are
isolated in the form of the formate.
Melting point: about 150 (decomposition~
IR (KBr~: 1750 cm (~-lactam)
NMR (DMSO-d6):S = 1.19 ppm (t, 3H, CH2 ~ )
= 2.0 ppm (s, 3H, CH~)
= 4.67 ppm [2~0 Hz] (s, 2H, O-CH2-)
~ = 9.~ ppm (d, lH, NHCO)
Example 22:
7-_[~-syn-Methoximino-~-~?-?mino-thiazol-4-yl)-acetamidol-3-
[2-(2 thienyl)-lH-1,3,4-triazol-5-yl-thiometh~ -3-ceph-em
4-carboxylic acid
In accordance with Example 6, using 4.15 g of 7_
amino-3-[2-(2-thienyl)-lH-1,3,4-triazol-5-yl-thiomethyl]-3-
cephem-4-carboxylic acid. 3.77 g of the title compound
are isolated.
IR (KBr): 1765 cm (~-lactam~
NMR (DMSO-d6): ~ = 3.Bl ppm (5, 3H, N_OCH3j
S = 5.06 ppm (d, lH, C_6-H)
~ = 5.70 ppm (q, lH, C-7-H)
= 6.6B ppm (s, lH~ thiazole-H)
= 7.14 ppm (t, 3H, NH2 + ~ H
:H S
= 7.62 ppm (d, 2H,
= 9.5 ppm (d, lH, CONH)
:
,
,
` ' : ' :
:. ,
,:
: ..... ; .
- ~6 -
pl~ 23:
7_r~-s~n-Methoximino~ -(2-amino-thiazol-4-yl)-acetamido]-
.~
~-(4,6 diamino-Pyrimidin-2-yl~thiometl~Ll~ ce
carboxYlic acid
In accordance with Example 6, using 3.7 g of 7-amino-
' 3-(~,6-diamlno-pyrimidin-2-yl-thiomethyl)-3-cephem-~-
carboxylic acid. 5.2 g of the title compound are isolatsd.
IR (KBr): 1755 cm (~-lactam)
NMR (DMSO_d6): ~ = 3.79 ppm (s, 3H, NOCH3) ~ H
10~ = 5.07 ppm (m, 2H, C_6_H + ~ J
N
= 5.65 ppm ~q, lH, C-7-H~
= 6.~ ppm (s, lH, thiazole-H)
~ = 9.5 ppm (d, lH, CONH)
Example 24:
7-~-[~-syn-Methoximino-~-(2-amino_thia~ol-~-yl)-acetamido]-
; 3-(5- ~
__
cephem-4-carboxyl acid
In accordance with Example 6, using ~.2 g of 7-~-
;~ amino-3-(5-carboxymethyl-4-methyl l ! 3-thiazol-2-yl-thio-
` 20
methyl)-3-cephem-4-carboxylic acid. 5.2 g of the title
compound are isolated.
IR (KBr~: 1770 cm (~-lactam)
NMR (D~SO-d6): d= 2.25 ppm (s, 3H, =C-CH3)
~= 3.75 ppm (s, 2H, ~CH2-C02H~
~ = 3.~5 ppm (s, 3H, NOCH~, syn)
= 6.75 ppm (5~ lH, thiazole-H)
= 9.50 ppm (d, lH, CONH)
.
3S~
~7
Example_2~
7 ~ do]-
3-(6-hydroxy-~-meth~1-5-oxo-1,2,4-triazin-3-yl-thiometh
~ be~ l s~g~ylic acid
In accordance with Example 6, using 3.9 g of 7-amino-
3-(6-hydroxy-~-methyl-5-oxo-1,2,4-triazin-3-yl-thiomethyl)-~-
cephem-4-carboxylic acid. 4.73 g of the title compound
are isolated.
IR (KBr): 1760 cm (~-lactam)
~- 10 NMR (DMSO_d6): ~ = 3 2g ppm (s, 3H, N- ~ )
: ~= 3.~? ppm (s, 3H, N-O-CH3)
- 5-75 ppm (q, lH, C-7-H)
= 6.72 ppm (s, lH, thiazole-H, syn)
~ = 9.54 ppm (d, lH, CONH)
Example 26:
7-~-syn-Methoximino-~-(2-amino-thiazol-4-y _-acetami~
3-(1-methyl-lH-tetrazol-5-yl)-thiomethyl-3-cephem-~-
carboxylic acid
In accordance with Example 6, using 3.3 g of 7-amino-
3-(1-methyl-lH-tetrazol-5 yl)-thiomethyl-3-cephem-4-
carboxylic acid. 4.32 g o~ the title compound are isolated.
IR (KBr): 1760 cm (~-lactam~
NMR (~MSO-d6): ~ = 3.9 ppm (s, 3H, N-CH )
CS = 3.~2 ppm (s, 3H, N-O- ~ )
~ = 5.62 ppm (q, lH, C-7-H)
= 6.71 ppm (s, lH, thiazole-H)
= 9.5 ppm (d, lH, NHCO)
, '
.. ~.
~ -.~ i ......
; ' '' . , , ' '
.
:
, ~ .
35~3
~ ,
` 4~ -
Example_27
?--L~-sy~Methoximino~ ( 2~midol ~3-.,
~5-methyl-1,3,~-thiadiazol-2~ thiomethyl-3-cephem-4-_
. carboxylic acid
In accordance with Example 6, using 3.5 g of 7-amino-
3-(5-methyl-1,3,~-thiadiazol-2-yl)-thiomethyl-3-cephem-~-
carboxylic acid. 4.2 g of the t1tle compound are isolated.
IR (KBr~: 1765 cm 1 (~-lactam)
NMR (DMSO-d6): ~ = 2.6g ppm (s, 3H, CH3)
S = 3.~2 ppm (s, 3H, N-O-CH3)
= 5.7g ppm (q, lH, C-7-H)
= 6.74 ppm (s, lH, thiazole-H)
= 9.5 ppm (d, lH, CONH)
' ''
,~
,
.
