Note: Descriptions are shown in the official language in which they were submitted.
/
The present invention relates to eertain novel 2
alkoxy-7~-benzylideneamino-3-cephem-4-earbonyl)-s-
triazolo [4, 3-a]pyrid-3-ones and to a proeess for preparing
them by introducing an alkoxy group into the 7a-position of
the eorresponding 2-(7-benzylideneamino-3-eephem-4-
. earbonyl) - s -triazolo [ 4, 3 - a ]pyrid - 3 - one .
The eephalosporin derivatives referred to in this
speeifieation are named with referenee to cepham, which has
the structure:
~; ~/6 2
18 N 5 3
~ O~` `
r' . [J, Amer Chem. Soc. 84 3400 (1962)] The term "cepham"
~` , refers to a compound in whieh the ring carbon atoms of this
strueture are all completely saturated; the corresponding
unsaturated compounds are designated by the term "eephem",
e. g. 3-cephem.
.
A number of methods is known for introducing an alkoxy
`~ group into the 7~-position of the cephem nucleus, including,
for e:~ample:
(a) diazotising 7-aminocephalosporanie aeid and then
`
~ ' .
: :. :
1(~495~
eonverting the substituent at the 7-position to an alkoxy group,
as is described in Japanese Patent Provisional Publication
No. 931/72;
(b) reacting a 7-benzylideneamino compound with a
dialkyl peroxide or the like, as described in Japanese Patent
Provisional Pubiication No, 42691/72;
. ':
(e) alkylthionating or fluorinating and acylating a 7-
benzylideneamino compound and converting the substituent
at the 7^position to an alkoxy group [J. Org. Chem. 38,
943 and 2857 (1973~]; and
,
(d) N-chlorinating the 7-acylamino group of a
eephalosporin derivative, converting the N-chlorinated group
to an acylimino group and then adding methanol [J. Amer.
Chem. Soe. 95, 2403 (1973)].
.
Eaeh of these methods, however, gives rise to diffieulties
lS in praetice and alternative methods for the introduction of alkoxy
groups at the 7a-position of the cephem nucleus are eagerly
sought. We have now diseovered certain eephalosporin derivatives
whieh are valuable intermediates for the preparation of cephalosporin
antibioties having alkoxy groups at the 7c~!-position of the cephem
'' ~ '
.~ ,. ~ .
nucleus .
The compounds of the present invention are the 2-
(7~-alkoxy-7,B-benzylideneamino-3-cephem-4-carbonyl)-
s-triazolo[4, 3-a] pyrid-3-ones of formula (I):
/ R R \
F''
, . \~N~.
i ,' O
whe rein:
. R represents a lower alko~y group;
R represents a lower alkyl group,
` a halogen atom, a cyano group or a nitro group;
10m is O or an integer from 1 to 4;
Q represents a hydrogen atom, a methyl group, an
azidomethyl group or a group of formula -CH2XR (in which X
re presents a sulphur or an oxygen atom and R2 represents an
acyl group, a lower alkyl group, or a 5- or 6-membered hetero-
. 15cyclic group);
R3, R, R5 and R are the same or different and eachrepresents a hydrogen at om, a lower alkyl group, a lower
3.
.
:
alkoxy group, a halogen atom, a cyano group or an alkoxy-
carbonyl group, or R3 and R4 together and/or R5 and R6
- ~ together form a carbocyclic ring fused to the benzene ring
to which they are bonded; and
n is 1 or 2
,
In accordance with the invention, compounds of
formula (I) are prepared by oxidising a 2-(7-benzylideneamino-
3-cephem-4-carbonyl)-s-triazolo ~4, 3-a]pyrid-3-one of
formula (II3:
/R3 ~\ .
HO L~ ~ CE~=N~ ~ (Il)
R~/n (R )
(wherein R, R, R, R, R, Q, m and n are as defined
above) with a benzoquinone having an electron-attracting
substituent, and reacting the product with a lower alkanol. In
- the compound of formula (II), the benzylideneamino group may be
16 present in either the 7,B-position or the 7cY-position.
4,
. .
~95~
Compounds of formulae(I) and (II) are novel compounds
and form part of the present invention.
.
Of the compounds of formula (I), and correspondingly
of the compounds of formula (II) from which they are prepared,
we prefer those compounds in which:
~, R represents a straight- or branched-chain alkyl
: group having from 1 to 4 carbon atoms (such as a methyl,
ethyl, propyl, isopropyl, n~butyl, isobutyl, sec-butyl or t-butyl
group), or a halogen atom, e. g. chlorine, bromine or fluorine;
R represents an alkanoyl group having from 2 to 5
`.~ carbon atoms (such as an acetyl, propionyl, butyryl or pivaloyi
group)? an aroyl group having from 7 to 11 carbon atoms (such
as a benzoyl, toluoyl, xyloyl or naphthoyl group), an arylalkanol
group, preferably having 8 or 9 carbon atoms (such as a phenyl-
acetyl, phenoxyacetyl or phenylpropionyi group), an arylalkenoyl
; group, preferably having 8 or 9 carbon atoms tsuch as a cinnamoyl
group)9 a carbamoyl or N-(lower alkyl)-carbamoyl group, a
straight- or branched-chain alkyl group having from 1 to 4 carbon
atoms (such as a methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
sec-butyl or t-butyl group), a 5- or 6-membered aromatic
heterocyclic group having 1 or 2 nitrogen atoms and optionally
another hetero-atom, e. g. an oxygen or sulphur atom, [such as a
2-pyridyl, 2-(1, 3, 5-triazolo), pyrazol-3-yl, 1-methyltetrazol-5-yl
5.
:: ~o~9s~
or 5-methyl-l, 3, 5-thiadia~ol-2-yl group] ;and
R, R, R and R, which are the same or different, are each a straight-
or branched-chain alkyl group having from 1 to 4 carbon atoms
(such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl or t-butyl group), an alkoxy group having from 1
to 4 carbon atoms (such as methoxy, ethoxy, propoxy, n-butoxy
or t-butoxy group), a halogen atom (such as chlorine or bromine) ;
or an alkoxycarbonyl group having from 1 to 4 carbon atoms in
the alkoxy moiety (such as a methoxycarbonyl, ethoxycarbonyl,
` 10 propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl or t-
butoxycarbonyl group).
~ ~ .
In the compounds of formula (I), R may be a straight-
or branched-chain lower alkoxy group having from 1 to 4
carbon atoms, such as methoxy~ ethoxy, propoxy, isopropoxy,
n-butoxy, isobutoxy, sec-butoxy or t-butoxy group.
Particularly preferred compounds of formula (I) and
(II) are those in which m is 0, R and R each represents a
lower alkyl group or a lower alkoxy group, R and R each
represents a hydrogen atom, n is 1, and Q represents a
methyl, (lower alkanoyl)-oxymethyl, azidometh~l or [l-(lower
alkyl)-tetrazol-5-yl]thiomethyl group In the compounds of
.
6.
.
,
. .
. . .
formula (I), R preferably represents a methoxy group Those
compounds in which R and R each represents a t-butoxy group
and Q represents a methyl, acetoxymethyl, azidomethyl or 1-
methyltetrazol-5-ylthiomethyl group are especially preferred.
` ' ' .,
; 5 The oxidising agent used in the process of the present
invention is a benzoquinone whose oxidising activity has been
enhanced by the presence of one or more electron-attacting
groups, preferred examples of which are: cyano groups;
halogen atoms, such as fluorine or chlorine; and nitro groups.
We particularly prefer to use benzoquinones having four electron-
attracting substituents, most preferably cyano groups and/or
halogen atoms.
The oxidising reaction will proceed to a sufficient extent
if the benzoquinone is used in a stoichiometric amount with respect
to compound (II). Use of a slight excess of benzoquinone will
still give good results, but we prefer not to use a large excess.
In general, the benzo~.uinone is used in an amount of from 1 to
1. 5 mols per mol of compound (II). The reaction temperature
is not particularly critical and, since the reaction proceeds
very smoothly, it is normally conducted at a temperature from
0 C to ambient temperature and is preferably conducted either
at ambient temperature without external temperature control or
,
,
.
O;, ,
~gs~ ,
by slight external cooling of the reaction mixture The time
required for the oxidatlon reaction may range from several
. minutes to scores of minutes;
.
.'
The oxidation reaction and the alkoxylation
6 reaction may be efIected essentially simultaneously in a
r single stage; alternatively, the reactions may be carried
out in two stages, the oxidation reaction being carried out
first, followed by the alko~ylation reaction. VVhere the
- ~ reactions are carried out in a single stage, compound (II)
` 10 is reacted with the benzoquinone in the presence of the lower
alkanol. In this case, the lower alkanol used for the alkoxylation
reaction may be empioyed as the reaction solvent. Alternatively,
` any inert organic solvent ~i. e. an organic solvent which is
inert to the reactants) may be employed in combination with the
lower alkanol. Examples of suitable organic solvents include:
aromatic hydrocarbons, such asbenzene, toluene or x-ylene;
ethers, such as dioxaneJ tetrahydrofuran or diethyl ether; and
halogenated hydrocarbons, such as chloroform and methylene
chloride .
2û Where the process of the invention is carried out in two
stages, compound (II) is first reacted with the benzoquinone in
an inert organic s olvent, such as those exemplified abo-,re, and
the reaction product is then reacted with the lower all~anol, either
'
. .
- ~ . ' ' , . ,
~95~
after isolation of the reaction product or without isolation.
In generalJ we prefer that the reaction should be carried out
in a single stage.
The lower al~anol used as the alkoxylating agent
preferably has from 1 to 4 carbon atoms, e. g. rnethanol,
ethanol, propanol, isopropanol, n-butanolJ isobutanol, or
sec-butanol. In generalj since the preferred 7~-alkoxy-
cephalosporin compounds are those having a methoxy group
at the 7~-positionJ methanol is the preferred lower alkanol.
,~ .
' 10 As in the oxidation reactionJ the reaction temperature
is not particularly critical and the reaction will normally be
conducted at a temperature from 0C to ambient temperature
- and preferably either at ambient temperature without any
. external temperature control or by slight external cooling of
the reaction mixture. The time required for the alkoxylation
reaction may range from several minutes to scores of minutes.
~'~ ` ' .
After completion of the reaction, the resulting compound
(I) is separated from the reaction medium by conventional
: proceduresJ e. g. by dlstilling off the solvent under reduced
pressure. The residue may then be purified by conventional
meansJ e. g. by recrystallisation or column chromatography.
, . . . . . .
:
S~ID
~lternatively, compound (I) may be used without intermediate
isolation in the preparation of a cephalosporin antibiotic.
E~:amples of compounds of formula (I) are as follows:
1. 2 -[ 7 ,8-( 4 -hydroxy- 3, 5 -di -t -butylbenzylideneamino) -
7~-methoxy-3-methyl-3-cephem-4-carbonyl]-s-triazolo-
[4J 3-~lpyrid-3-one
2. . 2 -[7,B-(4 -hydroxy- 3, 5 -di-t -butylbenzylideneamino) -
7~-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-
4-carbonyl]-s-triazolo[4, 3-a~pyrid-3-one
3. 2-[3_ acetoxymethyl-7~-(4-hydroxy-3, 5-di-t-butylbenzyl-
ideneamino) -7~-methoxy-3 -cephem -4 -carbonyl] -s-triazolo-
[4, 3-~lpyrid-3-one
4. 2-[3_ azidom~thyl-7,~-(4-hydroxy-39 5-di-t-butylbenzyl-
~ . ideneamino)-7~-methoxy-3-cephem-4-carbonyl]-s-triazolo-
., - 15 ~4, 3-~lpyrid-3-one
5. 2-[7,8-(4-hydroxy-3-methyl-S-t-butylbenzylideneamino)-
7~-methoxy-3-methyl-3 -cephem-4 -carbonyl] -s -triazolo-
- [4, 3-~lpyrid-3-one
6. 2 -[7 ,B-(4 -hydroxy- 3, 5-dimethylbenzylideneamino) -7~-
methoxy- 3 -methyl - 3 - cephem -4 - carbonyl] - s -t riazolo -
14, 3-~lpyrid-3-one
7 . 2 - [7 ,B-( 4 -hydroxy- 3, 5 -dimethoxybenzylideneamino) -
7~-methoxy-3 -methyl-3 -cephem-4~carhonyl] -s-triazolo-
[4, 3-~3pyrid-3-one
10.
.. . ~ . . . , , , .: . ". . . . : .. ..
- . . . . .. . . . .
. .: . , ~: ~ . .. .. . .
ilL09k9$00
. 8, 2-[7~-(4-hydroxy-3, 5-diisopropylbenzylideneamino)-
7~-methoxy-3-methyl-3-cephem-4-carbonyl]-s-tria~.olo-
t4, 3-a]pyrid-3-one
9. 2-[7,B-(3, 5-diethyl-4-hydroxybenzylideneamino)-7a!-
metho~y-3-methyl-3-cephem-4-carbonyl]-s-triazolo[4, 3-a]-
pyrid-3 -one
10. 2-[7~B-(3-ethyl-4-hydroxy-5-t-butylbenzylideneamino)-
7~-methoxy-3 -methyl-3 -cephem-4 -carbonyl~ -s-triazolo-
.` ~4, 3-a]pyrid-3-one
11. 2-[7,B-(4-hydroxy-3-methoxy-5-t- butylbenzylideneamino)-
7~-methoxy-3 -methyl-3-cephem-4-carbonyl] -s-triazolo-
[4, 3-~lpyrid-3-one
12. 2-[7,B-(4-hydroxy-4-isopropyl-3-methylbenzylideneamino)-
: 7~-methoxy-3-methyl-3-cephem-4-carbonyl]-s-triazolo-
. [4, 3-~1pyrid-3-one
13. 2-[3-carbamoyloxymethyl-7,B-~4-hydro~y-3, 5-di-t-
; butylbenzylideneamino)-7~-methoxy-3-cephem-4-carbonyl]-s-
. triazolo[, 3-a]pyrid-3-one
i 4 . 2 - [ 7 ,B-~ 4 -hydroxy - 3, 5 -di -t -butylbenzylideneamino) -
, 2 0 7a-methoxy - 3 -methyl - 3 - cephem - 4 - carbonyl] -4 -methyl - s -
triazolo[4, 3-~1pyrid-3-one
2-[7,B-(4-hydroxy-3, 5-di-t-butylbenzylideneamino)-
7~-metho~y-3-methyl-3-cephem-4-carbonyl]-6-methyl-s-
triazolo[4, 3-a]pyrid-3-one
11,
~. '
. . .
.... . ,. . :, .... . . .. . :
`
~4~5CD~
16. 4 chloro-2-[7,B-(4-hydroxy-3, 5-di-t-butylbenzylidene-
amino)-7a-methoxy-3-methyl- 3-cephem-4~carbonyl] -s-
triazolo[4, 3 -~1pyrid -3 -one
17 . 2 - [7 ,B-( 4 -hydroxy- 3, 5 -di -t -butylbenzylideneamino) -7a-
methoxy-3-methyl-3-cephem-4-carbonyl]-7-nitro-s-triazolo-
: ~ [4, 3-a~pyrid-3-one
- . . . -. - . . .
.1 ~
, . .. . .. . _ , . . .. .. _
. 18; 8-Cyano;2-[q,B-(4-hydroxy-3, 5-di-t-butylben~dene- ~~ ~~~~~~
amino)-7a~-methoxy-3-methyl-3-cephem-4-carbonyl]-4, 6-
dimethyl-s-triazolo[4, 3-~lpyrid-3-one.
..
, , .
.. , 10 Compounds of formula (Il) may be prepared, for example,
`~l . by reacting a compound of formula (III):
I L
! H~N.
~;;;C N~Q ( III)
'; ' ' C~O~
(in which Q is as defined above and ~ represents a subshtuted or
unsubstituted ammonium ion) with a benzaldehyde of formula (IV):
12.
.
.
. . . .. .
.
; . . . . . . .
': . . ' - ~. ,: ,'
~g5(~(~
/ lR3 R4\
HO ~ ~ CHO (IV)
R
: . \ / n
~in which R, R, R, R and a are as defined above), to give
a compound of formula (V):
i ': , ,
H~ CH=N~L (V)
coo~3 M~)
~` / n
S (in which R, R, R, R, ~, Q and M~ are as defined above)
~:, and reacting compound (V) with an anhydro-N'-halocarbonyl -3-
hydroxy-s-triazolo[4, 3-a]pyridinium hydroxide of formula (VI):
COX
I
- ~ (R )m (~TI)
;"'
~ (in which R and m are as defined above and X represents a
. ~
`~ lO halogen atom).
, ~ .
,~ 13
: .
' '
s~ ~
. ~eaction of compound (III) with compound (IV) may be
carried out at any temperature from -10C to 50 C, preferably
~- in an inert organic solvent, e. g. methylene chloride, chloroform,benzene, toluene, methanol, ethanol, diethyl ether or dioxane,
The reaction is preferably conducted in the presence of a
dehydrating agent, such as that sold under the trade name
"Molecular Sieves" by Linde Co., U.S. A. E~amples of the
substituted or unsubstituted ammonium ion ~3 include trimethyl-
ammonlum, triethylammonium, t-octylammonium, dicyclohexyl-
ammonium, diisopropylammonium, pyridinium, pyrrolidinium
and trimethylbenzylammonium, as well as ammonium itself.
The reaction of compound (V) with compound (VI) may
also be carried out at any temperature ~rom -10C to 50 C
and preferably in an inert organic solvent, such as those described
above.
The 2~7~-alkoxy-7,B-benzylideneamino-3-cephem-4-carbonyl)-
, s-triazolo[4, 3-~lpyrid-3-one derivatives of formula (I) obtained
by the process of the present invention may be ~onverted into
valuable cephalosporin antibiotics, e. g. as shown in the following
reaction scheme
14.
. . .
.
~9s~
C~ F~S
~R )m
Eydrazine or
hydrazine derivative
R
~ ,~ .
H2N j ~ ~
,~ . N~Q
"N ~
CON ¦ ~J (R )
(VII) ~r
.. ~ , O
~ Acylation
. ~
:. ~ .
.
~4~
. Acyl-NH ~ ~
i~ 3 (R )m
;~ . Metal salt of organic acid
(VIII)
,
,-
.. .
.. . .
~ R
: i : Acyl-NH ~S ~
, ~ ,~N~ Q ~ .
, `I
- ~ ~ . COOH
~ , (IX) '
... . .
: '
1~.
.
: - .. .. .:
~049~
In the above formulae, R, :R, R, R, ~, ~, Q,
m and n are as defined above- and "Acyl" represents an
acyl group. The production of cephalosporin antibiotics
by the process illustrated in the reaction scheme also
forms part of the present invention.
,
The debenzylidenation of the 7~x-alkoxy-7,~-benæylidene-
amino-3-cephem compound (I) is effected by contacting
compound (I) with hydrazine or with a hydrazine derivative
in a suitable inert solvent, and usually in the presence of an
acid catalyst. The nature of the inert solvent used in this
reaction is not critical and various inert organic solvents may
be used. Examples of such solvents include: lower alkanols,
such as methanol, ethanol, propanol, isopropanol, butanol,
isobutanol, pentanol and the like; aromatic hydrocarbons, such
as benzene, toluene, xylene and the like, halogenated hydrocarbons,
su~h as chloroform or methylene chloride, and dimethylformamide.
However, lower alkanols are normally preferred. Any acid normally
used for catalysing acid-catalysed reactions may be employed
in this reaction, but we prefer to use strong protonic acids,
for example inorganic acids (such as hydrochloride acid or
su~lphu~ic acid) and organic acids (such as_-toluenesulphonic acid,
trichloroacetic acid or trifluoroacetic acid). These acids may
17.
. . '' ' , . -
. .
' . .: ; - . , : .: , '
1(~49sa~!~
be used in the form of their ac;d addition salts with the hydrazine
or the hydrazine derivative, Apart from hydrazine itself,
it is also possible to use various substituted hydrazines capable
of reacting with benzaldehyde, for example hydrazine hydrate,
phenylhydrazine, 2,4-dinitrophenylhydrazine or a Girard
reagent (Girard P or Girard T). However, since it does not
require the presence of an acid and facilitates treatment after
reaction, a Gerard reagent is preferred. The reaction
temperature is not particularly critical and, for this reason,
the reaction is normally effected at ambient temperature;
however, the reaction will proceed evèn at higher or lower
temperatures. The time required for the reaction will vary,
depending mainly upon the natures of the starting material,
the hydra~ine reagent and the solvent, as well as the reaction
5 temperature; however, normally several tens of hours will
be required.
After completion of the reaction, the desired product
of formula (VII) may be recovered from the reaction medium
by conventional means. For example, where a Girard. reagent
;~ 20 is used, the reaction mixture is first extracted with a suitable
solvent (e. g. chloroform), the extract is washed with water
and dried with a suitable drying agent and then the solvent is
distilled off, giving the desired product. Alternatively, where the
.` 18-
- '
~LO~g59~
; reaction is carried out using 2, 4-dinitrophenylhydrazine and
~toluenesulphonic acid, the reaction mixture is first filtered,
the filtrate is concentrated by evaporation under reduced pressure
and is then evaporated to dryness; the residue is then washed with
ether, giving the ~-toluenesulphonate of the desired product.
This p-toluenesulphonate is treated with chloroform and an
aqueous solution of a weak base; the resulting organic layer is
separated and then the solvent evaporated off, giving the desired
product in crude form, This crude product may be further
.
~ ~ 10 purified by conventional means, e. g. column chromatography.
:, .
In the second step of the process illustrated in the above -
reaction scheme, the 7a-alkoxy-7,B~amino-3-cephem compound
(VII) is acylated. Prior art acylation processes require that
the carboxyl group at the 4-position of' the cephem nucleus should
be protected by esterification; however, in the process of the
present invention, the carboxyl group is already protected by a
specific i~nido group, i. e. the triazolopyridone group. We have
surprisingly found that this particular group affords good
` crystallinity, easy treatment after the reaction and a good yield
of the desired product at a high purity, compared with ester groups.
The reaction is carried out in the same way as in a conventional
acylation process, i. e by contacting compound (~TII) with an
acylating agent, e. g. a carboxylic acid or a reactive derivative
thereof, in a suitable solvent. We normally prefer to use.
19 .
,~ - '.
. ' ' .
i ,, "~, ~ . "" ",~, ,".,,~ ."'"'~ ,,;.~
:
~IL049S(~
as acylating agents acid halides (such as chlorides, bromides
or fluorides), acid azides, mixed anhydrides (such as mixed
anhydrides with alkyl esters of aliphatic acids or chlorocarbonic
, acid), acid anhydrides, active esters (such as the p-nitrophenyl
ester, the cyanomethyl ester or the phthalimido ester) or acid
, .
isoxazolium salts. If desired, the reactive derivative of the
carboxylic acid may be formed in situ from the acid and a
condensing agent and, in this case, a combination of the acid
' with a carbodiimide(e. g. N, N'-dicyclohexylcarbodiimide~
of the acid with a carbonyldiimide (e. g. carbonyldiimidazole
or carbonylditriazole) or of the acid with an alkoxyacetylene
(e. g. methoxyacètylene) is preferably employed. If asolvent
: i .
-~ is employed in the reaction, it should be inert to the reactants
'1 ~ and, provided this criterion is met, there is no limitation on
the nature of the solvent. Examples of silitable solvents include:
halogenated hydrocarbons, such as chloroform, methylene chloride,
` and ethylene chloride, di-(lower alkyl) ketones, such as acetone or
methyl ethyl ketone; acetic acid esters, such as ethyl acetate or
butyl acetate; ethers, such as diethyl ether, tetrahydrofuran or
~! 20 dioxane; aromatic hydrocarbons, such as benzene or toluene;
,, ~ .
~ acetonitrile; or dimethylformamide The man skilled in the art
`~ may readily select the appropriate solvent for use with the
- particular acylating agent chosen. The acid halide is normally
20,
. ~ .
~. .
'
. ~:
.
. . . ~
~L~4951~
:, the preferred acylating agent and, in this case, we prefer that the
reaction should take place in the presence of an acid binding
agent. The acid binding agent is suitably an organic or
:`
inorganic base. Examples of inorganic bases are: alkali
:: 5 or alkaline earth metal compounds, such as the hydroxides
;` (e. g. sodium hydroxide, potassium hydroxide, or calcium
hydroxide), the carbonates (e. g, sodium carbonate or potassium
carbonate) or the bicarbonates (e. g. sodium bicarbonate or
potassium bicarbonate). Examples of organic bases include,
,- I 10 for example: tertiary amines, e. g. triethylamine, tributylamine,
; dimethylaniline, N-methylpiperidine, N-methylmorpholine,
. ~ .
pyridine or quinoline. The reaction temperature is not
particularly critical and the reaction is, therefore, normally
effected at a temperature between about 0 C and ambient
temperature; however, the reaction will proceed at other
temperatures. The time required for the reaction depends mainly
upon the nature of the starting materials, the acylating agent
and the reaction temperature, but will normally vary from several
tens of minutes to several hours.
, ` .
When the reaction is complete, the desired ~roduct of
`` formula (VIII) may be recovered from the reaction mixture by
conventional means. For example, the reaction mixture is first
.
2~.
.~ ~
~ ' . ' ' ' . ' '
- - f
~49511~0
washed with water, the organic phase is separated and dried,
and the solvent is then distillecl off to give the desired product.
This product may be further purified by conventional purification
methods, e. g. column chromatography.
,
It is readily apparent from the above descriptlon that
each step of the process can be effected extremely smoothly
~mder mild conditions, giving the desired product in high yield.
After compound (VIII) has been produced, the protective triazolo-
pyridone group may very easily be removed.This may be effected by
contacting compound (VIII) with a metal salt of an organic acid, e~ g.
copper acetate, in a suitable solvent. The nat~re of the solvent iS nDTC/ jJ/`CQ
provided that it does not prevent the reaction; however, we
prefer to use a solvent capable of promoting contact between
compound (VIII) and the copper acetate. Such a solvent
preferably has a high polarity and a high sol~ating power for
the compound (VIII) and the copper acetate: preferred solvents
of this type are aqueous inert organic solvents. Examples of
inert organ;c solvents are: lower alkanols~ such as methanol,
ethanol, propanol and isopropanol: cyclic ethers, such as
dioxar.e and tetrahydrofuran; acetone: dimethylformamide:
and d;methylacetamide. The amount of copper acetate required
is stoichiometric for the reaction, but all excess does no harm
and we therefo~e normally prefer to use from 1 to 5 equ;valents
22.
`
~ss~ ,
. of copper acetate per mol of compound (VIII). The reaction
temperature is not particularly critical, but reaction at
:` relatively low temperatures gives better yield of the desired
.~
pro~ct with reduced danger of side reactions and, or this
reason, we prefer to effect the reaction at temperatures
between 0C and ambient temperature. The time required
for the reaction is usually several hours. After completion
! I
of the reaction, the desired cephalosporin antibiotic can be
recovered from the reaction mixture by conventional means.
For example, a water-immiscible solvent is added to the
reaction mixture, the resulting mixture is filtere~, the filtrate
is separated and the organic layer is collected. This organic
layer is washed with water and dried with a suitable drying
agent, after which the solvent is distilled off. The residue
may be purified by conventional means, e. g. column
chromatography.
; ~
` The invention is further illustrated with reference~ to
' ~ the following Examples. The preparation of the starting
`~ materials is illustrated in the following Preparations 1 to 4.
The preparation of 7,B-acylamino-7a-alkoxy-3-cephem compounds
from the compounds of formula (I) are illustrated in the
. I .
foUowing Examples 5 to 28.
- 23.
, ` :
.,
: :
49S~3~
PREPARATION 1
.
:~ 2-[3-Acetoxymethyl-7,B-(4-hydroxy-3, 5-di-t-butylbenzylidene-
amino)-3-cephem-4-carbonyl]-s-triazolo[4, 3-a]pyrid-3-one
272 mg of 3-acetoxymethyl-7~-amino-3-cephem-4-
carboxylic acid were suspended in 20 ml of chloroform;
0. 3 ml of triethylamine were then added to the mixture, which
was then stirred at room temperature, When the 3-acetoxy-
methyl-7,B-amino-3-cephem-4-carboxylic acid had completely
dissolved, 0. 2 ml of dimethylbenzylamine was added to the
solution and the solvent was then distilled off l;mder reduced `
pressure. The residue was dissolved in chloroiorm and the
olvent was distilled off under reduced pressure. The crystalline
residue was dried over phosphoric anhydride in a vacuum
, desiccator (l mm Hg) for 5 hours. The triethylamine which
' . .
separated was removed. The residue was dissolved in 20 ml
~ : of dichloroethane to which were added 234 mg of 4-hydroxy-3, 5-
.~ di-t-butylbenzaldehyde and "Molecular Sieves 4A" (a product
of Linde Co., U. S. A. ). The mixture was heated under reflux
for 2 hours, using a water separator, and the reaction mixture
was then cooled with ice-water. 200 mg of anhydro-l-chloro-
carbonyl-3-hydroxy-s-triazolo[4, 3-a]pyridinium hydroxide
were added to the mixture, which was then stirred whilst ice-
cooling for 15 minutes, and was then stirred for a further 30
minutes at room temperature. The reaction mixture was washed
24.
~`
,` `
~4~5~
with water and dried over anhydrous magnesium sulphate; the
` solvent was then evaporated off. The residue was purified by
chromatography, using 5 g of silica gel, giving 433 mg of the
desired produot as an amorphous powder.
UV spectrum ~l~ max (THF) nm:
229, 280, 359.
IR spectrum (Nujol - Trade Mark) ;) cm
1770, 1720.
NMR spectrum (CDC13) ~ ppm: 1 ~3
- 10 1. 45 (singlet, CH3-C- ),
CH3
2. 00 (singlet, CH3CO-),
`, . - . ' ".S~
3. 58 (quartet, CH2 at 2-position),
4.79 (quartet, ~ at 3-position),
~L 2 : -
5. 37 (multiplet, ~ at 6- and 7-position),
O= N~
5. 43 (singlet, OH), H H
6. 3 - 7. 8 (multiplet,~ N
H
8 40 ~singlet, -CH=N- ).
(THF = Tetrahydrofuran)
~95~0
PR:f3PA.:RATI ON 2
2 -[3 -Azidomethyl-7 ,B-( 4 -hydroxy- 3, 5 -di -t-butylbenzylideneamino) -
3-cephem-4-carhonyl]-s-triazolo[4, 3-a]pyrid-3-one
6. 3 g of 3-7~-amino-3-azidomethyl-3-cephem-4-carbox-ylic
-i 5 acid were suspended in 75 ml OI methanol, containing 4. 5 g of
dicyclohexylamine. To the mixture was added a solution of
5 8 g of 4-hydroxy-3, 5-di-t-butylbenzaldehyde in 75 ml of
. ~
. l chloroform. 25 g of anhydrous magnesium sulphate were added,
with stirring, to the mixture, which was then stirred at room
temperature overnight. The insolubles were filtered off and the
' filtrate was evaporated to dryness under reduced pressure. The
residue was dissolved in a mixture of 20 ml of chloroform, 30 ml
. ~j of isopropyl alcohol and 30 ml of isopropyl ether. The insolubles
`~; were filtered off and the filtrate was evaporated to dryness.
.
Thc residue was dissolved in a small amount of chloroform which
i,. was then added dropwise with stirring, to isopropyl ether. The
precipitates produced were separated by filtration and dried to
',~ give 12. 5 g of a crude dicyclohexylamine 3-azidomethyl-7-(3-
hydroxy - 3, 5 - di -t -butylbenzylideneamino) - 3 - cephem -4 - carboxylate .
12. 4 g of the crude product thus obtained were drssolved .
in 100 ml of anhydrous chloroform, to which 3. 7 g of anhydro-l-
chlorocarbonyl-3-hydroxy-s-triazolo[4, 3-~1pyridinium hydroxide
. were then added at 0 C, with stirring. The mixture was stirred
- 26,
.
.
9s~
for 15 minutes at 0 C and then for a further 30 minutes at room
temperature. The reaction mixture was washed with water,
dried over anhydrous magnesium sulphate and filtered. The
filtrate was evaporated to dryness, affording 9. 5 g of crude
2 -[ 3 -azidomethyl-7 ,B-(4 -hydroxy- 3, 5 -di -t -butylbenzylideneamino) -
3-cephem-4-carbonyl]-s-triazolo[4, 3-~lpyrid-3-one which can
be employed as a starting material without purification. The
crude product, if desired, can be purified by silica gel
.. . .
"J, ~ chromatography.
. . ' .
PREPAR~TION 3
) ~, , -. .
2-[7,B-(4-Hydroxy-3, 5-di-t-butylbenzylideneamino)-3-(1-
:
. methyltetrazol-5-yl)thiomethyl-3-cephem-4-carbonyl]-s-
. triazolo[4, 3 -~lpyrid -3 -one
:
; 3. 284 g of 7,B-amino-3-(1-methyltetrazol-5-yl)-
, 15 thiomethyl-3-cephem-4-carboxylic acid were suspended in
.
. 60 ml of methanol to whlch were then added 1. 81 g of dicyclo-
hexylamine; the mixture was stirred for one hour, To the
mixture were added 2. 40 g of 4-hydroxy-3, 5-di-t-butylbenz-
aldehyde, 20 ml of chloroform and 5 ml of "Molecular Sieves
3A" (a product of Linde Co., U. S. A. ); the resulting mixture
was stirred for 5 hours. The reaction mixture was then
filtered and the filtrate was evaporated to dryness under reduced
pressure The residue was extracted with a mixture of chloroform
27.
~.. . ~ . . .................. ... . .
. , ~ . .. .. .
~C~495~
and isopropyl ether (1: 1 by volume) and the extract was
concentrated under reduced pressure. To the residue was
added a large volume of isopropyl ether and the precipitates
produced were collected by filtration, giving 7. 04 g of
dicyclohexylamine 7,B-(4-hydroxy-3, 5-di-t-butylbenzylidene-
amino)-3-(1 -methyltetrazol-5 -yl)thiomethyl-3 -cephem-4-
carboxylate as a yellow powder.
` 7. 26 g of this product were dissolved in 50 ml of
methylene chloride, to whlch were then added 2. 0 g of
anhydro-1-chlorocarbonyl-3-hydroxy-s-triazolo[4, 3-~1-
pyridinium hydroxide; the mlxture was stirred for 30
minutes. The precipitates produced were filtered off
and the filtrate was washed with ice-water, dried over
anhydrous magnesium sulphate and evaporated to dryness
The residue was treated with n-hexane to give 6. 28 g of
crude 2-[7,1~-(4-hydroxy-3, 5-di-t--butylbenzylideneamino)-
3-(1-methyltetrazol-5-yl)thiomethyl-3-cephem-4 -carbonyl] -
s-triazolo[4, 3-~lpyrid-3-one as a yellow powder, which can
` be used as a starting material without purification. The crude
product, if desired, can be purified by recrystallization from
methanol to give crystals melting at 149 - 151C.
~ .
28,
f
1049500
PREPARATION 4
2-[7,B-(4-Hydroxy-3, 5-di-t-butylbenzylideneamino)-3-methyl-
-~
3-cephem-4-carbonyl]-s-triazolo[4, 3-~1pyrid-3-one
. _ . _ . . _ _
2.14 g of 7~-amino-3-methyl-3-cephem-4-carboxylic
acid werie suspended in 5 ml of water to which was added
1. 40 g of t-octylamine, with ice-cooling-, the mixture was
then stirred for 10 minutes The reaction m;xture was
evaporated to dryness and ethyl acetate was added to the
residue The resulting mixture was filtered, giving 3. 4 g
. , :
of the t - octylamine s alt .
. . ~ .
8, 2 g of the salt thus obtained were dissolved in 40 ml
; of methanol; to this solution was added a solution o 6. 20 g
of 4-hydroxy-3, 5-di-t-butylbenzaldehyde in 50 ml of chloroform.
.
The mixture was stirred at room temperature overnight. The
solvent was distilled off and the residue was washed with a small
amount of ethyl acetate and dried, giving 9. 9 g of t-octylamine
7,8-(4-hydroxy-3, 5-di-t-butylbenzylideneamino3-3-methyl-3-
cephem ~4 -carboxylate.
8, ~0 g o this salt were dissolved in 50 ml of methylene
chloride to which were then added 2. 0 g of anhydro-l-chloro-
carbonyl- 3 -hydroxy-s -triazolo[4, 3 -~lpyridimum hydroxide;
29
~'
.
:- ' -
~ '
1`,: . ` , ~ ~ . ' .
~ ZLgsa~a~
the mixture was stirred for 3û minutes. The reaction mixture
was then washed twice with ice-water, dried over anhydrous
magnesium sulphate and evaporated to dryness under reduced
pressure. To the residue was added n-hexane and the
precipitates produced were filtered to give 4. 95 g of 2-[7~-(4-
hydroxy-3, 5-di-t-butylbenzylideneamino)-3-methyl-3-
cephem-4-carbonyl]-s-triazolo[4, 3-a]pyrid-3-one as a yellow
powder.
EXA.MPLE 1
D 10 2-[7,B-(4-Hydroxy-3, 5-di-t-butylbenzylideneamino)-7~-methoxy-
3-methyl-3-cephem-4-carbonyl]-s-triazolo{ 4, 3-a]pyrid-3-one
- -- .
7, 02 g of 2-[7~-(4-hydroxy-3, S-di-t-butylbenzylidene-
amino)-3-methyl-3-cephem-4-carbonyl]-s-triazolo[4, 3~
pyrid-3-one were dissolved in 100-.ml of methanol, and a
.
i5 solution of 2. 73 g of 2, 3-dichloro-5, 6-dicyano-1, ~-benzoquinone
in 40 ml of methanol was added dropwise to the resulting solution,
with ice-cooling. After completion of the dropwise addition, the
mixture was agitated for 5 mïnutes with ice-cooling, and then
for 10 minutes at room temperature. The reaction mixture was
concentrated under reduced pressure and dried in vacuo. The
residue was extracted with a 1: 1 mixture of benzene and chloroform,
and the extract was passed through a column packed wi-th 50 g of
silica gel and then eluted with -the same solvent. The sol~,-ent was
distilled from the eluate, giving 4. 82 g of 2-~7~-(4-hydroxy-3, 5-
30.
,
`
``
:
9L9S~
di-t-butylbenzylideneamino) -7Or-methoxy-3 -methyl-3 -cephem-
4-carbonyl]-s-triazolo[4, 3-~lpyrid-3-one in an amorphous form.
."', '''.
I:R spectrum ( Nujol - Trade Mark), ~cm
1760, 1700, 1640.
U~F spectrum, ~max ( THF) nm:
`~ 230, 291, 358
NMR spectrum (CDCl3) ~ ppm:
; 1. 45 (singlet, (CH3)3C),
1. 96 (singlet, 3-position"~CEI3),
3. 40 (quartet, 2-position, ~[ ), -
3. 52 (singlet, 7-position, -OCH3~,
H S
. 26 (singlet, 6-position, ~~ ~ ),
5. 66 (singlet, HO-~ ),
.. ~ ' ~
,` ' ~ -
7. 71 (singlet, Ho4~ ),
~ .
15 8, 48 (singlet, -CH=N-).
` Thin layer chromatography (silica gel); developing solvent:
. chloroform containing 2. 5 v¦v % of methanol -
Rf value: 0. 57.
31.
.~ ~
: ~ . . . ..
; . .:: . - . . .:
~495q;D~
E~MPI.E 2
. .
2 -[7 ~-( 4 -Hydroxy- 3, 5 -di -t -butylbenzylideneamino) -7~-metho~y 3 -
. _ _
(I-methyltetrazol-5-yl)thiomethyl-3-cephem-4-carbonyl]-s-
triazolo[4, 3-~1pyrid-3-one
.. . . ., _ _
- 3, 58 g of 2-[7~-(4-hydroxy-3, 5-di-t-butylbenzylidene-
amino) -3 -~1 -methyltetrazol-5 -yl)thiomethyi-3 -cephem-4-carbonyl] -
Z s-triazolo[4, 3-~1pyrid-3-one were dissolved in ~0 ml of a
; mixture of methanol and tetrahydrofuran (1: l by volume), and
a solution of 1, 14 g of 2, 3-dichloro-5, 5-dicyano-1, 4-benzo-
quinone in 25 ml of methanol was added dropwise to the resulting
solution, with agitation and ice-cooling. After completion of the
dropwise addition, the mixture was agitated for 5 minutes with
i~ - -ice-cooling, and for 10 minutes at room temperature. The
reaction mixture was then evapora-ted under reduced pressure to
dryness. The residue was extracted with a mixture of benzene
and chloroform (1 1 by volume), and the extract was passed
through a column packed with 50 g of dry silica gel ( obtained
by drying silica gel for chromatography at 120C for 3 hours)
to adsorb the desired compound. The adsorbed compound was
eluted with chloroform. The solvent was distilled off under reduced
pressure from the eluate, giving 2. 31 g of the desired compound
~in an amorphous form.
,
32.
~0495Q~
IR spectrum (Nujol - Trade Mark), ~cm
1770, 1720.
UV spectrum, ~max (THF~ nm:
227, 2~1, 359.
NMR spectrum (CDCl3), ~ ppm:
1. 43 (singlet, (CH3)3C),
3. 50 (singlet, 7-position, -OCH3),
"~ S
3. 62. (quartet, 2-position, `¦< )'
3 84 (singlet, 3-position, tetrazole -N-CH3),
4. 26 (quartet, 3-position, -CH2-S-),
5, 23 (singlet, 6-position, ~ ~ j,
N~
`, ' . .
6. 3 - 7. 8 tmultiplet, 4-position,
:~ ~ H
N ~ ~,~,~
-CON I ),
N~
O H
H ~
7 69 (singlet, HO~ ~,
33.
.
` i
495~0
` ~
; 8, 47 (singlet, -CEI=N-).
~ Thin layer chromatography (silica gel): developing solvent:
; chloroform containing 2. 5 v/v % methanol -
Rf value: 0. 35.
EXAMPLE 3
. ~ .
2-[3-Acetoxymethyl-7~-(4-hydroxy-3, 5-di-t-butylbenzylidene-
_ _ _ _
amino)-7~-methoxy-3-cephem-4-carbonyl]-s-triazolo[4, 3-~1-
pyrid-3 -one
7. 0 g of 2 -[3-acetoxymethyl-7~-(4-hydroxy-3, 5-di-t-
butylbenzylideneamino)-3-cephem-4-carbonyl]-s-triazolo-
[4, 3-a]pyrid-3-one were dissolved in 100 ml of methanol; a
, ,:
~` ~ solution of 2. 73 g of 2, 3-dichloro,-5, 6-dlcyano-1, 4-benzoquinone
... .
-` in 40 ml of methanol was then added dropwise, with agitation and
; i
,~ ice-cooling. The mi~ture was agitated for 5 minutes with ice-
. . ,
cooling, and for 10 minutes at room temperature. The reaction
mixture was then evaporated to dryness under reduced pressure,
and the residue was extracted with benzene. The extract was
passed through a column packed with dry silica gel to adsorb the
.: .
desired compound. The adsorbed compound was eluted with a
' 20 mixl;ure of benzene and chloroform (1: 1 by volume); the
, solvent was distilled from the eluate, giving 5. 37 g of the desired
compound in an amorphous form.
34.
, ` ,
.,~
'~
,, , ~ .. ~
,;" ,
~ .
.
495C~
- IR spectrum (Nujol - Trade Mark), ~c~
1770, 1750 (Sh), 1730 (Sh).
- ("Sh" = "shoulder'~)
UV spectrum~ max (TI-llil) nm
~ 230, 292J 355,
: . ,
- 5 ~ NM:R spectrum (CDCl3), ô ppm ~
1.45 (singlet~ (CII3)3C)~ -
1. 98 (singlet, 3-position, OCO-CM3),
, I . . . . . . .
- . ~. H
. - ~. 50 ~quartet, 2-posltlon,~ ~ )J
i - . : . . . 3. 54 (singlet, 7-position, -O-CH3),
. .
o - ~. 74 (quartet, 3-posltion, -CM2-OCO-),
- ~ ; . : 5. 26 (singlet, 6-position, ~S ~ . ),
N--
.~ . . . .. . . . . .
,, ,, ' . ' ' \ ' ' '' '
5, 63 (singlet, Ho~
6. 3 - 7. ~ (multiplet, 4-position,
,
N ~i~, H
- CCIN
N ~~ H
;~ : O H
35,
.
~ --~- . . . .
. . . . ~: ... . .-
, , . . . : . .
S~
8 42 (singlet, -CH=N-).
Thin layer chromatography (silica gel); developing solvent:
,
chloroform containing 2. 5 v/v % methanol -
R t~ value : 0, 5 2;
E~MPLE 4
2-[3-A.zidomethyl-7,B-(4-hydroxy-3, 5-di-t-butylbenzylidene-
amino)-7~-methoxy-3-cephem-4-carbonyl]-s-triazolo[4, 3-a]-
pyrid - 3 - one
The procedure described in Example 3 was repeated,
except that 7. 34 g of 2-~3-azldomethyl-7,B-(4-hydroxy-3, 5-di-t-
butylbenzylideneamino)-3-cephem-4-carbonyl]-s-triazolo[4, 3-~1-
pyrid-3-one were employed instead of the 3-acetoxymethyl compound
- used in Example 3. 6.18 g of the desired compound were obtained' .
. IR spectrum ( Nujol - ~rade Mark), i~ cm
.: 15 2100, 1770, 1720.
UV spectrum, ~ max (THF) nm:
230, 292, 358
NMR spectrum (CDCl3)~ ~ ppm:
1. 45 ( singlet, (CH3) 3C),
` 20 3. 53 (singlet, 7-position, -OCH3),
~S~_
3 53 (quartet, 2-position, r~
36.
.. ''. . ~' - . ' '', , : ', ~ . ' : ' ' ' "~
. ~ . . ... . ~
9S~
4. 02 (broad, 3-position, -CH2-N3),
S. 27 (singlet, 6-position, ~/ \ ),
_ N--
5. 67 (singlet, HO~ ),
.
'
.l 6. 3 - 7. 8 (multiplet, 4-posihon,
E~:
~ ~/
O H
8 42 (singlet, -CH=N-).
.~
Thin layer chromatography t silic'a gel): developing solvent:
chloroform containing 2. 5 v/v lo c>f methanol -
Rf value: 0. 56.
EXAMPLE 5
2{7,B-Cyanomethylthioacetamido-7~-methoxy-3 -(1 -methyl-
tetrazol-5-yl)thiomethyl-3 -cephem-4-carbonyl] -s -triazolo-
[4, 3-~1pyrid-3-one
. 1. 04 g of 2-[7,B-(4-hydroxy-3, 5-di-t-butylbenzylidene-
amino)-7cr-methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-3-
37.
.
.. . . . .
.: . . , . - ~ : ,. ' . : : .
:~. ' . "' : ' ~ -
,: :
. . , . ~ ~ .
1~495~
cephem -4 - carbonyl] -s -triazolo~4, 3 a]pyrid- 3 -one were dissolved
in 9 ml of methanol, and 0. 9 g of Girard T reagent was added to
the resulting solution. The mi}~ture was stirred at room
;~ temperature for 20 minutes. 40 ml of chloroform were then
added, and the resulting solution was washed, in turn, with
'l the same volume of water and of a saturated brine solution.
The aqueous phase was washed with 10 ml of chloroform and all
the organic phases were combined and dried over anhydrous
magnesium sulphate. The solvent was distilled from the solution
under reduced pressure and the residue was dissolved in chloroform
and chromatographed using a silica gel column eluted with chloroform
;i . containing 3% ethanol. The solvent was distilled off from the
, eluate, giving 2-[7,B-amino-7~-nnethoxy-3-(1-methyltetrazol-5-
.i ~
yl)thiomethyl-3-cephem-4-carbonyl]-s-triazolo[4, 3-~1pyrid-3-one.
. 15 This compound was dissolved in 5 ml of tetrahydrofuran.
To the resulting solution were added 225 mg of cyanomethylthio-
. .
: acetyl chloride and 225 mg o~f diethylaniline, and the mixture was
stirred for 90 minutes. To the reactlon mixture were added
40 ml of ethyl acetate, and the orgaric layer was washed
sequentially with water, 0. lN hydrochloric acid, water, a 4%
aqueous sodium hydrogen carbonate solution and water. Eaeh
aqueous phas~e was extracted again with ethyl acetate and all
the organic phases were combined and dried over anhydrous
38
.~ .
4~
sodium sulphate. The solvent was distilled off from the solution
under reduced pressure and the residue was dissolved in a small
amount of ethyl acetate and chromatographed using i5 g of
dried silica gel eluted with a mixture of chloroform/ethyl
i 5 acetate (3: 1 v/v) The solvent was distilled from the eluate
and the residue was washed with ether and dried to give 672 mg of
the desired product.
.`,
' IR spectrum (Nujol - Trade Mark) ~cm
2250, 1770J 1650.
UV spectrum ~ma~ (THF) nm:
227, 260 (Sh), 35g.
, .. . . .
~ih ' ~ NMR spectrum (d -DMSO) ~ ppm:
3. 35 (singlet, -OCEI3 at 7-position),
: ,
3. 49, 3.77 (each singlet, -CH2-S-CH2-CO-
' 15 and -CH2-S-CH2-CO- at 7-position),
- ~S H
3.73~quartet, X at 2-position),
.~ H
3.91 (singlet, tetrazole -N-CEI3 at 3-position),
~, 4. 23 (quartet, -CH2-S- at 3-position),
H
5. 23 (singlet), ~ ~ at 6-~osltion),
~, . N
39
~ ,
~ " ,
~ ~ . ' . . : :'
4~51~0 ''
6, 5 - 8, 0 (multiplet,
H
N ~
- CON ¦ i at 4-position)
N ~H
O H
f
9; 50 (singlet, -CONH- at 7-position).
f ' Thin layex chromatography (silica gel):
a) Developing solvent: chloroform containing 10% methanol -
Rf value: 0. 63.
b) Developing solvent: butanol/acetic acid/water (4:1:1) -
- ` Rf value: 0. 59,
., .
-`, EXAMPLE 6
~ 10 2-[7~-Methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-7~-propargyl-
~ . _ . .
'~ thioacetamido-3-cephem-4-carbonyl]-s-triazolo[4, 3-a3pyrid -3-one
, ~; The procedure described in Example 5 was repeated,
f, except that 223 mg of propargylthioacetyl chloride were used
.
instead of the cyanomethylthioacetyl chloride; 714 mg of the
~` ~5 desired product were obtained.
~-
IR spect rum (Nujol - Trade Mark) i) cm
17q0, 1710, 1690, 1650.
UV spectrum 1 max (THF) nm:
227, 255, 359.
4o~
,
95QIo
NMR spectrum (d -DMSO) ~ ppm:
3. 07 (triplet, H-C-C- )9
3. 32 (singlet, O-CH3 at 7-position),
3 36 - 3- 45 (-CH2-S-CH2-CO- at 7-position),
~S H
3. 72 (quartet, X at 2-position),
H
3 88 (singlet, tetrazole -N-CH3 at 3-position),
.,1 ~ . I
i 4. 21 (quartet, ,~C~H2-S at 3-position),
i l H
5.18 (singlet, ~/ at 6-position),
-N
-6. 5 - 8. 0 (multiplet,
H
, 10 ~Nq~
'~ -CON ¦ ~ at 4-position),
~N~
O H ``
,.1 ,
~ ~ 9. 35 (singlet, -CONH- at 7-position).
Y Thin layer chromatography (silica gel):
' a) Developing solvent: chloroform containing 10% methanol -
. , . Rf value: 0. 65.
lS b) Developing solvent: butanol/acetic acid/water (4:1
i .
Rf value: 0, 64.
: .
~ 41.
;:
.
-
' ' ' . .
: . , ,
~9~;0~
E~AMPLE ?
2-17,~-Chloroacetamldo-7~-methoxy-3-(1-methyltetrazol-5-yl)-
thiomethyl-3-cephem-4-carbonyl]-s-triazolo[4, 3-~1pyrid-3-one
. ~
The procedure described in Example 5 was repeated,
except that 170 mg of chloroacetyl chloride were used instead
of the cyanomethylthioacetyl chloride, 622 mg of the desired
product were obtained.
. . . .
UV spectrum ~max (THF) nm -
- 227, 260 (Sh), 359.
Thin layer chromatography (silica gel): Developing sol~Tent:
chloroform containing 10% methanol -
Rf value: 0. 66.
,
~;' ` ' ,
EXA MPLE 8
2-[7~-Methoxy-3-(1 -methyltetrazol-5-yl)thiomethyl-7,B-(1, 3, 4-
: . - -- . . .
- 15 thiadiazol-2-yl)thioacetamido-3-cephem-4-carbonyl]-s-triazolo-
.~ - .
[4, 3-a]pyrld-3-one
704 mg of 1, 3, 4-thiadiazol-2-yl-thioacetic acid were
dissolved in 20 ml of tetrahydrofuran, and the resulting solution
was cooled to -5 C. 54~ mg of ethyl chlorocarbonate and 404 mg
of N-methylmorpholine were subsequently added, with stirring.
- Stirring was maintained at -5 C for 3 minutes, after which a
solution of 1.17 g of free 2-~7,B-amino-7~-methoxy-3-(1-methyl-
42.
~ .
. . , , , . . . . :. . . : . . -
'
tetrazol - 5 -yl)thiomethyl - 3 - cephem 4 - car bonyl] - s -triazolo -
~ [ 4, 3 -~ 1 pyrid - 3 - one in 5 ml of tetrahydrofuran ( prepare d from
;~ 1. 39 g of 2-[7,B-(4-hydroxy-3, 5-di-t-butylbenzylideneamino)-7~-
methoxy-3-(1-methyltetra~ol-5-yl)thiomethyl-3-cephem-4-
carbonyl]-s-triazolo[4, 3-a]pyrid-3-one and 1. 17 g of Girard
T reagent by the procedure described in Example 5) :wa~ added to
the solution. The solution was stirred at 0C for 2 hours, after
which the precipitated and undissolved materials were filtered
off, The filtrate was concentrated to 10 ml by evaporation under
reduced pressure, and 10 ml of ethyl acetate were added thereto.
The organic solution was washed with, in turn, water, û. lN
hydrochloric acid, water, a 4% aqueous solution of sodlum hydrogen
carbonate and water, and was then dried over anhydrous magnesium
. sulphate, The solvent was distilled from the solution under reduced
pressure and the residue was dissolved in a small amount of ethyl
acetate and chromatographed using a column of 20 g of dried
silica gel eluted with a mixture of chloroform/ethyl acetate (3: 1 v/v).
The solvent was distilled off from the eluate, giving the desired
product.
' .
IR spectrum (Nujol - Trade Mark) ~ cm
1770, 1700, 1650.
UV spectrum ~ max tTHF) nm:
227, 261, 359.
~3.
, .
.'' ' ' . ', ' ' ,,,','.' '";.' "' '
~g~4e3soo
NMR spectrum (CDC13) ~ ppm:
3. 43 (singlet, O-CH3 at 7-position),
3. 90 (singlet, tetrazole -N-CH3 at 3-position),
. . .
4. 2S (singlet, -S-CH2-CO at 7-position),
5. 24 (singlet, ~/ at 6-position),
, j --N _
H
: ~,
,, . ~ N ~ H
6. 3 - 7, 9 (multiplet, -CO-N I ).
, ~ N~H
O H
. .
9. 08 (thiadiazole, 7-position).
-- Thin layer chromatography (silica gel):
, .
a) Developing solvent: chloroform containing 10% methanol -
:
: ` 10 Rf value: 0. 56.
b) Developing solvent: butanol/ acetic acid/water ( 4: 1 : 1 ) -
~' Rf value: 0 47.
:, ~
EXAMPLE 9
2 -( 3 -Acetoxyme-thyl -7 ~8- cyanomethylthioacetamido -7~-methoxy- 3 -
.. . . _ _
cephem -4 - carbonyl) -s -triazolo[4, 3 -a]pyrid- 3 -one
. -- . . . _ . _
The procedure described m Example 5 was repeated,
.~ except that 955 mg of 2-[3-acetoxymethyl-7~-(4-hydroxy-3, 5-
di-t -butylbenzylicleneamino) -7a-methoxy-3-cephem-4-carbonyl] - `
.
: ~4,
' ' " ' '.
.
i
s-triazolo[4, 3-~1pyrid-3-one were used instead of the 2-[ 7,B-(4-
hydroxy-3, 5-di-t-butylbenzylideneamirlo)-7a-methoxy-3-(1-
methyltetrazol-5-yl~thiomethyl-3 -cephem-4 -carbonyl] -s -triazolo-
[4, 3-~1pyrid-3-one, 563 mg of the desired product were obtained
via 2-[3-acetoxymethyl-7,B-amino-7c~-methoxy-3-cephem-4-
carbonyl] -s -triazolo[4, 3 -a]pyrid- 3 -one as intermediate .
7-amino compound:
. - . IR spectrum (Nujol - Trade Mark) ;) cm
.. . .
1780, 1750 (Sh), 1730 (Sh).
. UV spectrum ~ l:nax (THF) nm -
. . 228, 258 (Sh), 358
,
. . N:MR spectrum (CDC13) 6 ppm:
- 1. 97 (singlet, OCOCH3 at 3-position),
2. 24 (broad singlet, NH2 at 7-position),
3, 44 (singlet, OCH3 at 7-position),
3. 56 (quartet, ~Sx at 2-position),
.1 .
4. 73 ~quartet, ~LCH2 at 3-position),
5 02 (singlet, ~/ at 6-posltion),
, --N~
., .
`
:: ~0~
6. 3 - 7. 8 (multiplet,
~N~EI
, CON l l at 4-position).
; \I~ ~\H
O EI
Thin layer chromatography ( silica gel) :
a) Developing solvent: chloroform containing l0% methanol -
Rf value: 0. 68.
b) Developing solvent ~ butanol/acetic acid/water (4: 1: 1) -
.
Rf value: 0.74.
- 2-~3-Acetoxymethyl-7,~-cyanothioacetamido-7cl!-methoxy-3-
cephem -4 -carbonyl) -s -triazolo[4, 3 -~lpyrid-3 -one:
IR spectrum (Nujol - Trade Mark ) ~ cm
;, 2250, 1770, 1750 (Sh), 1720.
UV spectrum ~max (THF) nm:
''! 230, 260 (Sh), 358
NMR spectrum tCDC13) ô ppm:
1.98 (singlet, -OCOCH3 at 3-position),
.,'' , ~ ,~ ' .
, 3. lS ~- 3.93 ( >,~ at 2-position,
EI
-CEI2-S~CH2CO, -CH2-S-C,~H2CO at 7-position),
3. 45 (singlet, O-CH3 at 7-position),
46.
.
. . .. . ~ . . -
: . . . . , . . . -
3~ 5~
4. 72 (quartet, -CI-I2 -OCO- at 3 -position),
,' , ~ ~/
5 27 (singlet, ¦ at 6-position),
--N ~ H
~N~J~H
6. 3 - 7. 8 (multiplet, CON
` ~H
O H
. Thin layer chromatography (silica gel): -
a) Developing solvent: chloroform containing 10% methanol -
Re value: 0 57,
b) Developing solvent ~ butanol/acetic acid/water (4:1:1) -
Rf ~ralue: 0. 65.
. . .
- EXAMPLE 10
2-(3-Acetoxymethyl-7a~methoxy-7~-propargylthioacetamido-3-
cephem-4-carbonyl)-s-triazoloE4, 3-a!]pyrid-3-one
.. . _
The procedure described in Example 5 was repeated,
~` except that 955 mg of 2-[3-acetoxymethyl-7~ (4-hydroxy-3, 5-di-t-butylbenzylideneamino) -7a!-methoxy-3 -cephem-4-carbonyl] -s -
triazolo[4, 3-~1pyrid-3-one were used instea~ of the 2~[7R-(4-
hydroxy-3, 5-di-t-butylbenzylideneamino)-7a!-methoxy-3-(1-
methyltetraz ol -5 -yl)thiomethyl - 3 - cephem -4 - carbonyl] - s -trlaz olo -
[4, 3-~lpyrid-3-one and 223 mg of propargylthioacetyl chloride were
used instead of the cyanomethylthioacetyl chloride; 670 mg of the
desired product were obtained.
47.
.
~495~0
: IR spectrum (Nujol - Trade Mark) ~ cm
1770, 1740, 1720.
.. . .
UV spectrum ~max ( ) nm:
259 (Sh), 3 58
NMR spectrum (CDC13) ~ ppm:
2. 00 (singlet, OCOCH3 at 3-position),
2, 37 (triplet, H C - C - ),
S H
3, 3 - 3 8 ( ~ at 2-position,
2 2 ~ -C~2S-CH~2CO at 7-position)
3. 45 (singlet, O-CH3 at 7-position),
4. 76 (quartet, ~LCH2 OCO- at 3-position),
;~l 5, 32 (singletJ ~ at 6-position),
. ` , \
~i 6. 3 - 7. 8 (multiplet,
~ N ~H
-! CON at 4-position). N ~ ~ H
1 5 Thin layer chromatography ( silica gel):
~, a) Developing solvent: chloroform containg 10% methanol -
Rf value: 0. 7 0.
.~
48,
.
- '
. ~
9s~
b) Developing solvent: butanol/acetic acid/water (4:1:1) -
.~ Rf value: 0 71
.,
. , .
E~:MPLE 1 1
2 -[3 -Acetoxymethyl-7~-methoxy-7,B-( 1, 3, 4 -thiadiazol-2 -yl)thio-
acetamido-3-cephem-4-carbonyl~-s-triazolo[4, 3-~1pyrid-3-one
.
~i The procedure described in Example 8 was repeated,
except that 1. 27 g of 2-[3-acetoxymethyl-7,B-(4-hydroxy-3, 5-
i di-t-butylbenzylideneamino)-3-cephem-4-carbonyl]-s-triazolo-
[4, 3-~lpyrid-3-one were used instead of the 2-[7~-(4-hydroxy-
3, 5-di-t-butylbenzylideneamino)-7~-methoxy-3-(1-metllyl-
tetrazol-5-yl)thiomethyl-3-cephem-4-carbonyl)-s-triazolo[4, 3
,, ,
pyrid-3-one, giving the desired product,
IR spectrum (Nujol - Trade Mark) ';) cm
:~i
,~! . 1775, 1750, 1?20.
UV spectrum ~max (THFl nm:
229, 260, 356.
NMR spectrum (CDC13) ~ ppm:
1. 97 (singlet, -OCOCH3 at 3-position),
3. 43 (singlet, O-CH3 at 7-positionj,
`~ 20 3, 48 (quartet, S)< at 2-posltion),
'
49,
'
: `
~ - ~0495~D
4, 32 (singlet, -S-CH2CO- at 7-position),
4, 70 (quartet"~LCH2-OCO- at 3-position),
H
5, 23 (singlet, ~ at 6-position),
,
- 6 3 - 7 8 (multiplet,
EI
CON ~fH at 4-position),
\~ N~
H
N N
9, 04 (singlet, ~ at 7-position)
: Thin layer chromatography ~ silica gel):
a) Developing solvent: chloroform containing 10% methanol - :
Rf value: 0 56,
b) Developing solvent butanol/acetic acid/water (4:1:1) -
Rf value : 0. 56.
.
`!' ' EXAMPLE 12
. .
2 -( 3 -Acetoxymethyl-7 ,~- chloroacetamido -7a-methoxy- 3 - cephem -4 -
. _ ~ . . _ . _ . . .. _
carbonyl)-s-triazolo[4, 3-~lpyrid-3-one
The procedure described in E~ample 5 was repeated,
except that 955 mg of 2-[3-acetoxymethyl-7,B-(4-hydroxy-3, 5-di-
t-butylbenzylideneamino) -7a-methoxy-3 -cephem-4-carbonyl] -s-
triazolo[4, 3-a~pyrid-3-one were used instead of the 2-[7,B-(4-
.
.
, , ~ . ~ . . .
:; ` ``
~;
~49
hydroxy-3, 5-di-t-butylbenzylideneamino)-7cY- methoxy-3-(1-
methyltetrazol-5-yl)thiomethyl-3-cephem-4-carbonyl]-s-triazolo-
`~ [4, 3-~lpyrid-3-one, and 170 mg of chloroacetyl chloride were
used instead of the cyanomethylthioacetyl chloride; 610 mg of the
~, ; 5 desired product were obtained.
; .
~ IR spectrum (Nujol - Trade Mark) ;) cm
.~ 1775j 1750 (Sh), 1720.
UY spectrum ~. max (THF) nm
226, 257 (Sh), 357.
NMR spectrum (CDCl3 ) ~ ppm:
-' ' 1. 97 (singlet, -OCO-CH3 at 3-position),
~r~ ,, . . 3, 48 (singlet, O-CH3 at 7-position),
S
3. 52 (quartet, ~H at 2-position),
, I H
.. , ,_
12 (singlet, ClCH~2CO- at 7-position),
4. 72 (quartet, ,~LCH2 OCO - at 3-position),
5, 27 (singlet, ~/ at 6-position),
--N
- 6. 3 - 7. 8 (multiplet,
H
~N~J~"_
CON I l at 4-position).
\I~N'~
O H
51
: : .
~, . . . .
.
`
1~ 5[1
Thin layer chromatography (silica gel) :
, a) Developing solvent: chloroform containing 10% methanol -
Rf value: 0. 7 0.
b) De~eloping s olvent: butanol/ acetic acid/water ( 4: 1 : 1 ) -
Rf value: 0. 70.
EXAMPLE 1 3
2 -( 3 -~zidomethyl-7 ~- cyanome thylthioacetamido-7a-methoxy-
. 3-cephem-4-carbonyl)-s-triazolo[4, 3-~lpyrid-3-one .
....
The procedure described in :13xample 5 was repeated,
except that 930 mg of 2-[3-azidomethyl-7,8-(4-hydroxy-3, 5-di-
t-butylbenzylideneamino)-7~-methoxy-3 -cephem-4-carbonyl] -
s-triazolo~4, 3-~1pyrid-3-one were used instead of the 2-1.7~3-
(4-hydroxy-3, 5-di-t-butylbenzylideneamino) 7~-methoxy-3-(1- -
' methyltetrazol-5-yl)thiomethyl-3-cephem-4-carbonyl]-s-triazolo-[4, 3-~lpyrid-3-one; 546 mg of the desired product were obtained
via 2-(7,B-amino-3-azidomethyl-7~-methoxy-3-cephem-4-
carbonyl)-s-triazolo[4, 3-~lpyrid-3-one as intermediate
7-amino compound:
IR spectrum (Nujol - Trade Mark) ~) cm
2090, 1760, 1710.
UV spectrum '~\max (THF) nm:
227, 251 (Sh), 357.
52.
.
~ ' . . ; '; ;~,, .. . :
: ....
`": ```
s~
NMR spectrum (CDC13) ~ ppm
2, 22 (broad singlet, NM2 al: 7-position),
3. 43 (singlet, O~CH3 at 7-position),
3, 57 (quartet, S~< at 2-position),
H
3. 99 (quartet, .~L CH2- at 3-position),
5. 01 (singlet, ~/ at 6-position),
N
6. 3 - 7. 8 (multiplet,
~N~H
C(~N l at 4-position).
N ~ ~ H
O H
Thin layer chromatography (silica gel):
10a) Developing solvent: chloroform containing 10% methanol -
Rf value: 0. 67.
b) Developing solvent: butanol/acetic acid/water (4:1:1) -
Rf value: 0. 83.
2-(3-Azidomethyl-7~-cyanomethylthioacetamido-7~-
15methoxy - 3 - cephem -4 - carbonyl) - s - triaz olo[ 4, 3 -~l pyrid - 3 - one :
IP~ spectrum (Nujol - Trade Mark) i) cm
2225, 2080, 1765.
53. : .
, " . ~ ,.
109L9~
. IJV spectrum lmax (THF) rlm:
227, 255 (Sh), 358
NMR spectrum (CDC13) ~ ppm:
3. 47 (smglet, -OCH3 at 7-position),
` 5 3. 55 (quartet, S~ at 2-position),
I H
3. 6 - 3. 7 (-CH2SCH2CO - at 7-position),
4, 00 ( quartet, J~ CH2 -N3 at 3 -position),
H
5. 29 (singlet, ~ at 6-position),
_ N~,~
~ 6. 3 - 7. 8 (multiplet,
: E
~o~ at 4-position~.
Thm layer chromatography (silica gel):
a) Developing solvent chloroform containing 10% methanol -
R~ value: 0. 63.
~, . .
b) Developing solvent: butanol/acetic acid/water (4:101) -
R~ value: 0. 70.
5~ .
.
.
:
.
...--
: . ,- ,
- , -
,
, , ' ~ ! ,
' ' , ' ,' ' ' . ' .` ~ ' ; i ' " ' '' .' ' . ' v
' , ' ~ ' . ' ~,
` ~
`:
~4~5~9111
EX~MPI,:3 14
. .
2-(3-A~idomethyl-7cY-methoxy-7~-propargylthioacetamido-3-
cephem-4-carbonyl)-s- t~iazolo[4, 3-a]pyrid-3-one
, The procedure described in Example 5 was repeated,
S except that 930 mg of 2-(3-azidomethyl-7,13-(4-hydroxy-3, 5-
. di-t-butylbenzylideneamino)-7~-methoxy-3-cephem-4-carbonyl]-
s-triazolo[4, 3 a]pyrid-3-one were used instead of the 2-[7~B-
(4-hydroxy-3, 5-di-t-butylbenzylideneamino)-7a-methoxy-
- ~ 3 ~ methyltetrazol - 5 -yl)thiomethyl - 3 - cephem -4 - carbonyl] - s -
triazolo[4, 3-~lpyrid-3-one, and 223 mg of propargylthioacetyl
chloride were used instead of the cyanomethylthioacetyl chloride;
645 mg of the desired product were obtained.
`. ` IR spectrum (Nujol - Trade Mark) ~ cm :
` - 2080, 1765.
UV spectrum ;~max (THF) nm:
227, 250 (Sh), 356.
NMR spectrum (CDCl3) ~ ppm:
2. 33 (triplet, H-C-C-~,
H
3. 2 - 3. 6 ( ~/ at 2-position,
I H
-C~H, 2 -S -CH2C O, -CH2S -CH2CO- at 7 -position),
55.
;, ~ . ,- . : . . - ~ . .
5~&~
: .:
. . . 3, 47 (singlet, O-CH3 at 7 ~position),
3- 99 tquartet, ~CH2 - at 3-position),
H
5, 28 (singlet, ~( at 6-position),
-- N
;; 6, 3 - 7, 8 (multiplet,
.~ H
. N J~ H
-CON ~ I at 4-position).
,, ` " 3~5,
Thin layer chromatography (silica gel ):
. a) Developing solvent: chloroform containing 10% methanol -
. R ~ value: 0. 6 6 .
~) Develping solvent: butanol/acetic acid/water (4:1:1) - -
` 10 Rf value: 0. 79 .
EXAMPLE 1 5
,- 2-~3-Azidomethyl-7,B-chloroacetamid'Q~7~-methoxy- 3-cephem
. ~ , .
4~arbonyl)-s-triazolo~4, 3-a]pyrid-3-one
; .
The procedure described in Exampie 5 was repeated,
,j .
except that 930 mg of 2-[3-azidomethyl-7,B-(4-hydroxy-3, 5-
di-t-butylbenzylideneamino) -7a-methoxy-3 -cephem-4-carbonyl] -s -
triazolo[4, 3-~lpyrid-3-one were used instead of the Z-[7,B-(4-
hydroxy-3, 5-di-t-butylbenzylideneamino)-7a-methoxy-3-(l-
methyltetrazol-5-yl)thiomethyl-3-cephem-4-carbonyl] -s -triazolo-
:'~ 20 [4, S-~lpyrid-3-one,and 170 mg of chloroacetyl chloride were used
: 56.
. '
,~
.
' ' . . . , ' '' : .'. ' '
~(~4951D~
instead of the cyanome-thyl-thioacetyl chloride; 568 mg
of the desired product were obtained.
`' .
IR spectrum (Nujol - Trade Mark) ~cm 1 :
, 5 2100, 1770, 1710.
`~ W spectrum ~max (~HF) nm:
230, 255 (Sh), 357-
NMR spectrum (CDCl3) ~ppm :
3.47 (singlet, 0-CH3 at 7-position),
3.5 - 4.2 (quartet, S ~ at 2-position),
H
3.5 - 4.2 (quartet, l CH _ at 3-position),
4.12 (singlet, -S-CH2- at 7-position),
. .
H
5028 (singlet, ~ at 6-position),
6.3 - 7.8 (multiplet,
H
~ ~ H
-CON ~ at 4-positlon).
H
~hin layer chromatography (silica gel) :
a) Developing solvent: chloro~orm containing 10%
methanol -
Rf value : 0.65.
b) Developing solven~t: butanoljacetic acidtwater
(4:1:1) -
R~ value : 0.63.
57-
5~a3
~XAMP~E 16
2-/ 3-Azidomethyl-7 ~-methoxy-7 ~-(1,3,4-thiadiazol-2-
_
! yl)thioace-tamido-3-cephem-4-carbonyl7-s-triazolo/ 4,3-a 7-
.
pyrid-3-one
~he procedure described in ~xample 8 was repeated,
except tha-t 1.24 g of 2-@-azidomethyl-7 ~-(4-hydroxy-
3,5-di--t-butylbenzylideneamino)-7~ -methoxy-3-cephem-4-
carbony~-s-triazolo r4,3-a ~pyrid-3-one were used instead
of the 2- r7 ~-(4-hydroxy-3,5-di-t-butylbenzylideneamino)-
7~-methoxy-3-(1-methylte-trazol-5-yl)thiomethyl-3-cephem-
;~ 4 carbony~ -s-triazolor 4,3-a ~pyrid-3-one, giving the
desired product.
'
IR spectrum (Nujol - ~rade Mark) ~cm 1 :
- 2100, 1770, 17100
- 15 W spectrum ~max (~HF) nm:
226, 260, 356.
NMR spectrum (CDCl3) ~ ppm :
3~42 (singlet, 0-CH3 at 7-position),
3.52 (quartet, S ~ ~ at 2-position)~
~3.99 (quartet, ~ CH2- at 3-position),
4.28 (singlet, -S-CH2~C0- at 7-position),
5.26 (singlet, H at 6-position),
5~.
:
'
,: . . . : .
. . . . . , -
4~ 0
... .
6.3 - 7.9 (mul-tiplet,
H
~ N ~ H
-CON l l at 4-position),
; ~ N ~ ~H
H
8.87 (singlet, -~H- ),
N - N
9.07 (singlet,
H ~ ~ \
' ~ ~
~hin layer chromatography (silica gel) :
a) Developing solvent : chloroform con-taining
~; 10% methanol -
; ; Rf value : 0~62.
b) Developing solvent : butanol/acetic acid/water
(4:1:1) -
Rf value : 0.63.
.,
EXAMP~E 17
7 ~-Cyanomethylthioacetamido-7 ~ -methoxy-3-(1-me-thyl-
. . ~
tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid
:, .
- 15 294 mg of 2- ~7~ -cyanomethylthioacetamido-7d-
methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-~-cephem-
4-carbony ~-s-triazolo~ 4,3-a ~pyrid-3-one (ob-tained
in ~xample 5) were dissolved in 5 ml of tetrahydrofuran,
and 2.5 ml of water and 200 mg of copper acetate mono--
hydrate were added. ~he mix-ture was stirred at room
temperature for 5 hours. ~o the reaction mixture were
59.
.~ :
;
--~ L
~L~4g5~
then added 25 ml of ethgl aceta-te and 1.25 ml of 0.5M
citric acid solution~ and the precipi-ta-tes were filtered
off. ~he fil-trate was decanted and the organic phase was
washed with water and dried over ~nhydrous magnesium
sulphate. ~he solven-t was distilled from the filtrate
under reduced pressure. ~he residue was dissolved in a
small amount of chloroform and subjected to coll~mn
chromatography using 5 g of dried silica gel eluted with
chloroform containing 5% methanol (v/v %). ~he solvent
was distilled from the eluate under reduced pressure,
giving the desired compound.
NMR spectrum (CD3CN f D2~) ~p. pm :
3.50 (singlet, 0-CH3 at 7-position),
- 3.5 - 3.7 (multiplet, S H at 2-position),
~H
3.60,3.70 (each singlet,
CH2-S-CX2C~ CH2SC~H2C at 7-position)~
3.98 (singlet9 tetrazole N-CH3 at 3-
position),
4.~ - 4.6 (quartet, ~ CH2- at 3-positlon),
5.10 (singlet, ~ at 6-position).
60.
: `````~
495~10
-~ EXAMPIES 18 to 28
r~he triazolopyridone compounds ob-tained in
Examples 6 to 16 were treated as described in Exaraple
17; the ~ollowing compounds were obtained :
7~-Methoxy-3-(1-methyl-tetrazol-5-yl)-thiomethyl-7~ -
propargylthioacetamido-3-cephem-4-carboxylic acid
. . . ~ . __
IR spectrum (~ujol _ r~rade Mark) ~ cm 1 :
, 1775-
¦ ~MR spectrum (d6 DMS0) ~ppm :
3.20 (triplet, HC _ C- ),
around 3.5 (multiplet, 0-CH3,
, -CH2SCH~2C0, -CH2SCH2C0- at 7-position),
3.90 (singlet, tetrazo~e ~-GH3 at
' - 3~position),
" 15 4.2 _ 4,3 (quartet, ~ CH2- at 3-position)7
: -,
5.05 (singlet, ~ at 6-position),
' - -N
.~`
. .
7 ~-Chloroacetamido-7 ~-methoxy-3-(1-methyl-tetrazo]-
~;~ 5-~l)thiomethyl-3-cephem-4-carboxylic acid
IR spectrum (Nujol _ r~rade Mark) ~ cm 1 :
- 20 1760,
W spec-trum 1 max ~m :
270.
NMR spec-trum (CD3C~ + D20) S ppm :
61,
.
~ .
.
~` ~0495;0a~
`. ,
; 3.43 (singlet, 0-C~3 a-t 7-position),
3.87 (singlet, tetrazole -N-CH3 at
3-position),
4.12 (singlet, -C~2C0- at 7-position),
4.20 (quartet, ~ CH2- at 3-position),
;~ H
5.0 (singlet, y at 6-position).
',
~ -N~
. ,~1 .
I ~ 70l-Methoxy-3-(1-methyltetrazol-5-yl)thiomethyl-7 ~-
(1,3,4--thiadiazol-2-yl)thioacetamido-3-cephem-4-carboxylic
... . . ~
acid
"
IR spectrum (KBr) ~ cm 1 :
S 1760.
W spectrum ~ max (pH 6.86 phosphorie aeid buffer solution)
' nm :
266.
NMR speetrum (CD3CN ~ D20) ~ppm :
3.5 (singlet, 0-CH3 at 7-position),
.s,
3.5 - 3.7 (multiplet S ~ at 2-position),
H
`~ 4.20 (quartet, ~ C~2- at 3-position),
62.
.
.
.
:. . : .
.. . . . .
~0~9S~
H
;~ 5.04 (singlet, ~ at 6-position),
~ I
-N ~
N N
9.28 (singlet, ~ at 7-position).
H ~ S ~ \
' ~hin layer chroma-tography (silica gel) :
Developing solvent : chloroform/me-thanol (1:1) -
Rf value : 0.38.
3-Acetox~methyl-7 ~-cyanomethylthioacetamido-7~-
.
methox~-3-cephem-4~carboxylic acid
IR spectrum (Nujol - ~rade Mark) ~ cm 1
1775.
UV spectrum ~max nm :
.
247, 2~7.
NMR spectrum (CD3CN) ~ ppm :
. .
~ 2.02 (singlet, -OCOC~3 at 3-position),
I S H
3O32 - 3.55 (quartet~ ~ at 2-position}
.`; ~ . ~w
153.42, 3.60 (each singlet, -GH2-S-CH2C0-,
-CH2-S~C~2C0- at 7-position),
3.52 (singlet, 0-C~H3 at 7-posi-tion),
i
4.76 - 5.06 (quartet, ~ CH2- at 3-p~ition)
..
63.
,
..
. . ' ' . ! . '
' ' " ' ~ ',, " ~ ' " ' , ~' '
4~5~
H
5.06 (singlet, ~ at 6-position),
. .
. . .
~ 3-Acetox~methyl-7~ -propargylthioacetamido-7 ~ -
.... . _ ~ .
~ methox~-3-cephem-4-carboxylic acid
,~ . .
'! IR sp~ctrum (~ujol - ~rade Mark) ~ cm 1 :
;` 5 1775-
W spectrum ~ m nm :
245, 268.
NMR spectrum (d5-DMsO) ~ ppm :
;i 1.98 (singlet, OCOCH~3 at 3-position),
3.05 (triplet, HC-C- at 7-position),
- 3.2 - 3.5 (multiplet, S at 2-position),
H
~ 3.36 (singlet, OCH3 at 7-position),
! ~ ~ 3.5 (singlet, -CH2SCH2CO,
-CH2-S-CH2CO at 7-position),
4.6 - 4.9 ( quaItet ~ ~CH2- at 3-position),
5.05 (singlet - ~ ~ at 6-position).
~ -N ~
;l 3-Acetoxymethyl-7 ~ -methoxy-7 ~ -(1,3,4-thiadiazo1-2-
1 yl)thioacetamido-3-cephem-4-carbox~lic acid
... ._. -- ,
IR spectrum (KBr) ~ cm 1 :
; 20 1760.
.
- . '
.
,
:: .
~Qg~95~3~
UV spec-trum ~ max (pH 6.86 phosphoric acid buffer solution)
nm :
26~
~MR spectrum (CD3CN -~ D20) ~ ppm :
; 5 1.98 (singlet, -OCOCH3 a-t 3-position),
:' ' ' ;~; '
3.2 - 3.5 (multiplet, S ~ at 2-position),
.
3.42 (singlet, OC~H3 at 7-position),
4.11 (singlet, -S-CH~2CONH- a-t 7-position),
4.73 (doublet, ~ CH2- at 3-positlon),
5.00 (singlet, ~ ~ at 6-position),
N --N
g , 1l\ /ll\ at 7-position).
~hin layer chromatograph~ (silica gel) :
Developing solven-t : methanol/chloro~orm (1~
Rf value : O. 45 .
3-Acetoxymeth~1-7 ~-chloroacetamido-7 ~-methoxy-3-
~ . . ~
cephem-4-carboxylic acid
. _ _ .
max (pH 6.86 phosphoric acid buffer
solution) nm :
264.
NMR spectrum (CD~CN + D20) ~ ppm :
65-
' '. ' ' . ' ' ~ ' .' , ', ~ . , "' ' ' ' '
5~0
'': S
3.2 - 3.5 (~ultiplet, ~ at 2-position)
, , . I ,
~; 3.55 (singlet, 0-CH3 at 7-position),
4.08 (singlet, Cl-CH2CO~H- at 7-position),
s
, 5~08 (singlet, ~ at 6-position).
....
N~
?~ I
I 5 Thin layer chromatography (silica gel) :
i Developing solvent : chloroform/methanol (1:13 -
R value : 0.41.
f
~,''`~ `
3-Azidomethyl-7 ~-cyanomethylthioacetamido-7 ~-
- methoxy-3-cephem-~-carboxylic acid
; i . -
10 IR spectrum (Nujol - Trade Mark) ~ cm 1 :
; 2250, 2100, 1760.
max (pH 6.86 phosphoric acid
!: buffer solution) nm :
267.
3-Azidomethyl-7d -methoxy-7 ~-propargylthioacetamido-
3-cephem-4-carboxylic aoid
: . .. . . . .
IR spec-trum (Nujol - ~rade Mark) ~ cm 1 :
` 775
NMR spectrum (d6-DMS0) ~ ppm :
3~15 (triplet~ HC _ C- at 7-position),
3~25 - 3~75 (multiplet, S ~ at 2-position,
H
., .
66.
,,
.
:
l04~sa0
-CH2S~2CO, -CTL2SC~~2CO-, OCH3 at
7-position),
4.16 (quartet"~CH2- at 3-posi-tion)?
5.15 (singlet, ~j/ at 6-position),
-N ~
9.4 (singlet, -CONH~ at 7-position).
3-Azidomethyl-7 ~ -chloroacetamido-7 ~ -methoxy-3-
_ _ . . . _ . _ . _ . _
cephem-4-carboxylic acid
. .
IR spectrum (Nujol - ~rade Mark) ~ cm~
2100, 1760.
UV spectrum ~ max - (pH 6.86 phosphoric acid buffer
solu-tion) nm:
264.
, , .
3-Azidomethyl-7i~ -methox~y-7 ~3-(1,3,4-thiadiazol~2-
yl)thioacetamido-3-cephem-4-carboxylic acid
IR spectrum (Nujol - ~rade Mark) ~ cm 1:
2100, 1760.
- W spectru~ X max (pH 6.86 phosphoric acid buffer
solution) ~m: ~`
263.
NMR spectrum (CD3CN + D20) ~; ppm:
, .
., ~ .
-..
.
~4~S~
2.93 - 3.68 (multiplet, S ~ ),
:` ¦ H
. ", '~
3.41 (singlet~ 0-CX3 at 7-position),
4O0 - 4.2 (multiplet, ~ CH2-, at 3-position,
-SCH2CO~H- a-t 7-position),
~ H
`; 5 5.01 (singlet, ~ at 6-posi-tion),
~ 9.23 (singlet, ~ at 7-position).
'. ' '
`;
~: .
~, , .
,' '~ ' , .
,
, ~.
,
68.
'
. . .
,. ...
.
