Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
B~3
Thiazole Derivatives
This invention relates to novel aminothiazoleacetic
acid derivatives which are useful as synthetic intermediates
for ~-lactam antibiotics, a prccess for preparing the same,
and a use thereof.
As synthetic intermediates useful for the production
of ~-lactam antibiotics having high antimicrobial activities,
such as penicillins, cephalosporins, etc., there are known
2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-
acetic acid derivatives. For example, some of them have
been used as the 7-side chain groups of ceftazidime, etc.
which are known as the so-called third generation anti-
biotics, while other have been considered to be promising
side chain moieties of azetidinones which are candidates
of the fourth generation antibiotics. It is therefore
expected thàt such and other 2-(2-aminothiazol-4-yl)-(Z)-
2-(carboxyalkyloxyimino)-acetic acid derivatives will be
utilized more often than they are today.
So far, many different processes have been proposed
for the production of such 2-(2-aminothiazol-4-yl)-(Z)-
2Q 2-(carboxyalkyloxyimino)-acetic acid d~rivatives, and
among these known processes, the commercially advantageous
processes may be classified into the following two major
categories. One of the categories includes the method
starting with an acetoacetic acid alkyl ester, which
comprises oximating the ester with an alkali nitrite to an
oxyiminoacetic~acid ester, etherlfying the oxime and, then,
`
8Z3
halogenating, and finally cyclizing the halogenation
product with thiourea. The other category includes the
method starting with 4-chloroacetoacetyl chloride, which
comprises reacting the chloride with ethanol, butanol or
the like to give a 4-chloroacetoacetic acid ester, oximat-
ing the ester with an alkali nitrite, cyclizing the oxime
with thiourea to give a 2-(2-amino~hiazol-4-yl)-(Z)-2-
hydroxyiminoacetic acid ester, and finally etherifying the
ester.
The 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxy-
imino)-acetic acid derivatives thus obtained are utilized,
each in the form of acid halide, acid anhydride or active
amide, as acylating agents in the synthesis of ~-lactam
antibiotics. In this acylation reaction, it is necessary
to use a 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxy-
imino)-acetic acid derivative whose amino group has been
protected so as to prevent occurrence of side reactions,
with the result that in the synthetic processes heretofore
used, 2-(2-aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-
acetic acid derivatives whose amino groups have beenprotected are mainly synthesized. Moreover, because the
carboxy group in the carboxyalkyloxyimino moiety and the
carboxy group in the acetic acid moiety of such 2-~2-
aminothiazol-4-yl)-(Z)-2-(carboxyalkyloxyimino)-acetic
acid derivatives are more or less alike in chemical
property, the carboxy group in the carboxyalkyloxyimino
moiety must be protected to prevent side reactions before
the derivatives are converted to reactive derivatives such
as acid halides, acid anhydrides, active amides, etc.
As protective groups for the carboxy group in the carboxv-
alkyloxyimino moiety, those groups which can be eliminated
by catalytic reduction, such as p-nitrobenzyl, have been
commonly employed but these groups are commercially
disadvantageous in that it is difficult to remove them
following the acylation reaction mentioned above. There
has also been employed a tert-butyl group which is thought
823
to be removable by acid hydrolysis but in the aforementioned
second method for producing 2-(2-aminothiazol-4-yl)~(Z)-2-
(carboxyalkyloxyimino)-acetic acid derivatives wherein the
earboxy group in the acetic acid moiety has been mostly
esterified by an alkyl group, the tert-butyl group is
also eliminated during the de-esterification reaction
prior to said conversion to reactive derivatives. Thus,
there has not been established an industrially profitable
method for producing an 2-(2-aminothiazol-4-yl) (Z)-2-
(earboxyalkyloxyimino)-aeetic aeid derivative whose amino
group and carboxy group in the acetic acid moiety have not
been protected but whose earboxy group in the earboxy-
alkyloxyimino moiety only has been proteeted.
The present inventors found that in utilizing an
2-(2-aminothiazol-4-yl)-~Z)-2-(earboxyalkyloxyimino)-aeetie
aeid derivative as an aeylating agent for the synthetie
produetion of ~-laetam antibioties, the steps of proteeting
the amino group prior to the aeylation reaetion to prevent
side reaetions and removing the protective group for the
amino group after the acylation reaction can be omitted
if the 2-(2-aminothiazol-4-yl)-(Z)-2-(earboxyalkyloxyimino)_
aeetie aeid derivative is used in the form of an aetive
thioester, and eonducted a study to develop a eommereially
advantageous proeess ior produeing an 2-(2-aminothiazol-4-
yl)-(Z)-2-(earboxyalkyloxyimino)-aeetie aeid derivative
of whieh the amino group and the earboxy group in the
aeetie aeid moiety are unproteeted and the earboxy group
in the earboxyalkyloxyimino moiety is proteeted. It was,
found, surprisingly, that among the various eonceivable
eombinations of reaction steps, the following process
provides a novel aminothiazoleacetie acid derivative of
the formula
~ . ..
:
8~3
-- 4 --
2 ~ ~
- N C-COW' (I)
OCCOOC(CH3)3
R2
wherein Rl and R2 each are a hydrogen atom or a lower alkyl
group, and W' is h~droxyl or 2-benzothiazolylthio, or a
salt thereof in good yield. Thus, this process comprises
reacting diketene with a halogen and then with a ~-lower
alkyl- or phenyl-thio- or sulfonyl-ethanol, oximating the
reaction product withnitrous acid or a salt thereof,
reacting it further with thiourea or a salt thereof,
etherifying the oxime, if necessary oxidizing the same,
and finally eliminatiny the protective group for the
carboxy group in the acetic acid moiety. ~his process
permits easy and selective removal of the protective group
from said carboxy group in acetic acid moiety. It was
further found that the compound tI) wherein W' is O~
thus obtained can be reacted with 2,2-dithiobis-benzo-
thiazole to produce an active thioester, i.e. the compound
(I) wherein W' is 2-benzothiazolylthio, which is an
advantageous synthetic intermediate for ~~lactam antibiotics.
The present invention is based on the above findings.
Thus, this invention relates to an aminothiazole-
acetic acid derivative (I), a use of the derivati~e (I) as
an intermediate for the synthetic production of ~-lactam
antibiotics, and a process for preparing the derivative
(I) characterized by:
reacting diketene with halogen;
reacting the resulting 4~haloacetoacetyl halide with
an alcohol of formula (II):
R-W-C2H4OH (II)
wherein R is lower alkyl or phenyl; and W is S or SO2;
reacting the resulting compound of formula (III):
CH2Coc 2CO 2 4 (III)
whereln X is~a halogen atom; and R and W are as defined
1~4~823
above with nitrous acid or a salt thereof;
reacting the resulting compound of formula (IV):
XcH2colclcooc2H4-~-R ~IV)
NOH
wherein the symb'ols are as defined above, with thiourea or
a salt thereof;
reacting the resulting compound of formula (V):
N~ ~_C-COOC H -W-R (V)
10 N
OH
wherein the symbols are as defined above or a salt thereof,
with a compound of formula (VI):
1 1
X'-C-COOC(CH3)3 (VI)
R2
wherein X' is a halogen atom; and other symbols are as
defined above, to produce a compound of formula (V')
N ~ C-COOC2H4-W-R (V')
N\ ll
O-CI-COOC(CH3)3
wherein the symbols are as defined above, or a salt5 thereof;
o~idizing further the reaction product (V') or a
salt thereof when W is S; and (i) hydrolyæing the resulting
compound of formula (VII):
Nl ~ C-COOC2H4SO2R (VII)
1 1
o-c-coac (CH3)3
R2
wherein the sybmols are as deined above, or a salt thereof,
in the presence of a base, to obtain the derivative (I)
wherein W' lS OH or (ii) hydrolyzing the compound (VII)
.
or a salt thereof in the presence of a base, and reacting
the obtained derivative (I) wherein W' is OH with 2,2-
dithiobis-benzothiazole to obtain the derivative (I)
wherein W' is 2-benzothiazolylthio.
Referring to the above formulas, Rl and R2 are the
same or different and each represents hydrogen or lower
alkyl. The lower alkyl group Rl or R2 may be a group
containing l to 4 carbon atoms, such as methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
etc. Preferred are the cases in which both Rl and R2 are
hydrogen or methyl, or one of Rl and R2 is hydrogen and
the other methyl. R is lower alkyl or phenyl. The lower
alkyl R may for example be a Cl 4 lower alkyl as mentioned
for Rl and R2. Preferred examples of R are methyl and
ethyl. The halogen X, X' may for example be chlorine,
bromine, iodine or fluorine. X and X' may be the same
halogen or different halogens. Frequently used examples
of X and X' are chlorine and bromine. W stands for S or
SO2 W' is OH or -S ~/S ~
In the method accoxding to this invention, diketene
is reacted with a halogen in the first place to give a
4-haloacetoacetyl halide. In this step, diketene may be
reacted with an equimolar or slig~htly less than equimolar
amount of a halogen under cooling. This reaction may be
conducted in a solvent. As the solvent, a halogenated
hydrocarbon such as methylene chloride, chloroform, etc.,
an ester such as ethyl acetate, etc., or an ether such
as ether, dioxane, etc., for instance, may be employed.
The reaction may be conducted under cooling, i.e. from
-70C to 10C. The reaction time may be very short and
generally the reaction may go to completion substantially
upon completion of addition of the halogen. It may be,
therefore! sufficient to stir the reaction system for
about 30 minutes after addition of the halogen. The
resulting 4-haloacetoacetyl halide can be separated and
purified by the conventional procedure, e.g. concentration,
... .
i323
solvent extraction, pH adjustment, crystallization,
chromatography, etc., but it is advantageous to submit the
reaction mixture as such to the next reaction step.
The 4-haloacetoacetyl halide is then reacted with
alcohol (II) to give compound ~III).
In this step, the 4-haloacetoacetyl halide is
preferably reacted with an equivalent or slightly less
than equivalent amount of alcohol (II). This reaction
may be conducted in a solvent. The solvent may be any
solvent that does not interfere with the reaction, and may be
preferably a halogenated hydrocarbon such as methylene
chloride, chloroform, carbon tetrachloride, etc. or an
ether such as tetrahydrofuran, dioxane, diethyl ether, etc.,
for instance. Further, this reaction is preferably carried
out in the presence of a base. As such a base, there may,
for example, be employed aromatic amines such as pyridine,
picoline, N,N-dimethylaniline, etc. and aliphatic tertiary
amines such as trimethylamine, triethylamine, etc. The
amount of the base is about 1-3 moles per mole of alcohol
(II). Generally, the reaction may be conducted under
cooling or at room temperature (at -20 to 40C). The
reaction generall~ goes to completion in tens of minutes
to a few hours. The resulting 4-haloacetoacetic acid
ester (III) can be purified by the conventional purification
procedure such as distillation, phasic transfer, recrystal-
lization, etc. but since this reaction proceeds in high
yield, the reaction mixture may be submitted to the next
reaction step without prior purification.
The 4-haloacetoacetic acid ester (III) is then
reacted with nitrous acid or a salt thereof to give the
oxime.
The reaction is generally carried out using compound
(III~ and nitrous acid in an approximately equimolar ratio,
although nitrous acid may be used in slight excess. While
nitrous acid may be used as it is, it can be used as a
salt with an~alkali metal su-h as sodium or potassium, for
3Z3
instance The reaction may proceed in a solvent~ The
reaction temperature may be under cooling or at room
temperature (at -50 to 50C, preferably -10 to 40C). The
solvent used for this reaction may for example be an
ether, e.g. tetrahydrofuran, dioxane, diethyl ether, etc.,
a fatty acid such as glacial acetic acid, or a mixture
thereof. The amount of water which may be added to such
solvent is virtually op~ional. As an alternative, an
aqueous solution of nitrite (e.g. sodium nitrite) may be
added to consequently introduce water into the reaction
system. The reaction time depends on the amounts of
starting compounds, the solvent, etc. The reaction may
go to completion in a very short time (20 minutes to 3
hours). The product oxime (IV) can be purified by the
known procedure such as distillation, solvent extraction,
concentration, recrystallization<, etc., but it is generally
unnecessary to purify it but the reaction mixture as such
may be used as the reactant for the next step.
The compound (V) or a salt thereof can be produced
by reacting this oxime compound (IV) with thiourea or a
salt thereof.
Generally, each mole of compound (IV) is reacted
with one mole or a slight excess of thiourea or a salt
thereof, although thiourea may be used in larger excess
unless the reaction is not thereby adversely affected. As
a salt of thiourea, there may, for example, be a salt with
an inorganic acid such as hydrochloric acid, hydrobromic
acid, sulfuric acid, phosphoric acid, etc. This reaction
is generally conducted in a solvent. The solvent is
preferably a mixture of water with a water-miscible
solvent such as an alcohol, eOg. methanol, ethanol, etc~,
a ketone, e.g. acetone, diethyl ketone, etc., an ether
e.g~ tetrahydrofuran, dioxane, diethyl ether, etc., an
acid amide, e.g. N,N-dimethylformamide, N,N-dimethyl-
acetamide, etc., or an organic amine, e.g. N-methyl-
piperidone, etc. Furthermore, the syn~isomer (V) is
323
selectively produced when the reaction is conducted in the
presence of a basic reagent. The basic reagent used for
this reaction may be an alkali metal or alkaline earth
metal salt of a lower aliphatic carbo~ylic acid, or an
inorganic or organic base having a pKa value of 9,5 or
more, preferably a pKa value of 9.8 to 12Ø Examples
of the lower aliphatic carboxylic acid salt include salts
of lower aliphatic carboxylic acids containing 1 to 6
carbon atoms, e.g. sodium acetate, potassium acetate,
calcium acetate, barium acetate, sodium formate, sodium
propionate, potassium hexanoate, etc. The inorganic base
may for example be a carbonic acid al~ali metal salt such
as sodium carbonate, potassium carbonate, etc. While,
the organic base is exemplified by tri-lower (Cl 4)alkyl-
substituted amines such as trimethylamine, triethylamine,tributylamine, etc. and N-lower (Cl 2)alkyl-substituted
5- to 6-membered cyclic amines such as N-methylpyrrolidine,
N-ethylpyrrolidine, N-methylpiperazine, N-ethylpiperazine,
etc. When any of said N,N-dimethylformamide, N,N~dimethyl-
acetamide and N-methylpyrrolidone is used as the solvent,
the above-mentioned base may not necessarily be added.
While the addition level of such base depends on the kinds
of starting material and solvent, it may range from O.S to
1.5 moles pex mole of compound (IV). The reaction is
generally conducted at 0 to 40C, although the reaction
system may be cooled or warmed to control the reaction
rate. The reaction may to completion in 10 minutes to 4
hours. The resulting compound of formula (V) can be
separated and purified by the conventional procedure such
as distillation, pH adjustment, crystallization, recrystal-
lization, etc. When the a -isomer i5 included as an
impurity, it-can be separated by the conventional procedure
such as fractional crystallization, chromatography, etc.
Since compound (V) has basic amino group in 2-position of
the thiazole ring, it may be converted to the salt with
an organic acid such as acetic acid, tartaric acid,
~4~23
-- 10 --
methanesulfonic acid, etc., an inorganic acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid,
phosphoric acid, etc~ or an acidic amino acid such as
arginine, aspartic acid, glutamic acid, etc. by the con-
ventional procedure and isolated as such salt.
The compound (V) or a salt thereof is then reacted
with compound (VI) and, if W is S, the reaction product
is further oxidized to a compound of formula (VII) or a
salt thereof.
The compound (V) may be one having a free amino
group or one in which the amino group has formed a salt
with one of the acids as mentioned above. Theoretically,
one molar equivalent of compound (VI) may be reacted with
one equivalent of compound (V) or a salt thereof. Usually,
however, 1.5 to 2.0 equivalents of compound (VI) may be
used per mole of compound (V) or a salt thereof. This
reaction is conducted in a solvent.
The solvnet is preferably a ketone such as acetone,
methyl ethyl ketone, etc. or a nitrile such as acetonitrile,
propionitrile, etc.
~ base may be added to the reaction system for the
purpose of conducting the reaction advantageously. The
base may be any base that will promote the reaction and
is preferably an alkali carbonate such as potassium
carbonate, sodium carbonate, sodium hydrogen carbonate,
etc. The amount of such base may be 1.5 to 10 molar
equivalents, preferably 1.5 to 5 equivalents, based on
starting compound (V). For a smooth conduct of the reac-
tion, it is preferable to add water to the reaction system,
and particularly to the solvent, and the addition level
of water may be 0.1 to 2% by volume, preferably 0.5 to
1.5% by volume, relative to the solvent. The reaction
temperature may be 10 to 60C and preferably 20 to 50C.
Under these conditions the reaction proceeds quantitatively
and the starting materials disappear in 0.5 to 3 hours.
rrhus, the reaction may be completed at this time point.
323
After completion of the reaction, the desired ~y~-isomer
(V') can be separated and purified by the conventional
procedure such as extraction, pH adjustment, chromatography,
etc.
When W of compound (V) is S, the resulting compound
of the formula [i.e. the formula (V') wherein W is S]:
N ~ C-COOC2H4SR (VII')
N\ ll
O-C-COOC(CH3)3
R2
wherein the symbols are as defined hereinbefore, is further
oxidized to compound (VII). This oxidation of sulfide to
sulfone is conducted using an oxidizing agent such as
hydrogen peroxide, ozone or a peracid (e.g. sodium meta-
periodate, perbenzoic acid, etc.). Among others, hydrogen
peroxide, etc. is employed. The reaction may be readily
accelerated by adding a catalyst to such oxidizing agent.
For example, when hydrogen peroxide is used as the
oxidizing agent, the addition of a catalytic amount of
ammonium molybdate, sodium tungustate or the like
accelerates the reaction. The amount of oxidizing agent
may ~e 2 to 15 molar equivalents, pre~erably 2 to 7
equivalents, relative to the sulfide. This reaction may
be conducted at 0 to 40C, and preferably at room tempera-
ture. The reaction may go to completion in 2 to 7 hours.
This reaction is conducted in a solvent. As the solvent,
there may be employed a hydrophilic solvent such as
acetone, acetonitrile, glacial acetic acid, etc~, for
instance,and these solvents may be used in admixture with
water.
The resulting sulfone (VII) can be separated and
purified by the conventional procedure such as extraction,
crystallization,~chromatography, etc. However, since
~2~23
- 12 -
this reaction is substantially not accompanied by side
reactions, the reaction mixture may be directly submitted
to the next reaction step, i.e. hydrolysis under alkaline
conditions, on completion of the oxidation reaction.
The compounds (V'), (VII') and (VII), as well as
compound (V), have an amino group in 2-position of the
thiazole ring and, therefore, can be converted to a salt
such as those mentioned for compound (V) before isolation.
However, the reaction mixture as such i~s preferably
submitted to^the next hydrolysis step without separation of
compound (VII) or a salt thereof.
The compound (VII) or a salt thereof prepared as
above is then hydrolyzed in the presence of a base to give
the desired compound (I) wherein W' is OH or a salt thereof.
While it is more convenient to use the reaction mixture
from the synthesis of (VII) than to employ the isolated
compound (VII), the latter may of course be employed either
as a free compound or in the form of salt referred to
above. Hydrolysis of compound (VII) or a salt thereof
may be conducted by permitting a base to act on (VII) or
a salt thereof. The hydrolysis may be conducted a hydro-
philic solvent. Water may be added to accelerate the
reaction. When a base was employed in the synthesis of
(VII), the addition of water alone to the reaction mixture
causes hydrolysis to take place in succession to the
formation of (VII). The hydrophilic solvent may for
example be an alcohol, e.g. methanol; ethanol, etc.; a
ketone, e.g. acetone, etc.; or a nitrile, e.g. acetonitrile.
The amount of the solvent may be 2 to 50 volumes, preferably
5 - 10 volumes, relative to the compound (VII). The
amount of water to be mixed with such solvent may be 0.5
to 10 volumes, relative to the solvent. The hydrolysis
temperature is preferably 5 to 50C. The base may be any
one showing pH ranging from about 9 to 12, and may for
example be an alkali carbonate such as potassium hydrogen
carbonate, potassium carbonate, etc. or an organic amine
~2~3Z3
such as triethylamine, isopropylamine, etc. The amount
of the base is preferably one molar equivalent to about
~ equivalents, relative to the compound (VII) or a
salt thereof and the hydrolysis generally may go to
completion in 30 minutes to 2 hours. The resulting com-
pound (I) wherein W' is OH can be separated and purified
by the conventional procedure mentioned hereinbefore.
However, the reaction mixture as such may be submitted
to the next step without separation of the compound (I)
wherein W' is OH. The product compound (I) wherein W'
is OH can be converted to an acid salt at the 2-amino
group of the thiazole ring just as mentioned for compounds
(V) and (VII), and because it has a carboxy group, can
also be converted to the salt of an alkali metal such as
sodium, potassium, etc. or an alkaline earth metal
such~às ~alcium, magnesium, etc. by the conventional
procedure.
The product compound (I) wherein W' is OH thus
` obtained can be easily converted to an active thioester
at the carboxy group thereof, i.e. the compound (I)
wherein W' is -S ~ ~ and can be used as an advantageous
acylating agent in the synthesis of ~-lactam antibiotics.
In this application, the steps of protecting the amino
group prior to the acylation reaction to prevent side
reactions and removing the protective group for the amino
group after the acylation reaction, which are necessary
in the conventional method for producing the ~-lactam
antibiotics, can be omitted~ N
` The compound (I) wherein W' is ~S~~s ~ is
produced by reacting the compound (I) wherein W' is O~
with 2,2-dithiobis-benzothiazole. 2,2-Dithiobis-benzo-
thiazole may be used in an amount of 1 to 4 moles per
mole of (I) wherein W' is OH. The reaction may be
conducted in an inactive organic solvent having no hydroxy
group in its molecule. A phosphine or phosphite may be
added to the reaction system to accelerate the reaction.
23
- 14 -
As such a phosphine, use may be made of aryl phosphines
such as triphenyl phosphine, and as such a phosphite~ use
may be made of tri-lower alkyl phosphites such a.s trimethyl
phosphite or triethyl phosphite. The phosphine or
phosphite is preferably used in an amount of 1 to 2 moles
per 1 mole of (I) wherein W' is OH~ The inactive organic
solvent in this reaction includes halogenated hydrocarbons
such as dichloromethane, chloroform, etc., nitriles such
as acetonitrile, propionitrile, etc., esters such as
ethyl acetate, isopropyl acetate, etc. Among them, nitriles
such as acetonitrile, for instance~ are especially
preferable. The amount of the solvent may be 10 -50 times
(weight) of that of the compound (I) wherein W' is OH. In
order to dissolve ~I) wherein W' is OH, a base may be
added to the solvent. For example, an organic base such
as pyridine, N-methylmorpholine, triethylamine, etc. may
be used as the base. The amount of the base may be 1- 2.5
moles per 1 mole of (I) wherein W' is OH. The reaction
temperature is normally -30C -50C, preferably -20C - 25C,
more preferably -5C -5C. The reaction time is usually
about 1 -20 hours. Generally, thus obtained compound (I)
wherein W' is 2-benzothiazolylthio(-S <N ~ ) f~rms
precipitation and so may be isolated by filtration. If
necessary, before the filtration, putting the obtained
reaction mixture into water, extracting the aqueous-solution
with such an organic solvent as mentioned above and then
adding n-hexane, etc. to the extract in this order may be
conducted to get the compound (I) wherein W' is 2-
benzothiazolylthio as precipitates. Thus, e.g. 2-(2-amino~
thiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-acetic
acid or 2-(2-aminothiazol-4-yl)-(Z)-2-(1-t-butoxycarbonyl-
l-methylethoxyimino) acetic acid may be converted to a 2-
benzothiazolethio ester, then the latter may be reacted
with 7-amino-3-pyridinomethyl-3-cephem-4-carboxylate, and
finally the protective group for the carboxy group may
be eliminated in the conventionlal manner to give 7-[2-(2-
323
- 15 -
aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido]
3-pyridinomethyl-3-cephem-4-carboxylate or ceftazidime
(U.S.P. 4,258,041).
In practicing the above method, 7-amino-3-pyridino-
methyl-3-cephem-4-carboxylate is reacted with the 2-
benzothiazolethio ester in a proportion of 1 mole of the
former to at least 1 mole, preferably 1-4 moles of the
latter. The reaction may be carried out in a solvent.
The solvent includes water, acetone, dioxane, acetonitrile,
methylene chloride, chloroform, dichloroethane, tetra-
hydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-
dimethylacetamide, pyridine and other common organic
solvents inert to the reaction. Hydrophilic solvents may
be used in admixture with water. The reaction may also
be conducted in thepresence of such a base as an alkali
metal carbonate, a trialkylamine (e.g. trimethylamine,
triethylamine, tributylamine~,N-methylmorpholine, N-
methylpiperidine , N,N-dialkylaniline, N,~-dialkylbenzyl-
amine, pyridine, picoline, lutidine, 1,5-diazabicyclo(4,3,0)-
non-5-ene, 1,4-diazabicyclo(2,2,2)octane or 1,8-diazabi-
cyclo(5,4,~)undecene-7. When the base
is a li~uid, it may also serve as the solvent. A
preferable solvent is a halogenated alkane such as methylene
chloride, etc., and as a base, for example, an trialkyl-
amine such as trimethylamine, etc. is advantageously used.
The reaction temperature is not critical but, generally,
the reaction is carried out in many cases with cooling
or at room temperature. The reaction is complete in
several minutes to a few scores of hours. The reaction
temperature and time are 0 -40C and a few minutes to
several hours, respectiveIy, to gain a good result. The
protective group for the carbo~yl group of thus obtained
compound may be removed in the conventional manner, e.g.
acid or base catalysed hydrolysis~ The reaction product
can be recovered and purified by per se known methods,
such as concentra~ion, pH adjustment, phase transfer,
8Z3
- 16 -
solvent extraction, crystallization, recrystallization,
fractional distillation and chromatography.
And, in the same manner as mentioned above, the 2-
benzothiazolethio ester of 2-(2-aminothiazol-4-yl)-(Z)-2-
(t-butoxycarbonylmethoxyimino)-acetic acid may be reacted
with 7-amino-3-methylthiomethyl or [(5-methyl-1,3,4-
thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid,
and then the protective group of the carboxyl group in
the t-butoxycarbonylmethoxyimino moiety may be removed to
produce disodium 7~-[2-(2-aminothiazo]-4-yl)-(Z)-2-
(carboxymethoxyimino)acetamido]-3-methylthiomethyl-3-
cephem-4-carboxylate [Compound (A)], or disodium 7~-[2-(2-
aminothiazol-4-yl)-(Z)-2-(carboxymethoxyimino)acetamido-3-
[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-
carboxylate [Compound (B)]. Thus obtained compounds
(A) and (B) show excellent activity against a broad
spectrum of bacteria inclusive of gram-negative bacteria,
such as Escherichia coli, Serratia marcescens, Proteus
. _ . ~ .
rettgeri, Enterobacter cloacae and Citrobacter freundii,
and are resistant to ~-lactamase. The Compounds (A) and
(B) may be used, for example as a disinfectant for
removing the aforesaid microorganisms from surgical instru-
ments or as an anti-infective agent. When -the Compounds
(~) and (B) areemployed as an antiinfective agent, for
example for the treatment of intraperitoneal infections,
respiratory organ infections, urinary tract infections
and other infectious deseases caused by the aforementioned
microorganisms, it may be safely administered to mammals
including humans; mice and rats at a daily dose level of
0.5 to 80 mg per kilogram body weight, preferably 1 to 20
mg on the same basis, in 3 to 4 installments daily. The
compounds (A) and (B) may be administered orally or
parenterally in varied dosage forms .such as injections,
capsules, powders, granules and tablets which may be
manufactured by estabIished or known arts. Where the
compound (A) or (B) is used as an injection, the carrier
~Z~8Z3
- 17 -
may for example be distilled water or physiological saline.
In the case the compound (A) or (s) is used as a capsule,
powder, granules or tablet, the compound (A) or (B) is
employed, for example in admixture with pharmacologically
acceptable, per se known excipients (e.g. starch, lactose,
sucrose, calcium carbonate, calcium phosphate), binders
(starch, gum arabic, carboxymethyl-cellulose, hydroxy-
propylcellulose, crystalline cellulose, etc.), lubricants
(e.g. magnesium stearate, talc, etc.), and disintegrating
agents (e.g. carboxymethyl calcium, talc, etc.).
The following working and reference examples are further
illustrative of this inventionO In these examples, NMR
spectra were determined with a Varian T60 spectrometer
(60 MHz)[manufactured by Varian Analytical Instrument
Division in U.S.A.] using tetramethylsilane as a reference
and the ~ values are expressed in ppm. In the spectra, s
represents a singlet, d a doublet, t a triplet, q a ~uartet,
m a multiplet, J a coupling constant, DMSO dimethyl sulfoxide,
br. broard, and arom. aromatic.
- lg -
Example 1
In 260 ml of methylene chloride was dissolved
87.9 g (1.407 moles) of diketene. ~he solution was
cooled to -35C and 74.2 g (1.045 moles) of chlorine
gas was bubbled into the solution at -35 to -30C for
about 2 hours to prepare a methylene chloride solution
of 4-chloroacetoacetyl chloride. Separately, 100 g
(0.805 mole) of methylsulfonylethanol was dissolved in
130 ml of methylene chloride followed by addition of
63.7 g of pyridine. To this solution was added the
above methylene chloride solution of 4-chloroaceto-
acetyl chloride at -5 to 0C dropwise over.a period
of about 1.5 hours. The mixture was then stirred
for 30 minutes and poured in water, and 800 ml of
methylene chloride was added to extract the reaction
product~ The water layer was further extracted with
methylene chloride and the organic layers were com-
bined and washed with water. The organic solution
was concentrated to dryness and the concentrate was
dissolved in 50 ml of methylene chloride and crystal-
lized by addition of 200 ml of isopropyl ether togive 156.3 g (yield: 80% based on m~thylsulfonylethanol)
of methyIsulfonylethyl 4-chloroacetoacetate as white
crystals.
23
- 19-
NMR (60MHz, CDCI 3 ) ~i: 3. 00 ~3H. s,
S 0 2 C H 3 ), 3 . 3 8 ( 2 H, t, J = 7 H z, - C H
~ S 0 2 - ~ . 3 . 7 2 ( 2 H . s, C O C H 2 C O ) 4 .
2 5 ( 2H. s, Cl CH2 CO) . 4. 60 ( 2H. t,
J=7HZ . COCH2 CH2 )
K B r
I R v ctn~l : 3 4 3 O. 1 7 4 5 . 1 7 3 0
~ a x
I, . ..
Example 2
In 315 ml of glacial acetic acid was suspended
156.3 g (0.644 mole) of methylsulfonyle-thyl 4-chloro
acetoacetate as obtained in Example 1. The suspension
was cooled to 50c or below and a solution of 44.4 g
(0.644 mole) of sodium nitrite in 140 ml of water was
added at 0-5 C over a period of about 2 hours. The
mixture was stirred for 30 minutes, poured in ice~water
and extracted with ethyl acetate. The organic layer
was washed with water and dried over anhydrous sodium
sulfate. The solvent was then distilled off to give
148.7 g of methylsulfonylethyl 4-chloro-2-hydroxyimino-
acetoacetate as an oil.
NMR ( 6;~0MHz~, DMSO- d6 ) ~: 1 . 90 (3H.
: s . S: 0 2 :C H 3 ) , 3 . 5 2 ( 2 H . t . J = 7 H Z
C ~S O 2 - ~ . 4 . 5: 8 ~ 2 H . t . J = 7 H Z . C H
: 2 C H 2 S 0 2 ) . 4 . 8 7 ( 2 H . s . C I C H 2 -' )
` I R ( N eat ~) cm~l: 3 2 5 0 . 1 7 5 0 . 1 7 1 0 . 1 6 3 5
i :
: :
:
~2~8;~3
-20-
Example 3
In a mixture of 594 ml of ethanol and 60 ml of
water was dissolved 148.7 g (0.613 mole) of oily
methylsulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate
as obtained in Example 2, and 50.0 g (0.656 mole) of
thiourea and 74.4 g (0.547 mole) of sodium acetate
were directly added. The mixture was stirred at 25-30C
f~r about 30 minutes and 300 ml of ethanol was added.
The mi~ture was cooled to 0C or below, and the crystalline
precipitate waS collected by filtration to give 104.3 g
of methylsulfonylethyl 2-(2-aminothiazol-4-yl~-(Z)-2-hydroxy-
iminoacetate as white crystals. (Yield: 55.2~ based ~n methyl-
sulfonylethyl 4-chloroacetoacetate)
Element~l analysis
Calcd. for C 8 H 1l N 3 0 5 S 2 = 2 9 3 . 3 1
C3 2. 76Yo, H3. 78%. N1 4. 33%
Found: C 3 2 2 2 %. H 3 . 7 2 %, N 1 3 . 9 5 %
INMR (60MHz, Dl~lS0-- d6 ) ~: 3. 00 (3H.
S , SO 2 CH3 ) . 3. 58 (2H. t . J=7HZ . --
CH2S02 ) . 4. 62 (2H. t . J=7HZ . COC
H 2 C H 2 ) . 6 . 9 0 ( 1 H . s, thiazole 5 - H ) .
7 . 1 0 ( 2 H. s . N H 2--)
KBr
I R ~ c7n~l: 3 4 5 0, 3 3 0 0. 1 7 2 0. 1 6 1 0.
a x
1 535. 1 408. 1 290
.. . .
3Z3
-21-
Example 4
In 200 ml of acetone was suspended 10 g (0.0341 rnole)
of methylsulfonylethyl 2-(2~aminothiazol-4-yl)-(Z)-2-hydroxy-
iminoacetate as obtained in Example 3. After a serial
addition of 9.98 g (0.0512 mole) of t-butyl bromoacetate,
O.6 ml of water and 18.85 g of anhydrous potassium
carbonate, the mixture was stirred at 40C for 2 hours
followed by addition of 200 ml of water. The mixture
was stirred at 30-35C for about an hour, whereby
the methylsulfonylethyl group was hydrolytically eliminated.
Then, ethyl acetate was added to the hydrolysis reaction
mixture. The organic layer was extracted
with water and the aqueous layers were
combined and adjusted to pH 2 with 2 N HCl. The resulting
white crystalline precipitate was collected by filtration
and dried to give 9.0 g of 2-~2-aminothiazol-4-yl)-(Z)-2-
(t-butoxycarbonylmethoxyLmino)acetic acid. (Yiled, 87.6%)
Elemental analysis
I Calcd. for C 1I H ~ N 3 0 s S 0. 5 H 2 0 :
20 1 C 4 2. 5 8 %? H 5 . 2 0 %. N 1 3 . 5 4 %.
S1 O. 33%
~ound: C 4 2 .. 6 2 %. H 5 . 2 3 %. N 1 3 7 4 %.
S1 0.: 8 7%
NMR (60MHZ . DMSO- d6 ) ~: 1. 42 (9H.
I s . C (CH3 ) 3 ) . 4. 55 ~2H, s . OCH2 CO)
6 . 8 2 ( 1 H. s, thiazole - H ) . 7 . 2 0 ( 2 H.
br., NH2 t
K B r
I R ~ : 3 3 5 O, 1 7 4 5. 1 6 4 0
. . m a x
~2~8Z3
-22-
O Isolation of the synthesi~ intermediate, i.e. methyl-
sulfonylethyl 2-(2-ami~othiazol-4-yl)-(Z)-2-(t-butoxy-
carbonylmethoxyimino)acetate,and its physical properties
The above-reaction mixture was poured in aqueous
hydrochloric acid and extracted with ethyl acetate. The
organic layer was washed with water and concentrated
to dryness and the concentrate was crystallized from
ethyl acetate-isopropyl ether (1:5) to give the desired
product.
I N M R ( 6 0 M H z, D M S O - d 6 ~ ~: 1 . 4 2 ( 9 H , s,
C (CH3 ) 3 ), 2. 99 (3H. s, CH3 SO2 ) .
3. 58 ( 2~. t . J=7Hz . -CH2 SO 2 ) .
4. 59 ( 2H. s, OCH2 COO), 4. 6 1 ( 2H. t,
J= 7Hz . -OC~_CH2 S02 ), 6. 9 8 ( 1 H. s,
¦ thiazole'- H ) . 7 . 2 6 ( 2 H, s . N H 2 - )
K B r
I R 1~ c~~l : 3 4 1 O. 1 7 5 O. 1 7 1 5. 1 5 2 3.
m a x
, 1 ~ 4 0
Example 5
In 120 ml of acetone was suspended 6 g (0.0205
mole) of methylsulfonylethyl 2-(2-aminothiazol 4-yl)-(Z)-
2-hydroxyimlnoacetate as obtained in Example 3,
followed by a serial addi:tion of 4.6 g (0.0307 mole)
of t-butyl chloroacetate, 0.36 ml of water,
lZ~323
-~3-
11.31 g of anhydrous potassium carbonate and 6.13 g of
sodium iodide. The mixture was stirred at 40C for
4.5 hours. To thisreaction mixture was added 120 ml o~
water~ and the mixture was stirred at 30-35C for an hour.
S Ethyl acetate was then added as an extxaction solvent.
The organic layer was separated and
extracted with water. The aqueous layers were combined
and adjusted to pH 2 with 2 N HCl. The resulting white
precipitate was collected by fil~ration and dried to give
4.63 g (yield, 75~) of 2-(2 aminothiazol-4-yl) ~Z)-2-(
t-butoxycarbonylmethoxyimino)acetic acid as white crystals.
Exampl~e 6
(1~ In 2.52 liters of methylene chloride was
dissolved 840 g of diketene, The solution was cooled to
-30C or below and 708 g of chlorine gas was bubbled
into the solution at -35 to~-30C for about 2 hours.
The solution was stirred for 30 minutes and a solution
of 953 g of methylsulfony}ethanol and 608 g of pyridine
in 1.2 liters of ethylene chloride was added at -20C
or below over a period - of within 30 minutes. The tem-
,
perature was increased gradually and the reaction was
allowed to proceed at -5C for about an hour. After
completlon of the reaction, 8 liters of methylene
chloride was added and the mixture was poured into
,
-
3Z3
_24-
7 liters of water. After phase separation, the aqueous
layer was extracted with methylene chloride. The
or~anic layers were combined, washed with water and
concentrated to dryness under reduced pressure to
give colorless crystals.
(2~ The above-obtained crystals were suspended
in a mixture of 1.875 liters of ethyl acetate and 3.75
liters of glacial acetic acid. The suspension was
cooled to 5C or below and a solution of 530 g of sodium
nitrite in 1.665 liters of water was added dropwise at
0-5C over a period of about 2 hours. After completion
of addition~ the reaction was allowed to proceed for
30 minutes, as the end of which time the reaction mixture
was àdded to lO liters of ice water to extract.
The aqueous layer was separated and further extracted
with 5 liters of ethyl acetate. The organic layers
were combined~ washed with water and concentrated to
dryness under reduced pressure to give an oil.
~3~ The above-obtained oil was dissolved in a
2Q mixture of 8.34 liters of ethanol and 0.43 liter of water,
and 530 g of thiourea and 1045 g of sodium acetate were
directly added. The reactlon was allowed to proceed at
room temperature for an houF. The reaction mixture
,
8Z3
-25-
was concentrated under reduced pressure and 8 liter
of ethanol was added to the residue. The mixture was
then cooled to 5C or below and the crystalline
precipitate was collec~ed by filtration and dried in
vacuo at 40C to give 1250 g of methylsulfonylethyl 2-
(2-aminothiazol-4-yl~-~Z)-2-hydroxyiminoacetate. (Yield:
55.5% based on methylsulfonylethanol)
N M R (60MHz . DMS0- d6 ) ~: 3. 02 (3H.
s, S02 CH3 ) . 3. 58 (2H. t . J=7Hz, C
H2S02 ) . 4. 60 (2H. t . J=7HZ . OC112
C H 2 ), ~ . 9 0 ( 1 H, s, thia~ole 5--H ), 7 .
1 6 (2H. s . NH2--~ -
i R ~KBr ) cm~l: 3450. 3300, 1 720.
1 61 0. 1 535, 1 4 1 0
Ex`ample 7
In 200 ml of acetonitrile was suspended 10 g of
methylsulfonylethyl 2-(2-aminothiazol-4-yl) (Z)-2-hydroxy-
iminoacetate as obtained in Example 3, and 7.7 g of
t-butyl chloroacetate was added~ Then, after a serial
addition of 1.2 ml of water~ 18.85 g of anhydrous
potassium carbonate powder and S.6 g of sodium iodide,
the reactlon was allowed~ to proceed at room temperature.
After completlon~of the reaction, the precipitate was
filtered off. To the filtrate was added 300 ml of
water~ and a 40~ solutLon of potassium carbonate was added,
lZ~L~8Z~
-26-
dropwise for hydrolysis while maintaininy pH at 10-lO.S.
The reaction mixture was then adjusted to pH 2 with
2 N hydrochloric acid, whereupon a white precipitate
separated out. After cooling to 5C or ~elow, the
crystalline precipitate was collected by filtration and
dried to give 7.09 g of 2-(2-aminothiazol-4-yl)-(Z)-2-
~t-butoxycarbonylmethoxyimino)acetic acid as white crystals.
NMR (60MHZ . DMSO- d6 ) ~: 1. 40 (9H.
s, C ~CH3 ) 3 ) . 4. 53 (2H. s, OCH2 CO)
6 8 0 ( 1 H, s, thiazole 5--H ) . 7. 2 0 ( 2 H. br.
~ KE3r
I R Y cm~l : 3 3 5 O. 1 7 4 5 . 1 6 4 0
~ a x
Example 8
(1) In 100 ml of acetone was suspended 5 g (0.017
2Q mole) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-
2-hydroxyiminoacetate and 5.33 g (0.0255 mole) of t-butyl
2-bromopropionate was added. After a serial addition
of 0.3 ml of water~ and 9.4 g of anhydrous potassium
carbonate, the mixture was stirred at 40C for about
2.5 hours. After completion Oe the reaction, the
insoLuble matter w~s fi1teFsd off~ To the filtrate was
323
-27-
added 100 ml of water and the mixture was exkracted
with 150 ml of ethyl acetate. The organic layer was
washed with 50 ml of saturated aqueous sodium chloride soluti~n
and dried over anhydrous sodium sulfate. The sodium
sulfate was filtered off and the filtrate was concentrated
to dryness under reduced pressure. The concent~ate was
crystallizel from-ethyl acetate-isopropyl ether (1:5, v/v). After
cooling to 0C or below, the crystalline precipitate
was collected by filtration and dried under reduced
pressure to give 5.4 g (yield, 75.4%) of methylsulfonyl-
ethyl 2-.(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-
l-methylmethoxyimino)acetate as white crystals.
Elemental analysis
Calcd. ~or C ~ H ~ N 3 0 7.S 2 = 4 2 1 . 4 ~
C4 2. 75%. H5. 50%, N9. 9 7%
, Found: C4 2. 98%. H5. 3 1 %, N9. 7 1 %
NMR ( 60MHz . DMS0- d6 ) ~: 1 . 3 1~1 . 4
4 ( 1 2H, m . CH~ -CH & C (CH3 ) 3 ) . 3. 0
2 t3H. s . S02 CH3 ) . 3. 49 (2H. t, J=
7Hz, C~2 SO2 ), 4. 5 0~4. 7 5 (3Hg m .
C 0 0 C H 2 ~ C H--C H 3 ), 6 . 9 6 ( 1 H . s, thia-
` zole 5--H ) . 7. 2 5 ( 2 H, s, N H 2 )
IR vmax cm : 3400-2995, 1750, 1720, 1630, 1550
(2) In a mixture of 12 ml of acetone and 6 ml of
water was dissolved 0.3 g (0.71 millimole) of methyl-
:
~ Z 3
-28-
sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-t-bu-toxycarbonyl-
l-methylmethoxyimino)acetate as obtained in (1). The
solution was warmed to 30-32C and a 40% aqueous solution of
potassium carbonate was added dropwise while maintaining the
pH at 10-10.5. The reaction mixture was ad]usted to pH
about 6 with lN HCl and the solvent was distilled off
under reduced pressure. Then, pH was further adjusted to
2 with lN HCl, whereupon a white crystalline precipitate
separ~ted out. A~ter cooling, the precipitate was
collected by filtration and dried to give 0.18 g (yield,
80.3%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-
l-methylmethoxyimino)acetic acid as white crystals.
,~. N M R ( 6 0 M H z , D M S 0 - d6 ) ~ : 1 . 3 0 ~
1 ~ 4 a ~ 1 2 H. m , C H 3 - C H & C ( C ~l~L~ _L) .
i 4. 5 5 ( 1 H. q . J = 8 H Z , - C H C H 3 ) .
6. 8 2 ( 1 H. s , thiazole - 5 - H )
K B r
I R . ~ 3 3 5 0~ 1 7 2 5. 1 6 5 0.
j m a x ~ -
i - 1 6 0 5. 1 4 5 5
Elemental analysis
calcd- for C12H17N35S H2
C, 43023%; H, 5.74%; N, 12.61%
Found: C, 43.07~; H, 5.65%; N, 12.36%
.
Z3
Example 9
(1) In 150 ml of methylene chloride was dissolved
39.5 g (0.470 mole) of diketene. The solution was
cooled to -30C or below and 33.4 g (0.47 mole) of
chlorine gas was bubbled into the solution at 35 to
-30C for about 1.5 hours. The solution was stirred for
30 minutes and a solution of 50 g (0.362 mole) of
ethylsulfonylethanol and 28.7 g (0.362 mole) of pyridine
in 75 ml of methylene chloride was added dropwise at
- -20C or below over a period of 30 minutes. The
temperature was increased and the reaction was allowed
to proceed at -5C for about 30 minutes. The reaction
mixture was poured into wa~er and 400 ml of methylene
chloride was added as an extraction solvent.
The aqueous layer was further extracted with methylene
chloride and the organic layers were combined, washed
with water and concentrated to dryness to give 87.0 g
of ethylsulfonylethyl 4-chloroacetoacetate. (Yield,
93.6% based on lethylsulfonylethanol)
INMR (60MHZ . C~CI 3 ) a: 1. 40 (3H. t
J 8HZ . CH2 CH~ ) . 3. O5 (2H n . J=8
HZ j S-O~ C~ CH3 ) . 3; 32 (2H. t . J=8
HZ . CH2 CH~SO2 ) . 3 71 (2H. S . CI C
~ H2 CO--) . 4~ 30 (2H. S . COCH2 CO) 4.
6 O ( 2 H t J = 8 H Z . C O O C H ~ C H 2 S )
. ~ . . . .. . ..
3Z3
- 30 -
IR vmax cm : 1740, 1730
(2) In a mixture of 190 ml of glacial acetic
acid and 75 ml of ethyl acetate w~s suspended 87 g
(0.339 mole) of ethylsulfonylethyl 4-chloroacetoacetate
as obtained in (1). The suspension was cooled to 10C or
belowanda solution of 23.4 g of sodium nitrite in
100 ml of water was added at 0-5C over a period of
about an hour. The mixture was stirred for about an
hour, added to ice water and extracted with ethyl
acetate. The organic layer was washed with water and
dried over anhydrous sodium sulfate. The solvent was
then distilled off under reduced pressure to give
84.8 g of ethylsulfonylethyl 4-chloro-2-hydroxyimino-
acetoacetate as white crystals. (Yieldj 87.6%)
NMR (60MHz . DMSO- d6 ) ~: 1. 20 (3H.
t . J=8HZ, CHz CH3 ), 3. 1 0 ( 2H> q . J
-`8Wz > SO2 CH_2 CH3 ), 3. 5 2 ( 2H. t, J
=8HZ: . CH2 SO2 CH2 ), 4. 60 ( 2H. t, J
1 =8HZ . COOCH2 CH2 ) . 4. 90 (2H. s . C
I C H ~ C O )
: ,. ' ' '
KBr ~ ~
Il I R ` v cm~l : 345C). 1 745. 1 71 O.
1l m a x
I 1 6 3 5
`
~`` ` ~ :
-31-
(3) In a mixture of 384 ml of ethanol and 38.4 ml
of water was dissolved 83.8 y (0.293 mole) of crude
ethylsulfonylethyl 4-chloro-2-hydroxyiminoaceto~cetate
as obtained in (2) and 22.3 g of thiourea and 39.9 g
of sodium acetate were added directly to the solution.
The mixture was stirred at 25-30C for about an hour
and the ethanol was distilled off under reduced pressure,
followed by addition l liter of water. The mixture was
cooledto 5Cor~below and the resulting crystalline
precipitate was collected by filtration to give 45.l g
of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-
hydroxyiminoacetate as white crystals. (Yield, 50.0~)
Elemental analysis
Calcd. ~or (, 9 H ~ N 3 0 5 S 2 = 3 7 3 4
C35. 1 7%. H4. 26%. N1 3. 67%.
S 2 0. 8 6%
Found: C 3 5 . 2 4 % . H 4 . 2 3 % . N 1 3 5 2 % .
S20. 68%: -
NMR (60MHz . DMS0- d6 ) ~: 1. 1 9 (3H.
It 7 J=8Hz . -CH2 CH3 )-. 3. 1 2 (2H. q .
= 8 H Z, S .0 2 C H 2 C H 3 ) . 3 . 5 2 ( 2 H . t .
J=8Hz . -CHz CH2S), 4. 53 (2H. t . J
= 8 Hz . C 0 0 C H z ) . 6 . 9 0 ( 1 H, s, thia~ole
- 5 - H ~ . 7 . 1 5 ( 2 H . s, N H 2 - )
.
K B r ~
I R ~7 C~ 3 4 00~3 1 00. 1 7 3 0.
.
~ax
1 61 S . 1 5 3 5
:
823
-32-
Example 10
(1) In 180 ml of acetone was suspended 6 y
(0.019 mole) of ethylsulfonylethyl 2-(2-aminothiazol-
4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 9
followed by a serial addition of 5.7 g (0.0292 mole)
of t-butyl bromoacetate, 0.9 ml of water and 10.8 g
of anhydrous potassium carbonate. The mixture was
stirred at 40C for 2 hoursand the insoluble matter
was filtered off. To the filtrate was added 200 ml
of water and 200 ml of ethyl acetate was added to
extract the reaction product. The aqueous layer
was further extracted with ethyl acetate. The
organic layers were combined, washed with water and
concentrated to dryness under reduced pressure to give
6.0 g of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-
(Z)-2-(t-butoxycarbonylmethoxyimino)acetate as white
crystals. (Yield~ 73.0~)
~ NMR (60MHz . DMSO- d6 ) ~: 1. 20 (3H.
1I t, J=8HZ, CH2 CH3 ) . 1 . 44 (9H. s, C
(CH3 ) 3 ) . 3. 1 2 (2H. q . J=8Hz, SCH
C H 3 ~ . 3 . 5 5 ( 2 H . t . J = 7 H z . C H 2 S ) .
4. 5 2~4. ~0 (4H. m . COOCH2 CO& COO
G H 2 C H 2 ) . 7 . O O ( 1 H, s, thiazole --5--H )
1 , 7 . 2 8 ( 2 H . s, ~N H 2 - )
~ ;:
. ~:
_33_ ~2~ 3
IR vrnax cm : 3400-2950, 1750, 1740, 1715, 1630
1615, 1550
(2) In 100 ml of acetone-water (1:1, vjv) was
dissolved 5.0 g (0.0119 mole) of ethylsulfonylethyl
2-(2-aminothiazol-4-yl)-(z)~2-(t-butoxycarbonylmethoxy-
imino)acetate as obtained in (1) and a 40% aqueous solution of
potassium carbonate was added dropwise at 30-35C while
maintaining the pH at 10-10.5. After completion of the reaction,
the solvent was distilled off and pH was adjusted to 2
with lN-HCl, whereupon white crystals separated out.
After cooling, the crystals were collected
by filtration to give 2.~ g of 2-(2-aminothiazol-4-yl)-(Z)-
2-(t-butoxycarbonylmethoxyimino)acetic acid. (Yield,
15 78.1%)
The NMR and IR spectra of this product were
in good agreement with those of an authentic sample.
Example 11
(1) In 100 ml of methylene chloride was dissolved
20 20.5 g (0.244 mole) of diketene,and 17.3 g (0.244 mole)
of chlorine gas was bubbled into the solution with cooling
~t -30C; o~ belo~. A solution of 35 g (0.188 mole)of phenyl-
sulfonylethanol and 14.9 g (0.188 mole) of pyridine in 75 ml ofrnethylene
chlorlde was added dropwise to ~the above solution with cool-
ingiat -25C or beI~ over a period of 30 minutes. The
_34~ 8 2 3
mixture was stirred at 0C for about an hour and poured
into ice water for separation. The aqueous layer was
further extracted with 140 ml of methylene chloride .
The organic layers were combined, washed with water
5 and concentrated to dryness to give 54.9 g (yield, 95.8%)
of phenylsulfonylethyl 4-chloroacetoacetate as an oil.
jNMR (60MHZ . DMS0- d~ 3. 49 (4H.
m, C H 2 S 0 2 & 0 C H 2 C 0 ) .4 . 2 0 ( 2 H, s,
C l C.H 2 C 0 ) . 4 . 4 9 ~ 2 H . t . J = 8 H z . C 0
o I V C H 2 C H z )
~. .
!Neat
I R v c7n-l : 1 7 5 5 . 1 7 3 ~ . 1 4 5 O.
~ a x 1 400
(2) In a mixture of 119 ml of acetic acid and
47 ml of ethyl acetate was dissolved 54.3 g (0.178 mole)
of oily phenylsulfonylethyl 4-chloroacetoacetate as
obtained in (1). The solution was cooled to 5C or below and
a solution of 12.3 g (0.178 moL~) of sodium-nitrite;in 63 ml of water
was added dropwise to the above solution over a period
of about an hour. The mixture was stirred for an hour,
poured into 300 ml of ice water and ex-tracted with 500
ml of ethyl acetate. The aqueous layer was further
extrac~ted with 100 ml of ethyl acetate. The organic
layers were ccmbined, wash^d with 100 ml of 5% aqueous
~2~Z3
sodium hydrogen carbonate and concentrated to dryness
-under reduced pressure to give 62.5 g (Yield, 105.2~) of phen~l-
sulfonylethyl 4-chloro-2-hydroxyiminoacetoacetate
as an oil. This oil contained a little amount of
acetic acid as impurity.
NMR (60MH z . CDCI 3 ) ~ : 3. 5 7 ( 2 H. t ,
J`= 8 H z, - C H 2 S O 2 ) . 4 . 5 0 ( 2 H . s . C I
C H 2 C O ~ . 4 . 6 2 ( 2 H . t, J = 8 H z . C O O C
H 2 C H 2 ) . 7 . 5 5 ~ 8 . O O ( 5 H . m, ~rom.)
N ea t
~ I R v cm~l : 3 3 0 0 . 1 7 5 O, 1 7 1 0.
I -~ m a x
~ 1 6 3 0 . 1 5 g 0. 1 4 5 0
(3) In a mixture of 273 ml of ethanol and 27.3 ml
of water was dissolved 62.5 g (0.187 mole, unadjusted-
for purity) of crude phenylsulfonylethyl 4-chloro-2-
hydroxyiminoacetoacetate as obtained in (2),and
14.1 g (0.185 mole) of thiourea and 25.1 g (0.184 mole)
of sodium acetate were added directly to the solution.
The mixture was stirred at 25-30C for about 5 hours
and 1 liter of water was added. The mixture was cooled
to 5C or below and the resulting crystalline precipitate
was collected by filtration to give 28.4 g of phenyl-
sulfonylethyl 2-(2-aminothiazol-4-yl~(Z)-2-hydroxyimino-
,
323
-36-
acetate as white crystals. (Yield: 44.9% based on phenyl-
sulfonylethyl 4-chloroacetoacetate~
Elemental analysls
Calcd. for C 13 H 13 N 3 0 s S 2 = 3 5 5- 3 3
C43. 94%, H3. 69%. N1 1. 82%.
S 1 8. 04%
ound: C 4 3 . 9 0 %. H 3 . 7 3 % . N 1 1 4 O % -
S1 7. 37%
NMR (60MHz . DMSO- d6 ) a: 3. 77 (2H,
, t, J =8 H2 . -CH 2 S ) , 4. 4 8 ( 2 H. t, J=.
8Hz . COCH2 CH2 ) . 6. 8 O ( 1 H. s, thia-
zole--5--H) . 7. 2 O ( 2H, s, NH 2 --) . 7. 5
0 ~ 8 . 0 0 ( 5 H . m, arom.
- K13r
R v c~ 3 4 0 0 ~ 3 1 0 0. 1 7 25.
: m a x -
I . 1 6 1 5. 1 5 3 5
Example 12
(1) In 100 ml of acetone was suspended 5 g
tO.0141 mole) of phenylsulfonylethyl 2-(2-aminothiazol~
4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11.
After a serial addition of 4.0 g (0.0205 mole) of
t-butyl bromoacetate, 0.3 ml of water and 7.7 g of
anhydrous potassium carbonate, the mixture was stirred
at 40C for 1.5 hours. After completion of the reaction,
the insoluble matter was~filtered oFf and 100 ml of
:
23
-37-
water and 100 ml of ethyl acetate were added to extract
the reaction product. The aqueous layer was further
extracted with ethyl acetate and the organic layers were
combined, washed twice with saturated aqueous sodium
chloride and dried over anhydrous sodium sulfate. The
solvent was then distilled off under reduced pressure
and ethyl acetate-isopropyl ether (1:5, v/v) was added
to the residue, whereupon white crystals separated out.
After cooling, the crystals were collected by filtration
to gi~e 4.1 g (yield, 62~) of phenylsulfonylethyl 2-(2-
aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-
acetate.
NMR ~60MHz, DMS0- d6 ) ~: 1. 40 (9H.
s, C ~ C H 3 ) 3 ~, 3 . 7 6 ( 2 H . t, J = 8 H z .
I C H ~ S 0 2 ) . 4 . 4 0~ 4; 6 0 ( 4 H, m,
G 0 0 C H 2 C H 2 & O C H 2 C 0 0 ) . 6 . 8 6 ( 1 H .
S, thiazole --5--H ) . 7 . 2 5 ( 2 H . ~ . N H 2 )
7 . 5 0~ 8 . ~0 0 ( ~ H, m, arom.
~K B r
I R v cm~~: 3 4 0 0~ 2 9 0 0 . 1 7 5 0 .
m a x
1 7 1 0. i 6 2 0. 1 5 5 0
(2) In 20 ml of acetone-water (1:1, v/v) was
dissolved 1 g (0. 00213 mole) of phenylsulfonylethyl
2-(2-aminothiazol-4-yl)-(Z1 -2- (t-butoxycarbonylmethoxy-
,
823
-38-
imino)acetate as obtained in (l), and a 40% aqueous
solution of potassium carbonate was added dropwise to the
solution while maintainLng the pH at 10-10.5. After completion of
the reaction, the mixture was adjusted to pH 6 with
l N HCl and the acetone was distilled off. Then, pH
was adjusted to 2 with 1 N HCl, whereupon white
crystals separated out. After cooling, the crystals
were collected by filtration to give 0.42 g (yield, 65.4%)
of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-
methoxyimino)acetic acid,
I NMR ( 60MHz . DMS0- d6 ) ~: 1 . 4 2 (9H.
s . C (CH3 ) 3~ . 56 (2H. s . 0C~_C0)
6 . 8 5 ( 1 H . s, thiazole -- 5 --tl ~ . 7 . 2 5
. ( 2 H. br, N H 2 - ) . .
.. ' ~ ; ' 'i ' ' :. . '
K 8 r
I R ~ 3 5 5 0~ 2 9 0 0 . 1 7 4 5 .
m a x
1 6 4 5 . 1 6`1 0. 1 5 8 0
Example 13
Using 2 g (0.00563 mole) of phenylsulfonylethyl
2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as
obtained in Example ll and 1.17 g (0.00559 mole) of
t-butyl 2-bromopropionate and following the reaction
- procedure of Example 12, there was obtained 1.63g (yièla, 60.0
of phenylsulfonyletbyl 2- (2-aminothiazol-4-yl)-(Z)-2-
,. ~
. . ~
:
L8;23
-39-
(t-butoxycarbonyl-l-methylmethoxyimino)acetate.
NMR ( 6 OMHz . DMSO-- d6 ) ~: 1 . 3 8~
1 . 4 2 ~ 1 2H. ~, C ~CH3 ) 3 & CH-C~) .
3 . 7 3 ( 2 H . t . J--7 H Z, C H 2 S O 2 ) .
! 4 . 4 5 ~ 4 . 6 0 ( 3 H . m, C O O C H 2 & C H C H 3 )
¦ 6 . 9 0 ( 1 H, s, thiazole - 5 - H ) . 7 . 2 0
(2H. s, NH2 ) . 7. 48~8. OO (5H. m,
aro~.
::
o 1: K B r
I R ~ 3400~2950. 1 745.
ax
~ 1 7 3 0. 1 6 3 O. 1 5 9 5 . 1 5 ~
The above-obtained phenylslllfonylethyl 2-(2-
15 aminothiazol-4-yl)-(z)-2-(t-butoxycarbonyl-l-methylmeth
imino)acetate (1.2 g, 0.00248 mole) was hydrolyzed to give
0.52 ~ (~ield,, 66.5%) of 2-(2-aminothiazol-4-yl)-(Z)-2-
(t-butoxycarbonyl-l~methylmethoxyimino)acetic acid.
The NMR and IR of this product was in good agreement
with those of the product obtained in Example 8.
Example 14
Using 5 g (0.0141 mole~ of phenylsulfonylethyl 2-(2-aminothiazol-
4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 11 and
4.7 g (0.0211 mole) of t-butyl 2-bromoisobutyrate and
following the reaction procedure of Example 12, there was
obtained`4.lg-(yie,ld,~58.4%) oiE phenylsulfonylethyl 2-
(2-aminothiazol-4-yl~-~(Z)-2-(t-butoxycarbonyl-1,1-
8Z3
-40-
: dimethylmethoxyimino)acetate.
NMR ( 60MHz . DMS0- d6 ) ~: 1 . 40 ( 1 5H.
s, C ~CH3 ) ~ &C (CH3 ) 2 ) .
3 ~ 7 2 ( 2 H . t, J = 8 H z . C H 2 S O 2 ) .
4. 60 (2H. t, J=8Hz . COOCH2 ) .
6 . - 9 0 ( 1 H . s ~ thiazole --5--H ), 7 2 7
~2H. s . NH2 ), 7. 49~7. 98 (5H~ m,
arom. )
I`" ~
I K B r : .
I R IJ cm-l : 3 4 0 0 ~ 3 0 0 0, 1 7 5 0,
` - ~ a x
1 71 5. 1 635. 1 595. 1 ~4
Then, the above ester compound was hydrolyzed
to give 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-
l,l-dimethylmethoxyimino)acetic acid. (Yield, 72.0~)
Elemental analysis
.
I Calcd.~o~ ~ H 19 N 3 0 5 S 0. 7 H 2 0 = 3 4 1 . 9 8
1 C 4 5 . 6 7 %, H 6 . 0 1 %. N 1 2 . 2 9 ~
¦ Found: C 4 5. 9 9 ,~, H 6. 3 2%. N 1 2 3 2%
!NMR ~60MHz, DMS0- d6 ) 8 :-1. 41 ~1 5H.
s, C (CH i ) 2 &C ( CH~ ) ~ ) . 6. 79 (s . 1
H, thiazole - 5 H ): . 7 . 2 0 ( 2 H, br~ - N H 2_)
~ : :
K B r
I R lJ c~ 3 4 0 0~ 2 9 0 0 . 1 7 2 0 .
`: m a x
: ~ 1 6 4 5, 1 6 0 0
.
~4~ 3
-41-
E~ample 15
(l) In 1.26 liters of methylene chloride was
dissolved 420 g (5.0 molesj of diketene. Ihe solution was o~oled
at -30 to -35C and 354 g (4.99 moles) of chlorine gas
was bubbled into the solution for about an hour to
prepare a 4-chloroacetoacetyl chloride solution.
244 ml of this solution (4-chloroacetoacetyl chloride:
109.2 g, 0.705 mole) was cooled to -30 to -40C
and a solution of 50 g (0.543 mole) of methylthioethanol
and 43 g (0.543 mole) of pyridine in 85 ml of methylene
chloride was added dropwise at -20 to -30C over a
period of about 30 minutes. After completion of
addition, the reaction was allowed to proceed at -5C
for 30 minutes. To the reaction mixture were added 500 ml
of methylene chloride and l liter of water to extract
the reaction product. The aqueous layer was further
extracted with 500 ml of methylene chloride. The
organic layers were combined, washed with 500 ml of
water and concentrated to dryness under reduced pressure
to give 114 y of methylthioethyl 4-chloroacetoacetate
as an oil.
NMR ~60MHz . DMSO-- d6 ) ~: 2. i O (3H.
s, S--CH 3 ) . 2. 7 1 ( 2H. t, J-8Hz . CH
2 S--(~H3 3 ~ 3. 7 2 ~ 2H, s, COC~CO~ 4.
25 ~2~H. t . J=8HZ . COOGH 2 CH2 ) . 4.
60 (2H. s . Ci CH 2 CO ) - ~
,,.
~ : :
8;23
-42-
IR vmaxa cm : 1750-1730, 1670
(2) In a mixture of 115 ml of ethyl acetate
and 230 ml of glacial acetic acid was dissolved 114 g
(0.541 mole) of crude methylthioethyl 4-chloroaceto-
acetate as obtained in (1). The solution was cooled to 5Cor below and a solution of 37.5 g (0.543 mole) of
sodium nitrite.in 118 ml of water was added dropwise to the
solution atl 5c or below over a period of about 2 hours.
The reaction mixture was poured into 1 liter of ice
water to extract the reaction product. The aqueous
layer was further extracted with 1 liter of ethyl
acetateO The organic layers were combined, washed with
400 ml of 5% aqueous sodium hydrogen carbonate and
concentrated under reduced pressure to give 130 g
of methylthioethyl 4-chloro-2-hydroxyiminoacetoacetate
as an oil.
NMR (60MHz . DMS0- d6 ~ ~: 2. 1 ~ (3H.
. s . S--CH 3 ) . 2. 75 (211. t . J=8Hz CH
2 CH2 S) . 4. 40 ~2H. t, J=8Hz . COOC:
`~2_CH2 ) . 4. 89 (2H. s . Cl CH~C0)
~ Neat:
I R ~ c7n~l: 3 1 5 0~3 0 0 0. 1 7 4 5 . 1 7 1 5
: - m a x
3Z3
- 43 -
(3) In a mixture of 520 ml of ethanol and 28 ml
of water was dissolved 130 g (0.542 mole) of methylthio-
ethyl 4-chloro-2-hydroxyiminoacetoacetate as obtained
in (2), and 41.3 g (0.543 mole) of thiourea and 73.9 g
(0.543 mole) of sodium acetate were added. The reaction
was allowed to proceed at room temperature for 60 minutes.
The solvent was then distilled off under reduced
pressure, followed by addition of 300 ml of water.
The mixture was cooled and the crystalline
precipitate was collected by filtration and dried
under reduced pressure to give 72.6 g (yield: 51.2% based on
methylthioethanol) of methylthioethyl 2-(2-aminothiazol-
4-yl)-(z)-2-hydroxyiminoacetate as white crystals.
Elemental analysis
Calcd. for C 8 ~ 1I N 3 0 3 S 2 = 2 6 1 . 3 1
C36. 77%. H4. 24%. N1 6. 08%
Found: ~ 3 6 . 7 1 % . H 4 . 2 3 % . N 1 5 . 9 4 %
NMR (60MHz . DMS0-- d6 ) 8 ::2. 1 1 (3H.
s, S-CH3 ) . 2. 77 (2H, t . J;=8HZ,
C 2 S ~ . 4 . 3 8 ~ 2 H . t , J = 8 H z .
C H 2 C H 2 S ) , 6 . 8 4 ( 1 H . s, thia~ole-
5 - H ) . 7 . 1 5 ( 2 H ,~ s . N ~ 2 )
~ ~ K~B r ~
I R v~ cm-l: 3 4 0 0~3 1 5 0, 1 7 2 0.
m a: x ~
1 61 0. 1 5 3 5
1;~4~2,3
~ -44-
Example 16
(1) In 100 ml of acetone was suspended 5 g
(0.0191 mole) of methylthioethyl 2-(2-aminothiazol-4-yl)-
(Z)-2-hydroxyiminoacetate as obtained in Example 15,
S and 4.32 g (0.029 mole) of t-butyl chloroacetate,
0.3 ml of water, 10.56 g (0.076 mole) of anhydrous
potassium carbonate and 3.15 g (0.021 mole) of sodium
iodide were added in that order. The reaction was
allowed to proceed at 40C for about 6 hours. The
reaction mixture was poured into 300 ml of water and
extracted with 500 ml of ethyl acetate. The organic
layer was washed with water, dehydrated with anhydrous
sodium sulfate and concentrated to dryness under reduced
pressure. Ether was added to the residue to give 6.56 g
~yièld, 91.5%) of methylthioethyl 2 (2-aminothiazol-
4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate as
white crystals.
Elemental anlaysis
I Calcd. for C t4 H 2~ N~3 0 3 S 2 = 3 7 5. 4 6
` C 4 4 . 7 9 %. H 5 . 6 4 %. N 1 1 . 1 9 ~q
Found:- C ~ 5 . 0 7 % . H 5 . 7 8 % . N 1 1 . 0 5 %
NMR (60MHz . D~ISO-- d6 ) ~: 1. -42 (9H.
l s, C H ~ x 3 ) . 2 . 1 0 ( 3 H . S, S C ~
¦ 2. 7 8 ( 2 H, t, J = 8 H z, C~S C H 3 ) .-
4 . 4 0 ~ 2 H. t, J =:8 Hz, COOC~2 CH 2 S ) ,
4. 57 (2:H. s, OGH~CO), 6. 02 (1H. s,
thiazole ~ --5--~ H~, 7 . 2 5~ ( 2 H, s, N H 2--)
;
~ .
Z3
-45-
IR vmax cm : 3400-2900, 1740, 1710, 1625, 1550
(2) In a mixture of 47 ml of acetone and 9.4 ml
of water was dissolved 6.0 g (0.0160 mole) of methyl-
thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-
carbonylmethoxyimino)acetate as obtained in (1), andO.05 g of ammonium molybdate was added. Further, 10.9 ml
(0.112 mole) of 35% aqueous hydrogen peroxide was added
at 25-30C and the reaction was allowed to proceed
for 6 hours. The reaction mixture was poured into
500 ml of water and extracted with 500 ml of ethyl
acetate. The organic layer was washed with 500 ml of
5% sodium sulfite and 500 ml of water and concentrated
to dryness. To the residue was added about 50 ml of
ether, whereby white crystals separated out. After
cooling, the crystals were collected by filtration to
give 6.1 g (Yleld, 93.6 %) of methylsulfonylethyl 2-(2-amino-
thlazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)-
acetate.
Elemental analysis
Calcd. for C ~ H 21 N 3 0 7 S 2 O- 5 H 2 O
~- = 4 1 6. 4~7; ~ ~ ~
40. 38%. H5. 32%. N1 :). O9%
Found: C 4 0 . 1 1 %. H 5 . 1 5 %. N 9 . 8 9 %
NMR ( 6 OMHZ . DMS0~-- d6 ) a: 1 . 4 2 ( 9 H.
~s .~ CH3 x3), 3. 00 (3H, s, SCH~ ) .
::
Z3
- ~6 -
3. 57 (2H, t . J=8Hz . C ~ Sc H 3 ) . 4.
¦ 55~4. 62 (4H, m, COOC~CHz& OCH 2
j C O O ), 7 . O O ( 1 H . s, thiazole - 5 - H ), 7 .
- 28 (2H. s . NH2-)
K B r
I R v cm-t : 3 4 0 0 ~ 2 9 9 5 . 1 7 5 0 .
m a x
1 7 2 Q. 1 6 2 8 . 1 5 4 5
(3) In a mixture of 200 ml of acetone and 200
ml of water was dissolved 4 g (0.00982 mole) of methyl-
sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-
carbonylmethoxyimino)ac~tate as obtained in (2), and a 40~
aqùeous solution of potassium carbonate was added dropwise to
the solution at 30-35C while maintaining pH at about 10.5. The
reaction mixture was washed with 500 ml of ethyl acetate.
The aqueous layer was adjusted to pH about 2 with 2 N
HCl, whereby~crystals separated out. After cooling
the crystalline precipitate was collected by filtration to
gi~e 2.5 ~ (yield~84.5~) of 2-(2-aminothiazol-4-yl)-
(Z)-2-(t-butoxycarbonylme~hoxyimino)acetic acid as white
crystals.
ElementaI analysis
~ . .. . .. . . .
Calcd. forC 1I H ~ N 3 O 5 S 0. 5 H 2 0 = 3 1 0. 3 2
. ~ C 4:2. 58 oi. H5. 20%. N1 3. 54%
Found: C 4 2 . 9 5 %. H 5 . 1 2 %. N 1 3 . 3 8 %
N M R ( 6 O M H z . D M S O - d 6 ) ~ 1 . 4 4 ( 9 H .
¦~: s . CH3 x3 j, 4. 5 7 ( 2H. s . OC712 CO) .
6 . 8 5 ( 1 H~. s, ~ thiazole --5--H ) 7 2 5
~ :( 2 H. br N H 2 )
l ~ 32~
-47-
IR vKBx cm : 3350-3000~ 1740, 1640, 1600, 1580
Example 17
(1) In 100 ml of acetone was suspended 5 g
(0.0191 mole) of methylthioethyl 2-(2-aminothiazol-4-
yl)-(Z)-2-hydroxyiminoacetate as obtained in ~xample 15,
and 6.4 g (0.0287 mole) of t-butyl 2-bromoisobutyrate,
0.3 ml of water and 10.56 g (0.076 mole) of anhydrous
potassium carbonate were added in that order~ The
reaction was allowed toproceed at 40C for 20 hours.
The reaction mixture was poured into 100 ml of water
and extracted with 100 ml of ethyl acetate. The organic
layer was washed with water and dried over anhyrous sodium sul-
fate and concentrated to dryness. To the residue
was added 50 ml of ether and the mixture was cooled.
The precipitate was collected by filtration to give
6.17 g (yield, 80~ b~) of methylthioethyl 2-(2-aminothiazol-
4-yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)-
acetate as white crystals.
Elemental analysis
l Calcd. for C 16 H ~ N 3 0 5 S 2 - 4 0 3 . 5 1
i ~ ` C4 7. 6~3%. H6. 24%. N1 O. 41%
Found C 4 7 :. 3 7 %, H 6: . 2 3 % . N 1 O . 3 4 %
Nl~tlR ( 6 0M:H z, DMSQ-d 6 ) ~ : 1 . 4 a ( 1 5 H.
~ s .: C :( CH 3 ) ~ & C ( CH 3 ) 2 ) . 2 . 1: 2
~ 3 H . S, --S C H .~ ~ . 2 . 7 8 ( 2 H . t, J 2 8 H2,
. ~ , ~ . - . . . . ,, - , .,
C H_2 S C H 3 ) . 4 . 4 1 ~ 2 H . t . J = 8 H ~ ~ - C
~C H 2 S ) . 6 . 8 8 ( 1 H . s, thia~ole~ - 5
7~ 26 (2H.~S .~NH: 2 - ) ~
:
3Z3
-48-
max cm : 3400_3000, 1735, 1730, 1630, 1550
(2) In a mixture of 25 ml of acetone and 5 ml
of water was dissolved 2.5 g (0.0062 mole) of methyl-
thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-
carbonyl-l,l-dimethylmethoxyimino)acetate as obtained
in (1) ~ and 0.029 g of ammonium molybdate was added,
Then, at 30C, 1.94 ml of 35% aqueous hydrogen peroxide
was added dropwise to the mixture.- The resulting
mixture was stirred at the same temperature for 7.5
hours, poured into 200 ml of water and extracted with
200 ml of ethyl acetate. The organic layer was washed
with 400 ml of 5% sodium sulfite and 200 ml of water
and the solvent was distilled off under reduced pressure.
To the residue was added 100 ml of ether, whereupon
white crystals separated out. After cooling~ the
crystals were collected by filtration to give 2.4 g (yield,
88.9%) of methylsulfonylethyl 2-(2-aminothiazol-4-yl)-
tZ)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)acetate.
Elemental analysis
~ Calcd. for C 16 H ~ N 3 0 7 S 2 = 4 3 ~. 5
C44. 1 3%, H5. 79%. N9. 65%
Found: C 4 4 . 1 5 % . H 5 . 3 3 % . N 9 . 6 0 %
NMR ( 60MHz, DMS0--d 6 ) 8: 1 . 40 ( 1 5H.
s, CH 3 X 5), 3. o4 (3H. s, SCH 3
3 . 5 8 ( 2 H . t, J = 8 H z . C~S C H 3 ) .
4 . 6 2 ( 2 H . t, J = 8 H z . C H 2 C H 2 S C H 3 j >
6~. 9 2 ( 1 H . s, ~thiazole --5--H ), 7 ~ ~3
(~2H. b r. NH 2 - )
~2~ 3
- 49 -
IR vma cm : 3350-3000, 1750, 1725, 1645, 1550
(3) In a mixture of 45 ml of acetone and 45 ml
of water was dissolved 2.2 g (0.00505 mole) of methyl-
sulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-
butoxycarbonyl-l,l-dimethylmethoxyimino)acetate as obtained
in (2), and a 40% aqueous solution of potassium carbonate was added
dro~wise to the solution at 30-35C while maintaining the pH at 10-
10.5. The mixture was stirred for about an hour and
washed with 100 ml of ethyl acetate. The aqueous
layer was adjusted to pH about 2 with 2 N HCl and then
cooled. The white crystals were collected b~ filtration
to give 1.29 g (yield, 77.6%) of 2-(2-aminothiazol-4-yl)-(Z)-
2-(t-butoxycarbonyl~ dimethy~methoxyimino)acetic
acid.
Elemental analysis
Calcd.~for C ~ H ~ N 3 0 5 S O . 7 7 H 2 0
= 3 4 3. 2 3
. C 4 5 . 4 9 % . H 6 . 0 2 % . N l 2 . 2 4 %.
. S 9 3 4 %
Found: C4 5. 4 9%. H 6. 2 2/~, N 1 2. 1 7%.
~ S9. 24%: : ~
NMR (60MHZ. D:MS0-d 6 ) ~i 1. 40 (1 5H.
s, (CH3 ) 3 & C (:CH_3 ) z ), 6. 79 ( 1 H, S,
........
thiazole - 5 - H ) . 7 . 2 0 ( 2 H, br, N H 2 - )
~ ~
K B r
R v cm-l : 3 5 5 0 ~ 2 8 0 0 . 1 7 2 0, 1 6 5 0 .
. m a x
. : 1 63~0. 1 61 0. 1 580. 1 560
.
3Z3
-50-
Example 18
Using 146 g (0.942 mole) of 4-chloroacetoacetyl
chloride (synthesi2ed from diketene and chlorine) and
lOO g (0.942 mole) of ethylthioethanol and following
the procedure of Example 15, there was obtained 138.8 g
of ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxy-
iminoacetate via ethylthioethyl 4-chloroacetoacetate
and ethylthioethyl 4-chloro-2-hydroxyiminoacetate.
(Yield, 53.5% basèd on ethyltllioethanol)
Elemental analysis
Calcd. for C 9 H ~ N ~ 0 3 S 2 = 2 7 5. 3 4
C39. 26%, H4. 76%. N1 5. 26%.
S23. 29%
Fo~ d: C 3 9 . 4 3 %. H 4 . 8 1 %, N 1 5 . O 1 %.
S 2 3. 0 7%
NMR (60MHz. DMSO--d6 ) ~i: 1. 28 (3H.
t . ~ = 8 H z . C H 2 C H 3 .) . 2 . 5 5 ( 2 H . q .
J = 8 H z . CH 2 S CH 2 ) . 2 . 8 0 t 2 H. t .
J 2 8 H z . C H 2_C H 2 S ) . 4 . 3 8 ( 2 H . t ,
J=8Hz. COOC~CH2 ) . 6. 86 (1 H. s,
thiazole ~ 5--H ) . 7 . 1 8 ( 2 H, s . N H z --
; KBr
I R s~ c7n~1: 3 4 0 0 ~ 3 1 0 0 . 1 7 3 0 . 1 6 2 0 .
~` m a x
~ 5 3 b -~
-51-
Physical characteristics of the intermediates
O Ethylthioethyl 4-chloroacetoacetate
¦ N M R ( 6 0 M H z, C D C 1 3 ) ~i : 1 . 2 5 ( 3 H, t,
J = 8 H z . C H z C H 3 ) , 2 ~ 5 5 ( 2 H, q,
J=8Hz, SCHz CH3i ), 2. 77 (2H, t,
J = 8 H z , C H 2 C ~ S ) . 3 . 6 ~ ( 2 H , s ~
COOCH2 CO) . 4. 30 (4H, m, COOCH2 &
C I C H 2 C O ), - - !
., , - . .
o N ea ~ -
I R iJ - cm-l . 1 7 5 0 . 1 7 3 0, 1 6 7 0,
~ a x
O Ethylthioethyl 4-chloro-2-hydroxyiminoacetate
I N M R ( 6 0 ~ H 7, C ~ C 1 3 ) ~ : 1 . 2 7 ( 3 H , t ,
~ J=8Hz, CH2 CH3 ), 2. 60 (2H, q,
J=8Hz, CH2 SCH2 CH3 ), 2. 8 2 ( 2H. t,
J = 8 H z, C H 2 S G H 2 ), 4 . 4 5 ( 2 H . t,
J=8Hz, COOCH2 ~, 4. 62 (2H, s,
C l C ~ 2 ) ,
N eat
I Rv cm i: 3350~2900, 1 740, 1 71 O.
m a x
1 6 2 0 - :
Example 19
(1~ In 300 ml of acetone was suspended 15 g
(0.0545 mole) of ethylthioethyl 2~(2-amlnothiazol-4-yl)-~)-2-
i.
hy ~ L~x~cetate as obtained in Example 18, and 12.3 g (0.0187 mole)
'
.
.
.A~Z3
-52-
of t-butyl chloroacetate, 0.9 ml of water, 30.1 g
(0.~18 mole) of anhydrous potassium carbonate and
8.98 g (0.0599 mole) of sodium iodide were added to
the suspension. The reaction was allowed to proceed
at room temperature for lO hours. The precipitate
was filtered off and 450 ml of ethyl acetate and
450 ml of water were added or effecting extrac-
tion. The aqueous layer was further extracted
with lO0 ml of ethyl acetate. The organic layers
were combined, washed twice with 5% aqueous sodium
chloride and dried over anhydrous sodium sulfate. The
solvent was then distilled off under reduced pressure
and 600 ml of acetone was added to the residue for
dissolution, followed by addtion of 1.5 liters of
water. The mixture was cooled to 5C or below and the
resulting crystalline precipitate was collected
by filtration to give 19.1 g (yiela, 90.0%) of ethylthio-
ethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl--
methoxyimino)acetate.
Elemental analysis
Ca1cd- for Cl5H23N3O5S2
C, 46.26%; H, 5.95%, N, 10.79~; S, 16.46
Found: C, 46.56%; H, 6.00%; N, 10.52%; S, 15.88
:
1%L~823
53 -
NMR t 60MH Z, DMSO--d 6 ) t~i 1 . 1 8 (3 H.
t , J = 8 H Z , C H 2 C H 3 ) , 1 . 4 4 ( 9 H , S
C (CH3 ) 3 ), 2. 55 (2H. q, J=8HZ,
SCH2 CH3 ), 2. 80 (2H. t, J=8Hz.
j CH2 SCH2 ), 4. 3 8 ~ 2H, t, J=8HZ,
C O O C H 2 C H 2 ), 4 . 5 6 ( 2 H . s, O C H 2 C O )
6 . 9 0 ~ 1 H, s, thiazole --5--H ), 7 . 2 2
( 2 H . S, N H 2--~
. -
o K B r
I R v - cm~l: 3 4 5 0~2 9 00. 1 7 60. 1 7 5 0.
m a x
1 6 2 0 . 1 5 5 5
.
.
-54-
(2) In a mixture of 200 ml of ace-tone and 40 ml
of water was dissolved 19.1 g (0.0~90 mole) of ethyl-
thioethyl 2-(2-aminothlazol-4-yl)-(Z)-2-(t-butoxy-
carbonylmethoxyimino)acetate as obtained in (1). To
the solution was added 0.23 g of ammonium molybdate and
8.3 g (0.073 mole) of 30~ aque~us hydrogen peroxide was
added dropwise with cooling at 30C or below. The
mixture was stirred for an hour to give an intermediate.
Further, 4.73 g (0.417 mole) of 30% aqueous hydrogen
peroxide was added dropwise. The mixture was stirred
at room temperature overnight and adjusted to pH about
7 with a 40~ potassium carbonate solution, and 200 ml
of ethyl acetate and 160 ml of water were added for
extraction. The aqueous layer was further extracted
with 100 ml of ethyl acetate. The organic layers were
combined and 5~ aqueous sodium sulfite was added with
cooling, followed by sha~ing. The organic solution was
then washed with 5~ aqueous sodium chloride and dried
over anhydrous sodium sulfate. The solvent was then
distilled off under reduced pressure and 100 ml of
ethyl acetate~isopropyl ether (1:5, v/v) was added to
the residue. The mixture was cooled to 5C or below and
the resulting crystalline precipitate was collected by
filtration to give 20.0 g (yield, 96.8~) of ethylsulfonylethyl
823
-55-
2~(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxy-
imino)acetate.
Elemental analysis
¦ Calcd. for C ~ H ~ N 3 O 7 S 2 = 4 2 1 . 4 8
~ C 4 2. 75%. H5. 50~. Ng. 97%.
S1 5. 2 1 %
Found: C 4 2 . 9 6 /0 . ~1 5 .8 6 % . N 9 . 8 5 %,
S 1 4 . 6 0 %
N M R ( 6 0 M H z . D M S O - d 6 ) ~ 1 . 2 0 ( 3 11.
o t, J=8Hz. CH2 CH3 ) . 1. 45 (9H. s,
C (CH3 ) 3 ) . 3. 1 4 (2H, q . J=8Hz.
SCH2 CH3 ) . 3. 55 (2H. t, J=8Hz.
C H 2 S C H 2 ) . 4 . 6 0 ( 4 H . m . C O O C H 2 &
O C H 2 C O ) , 7 . O O ( 1 H . s, thiazole - 5 - H )
7 . 2 8 ( 2 H. S . N H 2--)
. . , ' .
K B r
I R ~cm~l : 3 4 0 0 ~ 3 0 0 0 . 1 7 5 5 .1 7 4 O .
~ a x
--- 1 7 1 5 . 1 6 3 0. 1 6 1 0. 1 545
The filtrate obtained in the above procedure (2)
was poured~into water and extracted with ethyl acetate.
The extract was concentrated to dryness and the residue
25 was crystalli~ed from ethyl acetate-isopropyl ether
~l:l, v/v) to give ethylsulfinylethyl 2-(2-amino-
thlazo1-4-yl)-(Z)-2-~t-butoxycarbonylmethoxyimino)acetate.
. ~ ~
823
-56-
Elemental analysis
Calcd. for C 15 H ~ N 3 0 6 S 2 = 4 0 5 . 4 8
C44. 43/0, H5. 7 2%, N 1 O. 3 6%.
S1 5. 8 1 %
1 ~ound: C 4 4 . 5 0 % . H 5 . 6 8 %. N 1 0 . 1 7 %.
S 1 5 . 5 2 %
NMR (60MH~. DMSO--d6 ) 8; 1. 1 8 (3H.
t, J=8Hz. CH2 CH3 ) . 1 . 42 ~9H. s,
C ( CH 3 ) 3 ) . 2. 70~3. 20. (4H. m.
C H 2 S 0 C H z & C H 2 S O C H 2 ) , 4.. 6 0 ( 4 H .
m, OCHz CO ~COOCH2 CH2 ) . 7. 00 (1 H.
S , thiazole . - 5 - H ) . 7 . 3 0 ( 2 H . s . N H 2 -
.. . ... . ..
, :-. ., - -. ,:. . -
K B r - - -
I R u ctn~l: 3 3 5 0~ 2 g 5 0 . 1 7 4 5 . 1 7 2 0 .
a x -
1 6 2 0. 1 5 5 0
(3) :In 600 ml of acetone-water (l:l, v/v) was
dissolved 20 g (0.0475 mole) of ethylsulfonylethyl
2-~2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxy-
imino)acetate as obtained in (2), and a 40~ aqueous
solution of ~otassium carbonate was added.with warming at
30-35C:while maintaining the pH at lO-lO.5. The mixture
.
was stirred for about:an hour and ad~usted to pH about 6
with 2 N HCl and 300 ml of ethyl acetate-was added,
.: :
followed by snaking.~q'he organic layer was
extracted with 30 ml of 5% aqueous sodium chlrodle.
~ '
~2~ 3
-57-
The a~ueous layers were co~bined, adjusted to pH 2
with 2 N HC1 and coole~. The resulting crystalline
precipitate was collected by filtration to give 12.5 g (yield,
87.3%) of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-
carbonylmethoxyimino)acetate as white crystals. The
NMR and IR of this product were in good agreement with
those obtained in (3) of Example 16.
Example 20
(1) Using 6 g (0.0218,mole) of ethylthioethyl 2-~2-
amino ~ azol-4-yl)-(Z)-2-hydroxy~noace~te as obtained in Example 18 and
6.83 g (0.0327 mole) of t-butyl 2-bromopropionate and
following the procedure (1) of Example 19, there was
obtained 7.04 g (yield, 80.0%) of ethylthioethyl 2-(2-amino-
thiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxy-
imino)acetate.
Elemental analysis
Calcd- fox C16H25N3O5S2
' C, 47.63%; H, 6.24%; N, 10.40~; S, 15.80%
Found: Cj 47.62%; Hj 6.15~; N, 10.39%; S, 15.50%
' N M R ( 6 0 M H z . D M S O - d 6 ) ~ : 1 . 0 5 ~-1 . 4
O ( 1 5 H . m . C H 2 C H 3'&C H - C H ~ & C ( C H ~ )
`3 ) , 2 . 5 5 ( 2 tJ, q . J = 8 H z, S C t~ ? C H 3 ) .
: 2. 80 ( 2H. t, J=8Hz, -CH2 SCH2 CH~ )
:. 4. 39 (2H, t, J=8Hz. COOCH2 ) . 4.
4 8 ~ 1 H ~ q, J= 8 H z . C H C H 3 ~ . 6 . 9 0 ( 1 .
H. s . thiazole - 5 - H ) . 7 . 2 5 ( 2 H. s . N H
2 - ) '' ' ~ - , ' , ,
,. ~
~Z,~a~823
-58-
IR KBr cm : 3400-2900, 1730, 1620, 1540
(2) In 60 ml of acetone-water (5:1, v/v) was
dissolved 5 g (0~0124 mole) of ethylthioethyl 2-(2-
aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxy-
imino)acetate as obtained in (1) followed by oxidation in thesame manner as (2) of Example 19 to give 4.8 g (yield, 88.8%)
of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-
(t-butoxycarbonyl-l-methylmethoxyimino)acetate as white
crystals. The acetate was then hydrolyzed in the same
manner as (3~ of Example 19 to give 2.8 g (yield, 80.6%) of
2-(2-aminothiazol-~-yl)-(Z)-2-(t-butoxycarbonyl-1-
methylmethoxyimino)acetic acid.
. Elemental analysis
Calod. for C ~ H l7 N 3 0 s S 0. 2 H 2 0 = 3 1 8 .q4
. C4 5. 1 9%. H 5. 50%. N 1 3. 1 7%,
S10. 05%
¦ Found: C45. 40%. H5. 95%. N1 3. Oi7%.
S 1 0. 3 5%
N M R ( 6 0 M H Z , [) 1\/l S 0 - d 6 ) ~ 1 . 3 5 ( 3 H .
d, J = 8 H Z . C H - C ~ ), 1, 4 4 ( 9 H . s . C
(CH3 ) 3 ) . 4. 58 ( 1 H. q. J=8HZ. CH-
C H 3 ) . 6 . 8 3 ( 1 H, s, thiazole - 5 - H ) 7 .
2 5 ( 2 H . b r~ N H 2 - ) .
IR~vmax-cm : 3350-2900, 1725, 1650, 1610, 1590
.
8~3
-59-
Example 21
(1) Using 6 g (0.0218 mole) of ethylthioethyl
2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained
in Example 18 and 7.29 g (0.0327 mole) of t-butyl 2-
bromoisobutyrate and following the procedure of (1)of Examplel9, there was obtained 7.7 g (yield, 84.6%) of
ethylthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-
carbonyl-l,l-dimethylmethoxyimino)acetate.
Elemental analysis
... . .... . . .
¦ Calcd. for C V H 27 N 3 0 5 S 2 = 4 1 7 . 5 4
C48. gO~O, H6. 52%. N10. 06~.
S 1 5. 3 6% -
Found: C 4 8 . 9 6 %. H 6 . 4 5 % . N 1 0 . 2 9 % .
S1 5. 33%
, N M R ( 6 O M H z, D M S O - d 6 ) /~3 1 . 1 8 ( 3 H .
t, J=8Hz. CH2 CH3 3 . 1 . 40 ~ 1 5H. s,
C (CH3 ) 3 & C (CHi ) 2 ) . 2. 55 (2H. q.
- J=8Hz, SCH2 CH3 ) . 2. 79 (2H, t, J=
8 H Z, --C H:2 S ) . 4 . 3 8 ( 2 H, t, J = 8 Hz .
- C O O C H 2 - ) . 6 . 8 5 ( 1 H, s, thiazole - 5 -
H) . 7. 25 (2H, s, NH2--)
KBr
I R 2~ 3 4 0 0 ~ 3 0 0 0, 1 7 4 (:) . 1 7 3 0,
1 m a x :. -
¦ ~ 1 6 3 5. 1 5 5 0
:~2~ 3
-60-
(2) Ethylthioethyl 2-(2-aminothiazol~4-yl)-
(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyimino)acetate
(2 g, 0.0048 mole) as obtained in (1) was oxidized and
hydrolyzed in the same manner as (2) and (3) of Example 19
to give 1.1 g (yield, 69.6~) of 2-(2-aminothiazol-40yl)-
(Z)-2-(t-butoxycarbonyl-1,1-dimethylmethoxyiminO)acetic
acid.
NMR ~60MHz, DMS0-d6 ) 8: 1. 42 (1 5tf
s ~ C (CH 3 ) 3 & C ~ ) , 6. 78
1 H. s, thiazole - 5 - H ) . 7 . 2 0 ( 2 H . b r.
N H 2 ~ )
K E~ r
I R 2~ 3 4 0 0~ 2 9 0 0 . -1 7 2 0 . 1 6 4 5 .
1 m a x
I - 1 6 0 0. 1 ~ 9 0
Example 22
In 100 ml of methylene chloride was dissolved
35.4 g (0.421 mole) of diketene. The solution was
cooled to -30 to-35C and 29.5 g (0.415 mole) of chlorine
was bubbled into the solution for about an hour to prepare
4-chloroacetoacetyl chloride. The solution was cooled
to 40C or below and a solution of 50 g (0.324 mole)
of phenylthloethanol~and 2S.6 g (0.324 mole) of pyridine
in 52 ml of methylene chloride was added dropwise
to the solution at -20C or below over a period
of about an hour. After completion of addition,
~ , :
-61- ~2~
the reaction was allowed to proceed at -5C for about
an hour. To the reaction mixture were added 400 ml
of methylene chloride and 700 ml of water to extract
the reaction product. The aqueous layer was further
extracted with 200 ml of methylene chloride. The
organic layers were combined, washed with water and
concentrated to dryness under reduced pressure to give
88.5 g of phenylthioethyl 4-chloroacetoacetate as an oil.
The above oil (88.5 g) was dissolved in a mixture
of 90 ml of ethyl acetate and 180 ml of glacial acetic
acid. The solution was cooled to 5C or below and a
solution of 28.5 g of sodium nitrite in 80 ml of water
was added dropwise to the sorutlon at 5C or below over
a period of about 2 hours. The mixture was poured into
800 ml of water to for extraction. The aqueous
layer was further extracted with 1 liter of ethyl
acetate. The organic layers were combined, washed
with 500 ml of 5% aqueous sodium hydrogen carbonate
and concentrated under reduced pressure to give 89 g
of phenylthioeth~l 4-chloro-2-hydroxyiminoacetate as
an oil.
The above oil (89 g) was dissolved in a mixture
of 400 ml of ethanol and 40 ml of water, and 23 g of
thiourea and 41.2 g of sodium acetate were added.
-62-
The mixture was stirred at room temperature for 3 hours.
After completion of the reaction, 400 ml of water was
added and the mixture was cooled to 5C or below. The
resulting crystalline precipitate was collected by
filtration to give 40.1 g of phenylthioethyl 2-(2-
aminothiazol-4-yl)-(z)-2-hydroxyiminoacetate. Yield:
38.3% based on phenylthioethanol.
... .. . . ..
NMR (60M117. DMS(::--d 6 ) l~i: 3. 4û (~H.
t, J=8Hz, CH2 SC fi Hs ), 4. 40 (2H, t,
0 J = 8 HZ,--C H 2 C H 2 S ) . 6 . g O ( 1 H . s, thia-
zole - ~ - H ~ . 7 . 2 0~ 7 . 5 O ( 7 H . m, arom.
and N H 2 - ) -
.
K B r ~ ~
1 I R u cm-l : 3 4 0 0~ 2 9 0 0 . 1 7 3 0, 1 6 2 0 .
m a x
~ 1 6 0 0, 1 5 9 0. 1 5 4 5
Example 23
(1) In 100 ml of acetone was suspended 5 g
20 (0.0155 mole) of phenylthioethyl 2-(2-aminothiazol-4-
yl)-(z?-2-hydroxyiminoacetate as obtained in Example 22,
and 0~3 ml of water, 4.5 g (0.023 mole) of t-butyl
bromoacetate and 8.5 g of anhydrous potassium carbonate
- were added in that order. The reaction was allowed to
25 proceed at 40C for~6 hours. After completion of the
reaction, the insoluble matter was filtered off and
: ~:
.
-63~ 8Z3
200 ml of ethyl acetate and 200 ml of water were
added for effecting extraction. The organic
layer was washed with 200 ml of 5~ aqueous sodium
chloride and dehydrated by addition of anhydrous sodium
sulfate. The solvent was then distilled off under
reduced pressure and 100 ml of ethyl acetate-isopropyl
ether (1:5, v/v) was added to the residue. After
cooling, the crystalline precipitate was collected by
filtration to give 5.8 g (yield, 85.5%) of phenylthioethyl 2
(2-aminothiazol-4-yl)-(z)-2-(t-butoxycarbonylmethoxy-
imino)acetate as white crystals.
Elemental analysis
, _ . . .
Calcd. :Eor C 19 H 23 N 3 0 5 S 2 = 4 3 7 . 5 3
- - C 5 2 . 1 1 % . H 5 . 2 5 /0 . N 9 . 6 0 %.
, Found:` C 5 2 . O ~ %. H 5 . 2 9 %. N 9 . 1 1 %,
NMR (60MHz. DMSO-d6 ) 8: 1. 45 (9H.
! s, C ( C H ~ ) . 3 . 3 0 ( 2 H . t, J = 8 H z . C H
2 SC~ H 5 ), 4. 40 ( 2H, t, J=8Hz. COOCH
2 ) . 4. 60 ~2H. s, OCH2 CO),
. . . . . .. . ..
6 . 3 5 ~ 1 H. s, thiazole~ - 5 - H ) . 7. 2 O~
7 . 5 0 ( 7 H, m, arom. and ~ `, N H 2 - )
K B r
I R lJ ~ cm~l: 3 4 5 0 ~ 2 9 5 0~. 1 7 4 0 . 1 6 2 0 .
: `m a x
. . ~ ~ 1 5 9 0, 1 5 4 5
-64- 12~8Z3
(2) In a mixture of 50 ml of acetone and 10 ml
of water was dissolved 5.0 g (0.0114 mole) of phenyl-
thioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-
carbonylmethoxyimino)acetate as obtained in (1). To
the solution was added 0.05 g of ammonium molybdate
and, at 25-30C, 13 ml (0.115 mole) of 30% hydrogen
peroxide was added. The reaction was allowed to
proceed for 4 hours. The reaction mixture was poured
into 500 ml of water and extracted with 500 ml of ~
ethyl acetate. The organic layer was washed with 500 ml
of 5% sodium sulfite and 500 ml of water in that order
and concentxated to dryness. The residue was dissolved
in a mixture of 200 ml of acetone and 50 ml of water,
and a 40% potassium carbonate solution was added dropwise
at 30-35C at pH 10-11 for hydrolysis. The mixture
was stirred for about 2 hours and 100 ml of water was
added, followed by additlon of 500 ml of ethyl acetate
for extraction purification. The aqueous layer
was adjusted to pH about 2 with 2 N HCl, whereupon
crystals separated out. The mixture was cooled to 5C
or below and the crystalline precipitate was collected
by filtration to give 2.57 g ~yield, 74.8%) of 2-(2-amino-
thiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetic
acid as white crystals.
,
!
~LZ~32~
-65-
The NMR and IR spectra of this product were identical
with those of the compound obtained in Example 16.
Example 24
(1) Using 5 g (0.0156 mole) of phenylthioethyl
2-(2-aminothiazol-4-yl) (Z)-2-hydroxyiminoacekate as obtained
in Example 22 and 4.9 g (0.0234 mole) of t-butyl 2-
bromopropionate and following the procedure (1) of
Example 23, there was obtained 5.8 g (yield, 82.3%) of
phen~lthioethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-
butoxycarbonyl-l-methylmethoxyimino)acetate as white
crystals.
Elemental analysis
Calcd- for C20H25N3O5S2
C, 53.15%; H,.5.53%; N, 9.30%
Found: C, 53~30%; H, 5.50%; N, 9.07%
I NMR ( 60MHz, DMS0-d 6 ) ~ 1 . 35 (3H.
d, J = 8 H z . C H C H 3~) . 1 . 4 1 ( 9 H . s,
C ~ C H 3 ) ~ ), 3 . 2 8 ( 2 H . t, J = 8 H z .
C H ~S ) .: 4 . 4 0 ( 2 H . t , -J = 8 H z .
¦ CH2 CH 2 S) . 4. 6:0 ( 1 H. q. J=8Hz.
C H ~ C H 3 ~ . 6 . 9 0 ( 1 H . s, thia~ole - 5 - H )
7 . 2 0 ~ 7 ~ 5 0 ( 7 H, m, arom. and
N H 2 - )
K B r ` ` -
I R v cm-l: 3 4 0 0 ~ 2 9 5 0 . 1 7 4 0 . 1 7 2 5 .
a x
- . 1 6 3 0 . 1 5 9 5 . 1 5 5 0
- , ~
~2~L8Z3
_66-
(2) In the same manner as (2) of Example 23,
4.0 g (0.0089 mole) of phenylthioethyl 2-(2-aminothiazol-
4-yl)-(Z)-2-(t-butoxycarbonyl-1-methylmethoxyimino)acetate
as obtained in (1) was oxidized with aqueous hydrogen
peroxide and then hydrolyzed in an alkaline condition
adjusted with potassium carbonate. Adjustment of the pH to
about 2 gave 2~0 g (yield, 71.3~) of 2-(2-aminothiazol-4-yl)-
(Z)-2-(t-butoxycarbonyl-1-me~hylmethoxyimino)acetic acid as
white crystals.
The NMR and IR data confirmed that this product
was identical with the compound obtained in Example 20.
Example 25
(1) Using 5 g (0.0156 mole) of phenylthioethyl
2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as
obtained in Example 22 and 5.2 g (0.0233 mole) of
t-butyl 2-bromoisobutyrate and following the procedure (1)
of Example 23, there was obtained 6.0 g (yield, 82.6%)
of phenylthioethyl 2-(2-aminothiazole-4-yl)-(Z)-2-
(t-butoxycarbonyl-l,l-dimethylmethoxyimino) acetate as white crystals
Elemental analysis
CalCd- for C21H27N3O5S2
.: - -- - - - . .
C54. 1 3%, H5. 80%. N9. 02%
Found: C 5 4 . 4 7 %, H 5 . 6 4 % . N 8 . 7 8 %
NMR ~ 60MHz. DMS0--d 6 ) 8 1 . 4 0 ~ 1 5H.
s . C ( C H 3 ) 3 & C ( C H~ ) . 3 . 3 0 ~ 2 H,
t, J=8Hz. CH~S-) . 4. 40 (2H. t, J=
:81iz, COC~CH2 ) . 6. 90 ( 1 H. s, thia-
zole _- 5~ - H ) . 7 . 2 0 ~ 7 . 5 0 ( 7 H, m, arom.
and N H 2 ~ )
. .
.
-67- 1 ~ 4 48 2 3
IR Vma cm : 3400-2950, 1740, 1710, 1630, 1590,
1545
(2) In the same manner as (2) of Example 23,
5.0 g (0.0107 mole) of phenylthioethyl 2-(2~amino-
S thiazol-4-yl)-(Z)-2-(t-butoxycarbonyl-1,1-dimethyl-
methoxyimino)acetate as obtained in (1) was oxidized with
a~ueous hydrogen peroxide and then hydrolyzed. Adjustment of
the p~I to about2 gave 2.0 g (yield, 56.7~) of 2-(2-
aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonyl~ dimethyl-
methoxyimino~acetic acid as white crystals.
The NMR and IR data confirmed that this productwas identical with the compound obtalned in Example 21.
Example 26
In 140 ml of acetonitrile was suspended
5.42 g of 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxy-
carbonylmethoxyimino)acetic acid as obtained in
Example 4 followed by a serial addition of 2.96 ml of
N-methylmorpholine and 7.2 g of 2,2-dithiobis-
benzothiazole. The suspension was cooled to 0C
and a solution of 5.38 ml of triethyl phosphite in
35 ml of acetonitrile was added to the suspension
over a period of 4.5 hours. The mixture was stirred
for 30 minutes and cooled to -10C or below. The
resultlng preclpitate was colleoted by filtrationJ
-6~ 823
washed with 20 ml of cold acetonitrile and dxied in
vacuo at room temperature to give 6.2 g (yield,
76.5~) of s-~2-benzothiazolyl) 2-(2-aminothiazol-4-
yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)thioacetate as
light-yellow crystals.
N M R ( 6 0 ~1 H z . U M S O - d 6 ) 8: 1 . 4 7 ( 9 H .
s, C (CH3 ) 3 ), 4. 71 (2H. s, OCH2 CO)
7 . 0 5 ( 1 H, s, thia~ole 5 ~ H ) . 7 . 3 9 ( 2 H .
s, NH2 ) . 7. 45~7. 62 (2H. m~ arorn),
1 8. 00~8. 28 (2H, m, arom)
I R ( K B r ) cm-l: 3 4 2 5 . 3 1 5 0 . 1 7 4 0 .
1 71 O. 1 620. 1 540
Reference Exam_le 1
(1) In 40 ml of tetrahydrofuran-water (4:1j was
suspended 1.5 g of 7-amino-3-methylthiomethylcephem-4-
carboxylic acid, and 1.6 ml of triethylamine was added
at room temperature. Thenj 2.86 g of thioester
obtained in Example 26 was added
to the suspension and the reaction was allowed to
proceed at room temperature for 2 hours. After completion
of the reaciton, the solvent was distilled off and
50 ml of water was added to the residue. The mixture
was washed with ethyl acetate and the washings were
adjusted to pH about 2.5 with hydrochloric acid and
- 69 ~ 3Z3
extracted with 50 ml of ethyl acetate. l~he extract
was dried over anhydrous sodium sulfate and the solvent
was distilled off under reduced pressure. With ice-cooling,
20 ml of trifluoroacetic acid was added and the reaction
was allowed to proceed for 2.5 hours. A~ter completion
of the reaction, the trifl~oroacetic acid was distilled
off under reduced pressure and water and 10% aqueous
sodium hydrogen carbonate were added to the residue
q for dissolution. This solution was chromatographed on 200 ml
of Amberlite~XAD-II (manufactured by Rohm & Haas Co., V.S.A.),
elution being carried~out with water. The active fractions
were combined and lyophilized to give 1.8 ~ of disodium
7~-[2-(2-aminothiazol-4-yl)-(Z)-2-(carboxymet~oxyimino)acetamido]-
~ 3-methylthiomethyl-3-cephem-4-carboxylate as a white powder.
Elemental analysis
Càicd. for C 16 ~ 15 N 5 0 7 S 3 N a 2 5 H 2 0
. C.30. 90%. H4. 05%. N1 1. 31%
Found: C 3 0 . 9 5 %. H 3 . 8 6 %. N 1 1 . 2 6 Y0
~ NMR (60MHz. D 2 0 ) ~ : 2. 0 0 (3H. s,
S C H 3 ) . 3 . 1 0 ~ 3 . 9 5 ( 4 H . m,mephoYltinona2
and ~ S C H 3 ) . 4. 5 6 ( 2H, s,=N0CH 2 )
5 2 1 ( 1 H d J = 5 H Z protoin at ! 5 7
5 ( 1 H d J 5 H z protoin at ) 7 0 3 ( 1
H. s, thiazOle 5--H )
2s I R ( K B r ) c~ 3 4 0 0 . 1 7 6 0 . 1 6 1 0. 1535
~Z~3Z3
(3) Using 7-amino-3-[(5-methyl-1,3,4-thiadiazol-
2-yl)thiomethyl]-3-cephem-4-carboxylic acid and thiG-
ester obtained in Example 26, in the same manner as the
above reaction procedure (1), disodium 7~-[2-(2-aminothiazol-
4-yl)-(Z)-2-(carboxymethoxyimina)acetamido-3-[(5-methyl-1,3,4-
thiadiazol-2-yl)thio~ethyl~-3-cephem-4-carboxylate was obtained.
Elemental analysis
¦ Calcd.
`C31 . 44%. H3. 3 7%. Nl 4. 26%
0 Found: C 3 1 . ~ 0 % . H 3 . 3 7 %, N 1 3 . 4 8 %
NMR ~ 60MHz. D2 0) ~: 2. 80 (3H, S,
C H 3 ~ , 3 . 6 5 ~ 2 H, q . position 2 ) , 4 . 1 5
( 2 H . s . N 0 C H 2 C 0 ) . - 5 . 2 5 ( 1 H . d,
proton at ~ F ~ e ~ ~ proton at
position 6 J ~ ~ ~ ~ I H. d . position 7
157 . 0 0 ( 1 H, s, thiazole 5 _ H )
.
_71_ ~2~Z~
Reference Example 2
(1) In 140 ml of dry acetonitrile is suspended 5.42 g
(18 mmol) of (Z)-2-(2-amino-4-thiazolyl)-2-(t-butoxy-
carbonylmethoxyimino)acetic acid, 2.96 ml (27 mmol) of
N-methyl morpholine and then 7.2 g (21.6 mmol) of bis-
benzothiazol-2-yl disulfide are added, and the mixture is
cooled to 0C. A solution of 5.38 ml (31.4 mmol) of
triethyl phosphite in 35 ml of dry acetonitrile is added
dropwise over 4.5 hours and ~he mixture is stirred at the
same temperature for 30 minutes and then cooled to -10C.
The resulting crystalline precipitate is collected by
filtration, washed with a small amount of acetonitrile and
dried under reduced pressure to give 5.1 g of (Z)-2-t2-
amino-4-thiazolyl)-2-(t-butoxycarbonylmethoxyimino)acetic
15 acid 2-benzothiazolylthiol ester.
IRv (KBr~ cm 1 3400, 3120, 1738, 1710, 1620, 15~0,
1450, 1415, 1370.
NMR (d6-DMSO) ~: 1.50(9H, s, CH3 x3), 4.78(2H, s,
NOCH2COO), 7.10(1H, s, thiazole-SH),
7~4-7.65(2H, m, aromatic protons),
8.0-8.3(2H, m, aromatic protons).
(2) A flask of 1.0 Q capacity is charged with 0.06 kg
(0.2508 mole) of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-
azetidinone-l-sulfonic acid and 0.9 Q of methylene
chloride tomake a suspension, 0.070 Q (0.2508 x 2 mol) of
triethylamine and then 0.124 kg;(0.2508 x 1.1 mol) of
(Z)-2-(2-amino-4-thiazolyI-2-t-butoxycarbonylmethoxyimino)~
acetic acid 2-benzothiazolylthio ester obtained in (1) are
added to the suspension under stirring at 10-20C, and
the mixture is stirred at 25-27C for 4 hours. ~he
insoluble matter is filtered off and the filtrate is
further stirred for about an hour and extracted with 0.9 Q
of water. The a~-~eous layer is washed with 0.19 Q of
methylene chloride, 0.38 Q of ethyl acetate and 0.19 Q of
methylene chloride in that order. After degassing, 0.45 Q
of concentrated hydrochloric acid is added and the mixture
~4a~8z3
is stirred at 25C for about 2 hours. To the resulting
slurry is added 0.9 Q of water and the mixture is stirred
at about 25C for about 2 hours and then allowed to stand
at O ~2C overnight. The resulting precipitates are
collected by filtration and washed with about 0.6 Q of
cold water to give about 0.27 kg of (3S,4S)-3-[2-(2-amino-
4-thiazolyl)-(Z)-2-(carboxymethoxyimino)acetamido]-4-
carbamoyloxymethyl-2-acetidinone-1-sulfonic acid as wet
crystals.
[~]D6 45o (c=l, DMSO)
IRv mBaXCm 1 1760, 1715, 1670, 1640
NMR(d6-DMSO) ~: 3.9-4.4(3H, C4-H, C4-CH2), 4.66(2H, s,
NO-CH2), 5.28(1H, d.d, J=4.5, lOHz,
C3-H), 6.92(1H, s, proton at position 5
of the thiazole nuclear), 9.33(lH, d,
J=lOHz, c3-NH)
Antimicrobial potency (MIC) against K. pneumoniae TN 1711:
0 1 mcg/ml
