JPH0314039B2 - - Google Patents

Description

[Detailed description of the invention] The present invention provides 7-aminothiazolyl acetamide
Novel O-substituted oxime derivatives of cephalosporanic acid
Conductors, their manufacturing methods and assemblies containing them
Regarding products. The subject of the invention is the following formula ′ [[Here, B is Γ group - (CH₂)_o′−R_Five [Here, n' represents an integer from 1 to 4, R_Fiveis an azide group or a group [formula] (where R₆Reach BiR₇has a hydrogen atom and 1 to 4 carbon atoms
represents a group selected from the group consisting of alkyl groups.
or R₆and R₇is combined with nitrogen atoms to form a lid.
forming a limide or 1-pyridinyl group)
Wasu], or Γ group - (CH₂)_o′−R_5b [Here, n' represents an integer from 1 to 4, R_5bis the group [formula] (where R_6band R_7bbox imidazolyte together with the nitrogen atom to which they are bonded.
morpholinyl or N-alkylpiperazinyl
group (alkyl group has 1 to 4 carbon atoms)
] represents, R₁teeth, Γ an alkyl group having up to 5 carbon atoms, or
teeth Γ group−CH₂-S-R₁₂(Here R₁₂is 1-methyl
-1H-tetrazolyl (representing a group), or Γ Acetoxymethyl group or carbamoyl group
oxymethyl group represents, A is a hydrogen atom, or 1 equivalent of an alkali metal,
alkali earth metals, magnesium, ammonium or
or represents an organic amino base, or A can easily be
Represents a cleavable ester group]] compounds of formula , syn isomers, as well as compounds of formula ′
In salts with inorganic or organic acids. Group -(CH₂)_o′−R_FiveAs azidomethyl, azidomethyl
Doethylaminomethyl, methylaminomethyl, di-
Methylaminoethyl, dimethylaminoethyl, dimethylaminoethyl
Methylaminopropyl, phthalimidomethyl, phthalimidomethyl
Thalimidoethyl, phthalimidopropyl, N-
Pyridinylmethyl, N-pyridinylethyl, N-
Examples include pyridinylpropyl group. R_5bwithin the meaning of N-alkylpiperazine
-1-yl group, especially 4-methyl-, 4-ethyl
-, 4-propyl-, 4-isopropyl-, 4-
Butyl-, 4-sec-butyl and -t-butylpi
Mention may be made of the perazin-1-yl group. R₁Within the meaning of methyl, ethyl, propylene
isopropyl, butyl, isobutyl, t-butyl
tyl, pentyl, sec-pentyl, t-pentyl
I can give you the basics. Among the meanings of A, equivalent amounts of sodium and potassium
aluminum, lithium, calcium, magnesium and aluminum
I can give you ammonium. Also, organic salts
Among the groups, trimethylamine, diethylamine,
Triethylamine, methylamine, propylamine
N,N-dimethylethanolamine, Tris
(Hydroxymethyl)aminomethane, ethanol
Amine, pyridine, picoline, dicyclohexyl
Amine, N,N'-dibenzylethylenediamine,
Morpholine, benzylamine, procaine, lisi
arginine, histidine and N-methylglue
I can give you Kamin. Easily cleavable ester groups include methoxymethyl
, ethoxymethyl, isopropoxymethyl, α
-methoxyethyl, α-ethoxyethyl, methyl
Thiomethyl, ethylthiomethyl, isopropylthi
omethyl, pivaloyloxymethyl, acetoxy
Methyl, propionyloxymethyl, isobutyryl
isovaleryloxymethyl, isovaleryloxymethyl,
Ropionyloxyethyl, isovaleryloxyethyl
thyl, 1-acetoxyethyl, 1-acetoxyp
Lopyl, 1-acetoxybutyl, 1-acetoxy
Hexyl and 1-acetoxyheptyl groups
good. The compound of formula
Since it contains an amino group that can be formed, salt or organic
Can exist in the form of salts with organic acids. Forming a salt with the amino group of a compound of formula ′
Among the acids that can be produced, especially acetic acid and trifluorovine vinegar
acids, maleic acid, tartaric acid, methanesulfonic acid,
toluenesulfonic acid, p-toluenesulfonic acid, salt
acid, hydrobromic acid, hydroiodic acid, sulfuric acid or phosphoric acid
can be given. Also, B is −(CH₂)_o′−R_5bRepresenting the expression ′
The compounds can exist in the form of internal salts. More particularly, the subject matter of the invention is B is a group -(CH₂)_o′−R_Five [Here n' is equal to 1 or 2 and R_Fiveis the base
[Formula] (where R₆and R₇The meaning shown above has)] represents, R₁an alkyl group having 1 to 5 carbon atoms
or group -CH₂-S-R₁₂(Here R₁₂is 1-methyl
(represents a tetrazolyl group), or R₁
represents an acetoxymethyl group, A is a hydrogen atom or 1 equivalent of an alkali metal, alkali
Potassium earth metal, magnesium, ammonium or
is a compound of the above formula ' representing an organic amino base
It is in. More particularly, the subject of the invention provides that B is a phthalate.
Represents imidomethyl or aminoethyl group, R₁
is methyl, acetoxymethyl or 1-methyltet
represents a lazolylthiomethyl group, and A is hydrogen or
In the compound of formula ' above, which represents a thorium atom. In particular, the present invention provides that B represents an aminoethyl group.
,R₁is acetoxymethyl or 1-methyltet
The above representing a lazol-5-ylthiomethyl group.
Concerning compounds of formula '. More specifically, the present invention relates to the embodiments described in the Examples.
compounds, in particular the compounds listed below. 3-acetoxymethyl-7-[[2-(2-ami
Notiazol-4-yl]-2-(2-aminoeth
ximino)acetyl]amino]cef-3-M
-4-carboxylic acid, syn isomer and its alkyl
Potash metals, alkaline earth metals, magnesium, anhydride
salts with monium and organic amino bases, and their
Esters with easily cleavable groups. The above compound of formula ' is (i) in the form represented by the formula '; or (ii) The following formula_z form of the compound can exist. The compounds of the aforementioned formula ' that are the subject of the present invention are: The following formula (where R has the meaning given above and R₁₆Haa
Represents a group that protects a mino group, and A′ is a hydrogen atom or
represents an easily removable ester group) the compound of (a) The following formula Ha1−(CH₂)_o′−Ha1 When treated with a compound of and by treating this compound with pyridine,
The following formula_J or treated with azide to give the formula_K We obtained a compound with the formula_KThe compound is treated with a reducing agent.
The following equation′_K obtain a compound of, or (b) The compound of formula HNR₁₈R₁₉ (Here R₁₈For acid hydrolysis or hydrogenolysis
more easily removable groups or 1 to 4 carbon atoms
represents an alkyl group having R₁₉is a carbon atom or
represents an alkyl group having 1 to 4 carbon atoms
or R₁₈and R₁₉is combined with nitrogen atom
form a phthalimide group) After treatment with an amine derivative of_L or imidazole, morpholin
or N-alkylpiperazine to give the formula
′_L (Here R_5bhas the meaning given above) to obtain a compound of formula,_J,_K,′_K,
_L,as well as'_L hydrolysis or hydrogenolytic agents or thiolytic compounds.
Treatment with one or more agents selected from urea
and each Γ the general formula of_J (where n′ and R₁has the meaning given above) compound, Γ the general formula′_K (Here R₁has the meaning given above) compound, Γ the general formula of_L (Here n′, R₁and R₁₉has the above meaning;
R′₁₈has a hydrogen atom or 1 to 4 carbon atoms
(represents an alkyl group) compound, Γ the following general formula″_b (Here R₁and R_5bhas the meaning given above) compound, and then if desired the expression_J,′_K,_Lor
″_b salt formation or esterification in the usual manner.
and can be manufactured by a method characterized by
Ru. R₁₆Examples of groups protecting amino groups that can be represented by
For example, an alkyl group having 1 to 6 carbon atoms,
For example, preferably a t-butyl or t-amyl group
It is. Also, R₁₆is an aliphatic acyl group, aromatic
or a heterocyclic acyl group or a carbamoyl group
can be expressed. Among the acyl groups, for example
formyl, acetyl, propionyl, butynyl,
Isobutynil, valeryl, isovaleryl, oxa
Lower amines such as lyle, succinyl and pivaloyl
Lucanoyl group; e.g. methoxycarbonyl, ethyl
oxycarbonyl, propoxycarbonyl, 1-cycarbonyl
Chlopropylethoxycarbonyl, isopropoxy
cycarbonyl, butoxycarbonyl, t-butoxy
Cycarbonyl, pentyloxycarbonyl, t-
bentoxycarbonyl and hexyloxycarbo
lower alkoxycarbonyl or lower
Cycloalkoxycarbonyl group; benzoyl, to
oil, naphthoyl, phthaloyl, mesyl, phthaloyl
enylacetyl and phenylpropionyl groups;
Aryl like benzyloxycarbonyl
Examples include alkoxycarbonyl groups. These acyl groups include, for example, chlorine, bromine, and
May be substituted with elementary or fluorine atoms, e.g.
Chloracetyl, dichloroacetyl, trichlor
Acetyl, trifluoroacetyl or bromoacetyl
I can give you a chill. Also, the substituent R₁₆is benzyl, 4-methoxy
benzyl, phenylethyl, trityl, 3,4-
such as dimethoxybenzyl or benzhydryl
It can represent a lower aralkyl group. Also, the substituent R₁₆is like trichloroethyl
It can represent a haloalkyl group. Furthermore, the substituent R₁₆is chlorbenzoyl, p
-Nitrobenzoyl, pt-butylbenzoy
phenoxyacetyl, caprylyl, n-deca
It can also represent a noyl or acryloyl group. Also, the substituent R₁₆is methylcarbamoyl,
enylcarbamoyl or naphthylcarbamoyl group
and the corresponding thiocarbamoyl group
Can be done. The above enumeration is not an exhaustive enumeration.
Amine, a group known in peptide chemistry
It is obvious that other groups can be used, including
It is clear. base CO₂Within the meaning of A′, the following can be easily removed:
Ester groups formed with groups such as butyl,
Isobutyl, t-butyl, pentyl and hexyl
Esters formed with alkyl groups such as esters
I can give you a ru. Also, acetoxymethyl, propionyloxy
Methyl, butyryloxymethyl, valeryloxy
Methyl, pivaloyloxymethyl, 2-acetoxymethyl
ethyl, 2-propionyloxyethyl or 2
-Butyl and oxyethyl esters can be given.
can. Furthermore, 2-mesylethyl, 2-iodoethyl
Chil, β, β, β-trichloroethyl, vinyl,
Aryl, ethynyl, propynyl, benzyl, 4
-Methoxybenzyl, 4-nitrobenzyl, Fe
Nylethyl, trityl, diphenylmethyl or
3,4-dimethoxybenzyl ester
I can do that. Also, phenyl, 4-chlorophenyl, tolyl
Alternatively, t-butylphenyl ester may also be mentioned.
can. Pyridine for a compound of formula or
HNR₁₈R₁₉The action of the compound is preferably dimethyl
carried out in formamide. Preferably Ha1
is a compound with the formula representing a bromine or iodine atom.
However, compounds where Ha1 represents a chlorine atom can also be used.
I can be there. R₁₈Acid hydrolysis or hydrogenation can be represented by
Groups that can be easily removed by decomposition are preferably groups that can be easily removed by decomposition.
It is a lythyl group. However, the appropriate
Protecting groups can be used. formula_Kfor a compound of formula to obtain a compound of
The action of azide on the compound of formula
It is carried out under the same conditions as the addition of the code. formula_KThe compound of′_Kto convert to the compound of
The reducing agent used is preferably triethylamine.
hydrogen sulfide in the presence of
With triethylammonium bisulfide formed
It corresponds to that. The reaction is dimethylformamide
It is carried out in a solvent such as Also, other warm special reduction methods, such as water
Alkali sulfides (sodium, potassium, ammonia)
or stannous chloride.
You can also do it. A compound of formula and imidazole, morpholine or
The reaction with N-alkylpiperazine is preferably
is carried out in the presence of a hydrohalic acid acceptor.
Ru. This includes, for example, triethylamine
Organic bases can be used. Also, Natoriu
or other alkali metal carbonates or acidic carbons.
Inorganic bases such as acid salts can also be used. Also, compounds with formulas like diethylamine salts
It can also be carried out with respect to the salt. This reaction also
In the presence of quaternary ammonium salts such as ammonium
You can also do it with formula_J~′_Land the compound of V with the corresponding formula_J~
″_bIn all cases, the purpose of converting to a compound of
R₁₆protecting groups such as and in some cases A′ is
A′ and group R when different from hydrogen atom₁₈(_L)of
It is to remove. base R₁₆Removal can be carried out, for example, by hydrolysis.
be exposed. Hydrolysis may be acidic or basic, or
can use hydrazine. Preferably, the acid hydrolysis is performed on substituted
alkoxycarbonyl or cycloalco with
xycarbonyl group, e.g. t-pentyloxycarbonyl group
carbonyl or t-butyloxycarbonyl, substituted
Aralkoxycarbonyl that has been
group, such as benzyloxycarbonyl, or
Lythyl, t-butyl or 4-methoxybenzyl group
used to remove Preferred acids are hydrochloric acid, benzene sulfonate
acid, p-toluenesulfonic acid, formic acid or trifonic acid
It can be selected from the group consisting of fluoroacetic acid. However, using other inorganic or organic acids
can be done. The base hydrolysis is preferably performed using trifluorocarbons.
Used to remove acyl groups such as cetyl
It will be done. The preferred base is alkali gold hydroxide.
genus, such as sodium hydroxide or potassium hydroxide
Inorganic bases such as Also, magnesia, baryta, or alkali
Metal carbonates or acetic carbonates, e.g. sodium
or by using carbonates or acidic carbonates of potassium.
You can also do it. Also, sodium or potassium acetate may be used.
I can do that. However, other bases can also be used.
It will be done. Hydrolysis with todrazine preferably
used to remove groups such as phthaloyl
Ru. Also, the group R₁₆is removed by a zinc/acetic acid system.
(e.g. trichloroethyl group). Benzhydride and benzyloxycarbonyl
The group is removed by hydrogen, preferably in the presence of a catalyst.
be removed. The chloroacetyl group was created by Mr. Masaki from JACS.
90, 4508, 1968.
is induced by the action of thiourea in acidic medium.
removed. Also known in the literature for unprotecting amines.
Other means may be used. Among the preferred groups are formyl, acetyl, ethyl
Toxicarbonyl, mesyl, trifluoroacetyl
chloroacetyl, trityl, and trityl groups.
can. The acid used is preferably formic acid or triflic acid.
It is oracetic acid. Of course, substituents present on the oximino group
Due to (substituent R), in some cases certain preservation
Guardians must be avoided. Therefore, R is acetyl
or acyl group, R₁₆itself
should not represent an acyl group. because,
R₁₆This is because the removal of R may lead to the removal of R.
Ru. When A′ is different from a hydrogen atom, the removal of A′ is
R₁₆Under similar conditions as described above for the removal of
It is done. Among them, acid or base hydrolysis is used.
be able to. The acid is preferably substituted
Alkyl or substituted
Used to remove groups such as certain aralkyl
It will be done. Preferably, hydrochloric acid, formic acid, trifluoroacetic acid or
is selected from the group consisting of p-toluenesulfonic acid
acid is used. Others of the group A′ are
Removed by methods known to the trader. The reaction is preferably carried out under warm conditions, i.e.
done at a temperature or by heating warmly
Ru. Of course, for example R₁₆and A′ are of different types.
When the compound is a removable group belonging to
It can be reacted with several of the drugs listed above.
Ru. In the above reaction, in the following reaction
Similarly, part of the product obtained is 2-ceph
may consist of em products. In this case, the product △₂The part of product △₃fart
A conversion is performed. And this reaction
is known in the literature for compounds with a cefem nucleus.
It is carried out using the same method. This method is as follows. △₂Compounds containing the moiety of
oxidize to obtain oxide. m-chlor overrest
Peracids such as aromatic acid are preferably used. △₂
From the sulfoxide of △₃Conversion of to sulfoxide
occurs in the presence of a hydroxylated solvent or water. Sulfoxide△₃The reduction of acid halides or
is carried out in the presence of phosphorus trichloride. This kind of product△₂Product from △₃The conversion to
for example Mr. Kaiser et al. J.Org.35, 2430 (1970), Mr. Spree et al. J.Org.40, 2411 (1975), U.S. Patent No. 3705897, or German patent no. 1937016 It is described in. Examples of such reactions are further shown in the experimental section. Salt formation of compounds of formula is carried out by conventional methods.
can be done. Salt formation can occur, for example, with these acids or their solvates.
(e.g. ethanol solvate) or hydrate
Sodium or potassium hydroxide, acidic carbonate
Sodium or potassium or sodium carbonate
Or use an inorganic base such as potassium
It can be obtained by Also, phosphate
Salts of inorganic acids such as linodium may also be used.
can. Additionally, salts of organic acids can also be used.
Ru. As the organic acid salt, for example, 1 to 18, preferably
or saturated or unsaturated with 2 to 10 carbon atoms
Japanese linear or branched aliphatic carboxylic acids
I can give you um salt. These aliphatic groups
is one or more substances such as oxygen or sulfur.
May be interrupted by heteroatoms or e.g.
such as phenyl, thienyl or frilly
aryl group, one or more hydroxy
one or more radicals such as
or more halogen atoms, preferably salts
one or more carboxyl or
is a lower alkoxycarbonyl group, preferably meth
Oxycarbonyl, ethoxycarbonyl or
lopyloxycarbonyl, or one or more
or more aryloxy groups, preferably phenoxy
Optionally substituted with groups. In addition, as an organic acid, a sufficiently soluble aromatic
family acids such as benzoic acid, preferably lower alkyl
Benzoic acid substituted with groups is used. Examples of such organic acids are formic acid, acetic acid,
Acrylic acid, butyric acid, adipic acid, isobutyric acid, n-
Caproic acid, Isocaproic acid, Chlorcaprone
Acid, crotonic acid, phenylacetic acid, 2-thienyl vinegar
acid, 3-thienyl acetic acid, 4-ethyl phenyl vinegar
Monoethyl ester of acid, glutaric acid, adipic acid
hexanoic acid, heptanoic acid, decanoic acid, oleic acid
acid, stearic acid, palmitic acid, 3-hydro
Xypropionic acid, 3-methoxypropionic acid,
3-methylthiobutyric acid, 4-chlorobutyric acid, 4-phe
Nylbutyric acid, 3-phenoxybutyric acid, 4-ethyl benzoate
Mention may be made of aromatic acid and 1-propylbenzoic acid. However, preferably sodium acetate, 2
-Sodium ethylhexanoate or diethyl acetic acid
Sodium is used as the sodium salt. Additionally, salt formation can occur with triethylamine, diethyl
amine, trimethylamine, propylamine,
N,N-dimethylethanolamine or Tris
Organics such as (hydroxymethyl)aminomethane
This can be achieved by acting with a base. Also,
Arginine, lysine, methylamine, ethanol
Amine, pyridine, picoline, dicyclohexyl
Amine, procaine, histidine, N-methyl group
Effects of lucamine, morpholine and pentylamine
It can also be reached by This salt formation is preferably carried out using water, ethyl ether
such as alcohol, methanol, ethanol or acetone.
It is carried out in a suitable solvent or solvent mixture. Salts can be amorphous or crystalline depending on the reaction conditions used.
Obtained in form. The crystalline salt preferably contains the free acid as described above.
one of the salts of aliphatic carboxylic acids, preferably sodium acetate
Manufactured by reacting thorium. Optionally esters of compounds of formula
The conversion is carried out under standard conditions. Generally, this
is the following formula for the acid of the formula Z-R₂₀ (Here, Z is a hydroxyl group, fluorine, salt
Represents a bromine, bromine or iodine atom, R₂₀is the guide
ester groups to be incorporated, examples of which are listed above.
did) This is done by reacting derivatives of Also, the previously defined formula ′ which is the subject of the present invention
The compound has the following formula is treated with pyridine to form the formula_J or treated with azide to give the formula_K (Here R₁₈by acid hydrolysis or hydrogenolysis.
groups or 1 to 4 carbon atoms that can be easily removed by
represents an alkyl group having R₁₉is a hydrogen atom or
represents an alkyl group having 1 to 4 carbon atoms
or R₁₈and R₁₉together with phthaloid
(represents a do group) After treatment with an amine derivative of_L or imidazole, morpholine
Or treated with N-alkylpiperazine to form the following formula
′_L (Here R_5bhas the meaning given above) and these formulas,_J,_K,_LReach
Beauty'_Lor their derivatives with the following formula: or the following formula HNR₁₈R₁₉ (Here, A′ is a hydrogen atom or acid hydrolysis or
Represents a group that can be easily removed by hydrogenolysis,
R₁has the meaning given above) respectively, by reacting with a compound of the above formula,
_J,_K,_Las well as'_Land then this
et al.'s formula_J,_K,_L,′_Land the compounds mentioned above
The corresponding compound of formula ′ is converted into the corresponding compound of formula
manufactured by a method characterized by converting
You can also do it. Also, starting from a compound of formula_J,_K,
as well as_LIn order to produce the compound of formula
Formula starting from compound_J,_Kas well as_Lof the compound of
It can be carried out in the same manner as in manufacture. Imidazole, morpholin for compounds of formula
The action of N- or N-alkylpiperazine is
Same as when adding the compound to the compound of formula
carried out under conditions. In a preferred method of carrying out the above manufacturing method
is a compound of formula_J~_L,′_L
treated with a functional derivative of one of the compounds of and
Ru. This derivative can be a halide, symmetrical or
With mixed anhydrides, amides or activated esters
It's good to be warm. Examples of mixed anhydrides include, for example, chloroformic acid
Examples include those formed by isobutyl.
Examples of activated esters include 2,4-dinitroph
enol or 1-hydroxybenzo-1-tria
Examples include esters formed by sol.
Examples of halides include chloride or bromide.
can give. It is also possible to mention acid azides or acid amides.
Wear. The anhydride is a N,N'-disubstituted carbodiimide,
For example, N,N-dicyclohexylcarbodiimide
It can be formed on-site by applying
can. The acetylation reaction is preferably carried out using methylene chloride.
It is carried out in an organic solvent such as however,
Tetrahydrofuran, chloroform or dimethyl
Using other solvents such as formamide
You can also do it. Acid halide is the action of isobutyl chloroformate
When a mixed anhydride formed by
, the reaction is preferably carried out using sodium hydroxide, water
potassium oxide, sodium and potassium carbonate
and acidic carbonates, sodium acetate, triethyla
amine, pyridine, morpholine or N-methylmol
It is carried out in the presence of a base such as holin. The reaction temperature is generally equal to or below ambient temperature.
lower than. formula_J~_L,′_LCorrespondence of formulas of compounds of and
Conversion to the compound is carried out under the conditions described above.
Ru. Compounds of the above formula are prepared as follows. The following formula′ (Here R₁₆represents a group that protects an amino group,
R_ehas a hydrogen atom or 1 to 4 carbon atoms
(represents alkyl) The compound of Ha1−(CH₂)_o′−Ha1 (Here, n' represents an integer from 1 to 4, and Ha1 represents halo.
(represents a gen atom) Treated with a compound of the following formula ″ (Here R₁₆,R_e, n′ and Ha1 have the above meanings.
do) and R_ehas 1 to 4 carbon atoms
When representing an alkyl group having
It consists of treating the substance with a base and then with an acid. Group R that protects the amino group₁₆is in the above enumeration
You can choose from. Formula for a compound of formula ′ Ha1−(CH₂)_o′−Ha1 (where Ha1 is preferably an odor
The action of the compound (representing an elemental or iodine atom) is
Preferably, the hydrohalic acid that is generated is
It is carried out in the presence of a base. For example, Natoriu
In the presence of carbonates or acidic carbonates of aluminum or potassium
can be done. Also, known to those skilled in the art
It can also be carried out in the presence of organic amino bases.
Ru. R_ean alkyl group having 1 to 4 carbon atoms
The saponification of a compound of the formula
It is carried out under suitable conditions. For example, first
Salts such as thorium, potassium hydroxide or baryta
groups can be reacted. Next, dilute hydrochloric acid.
Although uric acid is used for the reaction, acetic acid or formic acid may also be used.
I can do that. Compounds of general formula ′ are staphylococcal and streptococcal
especially against Gram-positive bacteria such as penicilli.
Very good protection against resistant Staphylococcus bacteria.
Has biological activity. Also, gram-negative cells
Bacteria, especially coliforms, Glepsiella, and Salmonella
and Proteus spp.
Ru. These properties make the compound susceptible to sensitive microorganisms.
Treatment of infections caused by infections, especially those caused by e.g.
Staphylococcal sepsis, malignant facial or cutaneous staphylococcal
infections, purulent dermatitis, putrid or purulent ulcers,
Anthrax, cellulitis, erysipelas, early stage of acute influenza
or post-influenza staphylococcal infection, trachea
Staphylococcal infections such as pneumonia and pulmonary suppuration
This makes it suitable for use as a drug in therapy. These compounds also have been shown to be effective against colibacillosis and related infections.
infections, Proteus sp., Klepsiella sp. and Salmo
Infections caused by bacteria of the genus Nella, gram-negative bacteria
Used as a drug to treat other diseases caused by bacteria.
It can be used as The subject of the invention is therefore the use of drugs, especially antibiotics.
Compounds of formula ′ as defined above as substances and drugs
and their pharmaceutically acceptable inorganic or organic acids.
It is the salt of Therefore, the present invention provides a small number of drugs as defined above.
Pharmaceutical compositions containing at least one active ingredient
It even extends to things. These compositions can be administered orally, rectally, non-
Orally or topically for local application to the skin and mucous membranes
It can be administered directly. They may be solid or liquid and may be used in human medicine.
Pharmaceutical forms commonly used in pharmaceuticals, such as tablets or sugar
Coated tablets, gelatin capsules, granules, suppositories, preparations for injection
It can be provided in the form of compounds, ointments, creams, and gels.
They are manufactured by conventional methods. active ingredient
are commonly used adjuvants in these pharmaceutical compositions.
agents such as talc, gum arabic, lactose,
Starch, Magnesium Stearate, Cocoa Butter
-, aqueous or non-aqueous vehicle, animal or vegetable origin
fatty substances, paraffin derivatives, glycols, each
Seed wetting, dispersing or emulsifying agent and/or preservation
It can be blended into the drug. These compositions may also be prepared in a suitable vehicle, e.g.
For example, it is designed to dissolve immediately in pyrogen-free, sterile water.
It can be provided in the form of a powder as shown. Dosage depends on the condition being treated, the patient, the route of administration, and
and the compound under consideration. this is,
For example, for the compounds described in Examples 15, 38 or 43
is between 0.250g and 4g per day when administered orally in men;
Also 0.500g-1g by intramuscular route three times a day
It is between. Compounds of formula 'and their salts may also be used in surgical
It can also be used as a disinfectant for medical equipment. Compounds of the formula used at the start of the process of the invention
In particular, the following formula C compounds or derivatives of this acid, e.g. symmetrical anhydrides
The following formula The following formula is obtained by acting on the compound of , which is dissolved in an aqueous inorganic acid such as dilute hydrochloric acid.
produced by treatment with a liquid to obtain a compound of formula
can be built. In addition, the compound of formula C can be expressed by the following formula: (described in Belgian Patent No. 850662)
and treated with 2-methoxypropene.
It can be obtained by The compound of formula used at the beginning of the method is:
It can be manufactured as follows. The following formula The compound of is treated with 2-methoxypropene to give the following formula and convert it into a symmetrical acid anhydride, for example.
In the form of a derivative, the following formula The following formula is obtained by reacting with a compound of , which is dissolved in an aqueous inorganic acid such as dilute hydrochloric acid.
After treatment with liquid, the following formula We obtained the compound of Ha1−(CH₂)_o′−Ha1 Treatment with a compound of formula gives a compound of formula. formula'_KThe formula used at the beginning of the preparation of the compound_K
For example, a compound of formula
By reacting an azide such as azide
can be manufactured. Alternatively, the compound of formula can be reacted with azide to obtain
can be condensed with a compound of formula
can. Examples of such production are further illustrated in the experimental section.
vinegar. In addition to the examples of the present invention shown below, the following compounds
is the compound obtainable according to the present invention. Example 1: 3-acetoxymethyl-7-[[2-(2
-aminothiazol-4-yl)-2-phthalyl
midomethyloxyimino]acetyl]aminocef
tri-syn isomer of -3-em-4-carboxylic acid
fluoroacetate Step A: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2-
Phthalimidomethyloxyimino]acetyl]a
Diphenylene of minocef-3-m-4-carboxylic acid
methyl 0.085g of 3-aceto produced as follows
xymethyl-7-[[2-(2-tritylaminothi
Azol-4-yl)-2-hydroxyimino]
[acetyl]aminocef-3-em-4-carvone
diphenylmethyl acid, 0.12g bromomethylphthalate
lumide, 0.069 g potassium carbonate and 0.4 ml di
Stir the methyl sulfoxide vigorously for 15 minutes at ambient temperature.
Mix. Add 10 ml of 0.1N hydrochloric acid. The resulting sediment
Suction filter the phlegm, wash with water, dry, and remove 0.121 g of coarse
Obtain the organism, dissolve it in 1 ml of ethyl acetate, and
Treat with carbon charcoal, remove the solvent and then remove the residue
Grind the material with ether, dry it with suction, and collect 0.075 g of aliquots.
A sylated product is obtained. IR spectrum (CHC1₃) NH 3408cm^-1 β-lactam 1782cm^-1 Phthalimide Phthalimide 1730cm^-1 ester Amido 1665cm^-1 C=C, C=N 1614cm^-1 Aromatic 1599cm^-1 Amido 1511cm^-1 NH 1493cm^-1 C-N-OR 1033cm^-1 NMR spectrum (CDC1₃) 7.03ppm: aromatic, trityl-benzyl 7.8ppm: Phthalimide 6.9ppm: [Formula] 3.4ppm：CH ₂S Step B: 3-acetoxymethyl-7-[[2-(2
-aminothiazol-4-yl)-2-phthalyl
midomethyloxyimino]acetyl]aminocef
tri-syn isomer of -3-em-4-carboxylic acid
fluoroacetate To 0.32 g of the product obtained in step A, add 3 ml of trichloride.
Add fluoroacetic acid and stir vigorously for 10 minutes at ambient temperature.
Mix. Concentrate under reduced pressure at 30 °C and add 30 ml of isopropylene.
Add pyl ether, crush, suction dry, and
Wash with lopylether. Obtained 0.21g of initial compound
Ru. 3-acetoxymethyl-7-[[2-(2-trithi
Ruaminothiazol-4-yl)-2-hydroxy
Shiimino]acetyl]aminocef-3-M-4
- Preparation of diphenylmethyl carboxylate, syn isomer
Construction. A 3-acetoxymethyl-7-[[2-(2-t
lythylaminothiazol-4-yl)-2-[1
-methyl-1-methoxyethoxy]imino]a
cetyl]aminocef-3-em-4-carvone
Diphenylmethyl acid, syn isomer 4.15 g of 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2-
(1-methyl-1-methoxy]imino]acetyl]
Synthesis of aminocef-3-M-4-carboxylic acid
diethylamine salt with 40 c.c. of methylene chloride.
Introduce into 55 c.c. of 0.1N hydrochloric acid. Stir and decant for 10 minutes at ambient temperature.
and wash the organic phase twice with 25 c.c. of water. Then this phase
Dry, suction dry and wash with salt or methylene. 15 c.c. of 8% diazodiphenylmethane benzene
Introduce the solution for 10 minutes while stirring. ambient temperature
Stir at 30 °C for 15 min, then remove the solvent under reduced pressure at 30 °C.
evaporate to. Dissolve in isopropyl ether,
Triturate and evaporate the solvent under reduced pressure. isopropyl
After redissolving with ether, filter and wash.
After drying, 4.41 g of the expected compound are obtained. NMR spectrum (CDC1₃)60MH_Z Step B: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2-
(Hydroxy)imino]acetyl]aminocef-
diphenylmethyl 3-m-4-carboxylate,
syn isomer 2.775 g of the compound obtained above was added to 14 c.c.
and 4.5 c.c. of 1N hydrochloric acid. 2 hours at ambient temperature
Stir briefly and drive off the acetone under reduced pressure. Add 20 c.c. of ethyl acetate, stir, then remove.
to sing. The organic phase was diluted with 10 c.c. of weakly salted water.
Wash twice. The wash water is extracted with 5 c.c. of ethyl acetate.
Combine the organic fractions and dry. Vacuum dry and vinegar
Wash with ethyl acetate and then evaporate the solvent under reduced pressure.
Ru. The residue was dissolved in ether and crystallized.
Ru. Crush, suction dry and wash with ether. drying
Afterwards, 1.88 g of the expected compound are obtained. Rf=0.5 (eluent
= ether containing 20% acetone). NMR spectrum (CDC1₃)60MH_Z 6.88ppm: Proton of thiazole ring 7.33ppm: Proton of phenyl nucleus 3-acetoxymethyl-7-[[2-(2-trithi
Ruaminothiazol-4-yl)-2-[methyl-
1-Methoxyethoxyimino]acetyl]amino
syn isomer of cef-3-m-4-carboxylic acid
Production of diethylamine salt Step A: 2-(2-tritylaminothiazole-
4-yl)-2-(1-methyl-1-methoxyeth
(ximino) syn isomer of acetic acid 12.9 mg of 2-[(hydroxy)imino]-2-(2
-tritylaminothiazol-4-yl)acetic acid
syn isomer with 120 c.c. of methylene chloride and 12 c.c. of 2-
Stir in methoxypropypene for 20 minutes at ambient temperature.
Zeru. Concentrate to dryness and add again 60 c.c. of methylene chloride and 12
Stir in c.c. methoxypropene for 30 minutes and depressurize.
Concentrate to dryness. The desired compound is obtained and used in the next step. Step B: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2-
[1-Methyl-1-methoxyethoxy]imino]
[acetyl]aminocef-3-em-4-carvone
Diethylamine salt of syn isomer of acid 47.25g of 2-(2-tritylaminothiazole
-4-yl)-2-hydroxyiminoacetic acid
2- obtained according to the method described in step A
(2-tritylaminothiazol-4-yl)-2
-(1-methyl-1-methoxyethoxyimino)
Dissolve the syn isomer of acetic acid in 230 c.c. of methylene chloride.
do. 12.5g dicyclohexylcarbodiimide
and stir at ambient temperature for 1 hour. generate
Suction dry the dicyclohexyl urea and remove a small amount of it.
Wash with plenty of salt or methylene. Obtain 9.82g. the
Add 13.6g of 7-aminocephalosporanic acid to the solution
Soluble in c.c. of methylene chloride and 14c.c. of triethylamine.
Add to the dissolved solution. Stir at ambient temperature for 2 hours
Mix, wash with 350 c.c. of 1N hydrochloric acid in a funnel, and decane.
Wash with water, dry, and concentrate to dryness.
Dissolve the residue in 100 c.c. ethyl acetate and crystallize
start the transformation. Crystallize for 30 minutes and vacuum dry
and recover 5.5 g of starting material. Concentrate and dry the liquid
Solidify and dissolve the residue in 200 c.c. of isopropyl ether.
Stir for 30 minutes. Suction dry and dry
After that, 37.35 g of crude condensate are obtained. Do this carefully
To make it, proceed as follows. The product is dissolved in 148 c.c. of ethyl acetate. 5.5c.c.
of diethylamine and 650 c.c. of ether.
Stir vigorously to allow precipitation. suction drying
Washed with ether, dried, and weighed 26.35 g.
Obtain a compound. The liquid was then dried and poured into 50 c.c.
2.8 dissolved in Tel and fixed with primary yield in CCM
A secondary yield of g is obtained. This diethylamine salt is
Use as is. NMR spectrum (CDC1₃)60MH_Z Thiazole ring proton 6.78ppm Example 2: 3-acetoxymethyl-7-[[2-(2-
aminothiazol-4-yl)-2-phthalimide
Domethyloxyimino]acetyl]aminocef-
Sodium salt of 3-m-4-carboxylic acid, syn
isomer 0.21 g of the trifluoroacetate obtained in Example 1
Dissolve in 0.4ml methanol, then stir.
0.6ml of 1M sodium acetate in methanol
Add solution. Slowly add 2 ml of ethanol.
I can do it. Dry the precipitated sodium salt by suction and evaporate.
Wash with alcohol and then ether. 0.127g desired
Obtain the compound. UV spectrum HC1 N/10 (ethanol) max 217nm ε=46500 Inf 237nm ε=20000 max 252nm ε=16300 Inf 301nm ε=7400 Inf 320nm ε=5850 NMR spectrum (DMSO) 8.05ppm aromatic 2 ppm OAc IR spectrum (Nujiyol method) C=O 1776−1764−1724cm^-1 Amido 1689cm^-1 C=C, C=N 1659cm^-1 Aromatic 1611cm^-1 Amido 1545cm^-1 C.O.₂ 1525cm^-1 1511cm^-1 Example 3: 3-acetoxymethyl-7-[2-(2-a
minothiazol-4-yl)-2-(2-aminoe
Toxiimino)acetamide] Cef-3-M-
4-Carboxylic acid bistrifluoroacetate, syn
isomer Step A: 2-(2-tritylaminoethoxyimide
-2-(2-tritylaminothiazole-4-)
yl) syn isomer of ethyl acetate 12.2g of 2-(2-iodoethoxyimino)-2
-(2-tritylaminothiazol-4-yl)
The syn isomer of ethyl acetate was dissolved in 80 c.c. of anhydrous dimethyl fluoride.
lumamide and 12.4 g of tritylamine in an inert atmosphere.
Introduce it into the surrounding environment. Heat to 100℃ for 5 hours, 6.2g
of tritylamine. Leave at 100℃ for 7 hours
do. Return to ambient temperature and pour into distilled water at 1600 c.c.
Extracted 6 times with 250c.c. of benzene, washed with water, and then
Wash with saturated sodium chloride solution. dry,
23.5g of resin-like material was obtained and mixed with benzene and ether.
Chromatography on silica using substance (95-5) as eluent
to feed. The main fraction is then passed through silica to make it pure.
Elute with methylene chloride. Obtained 3.6g of pure compound
Ru. NMR spectrum (CDC1₃) 6.46ppm thiazole proton CH centered at 2.45ppm₂−NH Mie Line (J=5H_Z) Step B: 2-(2-tritylaminoethoxyimide
-2-(2-tritylaminothiazole-4-)
yl) syn isomer of acetic acid 2 g of ethyl ester produced in step A was added to 10 c.c.
of dioxane and 66 c.c. of absolute ethanol under nitrogen.
Introduce. Add 3 c.c. of 1N sodium carbonate.
After 65 hours, the resulting precipitate was suction dried and 3.5 c.c.
3 with dioxane-ethanol mixture (1-6.6)
Wash twice. 1.445g sodium salt as primary yield
get. The mother liquor was saponified again under the same conditions and 0.440 g of
Obtain the sodium salt. Primary yield of 1.445g is 3c.c.
of water and 30 c.c. of chloroform and stir vigorously.
While stirring, add 1N hydrochloric acid until the pH is 2.
(approx. 1.9c.c.). Decant the organic phase and add 10 c.c.
Wash with water 4 times until neutral. Wash water for each fraction
is re-extracted with 3 c.c. of chloroform. Chlorophor
All of the mucus phase is dehydrated and evaporated to dryness. Like that
Add 1 c.c. of dilorethane to the white powder obtained.
and then paste with 2 c.c. of isopropyl ether.
Make into a shape. Dry under reduced pressure until constant weight is reached.
and obtain 1.202 mg of compound. Mp=176℃ (min
solution). 0.440 mg of the secondary yield was treated in the same way,
0.325 g of desired compound is obtained. Mp=176℃ (min
solution). A total of 1.527 g of compound is obtained. Mp=176℃. NMR spectrum (CDC1₃) 6.65ppm 5th proton of thiazole 2.95ppm CH₂-N Step C: 3-acetoxymethyl-7-[[2-(2
-tritylaminoethoxyimino)-2-(2-t
lytylaminothiazol-4-yl)acetyl]
Amino] Cef-3-M-4-carboxylic acid diphene
syn isomer of nylmethyl Add 0.286 g of the acid produced in step B to 2 c.c.
Introduced into chilene. Stir the suspension and then
Obtain a solution of 1.4 c.c. of triethylamine and 10 c.c.
By mixing with enough methylene chloride to
Add 4 c.c. of the solution made more immediately. Cool to -20°C in a bath of acetone and dry ice.
and let stand for 5 minutes to prepare the solution, then
Obtain a solution of 1.25 c.c. pivaloyl chloride and 10 c.c.
By mixing with enough methylene chloride to
While stirring 0.4 c.c. of the solution made more immediately.
Drip. The bath was then returned to -10°C and left at this temperature for 30 minutes.
place Bring the solution to 10 °C for 10 min, then
0.176g 7-aminocephalosporanic acid diphene
Add the nyl methyl ester all at once and allow to return to ambient temperature.
vinegar. After 1 hour and 20 minutes, 17.6 mg of this ester was added again.
Add more. Stir for 30 minutes at ambient temperature, then refrigerate.
Leave for 15 hours, return to ambient temperature and evaporate to dryness under reduced pressure.
Solidify, filter through silica, and add benzene-ethyl acetate mixture.
Elutes with compound (8-2). 0.208g desired compound
collect things. NMR spectrum (CDC1₃) 1.99ppm [Formula] 4.38ppm N-O-CH ₂ 6.71ppm 5th proton of thiazole 6.88ppm CO₂CH−φ₂ Step D: 3-acetoxymethyl-7-[2-(2-
aminothiazol-4-yl)-2-(2-amino
ethoxyimino)acetamide] Cef-3-M
-4-carboxylic acid bistrifluoroacetate,
syn isomer 186mg of 3-acetoxymethylene produced in step C
Ru-7-[[2-(2-tritylaminothiazole
-4-yl)-2-(2-tritylaminoethoxy
imino)acetamide] Cef-3-M-4-ka
1.8 c.c. of pure trifyl diphenylmethyl rubonate
Introduced into oroacetic acid. surrounding the resulting yellow oil.
temperature for 3 minutes, then an ice water bath under an inert atmosphere.
Stir quickly and add 18 c.c. of isopropyl ether.
Add more. Stir for 10 minutes, vacuum dry, and
Wash with lopylether and then ethyl ether;
Dry to obtain 100 mg of white powder. Mp=approx. 210℃
(Disassembly). NMR spectrum (DMSO) 2.03ppm [Formula] 3.17ppm =N-O-CH₂ 6.85ppm 5th proton of thiazole 2-(2-iodoethoxy used at the beginning of Example 3)
imino)-2-(2-tritylaminothiazole-
The syn isomer of ethyl acetate (4-yl) is as follows:
manufactured. a 2-(2-bromoethoxyimino)-2-(2
-tritylaminothiazol-4-yl)acetic acid
ethyl ester, syn isomer of 4.94 g of 2-hydroxyimino-2-(2-t)
ethyl aminothiazol-4-yl)acetate
hydrochloride, syn isomer, in dimethylforma at 10 c.c.
under an inert atmosphere, and 4.14 g of
Introduce potassium carbonate for 3 minutes at ambient temperature.
Ru. Stir for 20 minutes at 20℃, 8.65c.c.
Add bromoethane. Stir for 30 hours, 100 c.c.
of distilled water and 20 c.c. of methylene chloride in a medium containing
and decantated with methylene chloride.
Re-extract, wash with distilled water, re-extract and extract the organic solution.
Dehydrate, suction dry, wash, and evaporate to dryness. raw
chromatograph the product on silica.
and eluted with benzene containing 5% ether.
do. Collect the first fraction and add it to methanol for 50~
After melting at 60℃, recrystallize and aspirate at 0 to +5℃.
Dry to obtain 1.16 g of milky white product. mp=117
℃. A homogeneous fraction of 1.258 g is then obtained. NMR spectrum (CDC1₃) Mie line 3.55ppm J=7H_Z CH ₂Br Mie line 4.51ppm J=6H₂ N-O-CH₂ Singlet 6.55ppm Thiazole ring proton b 2-(2-iodoethoxyimino)-2-(2
-tritylaminothiazol-4-yl)acetic acid
ethyl, syn isomer 6 g of 2-(2-brome) prepared in a) above.
Toxiimino)-2-(2-tritylaminothiazo
ethyl acetate, syn isomer, 60
c.c. of methyl ethyl ketone and 2.141 g of sodium iodide
Introduced to Rium. Reflux for 1 hour and 10 minutes. decrease
Evaporate under pressure and dissolve the residue in 120 c.c.
Dissolve in water and wash 5 times with 40 c.c. water. Each wash water
Re-extract with 2 c.c. of methylene chloride and dry the organic phase.
and evaporate to dryness. The obtained resinous material is
Mix with Le. Dry under reduced pressure to yield 6.22 g of product.
get. mp=110℃. NMR spectrum (CDC1₃) CH₂1 Triple line centered at 3.31ppm (J=7Hz) Thiazole 5th proton 6.53ppm Example 4: 3-acetoxymethyl-7-[2-(2-a
minothiazol-4-yl)-2-(2-aminoe
Toxiimino)acetamide] Cef-3-M-
syn isomer of 4-carboxylic acid 220 mg of bistrifluoroacetic acid prepared in Example 3
Place the salt in a test tube and add 1.6 c.c. of sodium acetate.
Add molar methanol solution. until completely dissolved.
Stir and wash the sides with methanol. 18.6c.c.
Add absolute ethanol. Precipitation occurs or the same
Starting from 100 mg bistrifluoroacetate in the method
Add the same mixture obtained above. 1 hour 50 minutes later
Then, the insoluble material was suctioned dry, and then ethanol was added.
Wash with water and dry under reduced pressure to a constant volume.
Obtain 181 mg of white powder. Mp = 270℃ (decomposition). Rf=0.12 (ethyl acetate-ethanol-water: 60-
25-15). This product is purified as follows. 120 mg of the above product are introduced into 1 c.c. of distilled water.
Stir for 5 minutes, then add pyridine to a pH of 7.0-7.2.
Add slowly until obtained. stir for 15 minutes
After soaking, suction dry, wash with 0.5 c.c. of water, and remove the solution.
Add 40c.c. of acetone to the solution, stir for 5 minutes,
Leave for a minute, suction dry, wash three times with acetone,
dry. Obtain 99.5 mg of white powder. UV spectrum Max 261nm E¹ ₁=348 Example 5: 3-methyl-7-[[2-(2-aminothia
sol-4-yl)-2-(2-aminoethoxy
mino)acetyl]amino]cef-3-m-4-
Bistrifluoroacetate of carboxylic acid, syn isomer
body Step A: 3-methyl-7-[[2-(2-trityl
aminothiazol-4-yl)-2-(2-trithi
aminoethoxyimino)acetyl]amino]se
diphenylmethylph-3-m-4-carboxylate
le, syn isomer Produced according to the method described in Example 3, Step B
0.923 mg of 2-(2-tritylaminothiazole-
4-yl)-2-(2-tritylaminoethoxy
Syn isomer of acetic acid with 6.5 c.c. of methylene chloride
Introduce 1.3 c.c. of triethylamine solution. this
The triethylamine solution contains 1.4 c.c.
Methyl chloride in sufficient quantity to obtain a solution of 10 c.c.
Obtained by mixing with Ren. After making it soluble, it was cooled to -20℃ and 1.3 c.c.
Pivaloyl chloride solution (1.25 c.c. pivaloyl chloride
with enough methylene chloride to obtain a solution of 10 c.c.
(obtained by mixing). Raise to -10 °C and keep at this temperature for 35 min. +
0.494 g of 7-amino deacetate
Addition of xicephalosporanic acid dibenzyl ester
I can do it. Bring to ambient temperature and stir for 1 hour and 20 minutes.
Ru. Then 77 mg of 7-amino deacetoxycefa
Rosporanic acid dibenzyl ester is added again.
Stir for 1 hour, evaporate to dryness under reduced pressure, and wash with silica.
Chromatography and benzene-ethyl acetate mixture
Elutes with compound (8-2). 504g desired compound
Collect. NMR spectrum (CDC1₃) 2.1ppm 3-position methyl 6.93ppm dibenzyl CHφ₂proton of Step B: 3-methyl-7-[[2-(2-aminoe
Toxiimino)-2-(2-aminothiazole-4
-yl)acetyl]amino]cef-3-m-4
- bistrifluoroacetate of carboxylic acid, syn
sexual body 357 mg of the compound obtained in step A was added to 3 c.c.
Introduce into fluoroacetic acid. the solution for 2 hours and 30 minutes
Stir, then place in an ice water bath and add 40 c.c.
Lopylether - Petroleum ether (64-75℃ distillation)
Add the mixture (50-50) quickly while stirring.
Ru. Stir for 10 minutes, suction dry, isopropyl
Wash with ether and then regular ether,
Dry to volume to obtain 200 mg of white powder. Mp=
Approximately 250℃ (decomposition). NMR spectrum (CH₃)₂S.O. 2.03ppm 3-position methyl 6.88ppm 5th proton of thiazole Example 6: 3-acetoxymethyl-7-[[2-(2-
aminothiazol-4-yl)-2-(2-azide
ethoxy)imino]acetyl]amino]cef-3
-m-4-carboxylic acid syn isomer Step A: 2-[2-tritylaminothiazole
-4-yl)-2-(2-azidoethoxy)imino
syn isomer of acetic acid 24.8g of 2-(2-tritylaminothiazole
-4-yl)-2-(2-bromoethoxy)imino
Sodium acetate, 125 ml dimethylformamide
and 7.5 g of tetramethylguanidine azide at 50
Stir for 1 hour in a water bath at °C, then stir for 45 minutes.
Mix to obtain a clear brown solution. cool to ambient temperature,
Add 500ml water and 50ml 2N hydrochloric acid. suction drying
and washed three times with water, then triturated with methylene chloride.
Decant the liquid, wash with water, then dry
do. Concentrate to 50ml under reduced pressure and add 250ml of ethyl
Add the ether slowly. Suction dry;
Obtain 15.58 g of acid. 2-(2-bromoethoxyimino)-2-(2-
Tritylaminothiazol-4-yl)acetic acid sodium
The thorium salt, syn isomer, is produced as follows:
Ta. Add 6g of pastel sodium carbonate to 280c.c.
Introduce water into ethanol. As you can put in the above example
28.2 g of 2-(2-bromoethoxy
imino)-2-(2-tritylaminothiazole-
4-yl) ethyl ester of acetic acid, syn isomer,
Add. Stir at ambient temperature for 65 hours. sodium salt
To separate. Dry this by suction and wash with ethanol.
Then vacuum dry. 29.82g of 12% solvate
The desired product is obtained. Step B: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2-
[(2-azidoethoxy)imino]acetyl]ami
Diethyl of cef-3-em-4-carbonylic acid
Ruamino salt, syn isomer 2.54g 7-aminocephalosporanic acid, 25ml
of anhydrous methylene chloride and 2.6 ml of triethylamine
Stir the mixture at ambient temperature for 15 minutes. 6.02g of 2-(2-tritylaminothiazole
-4-yl)-2-(2-azidoethoxy)imino
1-Hydroxy-1H-benzotriazole acetate
and stir at ambient temperature for 45 hours. 25ml water
and 5 ml of 1N hydrochloric acid. decantation,
The organic phase is washed with water, dried and concentrated to dryness under reduced pressure.
Ru. The residue is dissolved in 30 ml of ethyl acetate.
After dissolving, add 24 ml of diethylamine. to 0℃
Cool and vacuum dry 5.9 g of diethylamine salt.
Ru. The 2-(2-trityl acetate used at the beginning of step B)
Minothiazol-4-yl)-2-(2-azidoe
Toxi)iminoacetic acid 1-hydroxy-1H-ben
Zotriazole was produced by the following method. 9.84g of 2-(2-tritylaminothiazole
-4-yl)-2-(2-azidoethoxy)imino
Acetic acid, 2.93 g 1-hydroxy-1H-benzoto
Riazole, 4.86 g dicyclohexyl carbodi
Mix imide and 130 ml of anhydrous methylene chloride.
Stir at ambient temperature for 20 hours. The resulting dicyclohe
Suction dry the xylurea. The liquid is diluted with bicarbonate of soda.
Wash with thorium-added water, then with water only.
cormorant. Dry and concentrate to dryness under reduced pressure. the residue
Dissolve in ethyl acetate. Cool for 1.5 hours at 0℃
and then suction dry. Obtained 7.31g of product
Ru. An additional 1.5 g of product is recovered from the mother liquor. Step C: 3-acetoxymethyl-7-[[2-(2
-aminothiazol-4-yl)-2-[(2-a
Didoethoxy)imino]acetyl]amino]cef
syn isomer of -3-em-4-carboxylic acid 1.238 g of the product obtained in the above step and 6 ml of 70%
Stir the formic acid at 50°C for 15 minutes. The resulting triplicate
Suction dry the nylcarbinol and reduce the pressure of the liquid.
Concentrate to dryness. Dissolve the residue in water and crush
0.358 g of the desired acid.
obtain. Example 7: 3-acetoxymethyl-7-[(2-(2-
aminothiazol-4-yl)-2-(2-amino
ethoxy)imino]acetyl]aminocef-3-
syn isomer of em-4-carboxylic acid Step A: 3-acetoxymethyl-7-[2-(2-
tritylaminothiazol-4-yl)-2-[2
-aminoethoxy]imino]acetyl]aminose
Syn isomer of 3-M-4-carboxylic acid 0.752 g of 3-acetoxymethylene prepared in Example 6
Ru-7-[2-(2-tritylaminothiazole-
4-yl)-2-[2-azidoethoxy]imino]
[acetyl]aminocef-3-em-4-carvone
acid, 4 ml dimethylformamide and 0.7 ml
Mix water triethylamine. Add sulfur to this mixture.
Introduce for 15 minutes while bubbling hydrogen oxide. 40ml
Add water and then 0.7 ml acetic acid. Suction dry;
0.707 g of crude product is obtained. Step B: 3-acetoxymethyl-7-[[2-(2
-aminothiazol-4-yl)-2-(2-ami
Noethoxy]imino]acetylaminocef-3-
syn isomer of em-4-carboxylic acid 1.054 g of the product obtained above was added to 5 ml of 70%
Heat in formic acid at 50 °C for 15 min. The resulting triplicate
Suction dry the nylcarbinol and reduce the pressure of the liquid.
Concentrate below. Dissolve the dry residue with water and remove the insoluble matter.
remove. Dissolve the concentrated and dried liquid with ethanol.
Understand. Crush, vacuum dry, 0.125 g of desired acid
get. Example 8: 3-acetoxymethyl-7-[[2-(2-
aminothiazol-4-yl)-2-[2-(aminothiazol-4-yl)-2-[2-(aminothiazol-4-yl)
Noethoxy)imino]acetyl]aminocef-3
-M-4-carboxylic acid sodium salt, syn
sexual body Add 0.2 ml of 1 molar bicarbonate to the product obtained in Example 7.
Dissolve in sodium solution. 0.4ml ethanol
Add the solution slowly, suction dry the insoluble matter, and remove the liquid.
Concentrate to dryness under reduced pressure. Ethanol the residue
Wash and crush. Dry with suction to obtain 0.047 g of the desired salt. Example 9: 3-[(1-methyl-1H-tetrazole-
5-yl)thiomethyl]-7-[[2-(2-amino
thiazol-4-yl)-2-[(2-aminoeth
xy)iminoacetyl]aminocef-3-M-
syn isomer of 4-carboxylic acid Step A: 3-[(1-methyl-1H-tetrazole
-5-yl)thiomethyl]-7-[[2-(2-tri
thylaminothiazol-4-yl)-2-[(2-
Aminoethoxy)iminoacetyl]Amino]Cef
-3-M-4-carboxylic acid 3.91 g of 3-[[1-methyl-1H-tetrazo
-5-yl)thiomethyl]-7-[[2-(2-t
lythylaminothiazol-4-yl)-2-[[2
-azidoethoxy]imino]acetyl]amino]
Sodium cef-3-M-4-carboxylate 39
ml of dimethylformamide. 20ml
Slowly add water, then 9.75ml of triethylamine.
I add. While blowing hydrogen sulfide into this mixture
Introduce. After 45 minutes, 3.9 ml of triethylamine
and continue bubbling for another 45 minutes. The mixture
Pour the mixture into dilute hydrochloric acid solution at 10°C. at 30℃ for 15 minutes
Heat with stirring, then cool and absorb the precipitate.
Dry, wash until neutral, and dilute with ethyl ether.
2 g of the desired product are obtained. The 3-[(1-methyl-
1H-tetrazol-5-yl)thiomethyl]-7
-[[2-(2-tritylaminothiazole-4-
yl)-2-[[2-azidoethoxy]imino]a
cetyl]amino]cef-3-em-4-carvone
Sodium acid was produced as follows. 8.47 g of 2-(2-tritylamino obtained in Example 6)
thiazol-4-yl)-2-(2-azidoethoxy
c) syn isomer of iminoacetic acid, 50 ml methylene chloride
and 1.93g dicyclohexylcarbodiimide
Stir for 1 hour at ambient temperature. Generated jishik
Aspirate the lohexyl urea dry. This liquid is 3.07
g of 3-[(1-methyl-1H-tetrazole-5
-yl)thiomethyl]-7-aminoceph-3-e
Mu-4-carboxylic acid, 40 ml of anhydrous methylene chloride and
and 3.9 ml of triethylamine.
Add in minutes. Stir for another 1 hour and reduce pressure.
Concentrate to dryness. The residue was dissolved in 50 ml of acetic acid at 20°C.
Dissolve in chill and acidify with 0.2 ml acetic acid. suction
Dry, wash the solution with 1N hydrochloric acid, and then neutralize
Rinse with water until. Dry the organic phase and reduce to a volume of 50 ml.
Return to the stack. Add 1.7ml diethylamine.
The acid salt of the starting material crystallizes out and is dried by suction.
Ru. Then add 115ml of isopropyl ether to the solution.
Precipitate with Vacuum dry and remove 7.62 g of diethylua.
Obtain Min Salt. Take this 5.9g and add it to 60ml
A mixture of water, 60ml methylene chloride and 3.5ml 2N hydrochloric acid.
Dissolve in the mixture while stirring. Decantation
The organic phase was washed with water, dried and concentrated to dryness under reduced pressure.
harden Dissolve the residue in 20ml of isopropyl ether.
Dissolve under vacuum and dry with suction to obtain 5.6 g of free acid.
Combine this with 9.5ml methanol and 6.7ml 1M sodium acetate.
Dissolve in the mixture with methanol solution. Na
27ml 25% ethanol isopropano thorium salt
precipitate with 270 ml of isopropanol.
Dilute with water. 4.21 g of desired product are obtained. Step B: 3-[(1-methyl-1H-tetrazole
-5-yl)thiomethyl]-7-[[2-(2-ami
notiazol-4-yl)-2-[(2-aminoe
Toxy)iminoacetyl]amino]ceph-3-e
syn isomer of mu-4-carboxylic acid Mix 2 g of the product obtained above with 5 ml of formic acid.
Heat to 40-45℃ while stirring. Add 5ml of water
Well, keep this temperature for 15 minutes. Cool and produce
Dry the rifenyl carbinol and remove the liquid.
Concentrate to dryness under reduced pressure. 10ml of the residue
Dissolve in ethanol, crush, suction dry, ethanol
water, then ethyl ether, and 1.36 g of crude
The product is obtained, which is dissolved in 15 ml of 2N hydrochloric acid.
Suction dry the insoluble matter. Pour the liquid into 3ml of 1M vinegar.
Lithium oxide aqueous solution, then lithium hydroxide aqueous solution
Set it to PH4. Suction dry and the liquid under reduced pressure
Concentrate to dryness. Dissolve the residue in 30ml ethanol.
Dissolve, crush and vacuum dry. 515mg desired product
get. 133 mg of product are recovered in the mother liquor.
The two products are treated again in the same manner as above.
430 mg of white product are thus isolated. NMR spectrum (CD₃)₂S.O. 6.86ppm 5th proton of thiazole Example 10: 3-acetoxymethyl-7-[[2-(2-
aminothiazol-4-yl)-2-[(2-dime
thylaminoethoxy)iminoacetyl]amino]
Trifluoro of cef-3-m-4-carboxylic acid
Acetate, syn isomer Step A: 2-(2-dimethylaminoethoxyimide)
-2-tritylaminothiazol-4-yl)
Hydroiodide of acetic acid, syn isomer Mixing 120 c.c. of chloroform with dimethylamine
compound (9:1) and 10 mg of 2-(2-iodoethoxy)
(shiimino)-2-(2-tritylaminothiazole)
-4-yl) syn isomer of acetic acid at ambient temperature.
Stir for 3 hours. Evaporate to dryness at a temperature not exceeding 40℃ to 100c.c.
Dissolve in isopropyl ether and triturate at ambient temperature.
Stir for 15 minutes at 30°C, suction dry, and wash. 50c.c.
Dissolve in acetone, reflux for 5 minutes, then remove to ambient
Dry with suction at temperature and evaporate the solvent under reduced pressure.
let Obtained 9.33 g of product and dissolved it in 46 c.c. of water.
, stir, then suction dry and wash. 80c.c.
Dissolve in acetone, stir, vacuum dry, and vacuum
Dry underneath. Mp=208-210℃ (decomposition). NMR spectrum (D₂O＋C_FiveD_FiveN) Triple line centered at 4.55ppm (J=5Hz) =NO-CH ₂ 6.98ppm singlet 5th proton of thiazole 7.33ppm singlet -C (Ph)₃ UV spectrum (ethanol-N/10 hydrochloric acid) Inf1 270nm E¹ ₁=271 Max 275nm E¹ ₁ ε=14000 Inf1 284nm E¹ ₁=260 Step B: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2
[(2-dimethylaminoethoxy)iminoacety
Amino] Cef-3-M-4-carboxylic acid
nzhydryl, syn isomer 1 g of the acid produced in step A is mixed with 15 c.c. of chloroform.
of methanol and 1.5 c.c.
Add mg of triethylamine hydrochloride. 5 to 60℃
Heat for minutes and then evaporate to dryness. 15c.c. black
Dissolve in roform and bring to 0 to +5°C in an ice bath.
and 1.25 g of pivaloyl chloride in chloroform.
2 c.c. of pivaloyl chloride solution made as 10 c.c.
drip. Return to ambient temperature. 1.1 g of 7-aminocephalospora after 2 hours
Add benzhydryl phosphate again. After 1 hour and 30 minutes, evaporate to dryness and chromatograph on silica.
graphite and containing 5% methanol.
Elute with loform. 430 mg of desired product are obtained. Step C: 3-acetoxymethyl-7-[[2-(2
-aminothiazol-4-yl)-2-[(2-di
methylaminoethoxy)iminoacetyl]amino
trifle of cef-3-m-4-carboxylic acid
Oracetate, syn isomer 100 mg of the product obtained in step B and 1 c.c.
Stir the mixture with fluoroacetic acid at ambient temperature for 3 minutes.
Mix. Precipitated with ether and 0.2 c.c. methanol
and precipitate again with 2 c.c. of ether.
Make a paste with chloroform, dry with suction,
Wash with chloroform and then ether. 40 mg of desired product are obtained. Mp=23℃. NMR spectrum (CD₃)₂S.O. 6.8ppm singlet 5th proton of thiazole UV spectrum (ethanol) Max 234nm E¹ ₁=305 ε=15600 Inf1 254nm E¹ ₁=247 ε=12650 Inf1 296nm E¹ ₁=103 ε=5300 (ethanol-N/10 hydrochloric acid) Max 260nm E¹ ₁=279 ε=14300 Inf1 276nm E¹ ₁=243 Example 11: 3-acetoxymethyl-7-[[2-(2-
aminothiazol-4-yl)-2-[(2-1-
pyridinylethoxy)imino]acetyl]ami
trifle of cef-3-m-4-carboxylic acid
Oracetate, syn isomer (intramolecule of pyridinium)
salt) Step A: 2-(2-tritylaminothiazole-
4-yl)-2-[(2-1-pyridinylethoxy)
imino] syn isomer of acetic acid (molecule of pyridium
(within) Dichloroethane, obtained as described below
5 g of 2-(2-iodoethoxy) solvated with
imino-2-(2-tritylaminothiazole-
4-yl) acetic acid (i.e., 4.27 g of pure
compound) in 30 c.c. of pyridine at 60°C for 24 hours.
and then left at ambient temperature for 56 hours. The resulting sediment
Suction dry the phlegm, wash with pyridine, and then rinse with ether.
Wash with water and dry to obtain 1.66 g of product. Mp
=250℃ (decomposition). NMR spectrum (CD₃COCD₃−D₂O=1-1) 6.8ppm Thiazole H_Five 7.5~8ppm Pyridyl proton 4.58～5.08ppm=N-O-CH ₂-CH ₂ UV spectrum (EtOH-HC1・N/10) Max 260nm E¹ ₁=324 IR spectrum (Nujiyol method) C.O.₂ 1639cm^-1 C=C 1583cm^-1 C=N 1523cm^-1 Step B: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2-
(2-1-pyridinylethoxyimino)acetyl]
Amino] Cef-3-M-4-carboxylic acid benzene
Iodide of hydryl, syn isomer 540 mg of the product obtained above, 210 mg of pyridine hydride
Royodide, 420 mg dichlorhexyl carbo
Diimide, 350 mg 7-amino-3-acetoxy
Methylcef-3-M-4-carboxylic acid benzene
drill and 5 c.c. of anhydrous dimethylformamide.
Stir at ambient temperature for 20 hours. The resulting dicyclohexyl
Suction dry the silurea precipitate and dimethylformamide.
Wash with water and pour the liquid into 60 c.c. of ether. Ga
Causes mucous texture. Stir for 5 minutes at ambient temperature,
and remove floating objects. 60c.c. of gum quality
Place in ether and crush. Suction and dry the formed precipitate
to obtain 754 mg of crude product. Add 1.6g of this
7.5 c.c. dichloroethane with magnesium acid
Purify by stirring for 20 minutes. insoluble
Suction dry the item, wash with 0.5 c.c. dichloroethane,
The liquid is then evaporated to dryness. Step C: 3-acetoxymethyl-7-[[2-(2
-aminothiazol-4-yl)-2-[(2-1
-pyridinylethoxy)imino]acetyl]ami
trifle of cef-3-m-4-carboxylic acid
Oracetate, syn isomer 368mg of the product obtained above was added to 3c.c. of pure truffles.
Stir in fluoroacetic acid for 3 minutes at ambient temperature. No
Quickly aspirate the solution and remove the solution with 40 c.c. of ether.
Precipitate with water, stir for 5 minutes, suction dry,
Wash with tellu. Hygroscopic product with 0.35 c.c. of methanol
and precipitate with 4 c.c. of ether. suction drying
Dry and wash with ether to obtain 140 mg of desired product.
Ru. Mp=205℃ (decomposition). NMR spectrum (DMSO) 2.06 ppm OAc 6.86 ppm Thiazole H_Five UV spectrum (EtOH-HC1-N/10) Max 260nm E¹ ₁=318 IR spectrum (Nujiyol method) β-lactam 1777cm^-1 OAc 1740cm^-1 C.O.₂−1633cm^-1 c=NO-R 1037cm^-1 2-(2-iodoethoxyimide used at the beginning)
-2-(2-tritylaminothiazole-4-)
The syn isomer of acetic acid is prepared as follows:
Ta. a 2-(2-iodoethoxyimino)-2-2
(2-tritylaminothiazol-4-yl)
Ethyl acetate, syn isomer 6 g of 2-(2-bromoethoxylate prepared in Example 3)
(shiimino)-2-(2-tritylaminothiazole)
-4-yl) ethyl acetate, syn isomer at 60 c.c.
Tyl ethyl ketone and 2.141 g of sodium iodide
Introduce it inside. Reflux for 1 hour and 10 minutes. under reduced pressure
Evaporate and dissolve the residue with 120 c.c. of methylene chloride.
Dissolve and wash 5 times with 40 c.c. water. Add 2 c.c. of each wash water
Re-extract with methylene chloride, dry and evaporate the organic phase
Dry. Add the resulting resinous substance to ether
Ru. Dry under reduced pressure to obtain 6.22 g of product.
mp=110℃. b 2-(2-iodoethoxyimino)-2-(2
-tritylaminothiazol-4-yl)acetic acid
syn isomer of 6.7 g of the ethyl ester produced in step a)
5.5 c.c. of dioxane and 44 c.c. of absolute ethanol.
Introduce under activation. Then 5.5 c.c. of 2N sodium carbonate
um solution dropwise. Add 7 c.c. of absolute ethanol.
Eh, the sodium chloride produced by stirring overnight at ambient temperature
Suction dry the salt. 3c.c. of ethanol-dioxylene
Wash twice with San 4-1 solution, then rinse with ether.
Make it into a toast shape. The resulting product is placed in an ampoule.
Treated with 100 c.c. of water and 100 c.c. of chloroform.
Decant. Adjust the pH to 2 with 1N hydrochloric acid.
Ru. Decant the organic phase and remove sodium chloride.
Wash with a saturated solution of water, dry and evaporate under reduced pressure.
Ru. The resulting resinous material was heated to 40°C with 35 c.c. of dichloromethane.
Dissolves in tan. Initiate crystallization and at ambient temperature
Leave it for 72 hours, suction dry the formed precipitate, wash it,
5.4 g dry, white solvated dichlorothane
The product is obtained (4.61 g of pure product). mp=161℃. Analysis: C₂₆H_{twenty two}O₃N₃SI=583.35 Calculation: N%6.16 S%4.70 Actual measurement: 5.9 4.8 UV spectrum (ethanol/N/10 hydrochloric acid) Max 278nm E¹ ₁=235 NMR spectrum (CDC1₃) 6.58 5th proton of thiazole Example 12: 3-acetoxymethyl-7-[(2-(2-
aminothiazol-4-yl)-2-[(2-(imi
dazol-1-yl)ethoxy)imino]acetyl
[amino]cef-3-em-4-carboxylic acid
Trifluoroacetate, syn isomer Step A: 2-(2-triethylaminothiazole
-4-yl)-2-(2-imidazol-1-yl
ethoxyimino) syn isomer of acetic acid (imidazoly
(as an inner salt of Ni) 3 g of 2-(2-
tritylaminothiazol-4-yl)-2-(2
- iodoethoxyimino) acetic acid syn isomer (imino)
2.56 g of pure compound), 4.2 g of imidazole and
10 c.c. of dimethylacetamide at ambient temperature for 3 hours.
Stir. Add 10 c.c. of dimethylacetamide again.
Add and continue stirring at ambient temperature for 40 hours. 200c.c.
of isopropyl ether and stir for 30 minutes.
Then, decant and remove the floating material.
Crush the gum with 200c.c. of isopropyl ether.
This treatment was carried out with 300 c.c. of ethyl ether.
repeat. Stir for 30 minutes, suction dry,
Dissolve in 30 c.c. acetone and stir for 1 hour.
Mix, vacuum dry, with acetone and then ether.
Wash and dry to obtain 1.24 g of product. Mp=280
°C (decomposition). NMR spectrum (DMSO) 4.35ppm N-CH ₂-CH ₂-N 6.8 ppm Thiazole H_Five 7.82ppm [Formula] UV spectrum (EtOH-HC1・N/10) Max 277nm E¹ ₁=259 IR spectrum (Nujiyol method) C.O.₂ 1614cm^-1 Aromatic 1492cm^-1 Heterocycle 1527cm^-1 Step B: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2-
[(2-imidazol-1-ylethoxy)im
[Acetyl]Amino]Cef-3-M-4-ka
Benzhydryl rubonate 780 mg of the product obtained above, 315 mg of pyridine hydride
Royodide, 630 mg dicyclohexyl carbo
Diimide, 600 mg 7-amino-3-acetoxy
Methylcepha-3-M-4-carboxylic acid benzene
hydryl and 6 c.c. of anhydrous dimethylformamide.
Stir vigorously in an ice water bath. dicyclohexyl
Urea precipitates. Bring to ambient temperature and stir for 20 minutes
continue. Suction dry the insoluble matter and dimethylforma.
Wash with mido. Precipitate the liquid with 120 c.c. of ether.
Ru. Stir for 20 minutes, decant and float.
After removing the solids, the resulting gum was mixed with 100c.c. of ether.
Take and crush. Stir for 10 minutes at ambient temperature and vacuum dry.
Dry, wash with ether, dry, 1.3 g of product
This is obtained and chromatographed on silica.
A mixture of ethyl acetate, ethanol and water (8-1
−0.5) to give 332 mg of the desired product. NMR spectrum (CDC1₃) 2ppmOAc 6.75ppm synthiazole H_Five IR spectrum (CHC1₃) β-lactam
1788cm^-1 Ester and OAc 1759cm^-1 Heterocycle 1525cm^-1 Step C: 3-acetoxymethyl-7-[(2-(2
-aminothiazol-4-yl)-2-[(2-y
midazol-1-ylethoxy)imino]acetyl
[amino]cef-3-em-4-carboxylic acid
Trifluoroacetate, syn isomer 230 mg of the product obtained above and 2 c.c. of pure trifluoro
Stir the acetic acid at ambient temperature for 3 minutes. obtained
The solution was mixed with isopropyl ether and ethyl ether.
Pour into mixture (1-1) and stir at ambient temperature for 20 minutes.
Mix, suction dry the resulting precipitate, and dilute with ethyl ether.
Wash with water, dissolve in 0.4 c.c. of methanol and dissolve in 4 c.c.
Precipitate again with ether for 10 minutes at ambient temperature.
Stir, suction dry, wash with ether, dry,
140 mg of desired product are obtained. Mp=205℃ (decomposition). NMR spectrum (DMSO) 2.03ppmOAc 6.8 ppm synthiazole H_Five 7.66 and :H_Fourand H_Five 7.71ppm Imidazole 8.95ppm:H₂ UV spectrum (EtOH-HC1・N/10) Max 260nm E¹ ₁=271 Example 13: 3-acetoxymethyl-7-[[2-(2-
aminothiazol-4-yl)-2-[(2-mol
holinoethoxy)imino]acetyl]amino]ce
Syn isomer of 3-M-4-carboxylic acid (min.
(as konai salt) Step A: 2-(2-tritylaminothiazole-
4-yl)-2-(2-morpholinoethoxy)imi
syn isomer of noacetic acid (as inner salt) 2 g of 2-(2-
tritylaminothiazol-4-yl)-2-(2
-iodoethoxy) iminoacetic acid syn isomer (iminoacetic acid)
1.71 g of pure compound) is dissolved in 7 c.c. of morpholine.
do. Stir the solvent for 1 hour at ambient temperature and then
Concentrate in a nitrogen stream. With 30 c.c. of ethyl acetate
Dissolve, stir for 20 minutes at ambient temperature, and suction dry.
and wash with ethyl acetate. This product was mixed with 15 c.c.
Stir in toxypropane for 15 minutes, then aspirate
Dry and wash with the same solvent. Dissolved in 15 c.c. of ether
Stir for 15 minutes, suction dry, and wash with ether.
23 g of product are obtained. Mp=180℃ (decomposition).
This will be used as is in the next step. Reconstitute 100 mg of this product in 0.5 c.c. of ethanol.
Crystallize and purify to obtain 46 mg of recrystallized product.
Mp=182-184℃ (decomposed). NMR spectrum (CDC1₃) 7.33ppm trityl 6.75ppm synthiazole H_Five UV spectrum (EtOH-HC1・N/10) Max 276nm E¹ ₁=172 IR spectrum (CHC1₃) C.O.₂ and aromatic 1606-1529 and 1495cm^-1 −NH 3399cm^-1 Step B: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-[2-
(2-morpholinoethoxy)imino]acetyl]
Aminocef-3-M-4-carboxylic acid benzene
Drill hydroiodide, syn isomer 1 g of the product obtained above, 0.38 g of pyridine hydride
Royodide, 0.63g dicyclohexylcarbo
imide and 0.60 g of 3-acetoxymethyl-7-
Aminocepha-3-M-4-carboxylic acid benzene
Dissolve the hydryl in 5 c.c. of anhydrous dimethylformamide.
Stir this solution for 30 minutes at ambient temperature.
Ru. Dry the resulting dicyclohexyl urea by suction.
Ru. Add 100 c.c. of ether to the solution. 10 minutes
Stir briefly, dry with suction, wash with ether, and remove silica.
Chromatographed with ethyl acetate-ethanol
Elute with mixture (7-1). Production of 0.524g
get something Mp=167℃ (decomposed). NMR spectrum (CDC1₃) 2.03ppmOAc 3.72ppmCH ₂C 6.75ppm synthiazole H_Five UV spectrum (EtOH-HC1・N/10) Max 268nm E¹ ₁=165 ε=15900 IR spectrum (CHC1₃) β-lactam 1791cm^-1 Ester and OAc 1740cm^-1 Amido 1678cm^-1 Step C: 3-acetoxymethyl-7-[[2-(2
-aminothiazol-4-yl)-2-[(2-mo
ruphorinoethoxy)imino]acetyl]amino]
syn isomer of cef-3-m-4-carboxylic acid
(as inner salt) 0.42 g of the product obtained in step B and 3 c.c. of trifle
Stir the oracetic acid at ambient temperature for 10 minutes to remove insoluble material.
Suction dry and wash with trifluoroacetic acid. So
of solution was collected in 30 c.c. ether and heated at ambient temperature for
Stir for a minute. Suction dry the formed precipitate and
Wash with tellu. Then dissolved in 0.5 c.c. methanol,
Precipitate again with 5 c.c. of ether. stir for 5 minutes
Dry with suction and salt formation, especially with trifluoroacetic acid.
Obtain 208 mg of product. Mp=212~214℃
(Disassembly). NMR spectrum 2.05ppmOAc 3.17～4.66ppmCH ₂-N and CH ₂-O 6.85ppm synthiazole H_Five UV spectrum (EtOH-HC1・N/10) Max 260nm E¹ ₁=253 IR spectrum (CHC1₃) β-lactam 1797cm^-1 C.O.₂ 1634cm^-1 Amido 1667cm^-1 Example 14: 3-acetoxymethyl-7-[[2-(2-
aminothiazol-4-yl)-2-[2-(4-
methylpiperazin-1-yl)ethoxyimino]
acetylamino]cef-3-em-4-carvone
syn isomer of acid, inner salt (trifluoroacetic acid
as salt) Step A: 2-(2-tritylaminothiazole-
4-yl)-2-[2(-4-methylpiperazine-
1-yl) ethoxyiminoacetic acid syn isomer, min
As konai salt 2.22 g of N-methylpiperazine and
dichloroethane is solvated.
3.325 g of 2-(2-tritylaminothiazole)
(4-yl)-2-(2-iodoethoxy)imi
syn isomer of noacetic acid (i.e. 2.84 g of pure compound)
vigorously in 15 c.c. of dioxane at ambient temperature for 16 h.
Stir. The resulting N-methylpiperazine hydroiodide
Dry by suction, and concentrate and dry the liquid under reduced pressure to about 5 c.c.
solidify, then add 200 c.c. of isopropyl ether.
Well, stir for 30 minutes. Vacuum dry the product for 10 minutes.
Dissolve in c.c. dimethoxypropane and stir for 30 minutes.
Vacuum dry, dissolve in 24 c.c. water and stir for 10 minutes.
Mix and then suction dry. Insoluble matter in 100 c.c.
Sopropyl ether-ethyl ether mixture (1
-1) Stir inside for 2 hours. Suction dry, 100
Recrystallize in ethanol at °C. 1.47g product
get. Mp = 220℃ (decomposition). NMR spectrum (CDC1₃) 2.52ppm −NCH ₃ 3.0 ppm CH₂N 6.7 ppm Thiazole H_Five UV spectrum (EtOH-HC1・N/10) Max 277nm E¹ ₁=257 ε=14300 IR spectrum (Nujiyol method) C.O.₂ 1602cm^-1 Heterocycle 1529cm^-1 C.O.₂Absence of H Step B: 3-acetoxymethyl-7-[[2-(2
-tritylaminothiazol-4-yl)-2-
[2-(4-methylpiperazin-1-yl)ethoxy
C]Imino)Acetyl]Amino]Cef-3-M
Syn isomer of benzhydryl -4-carboxylate 560 mg of the product obtained above and 140 mg of triethyla
Minion hydrochloride was mixed with 5 c.c. of chloroform and 5 c.c. of methane.
Heat to 60°C for 10 minutes in a microwave oven. Remove solvent under reduced pressure
Evaporate. The residue was dissolved in 20 c.c. of methylene chloride.
Dissolve and then cool to -20°C. 12.5% chloride
Add 1 c.c. of methylene chloride solution containing pivaloyl for 1 minute.
Add in between and stir at ambient temperature for 1 hour. The melt
The liquid was cooled to -10°C and 350 mg of 7-amino-3-
Acetoxymethylcepha-3-em-4-carbo
Add the benzhydryl phosphate all at once. 3 hours of scraping
Mix and then concentrate to dryness under reduced pressure at a maximum of 30°C.
The residue was mixed with 50 c.c. of benzene-ethyl acetate mixture.
Dissolve in (8-2). Remove insoluble matter and remove solution
Evaporate to dryness under reduced pressure. The residue is diluted with 25 c.c.
Dissolve 1.5 g of activated silicate in chloroethane.
Add the magnesium and stir for 30 minutes. suction drying
Wash with dichloroethane and heat the solution to a maximum of 30°C.
Evaporate under reduced pressure to obtain 870 mg of white resin. NMR spectrum (CDC1₃) 2.02−2.03ppm OAc 6.87ppm Thiazole H_Five 2.45ppm N-CH₃ UV spectrum (EtOH-HC1・N/10) Max 267−268nm ε14700 Step C: 3-acetoxymethyl-7-[[2-(2
-aminothiazol-4-yl)-2-[2-(4
-methylpiperazin-1-yl)ethoxy]imie
]acetylamino]cef-3-m-4-cal
syn isomer of bonic acid, inner salt (trifluoroacetic acid
as acid salt) 524 mg of the product obtained above was added to 3 c.c. of pure trifluoride.
acetic acid and let the solution stand for 1 minute at ambient temperature.
Mix it up. Precipitated with isopropyl ether at 30 c.c.
Stir for another 5 minutes, vacuum dry, and remove 320 mg.
of hygroscopic product, which was dissolved in 1 c.c. of methanol.
Dissolve and precipitate with 10 c.c. ethyl ether for 5 minutes.
Stir, vacuum dry, and wash with ethyl ether.
Make a paste with chloroform and then ether.
and 220 mg of salt-formed product (triflu
oracetate). Mp=245℃. NMR spectrum (DMSO) 2.03ppmOAc 2.75～3.67ppmCH ₂N 6.78ppm Thiazole H_Five UV spectrum (EtOH-HC1・N/10) Max 262nm ε14700 IR spectrum (Nujiyol method) β-lactam 1773cm^-1 OAc 1726cm^-1 C.O.₂ 1627cm^-1 C=NO− 1035cm^-1 Example 15: 3-acetoxymethyl-7-[2-(2-a
minothiazol-4-yl)-2-(2-aminoe
Toxiimino)acetamide] Cef-3-M-
4-Carboxylic acid bistrifluoroacetate, syn
isomer Step A: 2-(2-tritylaminoethoxyimide
-2-(2-tritylaminothiazole-4-)
yl) syn isomer of acetic acid 75g triethylamine, 50g 2-(2-butylamine)
Romuethoxyimino)-2-(2-tritylamino)
thiazol-4-yl)ethyl acetate and 100 c.c.
Dimethyl sulfoxide mixture under argon atmosphere
put it inside. This suspension is stirred at 60°C for 82 hours. then
Return to ambient temperature and precipitate with 10 volumes of water. suction drying
Dry and wash with water. The obtained precipitate was immersed in 1 chlorophore.
solution in a vacuum, washed with water, and then diluted with sodium chloride.
Wash with a saturated solution of water. Dry and temperature lower than 40℃
Evaporate under reduced pressure. The crude product was heated to 320 c.c.
xane, 2 parts absolute ethanol and 200 c.c. 2N carbonic acid
Dissolve in a mixture with sodium. 24 at ambient temperature
Stir for an hour, then under reduced pressure at a temperature below 40℃.
Evaporate to dryness. This product was mixed with 60 c.c. of dioxane-methanol.
Make a paste 5 times with compound (1-7). then
Mixing the product with 1 part chloroform and 1 part water
Dissolve in things. Stir enough 1N hydrochloric acid to obtain a pH of 2.
Add while doing so. Decant the organic phase and add water.
Wash and then with saturated sodium chloride solution. dry
Dry and evaporate to dryness under reduced pressure at a temperature below 40°C.
Ru. The resulting product was dissolved in 300 c.c. of dichloroethane.
Suspend in water and heat at 50°C for 15 minutes. under weak vacuum
After returning to ambient temperature, vacuum dry. Dichlorue
ethyl ether, then isopropyl ether, then ethyl ether.
Wash with ether. Dry to constant weight, 40mg
Get the powder. Mp=176℃. NMR spectrum (CDC1₃) 6.68ppm 5th proton of thiazole 2.95ppmCH ₂-N Step B: 2-(2-tritylaminoethoxyimide
-2-(2-tritylaminothiazole-4-)
yl) Hydroxybenzotriazole acetate, syn
isomer 6.97 g of the acid obtained in step A and 1.54 g of hydro
xybenzotriazole to 35 c.c. of methylene chloride
Introduce. Stir in an ice bath, 2.44 g dicyclo
Hexylcarbodiimide to 35c.c. of methylene chloride
Drop the dissolved solution. Return to ambient temperature and stir for 3 hours and 30 minutes. arising
The dicyclohexyl urea was suctioned dry, and the dicyclohexyl urea was extracted with methane chloride.
Wash with Len. Wash the solution with sodium bicarbonate solution.
Wash with water, then with saturated sodium chloride solution.
cormorant. Dry and evaporate to dryness under reduced pressure. the obtained tree
Dissolve the fatty substance with 50 c.c. of isopropyl ether,
Stir vigorously for 1 hour at ambient temperature. The obtained sediment
Suction dry the phlegm, wash with isopropyl ether,
Dry to a certain weight. 8.046 g of product is obtained.
Mp=150-152℃ (decomposition). NMR spectrum (CDC1₃) 6.68ppm 5th proton of thiazole 2.36ppmCH ₂-N Step C: 3-acetoxymethyl-7-[2-(2-
tritylaminoethoxyimino)-2-(2-tri
thylaminothiazol-4-yl)acetamide
Diphenyl cef-3-m-4-carboxylate
Methyl, syn isomer 11.55g of activated ester raw material produced in step B
product and an equivalent amount of 7.65 g of 7-aminocephalo
Salt of sporanic acid diphenyl methyl ester 75c.c.
Introduced into methylene chloride. Stir at ambient temperature for 18 hours
evaporate under reduced pressure and chromatize on silica under pressure.
benzene-ethyl acetate mixture
Elutes at (85−15). Obtained 9.1 g of desired product.
Ru. Step D: 3-acetoxymethyl-7-[2-(2-
aminothiazol-4-yl)-2-(2-amino
ethoxyimino)acetamide] Cef-3-M
-4-carboxylic acid bistrifluoroacetate,
syn isomer 186mg of 3-acetoxymethylene produced in step C
Ru-7-[[2-(2-tritylaminothiazole
-4-yl)-2-(2-tritylaminoethoxy
imino)acetamidoceph-3-M-4-cal
Diphenylmethyl bonate was converted to 1.8 c.c. of pure trifluorocarbonate.
Introduced into acetic acid. Bring the resulting yellow solution to ambient temperature.
for 3 min, then in an inert atmosphere in an ice water bath.
Stir and quickly add 18 c.c. of isopropyl ether.
Add. Stir for 10 minutes, suction dry, and remove isopropylene.
Wash with pyl ether then ethyl ether and dry.
Dry to obtain 100 mg of white powder. Mp=approx. 210℃
(Disassembly). Example 17: 3-acetoxymethyl-7-[[2-(2-
aminothiazol-4-yl)-2-[(2-azi
doethoxy)imino]acetyl]amino]cef-
Sodium salt of 3-m-4-carboxylic acid, syn
isomer Add 0.385 g of the acid obtained in Example 6 to 1 ml of 1 molar vinegar.
Mix with a methanol solution of sodium chloride. the
Add 5 ml of ethanol to the clear solution obtained in this way.
Add slowly. Suction dry, ethanol,
Then wash with ethyl ether and add 0.215g of natri.
Obtain um salt. Analysis: C₁₇H₁₇O₇N₈S₂Na＝532.49 Calculation: C% 38.4 H% 3.2 N% 21.0 Actual measurement: 38.3 3.2 20.4 Calculation: S% 12.0 Actual measurement: 12.1 NMR spectrum, (CD₃)₂S.O. 1.98ppm [Formula] 4.18ppm triple line =N-O-CH ₂−J=
5H_Z 6.76ppm 5th proton of thiazole Example 18: 3-[(1-methyl-1H-tetrazole-
5-yl)thiomethyl]-7-[[2-(2-amino
thiazol-4-yl)-2-[(2-azidoeth
xy)imino]acetyl]amino]ceph-3-e
Mu-4-carboxylic acid, syn isomer Step A: 3-[(1-methyl-1H-tetrazo
-5-yl)thiomethyl]-7-[[2-(2-t
lythylaminothiazol-4-yl)-2-[(2
-azidoethoxy)imino]acetyl]amino]
Cef-3-M-4-carboxylic acid, syn isomer 0.652 g of 7-amino-3-[(1-methyl-1H
-tetrazol-5-yl)thiomethyl]cef-
3-M-4-carboxylic acid, 6.5 ml methyl chloride
and 0.56 ml triethylamine for 15 minutes at ambient temperature.
Stir for a while. By the method described in Step B of Example 32.
1.29 g of 2-[(2-azidoethoxy
c) imino]-2-[2-tritylaminothiazole
(4-yl) 1-hydroxy-1H-ben acetate
Add zotriazole. Stir for 20 hours at ambient temperature
Mix. Add 10 ml of water and 3 ml of 2N hydrochloric acid. de
Cantation, wash the organic phase with water, dry and reduce
Concentrate to dryness under pressure. Dissolve the residue in 5 ml of acetic acid.
Dissolve in chiller and then add 10ml of ethyl ether.
I can do it. Stir for half an hour at ambient temperature, suction dry,
1.416 g of crude product is obtained. Step B: 3-[(1-methyl-1H-tetrazole
-5-yl)thiomethyl]-7-[[2-aminothi
azol-4-yl)-2-[(2-azidoethoxy)
c) Imino]acetyl]amino]cef-3-M
-4-carboxylic acid syn isomer 1.336 g of the above product was mixed with 7 ml of formic acid at 50°C.
Stir for 15 minutes. The generated triphenylcal
Dry the vinyl by suction and concentrate the liquid under reduced pressure.
Dry. Dissolve the residue with water. Crush and suck
Dry by pulling to obtain 0.77 g of crude product, which is reduced to the minimum amount.
Dissolve in 10% sodium bicarbonate solution. 0.07g
Add activated charcoal. Suction dry, and the liquid has a pH of 2.
Add formic acid until Suction dry the purified acid
Dry to obtain 0.171 g of desired product. Example 19: 3-[(1-methyl-1H-tetrazole-
5-yl)thiomethyl]-7-[[2-(2-amino
thiazol-4-yl)-2-[(2-azidoeth
xy)imino]acetyl]amino]ceph-3-e
Sodium salt of mu-4-carboxylic acid, syn isomer 0.162 g of the purified acid obtained in Example 18 was added to 0.3 ml of 1
Dissolve in molar sodium bicarbonate solution. 1 ml of
Add tanol. Suction dry the insoluble matter, and
The liquid was concentrated to dryness under reduced pressure. Ethanol the residue
Dissolve in a boiler. Crush, suction dry, and remove 0.09 g of natrium.
Obtain thorium salt. Analysis: C₁₇H₁₇O_FiveN₁₂S₃Na＝588.584 Calculation: C% 34.7 H% 2.9 N% 28.5 Actual measurement: 34.5 3.2 25.3 Calculation: S% 16.3 Actual measurement: 15.3 NMR spectrum (CD₃)₂S.O. 3.9ppm N-CH ₃ 6.76ppm 5th proton of thiazole 9.35−9.48ppm−CONH− Example 20: N-[2-[[[2-[[2-carboxy-3-
Methyl-8-oxo-5-thia-1-azabicic
b[4.2.0]oct-2-en-7-yl]ami
]-1-(2-aminothiazol-4-yl)-
2-oxoethyl]imino]oxy]ethylpyri
Zinium double salt (iodide and trifluoride)
acetate), syn isomer Step A: 3-methyl-7-[[2-(2-trityl
aminothiazol-4-yl)-2-[(2-bro
muethoxy)imino]acetyl]amino]cef-
Benzhydryl ester of 3-M-4-carboxylic acid
ter, syn isomer 536 mg of 2-(2-bromoethoxyimino)-2
-(2-tritylaminothiazol-4-yl)
syn isomer of acetic acid, 380 mg of 7-amino-3-de
Benzhydryl of acetoxycephalosporanic acid
ester and 6 c.c. of anhydrous methylene chloride in an inert atmosphere.
Introduce it under an enclosed atmosphere. Cool in an ice bath and after 5 minutes
Add 230mg dicyclohexylcarbodiimide,
Wash with 2 c.c. of methylene chloride. 2 hours at 0°~+5°C
and then at ambient temperature for 1 hour. absorbs insoluble matter
Dry, wash three times with methylene chloride, and remove 111 mg of raw
Collect artifacts. Dry the liquid and leave 1.02g of resin.
isolate something This product was purified as follows
Ru. This product was adsorbed onto 100g of silica and
Elute with a zene-ethyl acetate mixture (17-3).
Collect 548 mg of resinous material. Rf=0.27~0.28 (above
solution). NMR spectrum 6.75ppm 5th proton of thiazole Triple line centered at 3.58ppm -CH ₂−Br (J=7H_Z) Step B: N-[2-[[[2-[[2-diphenylmethylene]
carboxy-3-methyl-8-oxo-5-thi
A-1-Azabicyclo [4.2.0] Octa-2-E
-7-yl]amino]-1-(2-tritylamine
Notiazol-4-yl)-2-oxoethyl]
imino]oxy]ethylpyridinium iodine
do, syn isomer 500 mg of the product obtained in step A and 115 mg of piri
Inactivation of dine iodohydrate to 5 c.c. of pyridine
Introduce in atmosphere. Heat to 50℃ for 15 hours, then lower temperature to 40℃
Evaporate under reduced pressure. Dissolve in methanol and evaporate four times in succession to remove the residue.
Eliminate pyridine. Dry under vacuum, 620mg
A crude product is obtained. Chromatography on silica and chloroform
Purification by elution with a methanol mixture (85−15)
do. Collect 348 mg of resinous product. NMR spectrum, (CD₃)₂S.O. 6.81ppm 5th proton of thiazole Step C: N-[2-[[[2-[[2-carboxy-3
-Methyl-8-oxo-5-thia-1-azabisi
Chlo[4.2.0]oct-2-en-7-yl]a
[mino]-1-(2-aminothiazol-4-yl)
-2-oxoethyl]imino]oxy]ethyl]
Double salt of pyridinium (iodide and triflu)
oracetate), syn isomer Introducing 300 mg of the product obtained in step B and then
Then add 3 c.c. of pure trifluoroacetic acid. This melt
Stir the solution at ambient temperature for 3 minutes and then in an ice bath for 20 seconds.
Cooling. 40 c.c. of isopropyl ether-essence B
(bp=65-75℃) Precipitated with mixture (1-1)
Ru. The resulting precipitate was dried by suction and diluted with isopropyl ether.
ether, then ethyl ether and dry.
Ru. Obtain 152 mg of powder. mp#222℃. Rf=0.05 (acetic acid-ethyl acetate-water 70-35-10). UV spectrum (ethanol-N/10 hydrochloric acid) Max 260nm E¹ ₁=355 IR spectrum β-lactam 1768cm^-1 O=N-OR 1038cm^-1 NMR spectrum (CD₃)₂S.O. 6.76ppm 5th proton of thiazole Formulation Example 1: Prepare the following formulation for injection.
Ta. 3-acetoxymethyl-7-[2-(2-amino
Thiazol-4-yl)-2-(2-aminoeth
ximino)acetamide] Sefa-3-M
-4-carboxylic acid syn isomer ...500mg Aqueous sterility adjuvant...enough amount to make 5 c.c. Formulation example 2: Gelatin capsule corresponding to the following formulation
A sample was prepared. 3-acetoxymethyl-7-[2-(2-amino
Thiazol-4-yl)-2-(2-aminoeth
ximino)acetamide] Sefa-3-M
-4-carboxylic acid syn isomer ...250mg Auxiliary agent: 1 400mg gelatin capsule
sufficient amount to Formulation Example 3: Prepare the following formulation for injection.
Ta. 3-[[(1-methyl 1,2,3,4-tetrazo
-5-yl)thio]methyl]-7-[[2-
aminoethoxy)imino]-2-(2-aminothi
azol-4-yl)acetyl]amino]ceph
syn isomer of A-3M-4-carboxylic acid ...500mg Sterile aqueous adjuvant...enough amount to make 5 c.c. Pharmacological studies of compounds of the invention In vitro activity Dilution method in liquid medium A series of trials in which the same amount of sterile nutrient medium was distributed
Prepare a test tube. Study increasing amounts in each test tube
Dispense the compound and then inoculate each tube with the bacterial strain.
Ru. 24 hours at 37℃ in incubator
(24H) or 48 hours (48H) incubation
After that, inhibition of proliferation is evaluated by light transmission.
This is the minimum inhibitory concentration M.I.C (expressed in μg/c.c.)
Let them decide. The following results were obtained. 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 【table】 Additionally, following the dilution method in a liquid medium as described above
The prior art formulation of the compounds of Examples 3 and 9 of the present invention
Compound [Cefotaxim, Applicant]
It is widely sold and known to be highly active.
M.I.C.
compared. The following results were obtained. 【table】 These results demonstrate that the strain of the present invention
commercially available third-generation serums against negative bacteria.
Fuat, one of the phalosporin compounds
It has been shown to be more active than xime.

Claims (1)

[Claims] Linear formula' [[Here, B is (a) group -(CH ₂ ) _o' -R ₅ [Here, n' represents an integer of 1 to 4, R ₅ is an azide group or a group [Formula] (Here, R ₆ and R ₇ represents a group selected from the group consisting of a hydrogen atom and an alkyl group having 1 to 4 carbon atoms, or R ₆ and R ₇ together with a nitrogen atom form a phthalimide or 1-pyridinyl group ), or (b) a group -(CH ₂ ) _o '-R _5b [where n' represents an integer from 1 to 4, and R _5b represents a group [formula] (where R _6b and R _7b together with the nitrogen atom to which they are attached are imidazolyl, morpholinyl or N-alkylpiperazinyl groups (alkyl groups have 1 to 4 carbon atoms)
], R ₁ represents Γ an alkyl group having up to 5 carbon atoms, or Γ group -CH ₂ -S-R ₁₂ (wherein R ₁₂ represents a 1-methyl-1H-tetrazolyl group); ), or Γ represents an acetoxymethyl group or a carbamoyloxymethyl group, A represents a hydrogen atom, or 1 equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium, or an organic amino base, or A can be easily cleaved. representing an ester group]], syn isomers, and salts of compounds of formula ' with inorganic or organic acids. 2 B is a group -(CH ₂ ) _o '-R ₅ [where n' is equal to 1 or 2, and R ₅ is a group [formula] (where R ₆ and R ₇ are as described in claim 1) ] and R ₁ is an alkyl group having 1 to 5 carbon atoms or a group -CH ₂ -S-R ₁₂ (where R ₁₂ is a 1-methyltetrazolyl group) ) or R ₁
2. A compound of formula ' according to claim 1, wherein A represents an acetoxymethyl group, and A represents a hydrogen atom or one equivalent of an alkali metal, alkaline earth metal, magnesium, ammonium or an organic amino base. 3 B is phthalimidomethyl or aminoethyl,
A compound of formula ' according to claim ₁ , wherein R 1 represents a methyl, acetoxymethyl or 1-methyltetrazolylthiomethyl group, and A represents a hydrogen or sodium atom. 4. A compound of formula ' according to claim 1, wherein B represents an aminoethyl group and R ₁ represents an acetoxymethyl or 1-methyltetrazol-5-ylthiomethyl group. 5 3-acetoxymethyl-7-[[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetyl]amino]cef-3-em-4-carboxylic acid, syn isomer and its salts with alkali metals, alkaline earth metals, magnesium, ammonium and organic amino bases, and its esters with easily cleavable groups.