JPS625988A - Cephem or cepham compound and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I {R<1> is group of formula II [R<5> is (protected) amino] or haloacetyl; A is CH2 or C=N-OR<2> (R<2> is H or 1-8C alkyl); R<3> is OH or OR<6> (R<6> is H or acyl); R<4> is carboxy or its ester; dotted line is 3-cephem or cepham; when R<1> is group of formula I, A is C=N-OR<2>, when R<1> is haloacetyl, R<3> is H and dotted line is 3-cephem, when R<1> is group of formula I and R<3> is H, A is C=NOH, and when R<3> is OR<6>, dotted line is cepham] or its salt. EXAMPLE:7-[2-( 2-Aminothiazol-4-yl )-2-methoxyiminoacetamido]-3-hydroxy-3-ce phem-4-carboxy-lic acid 4-nitrobenzyl ester hydrochloride. USE:Antibacterial agent and its intermediate. PREPARATION:The compound of formula III or its reactive derivative is made to react with the compound of formula R<1>ACO2H or its reactive derivative.

Description

[Detailed description of the invention]

This invention relates to novel cephem compounds, cepham compounds, and methods for producing the same, and further details of IC
has antibacterial activity, and also has better antibacterial activity (7-substituted-
This invention relates to 6-cephem-4-carboxylic acids, salts thereof, and methods for producing them. For the purpose of the present invention, a compound containing Durham-negative bacteria and Durham-positive bacteria has excellent antibacterial activity against pathogenic bacteria, and is also useful as an intermediate for producing a compound having more excellent antibacterial activity. The object of the present invention is to provide novel Z7-f*m-3-cephem (or cepham)-4-lefonic acid, its extract, a method for producing the same, and antibacterial compounds contained as all active ingredients thereof. The cepham compound and cepham compound provided by the present invention are represented by the following general formula (1). A thiazolyl or haloacetyl group represented by a hydrogen atom or a group represented by a C□-C8 alkyl, a group represented by a hydrogen atom or a C□-C8 alkyl group, and a group represented by a hydrogen atom or a C□-C8 alkyl group; ('] -R6 1 where 86 and 2 mean all elementary atoms or acyl groups), B r6 carbon 4%? or its ester, dotted line t
ab-means cephem nucleus or cepham nucleus, respectively;
However, in the case of a thiazolyl group shown in (2) Formula 6, A is a haloacetyl group, R3 is a hydrogen atom, and the dotted line is a 3-cephem nucleus. and 4) when R3 is a group represented by the formula -0-R' (where R' means an acyl group), , the dotted line means a cepham nucleus] The above compound (I) is a compound useful as an antibacterial agent,
It includes both intermediates useful in making it. A compound useful as an antibacterial agent is represented by the following general formula (I'), and this compound is also useful as an intermediate for producing a compound with excellent antibacterial activity. (wherein R2, R3, R4 and R5 are the same as above) On the other hand, an intermediate useful for producing the above compound 11') is represented by the following general formula +ll. (In the formula, Rλ means a haloacetyl group, R4 and A
is the same as above) is known to have a tautomeric relationship with the thiazolinyl group represented by the following balanced formula. (In the formula, R5 and R5 are the same as above.) Both of these tautomeric isomers are generally treated as substantially the same substance. Therefore, in this specification, for convenience, R5n including both isomers
(same as above), but both isomers based on the above tautomerism are included within the scope of the original invention. Furthermore, in addition to the 6-bitroxy-6-cephem compound represented by the partial structural formula, there are also 3-oxocepham compounds represented by the partial structural formula and the so-called keto-cephalic compound represented by the partial structural formula.
Due to enol tautomerism, the former enol isomer is usually more stable than the latter keto isomer. Therefore, both of these isomers are included in the scope of this invention,
In this specification, both are referred to as more multistable -14= enol isomers, ie, 6-bitroxy-6-cephem compounds. Next, various definitions in the general formulas representing the raw material compound and target compound of this invention will be explained in detail. "Lower" means carbon number 1 to 6 unless otherwise specified.
means the group of Methyl, ethyl, propylene 7, isopropyl, butyl, isobutyl IV to the C knee 08 alkyl group of R2. It means a residue of a linear or branched chain alkane having 1 to 8 carbon atoms such as t-butyl, pentyl, neopentyl, hexyl, heptyl, orofnal, and preferable examples include lower alkane More preferable examples of the group include an alkyl group having 1 to 4 carbon atoms. Practical examples of the "ester of carboxine group" for R4 include methyl entenope ethyl ester V1 proyl ene te IV, isopropyl ester, butyl ester, isobutyl ester, t-7"1,000 non ester, bentyl ester , t-pentyl ether, hexyl ester,
Heptyl enute JV, octyl ester, 1-cyclopropylethyl ester, etc. cD Atelekylenute IV 1 Vinyl ester, allyl ester, etc. (07 Alkynyl ester V such as lekenyl ester ester, phlopinyl ethyl ester, etc.)
1 methoxymethyl ester, ethoxymethyl ether,
Alkoxyalkyl V esters such as isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, methylthiomethyl ester, ethylthiomethyl ester, ethyl rethioethyl ester,
Alkyl rethioalkyl esters such as isopropylthiomethyl esters, 2-iodoethyl esters, 2,2
．． 2-) IJ Haloarylene esters such as chloroethyl esters, acetoxymethyl esters, probionyloxymethyl esters, butyryloxymethyl esters, valeryloxymethyl esters, etc. V ester, hivaloyloxymethyl ester, hexanoyloxymethy7
V ester, 2-acetoxyethyl ester)1. ', 2
7'lopionyloxyethyl ether, alkanoyloxyalkyl esters such as palmitoinoleoxymethyl ester, alkanyloxyalkyl esters such as pemyl methyl ester, 2-nosylethyl ether,
Penzyl ester, 4-methoxybenzyl esternope 4
- ditropenyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc. Substituted or unsubstituted aralkyl esters, phenyl esters, tolyl esters,
Substituted or unsubstituted aryl esters, triethylsilyl ester, triethylsilyl ester, etc.
Dimethylmethoxysilyl-enuter, dimethylethoxysilyl! esters with xylysilyl compounds such as esters, diethylmethoxysilyl esters, trimethylsilyl esters, triethylsilyl esters, triethylsilyl esters, dialkylalkoxysilyl compounds or trialkoxysilyl compounds, etc. can be mentioned. As a protecting group for the "protected amino group" of R5, a conventional N-protecting group such as benzyl, benzhydryl, trichloride, 4-methoxybenzyl, 6,4-dimethoxybenzyl, etc. may be substituted or unsubstituted. Al

[Lower] Alkyl group, trichloromethyl, trichloroethyl,
Examples include halo+low i1 alkyl groups such as trifluoromethyl, substituted phenylthio groups, substituted alkylidene groups, substituted aralkylidene groups, substituted cycloalkylidene groups, and acyl groups. Acyl groups suitable as N-protecting groups include, for example, substituted or unsubstituted lower alkanoyl groups such as evaformyl, acetyl, chloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxy groups. luponyl, impropoxycarbonyl, butoxycarbonylbonyl, benzyloxycarbonyl, t-bentyloxycarbonyl, hexyloxycarbonyl, trichloroethoxycarbonyl, 2-pyridifremethoxyl
Substituted or unsubstituted lower alkoxycarbonyl groups such as levonyl, benzyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, substituted or unsubstituted al(lower) alkoxycarbonyl groups such as levonyl, cyclopentyl Examples include lower cycloafrekoxyl groups such as oxycafflebonyl, cyclohexyloxycarbonyl, 8-quinolyloxycarbonyl groups, and phthaloyl groups. Furthermore, silicon, boron, a! Reaction products of reminium or phosphorus compounds with amino groups are also included in the N-protecting groups. Such compounds include trimethylsilyl chloride,
trimethoxysilyl chloride, boron trichloride, butoxy boron dichloride, aluminum trichloride, jetoxy aluminum chloride
Examples include reminium, phosphorus dibromide, and phenyl phosphorus dibromide. Examples of the "AJV group" of R6 include formyl, acetyl,
Lower alcanoids such as butyryl, isobutyryl, isovaleryl, hivaloyl, pencilyl, 1-yv
Aroyl group such as oil, methylethanesulfonyl, 1-
Examples include lower alkane sulfonyl groups such as methylethanesulfonyl, furopanesulfonyl, and butane sulfonyl groups, and noa v-nesulfonyl groups such as benzenesulfonyl and tosyl. In this invention, R5's "protected amino group" and R4's "carboxylic ester group" specifically mean the groups described above, but these are intended to be achieved by chemical or biological methods. This includes cases where it is used for the purpose of temporarily protecting the amino group and levoxy group, respectively, during the production of a compound, and cases where it is used for the purpose of improving the physiological or pharmaceutical properties of the target compound itself. That is, the meaning of these groups in terms of production is as will become clear from the explanation of the production method described below. For example, F is a free amino group and IB' is a free carboxy group, and In cases where the group may cause unfavorable side reactions during the reaction (σ, if necessary, the protected amino group and +'1
The Jcul carboxy group is converted to ester) V to prevent such side reactions, and after the reaction, the protected amino group and I'! fc) esters of carboxy groups and optionally free amino groups and

[ox] refers to the replacement of a free carboxy group. On the other hand, the meaning of using a chemical group for the purpose of improving the physiological properties or pharmaceutical properties of the target compound is to refer to active substances that have free amino groups and (or) levoxy groups. In order to improve the properties such as solubility, stability, absorption, solubility, etc., these free radicals are converted into esters of protected amino groups and (more importantly) levoxy groups. As a salt of the target compound [1], rainbow, a salt with an inorganic base or an inorganic acid, such as an alkali metal salt such as a sodium salt or a potassium salt, power! Alkaline earth metal salts such as lesium salts and magnesium salts, ammonium salts, hydrochlorides, mate salts of bromide 7, sulfates, phosphates, salts with carbon bases or organic acids,
For example, trimethylamine salt, triethylamine salt, pyridine salt, procaine salt, picoline salt, dicyclohexylamine 4, N,N-dibenzylethylenediamine 4,
Amine salts such as N-methylglucamine salt, jetanolamine salt, triethanolamine salt, tris [hydroxymethifleamino] methane salt, phenethylbenzylamine salt, acetate, maleate, lactate, tartrate, methanulphon acid salt, benzenesulfonate, ) 7 rayenne l
Organic acids such as lephonates, bonic acids or sulfonates, a! Examples include basic or acidic amino acid salts such as reginine salt, aspartate, glutamate, lysine salt, and serine salt. The object compound (1) of this invention can be produced by any of the following methods. Method A: N-Acylation = 22-Method B: c-Nitrosation Method C: Etherification violet! : Thiazole ring formation first step: Amino protecting group removal method F: 3-hydroxycephamno formation method G: O-acylation method H: Carpoxy formation OOH (wherein, C□-08 alkyl group, R means an ester of a carboxyl group, Rλ means a protected amino group, R2 means an acyl group, R, Ra, R. R3, R4, R5, A, 1.- and dotted lines are all the same as above. ] Each of the above methods will be explained in detail below.Method A: N-acylated target compound (1) and its salt are prepared using 7-amino-6-cephem (J σ cepham compound M) A carboxylic acid dll) or a reactive derivative thereof at a carboxy group or a salt thereof is added to a reactive derivative at an amino group or a salt thereof, which is well known in the field of so-called β-lactam compounds such as penicillin and cephalonuporin. It is produced by acting according to the conventional method applied to the amidation reaction. Among the raw material compounds 11), novel compounds can be produced according to the method described below. The reactive derivatives at the amino group of compound (II) include all the various derivatives that can be used in the so-called amidation reactions, such as isocyanato, inthiocyanato, or trimethyl IV silylacetamide, vinyl( acetaldehyde, acetaldehyde, acetaldehyde,
Aldehyde compounds such as isobentaldehyde, benzaldehyde, salicylaltehyde, phenylacetaldehyde, p-nitrobenz 7) redehyde, m-chlorobenzaldehyde, hydroxynaphthaldehyde, fanfural, thiophenecarpoaldehyde! In particular, derivatives formed by reaction of these aldehyde compounds with reactive derivatives such as hydrates, acetals, hemiacecous, enolates, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetyl IV acetone, and ethyl acetoacetate ( Derivatives formed by reactions with reactive derivatives such as ketals, hemiketals, and enolates, and reaction products with phosphorus compounds such as phosphorous oxychloride and phosphorous trichloride. , a reaction product with a sulfur compound such as thionyl chloride, etc. Examples of the salt of compound (1) include those exemplified as the salt of compound (1). Examples of reactive derivatives at the carboxyl group of compound C!1) include acid halides, acid anhydrides, active amides, active esters, etc. More specifically, acid halides such as acid chlorides and acid bromides, dialkyl) Phosphoric acid mixed acid anhydride, phenyl phosphoric acid mixed acid anhydride, diphenyl phosphoric acid mixed acid anhydride, diphenyl phosphoric acid mixed acid anhydride,
Substituted phosphoric acid mixed acid anhydride, such as halogenated phosphoric acid mixed acid anhydride 7X, sialgyl phosphorous acid mixed acid anhydride, sulfite mixed acid anhydride, thiosulfuric acid mixed acid anhydride, sulfuric acid mixed acid anhydride,
Anonki) V carbonic acid mixed acid anhydride, aliphatic acid) V bonic acid (
For example, pivalic acid, pentanoic acid, isopentanoic acid, 2
-ethyl butanoic acid, trichloro)V acetic acid] mixed acid anhydride,
aromatic carboxylic acid

[For example, benzoic acid] mixed acid anhydride,
Acid amides with symmetrical acid anhydrides, etc., imidazole, 4-substituted imidazole, dimethyzole, triazole, tetrazole, etc., cyanomethyl ester, methoxymethyl ten-estea 1/, dimethyliminomethyl [CH312N
-CH-J ester, hinyl ester, phlopargylnis T), p-di-l-roamyl ester, 2.4-
Dinitrofeni! Reester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylasophenyl ester! V, phenyl 7-rethioester, p-nitrophenyl thioester, p-talesyl thioester, carboxymethyl thioester, pyranyl ester, pyranyl ester, hibericyl ester, 8-quinolyl thioester, or N
, N-dimethylhydroxylamine, 1-hydroxy-
2-[IH]-pyridone, N-hydroxysuccinimide, N-hydroxyfucurimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chloro-1H-
Examples include esters such as esters with benzotriazole and the like. The reactive derivatives of compounds (ll) and α■) are appropriately selected from among the above depending on the types of starting compounds (It) and (III) and reaction conditions such as other reagents, solvents, and temperature. Salts of compound ■1) include alkali metal salts such as sodium salts and potassium salts, and power! Salts with inorganic bases such as alkaline earth metal salts such as lesium salts and magnesium salts; salts with organic bases such as 6th class amine salts such as triethylamine salts, triethylamine salts, N,N-dimethylaniline salts, and pyridine salts; Examples include salts with inorganic acids such as hydrochloride and hydrobromide. This reaction usually involves water, acetone, dioxane, acetonitrino(V1), chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate),
The reaction is carried out in N,N-dimethylformamide, pyridine, other solvents that do not adversely affect the reaction, or a mixed solvent thereof. In this reaction, when compound (III) k is used in the form of a free acid or its salt, for example, N, N-
The power of zincrohexyl! V-posiimide, N-cyclohexyJV N-morpholinoethyl)V-carbodiimide, N-
Carbodiimide compounds such as cyclohexyl-N-+4-diethylaminocyclohexyl)carbodiimide, N,N-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N-+3-dimethylaminopropyl)carbodiimide, N,N-carponylvinyl( 2-methylimidazo-1), imine compounds such as pentamethyleneketene-N-cyclohexylimine, cyphenyleneketene-N-cyclohexylimine, ethoxyacetylene, β-chlorovinylethyl iv ether, etc. Olefinic compounds are acetylenic compounds, 1-+4-chlorobenzenesulfonyloxy]-6-rio. -1H-benzotriazole, N-ethylbenzisoxazolium salt, N-ethyl-5-phenylisoxazolium-6-sulfonate, polyphosphoric acid, phosphorous acid') realkyl ester, polyphosphoric acid ethyl ester , polyphosphoric acid isopropyl ester, phosphorus oxychloride, 3Jm phosphorus, diethyl chlorohonupite, olethophenylene chlorophosphite, etc., dimethyl chloramide thionyl chloride, phosphorus oxychloride or honogen, etc. Billenmeyer 11-Sme prepared by the reaction
Preferably, the reaction is carried out in the presence of a condensing agent, such as an ier + reagent. In this reaction, compound (11) and oxyiminoa'
If the reaction with the syn isomer of the syl compound ω1) is carried out under relatively mild conditions around neutrality in the presence of a V Smeyer reagent as described in 2), the reaction with the syn isomer of the oxyimino compound (e compound (1) The syn isomer of Method B: C-nitrosation target compound (1a) and its salt are compound (lv)i
It is produced by exposing the salt to the full action of a nitrosating agent. The starting material α) corresponds to the above 6-cephem compound (1) when R1 is a haloacetyl group, R3 is a hydrogen atom, and A is a methylene group, and is prepared according to the above method A.
Specifically, it can be produced by reacting compound (n) with diketene and a halogen such as chlorine or bromine. Compound (IV) produced in this manner may be used in this method without particular isolation or purification. Preferred examples of nitrosating agents include: - nitric acid and its derivatives, such as nitrosyl halides such as nitrosyl chloride and nitrosyl bromide, alkali metal salts of nitrite such as MMMffz 1-lium, potassium nitrite, and nitrous acid. Examples include butyl esters, alkyl nitrites such as pentyl nitrite, and the like. When using nitrous acid as a nitrosating agent, inorganic substances such as hydrochloric acid, sulfuric acid, formic acid, and acetic acid can also be used! -2〈 is preferably carried out in the presence of an organic acid. When the cleaved nitrite is used as a nitrosoy agent, the reaction is preferably carried out in the presence of a strong base such as an alkali metal alkoxide. This reaction is usually carried out in a solvent, such as water,
Acetic acid, benzene, methanol, ethanol, tetrahydrofuran, and other solvents that do not adversely affect this reaction can be used. Reaction temperature J9: is not particularly limited, but it is usually preferable to carry out the reaction under cooling or at room temperature. Compound (1a) and its salts thus obtained are used as starting materials in the following methods C and D. Method C: Etheno-V conversion can also be produced by reacting the target compound (1b) and its salt with C□-08 alkyl and other agents. The starting material (V) corresponds to the above compound (1) when the group A is an N-hydroxyiminomethylene group, and can be produced by the above methods A and B1 or the following method. can. Preferred examples of C□-C8 alkylating agents include di(C□-08)alkylating agents such as dimethyl sulfate and dimethyl sulfate.
Diazo (C□-
08) Common C-C8 alkylating agents such as alkanes, halogenated C□-C8 alkyls such as iodomethyl, iodoethyl, and bromoethyl, and sulfonic acid C-C8-a7-lekylene esters such as toluenesulfonic acid methyl ester. C□-08 As an alkylating agent, diazo

[C□-08]
When using alkanes, usually diethyl ether,
It is preferable to carry out the reaction in dioxane or other solvents that do not adversely affect the reaction, at room temperature or under cooling. When using other C-08 alkylating agents, this reaction is usually carried out in water, acetone, ethanol, diethyl ether, dimethylformamide, sono, or other solvents that do not adversely affect the reaction, preferably under cooling or heating. The oxidation is carried out either neat or in the presence of an organic base such as that used in the basic decomposition step 7 in Method E below. Method D: The compound (la: + −
It can also be produced by reacting a thiourea compound (Vl)'e with a salt of perilla. Raw material compound +]alff, R1 is a haloacetyl group, corresponds to compound (1), and can be produced by the above methods A and B. This reaction is usually carried out at room temperature or under heating in water, alcohols such as methanol and ethanol, benzene, dimethylformamide, tetrahydrofuran, and other solvents that do not adversely affect the reaction. In this method, compounds having antibacterial activity (IC), especially R
Compound +1cli when 5 is an amino group is an advantageous method to prepare via method B above. Method E: Elimination of the protecting group of the amino protecting group The target compound (1d) and its salt can also be produced by subjecting the salt of the compound (Vl) to the elimination reaction of the protecting group at the protected amino group of Rλ. It corresponds to the above compound (]) when R" means an Irl-protected amino group), and R is the same as above), and for example, by the above method A. This elimination reaction is carried out according to conventional methods such as decomposition and reduction of m7.The method of Koharu et al. is selected as appropriate depending on the type of protecting group to be eliminated. ? (acidic side 7X decomposition), a method using a base (decomposition to basic 7X), a method using hydrazine, etc. Among these methods, the 7X decomposition using acid is the above-mentioned N- Among the protecting groups, for example, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, lower cycloalkoxycarbonyl, etc. acyl group, substituted phenylnao group, substituted alkylidene group, substituted ara) V kylidene group, substituted cycloa I
Suitable for removing protective groups such as V-kylidene groups. The acids used in the decomposition of this acidic 71 [17 include formic acid,) lifluoroacetic acid, benzene-nulphonic acid, p
Examples include inorganic and organic acids such as -tonolenin sulfonic acid and hydrochloric acid, and cationic ion exchange resins. Among these, preferred acids are those that can be easily separated from the reaction product by conventional methods such as neutralization or distillation under reduced pressure;
Examples include formic acid, trifluoroacetic acid, and hydrochloric acid. It is preferable to select an acid suitable for this reaction, taking into account all the chemical properties of the starting compounds and reaction products and the type of protecting group to be removed. This acidic decomposition into 711]7 is
The reaction can be carried out in the presence or absence of water, a conventional organic solvent, or a mixed solvent of these and other solvents. Note that when trifluoroacetic acid is used as the acid, the reaction is accelerated by adding anisole to the reaction system. base? The hydrolysis used may include protecting groups such as acyl groups, i
It is applied to the elimination of herooallecanoyl groups such as trifluoroacetyl. The bases used here include alkali metal hydroxides such as IJum and potassium hydroxide, hydroxides such as magnesium oxide, calcium oxide, etc.
] Earth gold FA, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkaline earth metal carbonates such as magnesium carbonate and cuff Vium carbonate, hydrogen carbonate),
Carbonic acid 7 such as potassium hydrogen carbonate, elemental a7 recali metal, magnesium phosphate, phosphoric acid power! Alkaline earth metal phosphates such as lesium, inorganic bases such as alkali metal hydrogen phosphates such as dibasic sodium phosphate, dipotassium hydrogen phosphate, acetic acid)
Alkali metal acetates such as IJium, potassium acetate, trimethylamine, trialkylamines such as trimethylamine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo 4.3. O] -]5
Examples include organic bases such as -nonene 1,4-diazabicyclo[2,2,2)octene and 1,5-diazabicyclo[5,4,OJ -7-undecene, and anionic ion exchange resins. For hydrolysis using these bases,
Usually, the reaction is carried out in a commonly used organic solvent or a mixed solvent thereof. It is applied to the decomposition using hydrazine and the removal of protecting groups such as dibasic acyl groups such as succinyl and phthaloyl. Elimination by reduction leads to kihalo(lower)alkoxycarbonyl, benzyloxycarbonyl, such as trichloroethoxycarbonyl)Vbonyl, and substituted or unsubstituted alkoxycarbonyl, such as p-nitrobenzyloxycarbonyl, The reduction can be applied to the removal of protecting groups such as aralkyl groups such as -y-alkoxylponyl, 2-pyridylmethoxycarponyl, benzyl, benzhydryl, and trityl. Examples of the method include reduction using a potassium metal such as sodium boron hydride, and catalytic reduction using a common catalyst. , 8-
Protecting groups such as quinolyloxycarbonyl group can be used to protect copper,
It can be desorbed by treatment with heavy metals such as zinc. The reaction temperature is not particularly limited, and is selected taking into account the chemical properties of the raw materials and reaction products, the type of N-protecting group, and the application method, but usually under cooling, at room temperature, or under heating. It is preferable to carry out the reaction under such mild conditions. When R4 of the starting compound (', 111) is an ester of a carboxyl group, it is 9A during this reaction or after ζ1.
Although it may be converted to a free carboxy group during the treatment, such cases are also included within the scope of this method. For the purpose of this method, compounds obtained by other methods (v
The object of the present invention is to produce a compound (1) having an aminothiazo I47 group, which generally exhibits stronger antibacterial activity, by removing the protecting group in the protected amino group of ll). Method F: Formation of 3-hydroxycepham (obtained by reducing compound i'iij + salt of oxabato to compound e (1e) and its salt; R is the same as above) thiacyly) V group, and R
3 is a group represented by the formula -〇-R6T, where R6 and 7 represent an elementary atom), and A is a group of the formula (corresponding to 1). can be produced, for example, by the above-mentioned method A. The reduction method that can be applied to this method is a method that can convert the tautomer, including the enol form, into the ketonic carbonyl group hydroxymethylene group. Specifically, reduction with 1i'JJ elemental alkali gold gK such as sodium borohydride, and acids such as hydrochloric acid, sulfuric acid, formic acid, acetic acid, and metals such as zinc, iron, copper, etc. Reduction by combination of
Alternatively, catalytic reduction using a conventional catalyst such as palladium on carbon, palladium sponge, Raney nickel, platinum, platinum black, etc. is exemplified. This reaction is often carried out in water, alcohols such as methanol and ethanol, dimethylformamide, tetrahydrofuran, and other solvents that do not have an adverse effect under cooling or heating. Compound (1e) and its salts obtained in this way exhibit antibacterial activity, but they can be obtained by the following method, which is useful as an intermediate raw material for producing a highly active 3-cephem compound (1e). Method G: 0-acylated target compound (1f) and its salt are produced by reacting compound (1e) or its salt with compound (1), its salt, or its reactive derivative. R3 of compound (1) Examples of the acyl moiety represented by 11 include those exemplified as the acyl group of R6 in compound (J). ) are exemplified here as well, such as acid halides, acid anhydrides, acid azides, active esters, active amides, etc. Also, specific examples include acetyl 7-rechloride. Lower alkanoyl halides such as benzoyl chloride, aroyl halides such as benzoyl chloride, alkanesulfonyl halides such as mesyl chloride, mesyl bromide, ethanesulfony 7-rechloride, acyl hafides such as arenenuno V honyl halides such as tosyl chloride, mesyl acyl halides, etc. Lower alkane sulfonyl 7 reazide, tosyl azide such as acyfuraesite such as chiarene sulfonyl azide 1-' are mentioned, and preferable examples include lower alkanesulfonyl 1 revalide and arenes !rephonyl halide as mentioned above. This reaction (trf) is usually carried out in dimethylformamide, chloroform, methylene chloride, or other solvents that do not adversely affect the reaction, under cooling, at room temperature, or under heating. Acyl is used as an acylating agent. When all halides are used, this reaction is preferably carried out in the presence of a base as exemplified in Method E above.
] from] 5-acyloxycepham compound + If I
3-cephem compound []hl-W, which is more active after k
This is the first process of making. Method H: Formation of Carpoxy This method generally shows better antibacterial activity than the free force! The target compound tl&+1R5 having a levoxy group is a thiazolyl group represented by (same as above) and a compound [117]'i, which is a group represented by (a), and is produced from the corresponding carboxylic acid ester (X). . Therefore, the purpose of the ester of the carboxy group in compound α) is to temporarily protect the free force) V-boxy group during the production of the target compound by the chemical or biological method explained above. The point is that it is used in This method is carried out by converting the ester of the caffleboxy group of the starting material α) into a free carboxy group, and as a preferred example of the ester of the carboxyl group represented by R4 of the compound α), the compound (+) Examples include esterified carboxy groups as exemplified in the explanation of the group R4. In this method, conventional methods such as hydrolysis and reduction are applied. [771] 7. Decomposition methods include conventional methods using acids, bases, enzymes, enzyme preparations, etc. Preferred examples of acids and bases include those exemplified in Method E above, and the acidic or basic 7JOX decomposition reaction is carried out in the same manner as in Method E above. Enzymes and enzyme preparations include anything that exhibits esterase activity, and specific examples include microbial cultures or processed products thereof, and processed products of animal or plant tissues. Esterases conveniently used in enzymatic heptahydrolysis include purified as well as crude 1'f,
But that's fine. Such esterase activity is associated with microorganisms such as soil samples, etc., which can be easily isolated by conventional methods, or 'ATCC. It has been confirmed that it is widely present in various microorganisms that are easily selected from deposited bacteria available from microbial depository institutions such as Microbial Industry OF Research Institute, and such microorganisms include:
Bacillus, Corynebacterium, Micrococcus, Flavobacterium! Lemonella, Staphylococcanus, Vibrio, Microbacterium, Escherichia, Arthrobacter, Azotobacter,
a! Examples include microorganisms belonging to the genus Lecaligenes, Rhizobium, Brevibacterium, Kluybella, Proteus, Vshina, Pseudomonas, Xanthomonas, Protaminobacter, and Comamonas. Specific examples of these microorganisms include, for example, Baternu supuchinue A, M-1069, Baternu suptirinue A, M-1069, Baternu suptilinue A, Baternu suptirinue I
AM-1214, Bacillus sphaericus IAM-1
286, Corynebacterium efie AM-1308
, Micrococcus variannus IAM-1314, Flavobacterium ligaeunae AM-12,38, Salmonella typhimuriume AM-1406, Nutaphyllococcus avidermizoinus AM-1296, Microbacterium flavum IAM-1642, Alcaligenes・Faecalis ATCC-8750, Azotobacter symplesochnu ATCC-6946, Azotobacter vinelandii AM-1078, Escherichia
Cori AM-1101, Rhizobium japonicumae AM
-0001, Vibrio mechnikobii IAM-1039
, Brevibacterium ) Vpormuae AM-1637
, 7” Rotaminobacter alpoflavumue AM-10
40, Comamonas terrigenae FO-12685, sp.
v. Sina lutea IAM-1099, Pseudomonas schlikiliensisae AM-1[]55, Xanthomonas trifolii ATCC-12287, and the like. In enzymatic 7Jn water decomposition, it is convenient to use esterase in the form of a culture obtained by appropriately culturing esterase-producing microorganisms, or in the form of a processed product thereof. This can be carried out using conventional methods for culturing microorganisms. The medium used includes assimilable carbon and nitrogen sources and inorganic salts as nutritional sources. Examples of carbon sources include glycone, sucrose, lactose, sugar, glycero-1, and starch. In addition, nitrogen sources include internal sore throat fluid, peptone, ryvten meal,
Corn meal, cottonseed meal, soybean flour, corn nutcheap
Examples include liquor, yeast extract, casein hydrolyzate, amino acids, ammonium salts such as ammonium sulfate, ammonium nitrite, and ammonium phosphate, and inorganic or organic nitrogen compounds such as sodium nitrite. If desired, further calcium carbonate, sodium phosphate,
Metal salts such as potassium phosphate, magnesium salts, copper salts, or various vitamins may be added to the entire medium. The pH of the medium, the temperature during cultivation, the cultivation time, etc. are determined as appropriate depending on the type of microorganism, but the culture is usually in the range of pH 5 to 8 and at a temperature of 20 to 35°C for 20 to 120 hours. The term "processed products of the culture thus obtained" refers to all of the various processed products obtained by conventional methods in order to increase esterase activity. When the esterase activity is mainly present within the bacterial cells, a processed product of the culture can be obtained, for example, in the following manner. (1) Bacterial cells: They are isolated from the culture by conventional methods such as filtration or centrifugation. (2) Dried bacterial cells: Obtained by drying the above bacterial cells by a conventional method such as freeze drying or vacuum drying. (3) Sterile cell extract; obtained from the above-mentioned bacterial cells or dried bacterial cells by a conventional method such as crushing with siea IV mina, sea sand, etc., or treating with ultrasonic waves. (4) Enzyme solution; obtained by partially or fully purifying the above-mentioned sterile body extract by a conventional method. In addition, when esterase activity is mainly present outside the microbial cell, it can be obtained from the processed product of the culture in the following form. (1) Supernatant liquid or PH; obtained from a culture by a conventional method. (2) Enzyme solution; obtained by partially discarding or thoroughly purifying the above supernatant or filtrate using conventional methods. Enzymatic hydrolysis is carried out by adding compound (X) to a microbial culture or its treated product in a solution such as water or a buffer such as a phosphate buffer, preferably with a conventional surfactant. This is carried out by adding the compound α) to an aqueous solution or suspension of the shading material, or of the culture or its treated material by contacting it in the presence of the shading agent. In some cases it may be preferable to stir the reaction mixture. The pH of the reaction mixture, the concentration of the substrate, the reaction time, the reaction temperature, etc. are determined as appropriate depending on the nature of the culture or its treated material, and the compound α) used, but it is usually preferable to use a pH of 4. -10, more preferably pH 6-8, 20-50" C1, more preferably 25-5"
C, and is appropriately determined within the range of 1 to 100 hours. Further, the concentration of compound (x) used as a substrate in the reaction mixture is preferably about 0.1 to 100"Iy/g, preferably about 1 to 20"Iy/g. It is carried out in the same manner as the reduction method in method E. Note that during this reaction or post-treatment, R1 of compound α)
Chiashiri! The scope of this method also includes the case where the protecting group in the protected amino group of R5 that is not substituted with the group is removed. The target compounds obtained by the various methods of this invention are isolated and purified by conventional methods. When R4 of the target compound (1) is a free carboxy group and when R5 is a free amino group, it can be converted into a salt by a conventional method (C). Target compound (1) Among them, compound (1) and its salts have excellent antibacterial activity that inhibits the growth of pathogenic bacteria in a wide range including Durum-negative bacteria and Durum-positive bacteria, and are useful as antibacterial agents. A novel Ro-Cefem (e compound) with stronger antibacterial activity, manufactured by
It is also useful as a synthetic intermediate for 1h) and its salts. Method 1 Method 2 Method 6 (wherein, RA, R;, R4, n 5 Oyohi R, fd above (!: same meaning) The above methods 1 and 2B are substantially the same as the above methods and C, respectively. In addition, preferred examples of bases used in Method 3 include metal oxides such as 7x oxide, potassium hydroxide, sodium carbonate, potassium carbonate, Metal carbonates such as magnesium carbonate, inorganic bases such as metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, tertiary amines such as trimethylamine, triethylamine, and pyridine, and alkali metal alkoxides such as sodium methoxide and sodium ethoxide. Examples include organic bases. The reaction fd of Method 6 is usually carried out in alcohol, dimethylformamide, chloroformamide, methylene chloride, or other solvents that do not have any adverse effects on this reaction, either under cooling, at room temperature, or under heating. In addition, compound (1) and its salt are all novel,
the above compounds

It is useful as an intermediate for producing [1'] and a novel 6-cephem compound +]b+ having stronger antibacterial activity and salts thereof. To demonstrate the usefulness of the amount of a compound with antibacterial activity,

Test results for representative compounds of [1] and a new 3-cephem compound (1) produced from Ini compound (I)
The test results for the old model are shown below. In vitro antibacterial activity test (1) Test method: Antibacterial activity was measured using the conventional agar plate dilution method and IC method. One loopful of a 100-fold dilution of a culture of each R-tested strain grown overnight in Trypticene soy broth was added to Heart Infusion containing the test compound at graded concentrations.
Agar (HI-agarl was inoculated and cultured at 67'C for 20 hours. Minimum inhibitory concentration TM C]'i was measured,
Expressed in μQ/ml. (2) Test compound: Compound (1) 7-[1-+2-amino-4-thiazolyl)=2-hydroxyiminoacetamide J-3-cephem-4-carboxylic acid

[Syn isomer) (hereinafter referred to as Compound 1) Compound (1h) 7-i-+2-amino-4-thiazolyl)-2-methoxyiminoacetamide]-3-cephem-4-ruponic acid (syn isomer) ) (hereinafter referred to as compound A) 7-[2-+2-amino-4-thiazolyl)-2-ethoxyiminoacetamide]-6-cephem-4-carboxylic acid (syn isomer) (hereinafter referred to as compound B) ) 7-42-12-amino-4-thiazolyl)-2-n-
Propoxyiminoacetamide]-6-cephem-4-
Carboxylic acid (syn isomer) (hereinafter referred to as compound C) (3) Test results: MIC+μgAII/11 Target compound of this invention (1) C. Capsules, tablets, granules, troches, plain It is administered to patients in the form of solid preparations such as scrapings, ointments, or liquid preparations such as solutions, suspensions, and emulsions, by oral administration, rectal administration, or parenteral administration such as injection. Various preparations as exemplified above contain necessary (as appropriate) ordinary additives such as excipients, binders, stabilizers, suspending agents, emulsifiers, solubilizing agents, flavoring agents, and buffering agents. The dosage may be determined as appropriate depending on the age, weight, etc. of the patient, the type and severity of the disease, and the type of drug, but usually 1.
It is administered as a preparation containing 0, 50 mg, 100, 250, 500, etc. And, generally speaking, it is 1m da/to 'j ~ 100 ■/nq (DfJ1 area, good i L"I'i 5 m9/k
tl to 50 mQ/kg]. The raw material compound ω1) used in the above method A can be produced by the following method. (In the formula, R: and Rλ have the same meanings as above, X means a halogen 1, and Z means a lower alkyl group, respectively.) Next, the present invention will be explained with reference to Examples. Manufacturing method Example A of raw material compound (1) Ethyl ester of 2-ethoxyimino-6-oxobutyric acid (syn isomer, 48.il and acetic acid +1
Sulfuryl chloride '35.2 in a solution consisting of 49ml+
Add g+2 all at once while stirring at room temperature, and then stir at the same temperature for 1 hour. Add the reaction solution to zx+200ynl+,
This is extracted with methylene chloride. The extract was washed with a saturated aqueous solution of total sodium chloride, neutralized with an aqueous solution of sodium carbonate, and then washed with water. This was dried over magnesium sulfate and concentrated under reduced pressure to give a pale yellow oily 2- Ethyl ester of ethoxyimino-6-oxo-4-chlorobutyric acid 11.' (syn isomer, 53.81f7) is obtained. (2) Ethyl ester of 2-ethoxyimino-6-oxo-4-chlorobutyric acid) V (Syn R-isomer, 38.79
+, thiourea 113.2171, sodium acetate +14
．． 39), methanol-yv (95 ml l and water [95
The mixture consisting of y+1 is stirred at 48°C for 40 minutes. The reaction solution was adjusted to H6,5 [T) with an aqueous solution of sodium bicarbonate, and after removing the precipitate, diisopropyl ether "T'
fk purification/B, 2-(2-aminothiazole-4
-yl)-2-ethoxyiminoacetic acid ethyl ester [
syn isomer, 14.79 l kTa. □, 130-161°C TrR, νBonyan-”: 3450, 3275.3125.
1715゜1620C〃"1 (3) 2-+2-aminothiazole-4-yz+zl-
Ethyl ester of 2-ethoxyiminoacetic acid (syn isomer, 5171) was added to IN7 in aqueous solution i5
．． 9πt] and ethanol+30*+l+ and then stirred at room temperature for 5 hours. Ethanol was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in 7+(+60ynl).
], then adjust the DH to 2.0 with 10% hydrochloric acid. This solution is completely salted out, the precipitate is removed and dried, and 2-(2
-aminothiazole-4-inovl. 2-Ethoxyiminoacetic acid [syn isomer, 2,9171] is obtained. I, B,, νpukai-”: 3675.32.25+Shoulder 1,3100.1650°1615on N, M, R, δ [DMSO-d6.ppm+: 1.20
13H, t. J=7Hz], 4. Q9+2H, C1, J=7Hz
＋. 6.82+ I H, 81, 7, 24 [2H, broa
'd, 1 (412-f2-aminothiazol-4-inoL/1-2-ethoxyiminoacetic acid (syn isomer, 10
[] +71, formic acid +85. EMl and no 7X oxacid f1
When 90.17+ is processed in the same manner as Example B-(5),
2-(2=formamidethiazo-)V-4-ia/
]-]2-Ethoxyiminoacetic acid syn isomer, 99.11
7+2iru. ■, R, v”” ”: 320[], 3140.305
1], 17DQc1++ 1ax N, M, R, δ (DMSO-d6. ppm l co1
．． 1 3t 3H,t. J=6Hz +, 4.22f2H,q, J=63z l
. 7.56 (IH,s +, 8.56t iH,q +. 12.62 + 1 H, 'broad, ,si Example B (1) Ethyl ester of 2-hydroxyimino-6-oxobutyric acid 7t/ (syn isomer, 15g], potassium carbonate + 19.(3Q) and acetone 17!5ml]
Add propyl iodide (16.2 g) to the suspension and stir at room temperature for 1.5 hours. Remove insoluble matter,
Wash this with acetone. The p solution and washing solution are combined and dried under reduced pressure. Residue [Add water and extract twice with chloroform. After washing the extract with a total sodium chloride aqueous solution,
Drying over magnesium sulfate followed by drying under reduced pressure gives the oily ethyl ester of ro-oxo-2-propoxyiminoacetic acid (syn isomer, 15.4 g). (2) Ethyl ester of 3-oxo-2-propoxyiminobutyric acid 15.4 g + souffle chloride (10,6 Q 1 acid + 1
5.4 m/][, Vci under stirring at 35-40°C
The mixture was added for 0 minutes, and after being dissolved, the mixture was stirred at room temperature for 6 hours. Pour reaction # into +200yxJ+ on ice 7 and extract it twice with chloroform. The extract was washed twice with a saturated aqueous solution of IJ and then once with a saturated aqueous solution of IJ, dried over magnesium sulfate, and evaporated to dryness under reduced pressure to form an oily 4. -chloro-
6=ethyl ester of oxo-2-propoxyiminoacetic acid [syn isomer, 15.417+y obtained. 1, R, Sihui'': 1740.1710, 1695.1
45 (ax (3) 4-10 rho 3-oxo-2-propoxyiminobutyric acid ethyl ester JV (syn isomer, 15.4 g
), thiourea [4,97171 and sodium acetate +s, a9gl are dissolved in a mixture consisting of X[40y+l] and ethanol +50ml and stirred at 40°C for 1 hour. The reaction solution was cooled with a saturated aqueous solution of potassium carbonate [
After adjusting the pH to 6.5, the mixture was stirred at the same temperature for 30 minutes. All precipitated crystals were collected, washed with 7 and diisopropyl ether, and dried to form crystalline 2-(2
-aminothiazo-1v-4-inov +-2-propoxyiminoacetic acid ethyl ester (syn isomer, 1 [1
,55y) x obtained le. m9142~144°C ■, R1 shift'yaw': 3460, 3260, 3120
．． 1720°aX 1620, 1540m N, M, R, δ+d,, -DMSO, vpm): [l,
33+RoH, t. J=7az31,27+3n,t,y=6Hz31.6
0 t 2H, 5extet, J=7 Hz +
, 4.04+2H,t, J=7Hzl, 4.28f2
H,q. J=6Hzl, 6.86+1H, 81,7, Ro2+2H
,5)(4)2-(2-aminothiazol-4-i)V
) - Ethyl ester of 2-propoxyiminohyperF acid isomer, 10! &l Tetrahydrofuran (39)
Dissolve 〃l in a mixture of 59 ml of tutanol and 175.8 ml of an aqueous sodium oxide solution in IN7 and stir at 65 to 40''C for 5 hours.The reaction solution was concentrated under reduced pressure, and the residual liquid was diluted with 10% hydrochloric acid. Adjust the pH to 2.5. The precipitate is taken as f1 and dried to obtain 2-(2-aminothiasonon-4-yl)-2-propoxyiminoacetic acid (syn isomer, 6.29 l k. mp161° C (decomposition) 1, R, ν""'V: 3380.312[]1ro
ad 1.1630゜a
9+3H,t. , T=7Hz+, 1.63f2H, 5extet, J=
7Hzl, 405t2a,t,,J=7Hz). 6.8311 H, Fl 1 , 6.9-8.8+ 3
H, 'broadl (5) no acetic acid (filter 3.8ii'
17.5 g of formic acid was added dropwise to the solution over 3 to 4 minutes under water-cooling and stirring, and the mixture was stirred for 1 hour at 1°C. Add 2-(
2-Aminothiasofurei 4-yl l-2-n-propoxyiminoacetic acid (syn isomer, 21.3&+y) was added with stirring under water cooling and allowed to react at room temperature for 2.5 hours. The reaction solution was completely dried to dryness under reduced pressure. When diisopropyl ether is added to the residue and powdered, 2-12-hononomamide naazo=)
V-4-yv l-2-n-propoxyiminoacetic acid (
Syn isomer, 19.2171y is obtained. mp164°C (decomposition) 1, R, ν""v: 3200.3120.3050.1
700°ax N, M, R, δIDMsO-a6. ppm+:0.92
+3H,t. J=7Hzl, 1.67F2H, 5extet, J=7
H2l, 4.12t2H,t, J=7Hz+. 7.53i1H, sl, 3.54+ iH, S1 Example C (1) Ethyl ester of 2-hydroxyimino-6-oxobutyric acid (syn isomer, 4017], potassium carbonate + 52.7g], N,N-dimethyl Formamide (20
0πt] and isobutyl bromide (134.94 g) 2 When treated similarly to Example B-(1), the ethyl ester of 2-isobutoxyimino-3-oxobutyric acid (syn isomer,
42g]'(r get. ■, R, v Nujo": 1740, 167Dtbroa
a+a'aX (2) Ethyl ester of 2-inbutoxyimino-5-oxobutyric acid, 42Ql, 127.1g+ of sulfuryl chloride and acetic acid [42π/li Example B
-When treated in the same manner as (2), 2-isobutoxyimino-
Ethyl ester of 4-chloro-6-oxobutyric acid (syn isomer, 31.qy) is obtained. 1, R, ν-bon', ”: 1750.172D, 1681J
y++' (3) Ethyl ester of 4-chloro-5-oxo-2-isobutoxyiminobutyric acid) V (syn J% isomer,
31.9g), thiourea [9.72g+, sodium hexate hydrate [17.4+71, aminothiazol-4-yl
) Ethyl ester of -2-isobutoxyiminoacetic acid! The syn isomer, 17.17] is obtained. mp122-124°C T, R, l""": 3470.326D, 3120.
1730°aX 1620.1545-1? Nol N, M, R, δIDMsO-(16, ppm 1:Q, 8
6+/)H,d. J=;7az+y1,28+3a,t,J=7Hz+. 1.6~2.2+ 1H, m +, 3.86+2n, d
, J=7Hz 1.4.23+2H,q, J=7Hz
+. 6.86+ IH,S 1.7.22t2H,s 1(
4) 2-+2-aminothiazole-4-inov)-2-
Ethyl ester of isobutoxyiminoacetic acid isomer, 19.6+7], 2N hydroxyl 1'', solution in sodium 7 (72,2πl), methanol (72,2ml+ and tetrahydrofuran [72,2trtl]), real Mi Example B - Working up analogously to (4) gives 2-(2-aminothiazo-71/4-yl)-2-isobutoxyiminoacetic acid (syn isomer, 16.1171. mp180''C (decomposition) 1 ,R,Sif'Yo":3375,3300.3130
．． 305 [J. aX 164[]a+i' N, M, R, δN) MSO-46, ppm1:Q, 91
t 6H1d. J=7H21,1,5~2.3+IH,m+,3.90
(2H1σ, J near H21,6,8711H,Fl+. 7.26 + 2H,'broad s 1(5)2-
(2-aminothiazol-4-yl)-2-isobutoxyiminoacetic acid (syn isomer, 11.5Q+, formic acid 187
g+ and inert (acetic acid t19.317+ all examples B-(
When treated in the same manner as in 5), 2-+2-formamidothiazole-4-ia L/+2-isobutoxyimino# acid [
The syn isomer, 11.15+7+ is obtained. mp163°C (decomposition) Wang, R1 Shift'yaw": 3175.3110.3050
, 1695°aX 1550C horn! N, M, R, δfDMSO-d6. ppm1:Q, 91
f6H,d. J=7Hz l, 1.7~2.3+1
H, m + , 3.92+ 2a, d,,
J = 7nzl, 7.52 + 1 H, s +. 8.52+IH, 8], 12.58+1H,'broa
d81 Example 1 (1) 7-+2-Phenylacetamide] 4-nitrobenzinone ester of -6-hydroxy 6-cephalic acid 4-carboxylic acid (10 g) Methylene chloride + 2
Triethylamine (2
, filter 7Q+, dimethylaniline + 7.12 g) and trimethylsilyl chloride + 3.93 y) 2 were added under stirring, and the mixture was stirred at room temperature for 1 hour. Add phosphorus pentachloride +
4.8817) Add at 30~-25'C, -25~
Stir at -20"C for 6 hours, methanol

[42M1]
was added at -25 to -20'C and stirred for 1 hour. Add 35 mJ of water + 25 to -20°C and stir for +1° at room temperature. The precipitate kP was collected, washed successively with methylene chloride and diethyl ether, and dried.
-4-nitrobenzyl ester of amino-5-hydroxy-6-cephem-4-carboxylic acid [5,2y)xT
'4 le. mp148°C [decomposition] ■, R1v"yo": 3440, ro 300.17
60.174 [an-1aX N, M, R, δ+ DMSO-R6, ppm): 2.
8~3°7 (2H. m+, 4.90tIn, t, J=4nz+, 5.29[
IH, 6, J==4Hz+, 5.33t2H, s l. 7.71+2H, d, r=3Hz38.26+2H. +1, J=3I(z) (2) Phosphorous oxychloride +2.87171 to N,N-dibutylformamide +1.37g+ and ethyl acetate 110
M? VC was added dropwise at 5-10° C., and then ethyl acetate (40 rt) was added, followed by stirring for 40 minutes under water cooling. Add 2-(2-formamide-4-
Thiazolyl)-2-methoxyiminoacetic acid [syn isomer,
Add 3.58171 and stir at 0-5°C for 40 minutes. This solution was added to
5//], Aj6ethyl (50πl), trimethylsili! A mixture consisting of rareacetamide 14.3g1- and binu(trimenalsilyl)7set7mi)-+5.817+!
Add all at once at VC-15°C and stir at -20 to -15°C for 1.2 hours. Add 7 to the reaction solution + 50+/]'
After addition at -25 to -20°C, stir at 1 to raise the temperature to 5"C. Separate the water belly and extract with ethyl acetate. Combine the ethyl acetate layer and the extract. Wash with a saturated aqueous solution of sodium salt and dry with magnesium sulfate. Concentrate under reduced pressure in a flf 50 ml tube, remove the precipitate, and wash with ethino-V acetate to obtain 7"-[2-12-formamide- 4-thiazolyl)-2-methoxyiminoacetamide]-5-hydroxy-6-cephem-4-
4-nitrobenzyl ester of carboxylic acid) V (syn isomer, 3.5 g + total obtained. mp 163°C' decomposition) Wang, R9 Schif'Yo': 3210.3160.6050
．． 1780. aX 16652? n N, M, R, δ+DMso-66, ppm1:3.0~
4.2+2H. ml, 3.95+3H,s+, 5.2811H,d. J=4Hz +, 5.41+2H, S1, 5.6411
H. dd, J=4Hz, 9Hz l, 7.49+ 1H,
S37.67+2H,d, J=8Hzl, 3.21+2
H. d, r=3nz), 3.5ONa, t, J=9Hz+(
3) Previously obtained compound (1 g), Methano-IVt 1
A solution consisting of 5z++7 +, tetrahydrofuran [5πt) and a-hydrochloric acid [0,72zo] is stirred at room temperature for 1 hour. Add 100 yxl of diethyl V ether to the reaction solution and crystallize. When the precipitated crystals are separated by F, 7-
(2-12-aminothiazol-4-yl)-2-methquiniminoacetamide]-6-hydroxy-6-cephemu-4-katV-hydrochloride 'M' syn isomer of 4-nitrobendiW ester of Vponic acid, We get 0.65171. Wang, R1 Schiff'/Yo": 318[], 1780.16
80.1670゜aX 164 QC〃! N, M, R, δ(DMSO-d6.ppm + :3.
2-4.0 + 2H. ml, 3.97+3n, +q+, 5.27+In, a
. J=4Hzl, 5.41+2H, sl, 5.60fIH
,dd,,,T=4H2,3H2l,7.1Q+IH,
81,7,66T2H,cl,J=9Hzl. 3.25+2H,d,, J=9Hz +, 9.73(I
H. d,, T=8H21 Example 2 7-+2-ho)V-mamidothiazol-4-yl)-2
-Propoxyiminoacetic acid (syn isomer, 0.51517
+,N,N-dimethylformamide f0.161g+,
Phosphorus oxychloride +0.3379+ and ethino acetate"7.
9 ml+ is treated as in Example 'l-(2) to obtain a solution of activated acid. On the other hand, trimethylsilifuracetamide+1.35g+ and bis(trimethylsilifuracetamide)+1.60! )+7-amino-
4- of ro-hydroxy-6-cephem-4-carphonic acid
Nitrobenzyl ester (703 g) and ethyl acetate (1 D ml) are added to the suspension and stirred for 1 hour at room temperature. To this solution is added 1 oz of the activated acid solution previously obtained. -C at once and stirred at the same temperature for 1 hour.To the reaction solution was added 120 ml of water and ethyl acetate pvf.
2 (Jmll'r), separate the organic layer, add solution to saturated sodium bicarbonate +8yxl+ and water (14πl
) and then dried with magnesium sulfate. This was concentrated under reduced pressure, and the residue was powdered with ethyl)V ether, and the precipitate +p was collected. 5-cephem-4-levonic acid 4-2) lobensylester 7

[Syn isomer, 0.75J71 is obtained. ■, R0 shift "yaw": 325D, 1765.1740
．． 1670Cy++ 'aX N, M, R, δD) MSO-d6. ppm1:Q, 9Q
t 3H, t. J=8Hzl, 1.67f2H, ml, 3,4Q, +2
H. Al3-(1, J:20H2l, 4.oa+2H
, (1. J=8Hz +, 5.03~5.83+4n, m 37
．． 4ONn, S), 7.70+2H,d, J=9HzI
, 3.27+2H, cl, J=9Hzl. 8.53F IH, 81, 9, 50 [IH, d, J=8
Hz + , 12.60+1H, broacl, 81 Example 6 2-(2-formamidothiazol-4-yl)-2-
Isobu-1-ximinoacetic acid (syn isomer, 0.54/I
+, N, N-dimethylformamide 1.1617+, oxysalt I to phosphorus (0, filter 4 &+ and ethyl acetate I 10
ytl)pProcess in the same manner as in Example 1-(2) to obtain a solution of activated acid. On the other hand, trinotyl resilyl acetamide +1.851+ and bis(trimethylsilyl
) 1.62 g of acetamide + 4-nitropencyl ester of 7-amino-6-hydroxy-6-cephemu 4-carboxylic acid f0.7171 and ethyl acetate +
10 ypt') and stirred in the dark for 60 minutes at 40°C. To this solution, the previously obtained activated acid solution was added all at once at -20°C, and the mixture was stirred for 1 hour at the same temperature. Add zKt, IDml) to the reaction solution and separate the organic layer, which is washed sequentially with water, dissolved in saturated sodium bicarbonate solution (7), and dissolved in IJ ram saturated solution (7), and then dried. After concentrating this under reduced pressure and powdering the residue with diisopropifurether, the precipitate sound P was collected. iminoacetamide]-3
-4-nitrobenzyl ester of hydroxy-6-cephem-4-carboxylic acid (SynUIItJ, 1.099
). ■, R0ν8′ Yaw”: 3250.3050.175
0.1650. ax 610cm N, M, R, δN) MSO-d6. pvml:0.9
7 [6H, d. J=6Hz+, 2.0[IH, m+, 3.60+2H
. AB-q, J=[Hzl, 3.951zI(,d,. J=6H2], 5.1~5.814H,m],
7.53[1'H,F+1,7.63+2H,d,,
J=3Hz38j3t2H,d, J==8Hz), 3
．． 58tIH. sl, 9.47+In, d,, r-=9Hz). 12.77 + I H, broacl s + Example 4 N,N-dimethylphoremamide 10.114 g +, phosphorus oxychloride (0,249 g + and ethyl acetate + Q,
5m/I'! i=Pirnemeyer reagent is prepared by processing according to a conventional method. Add ethyl acetate + 5tyl to this solution
) and 2-12-formamidethiazole tv 4-
Ipv l-2-ethoxyiminoacetic acid (syn isomer, 0
．． 35171 crystallinity was added over a period of 60 minutes to obtain a solution of activated acid. On the other hand, ■ - Limethylsilinone acetamide N, 3171 and binu(trimethylsilyl)acetamide +1.14g+ were added to 4-2l□ lobezolyl ester of 7-amino-6-hydroxy-3-cephem-4-carboxylic acid, 50g) and ethyl acetate +7
．． Add 5g/+ of Iken's suspension and stir at room temperature for 1 hour. Add 10% of the activated acid solution obtained earlier to this solution.
Add all at once at °C and stir for 60 minutes at the same temperature. Add 15 ml of 7KA to the reaction solution and 15 ml of ethyl hetamine acid to the reaction solution.
ml + 157111) and 7xlo, separate the organic layer and add a solution to saturated sodium carbonate (7+157111) and 7xlo
After washing with Fll, drying with magnesium sulfate. After concentrating this fI- under reduced pressure and powdering the residue with dienal ether, the precipitate was taken off to give 7-[2-(2-holemamidothiazole-4-yl)-2- Ethoxyiminoacetamide J-lohydroxy-6-cephem-4
0.664 g of 4-21-lobenzyl ente W (syn isomer) of -kV-boxylic acid is obtained. ■, R0ν”” ”: 3220.1760.1740.
1670Cy+ 1aX N, M, R, δ [DMSO-c16. ppm): i, 2
4t 3H,t. J=8H2l, 3.36 + 2H, AB-+q
, J=20Hz], 4.15T2H,q, J=3Hz
35.10~5.60+4n, m), 7.37+IH,
81゜7.65+2n, 6y, J=9Hz +, 8.2
212H1d,, J=9Hz+, 8.48(IH, R1
,9,52Nu,d,J=3nz+,12.58tIn
. 'broad I't1 Example 5 (1) 4-nitropezolyl ester of 7-amino-6-cephem-4-carphonic acid + 5171-4 trimethylsilylacetamide + 13.13g+ and 110ml of binu(trimethylsilylacetamide) and Dry ethyl acetate and dissolve in a solution consisting of 50 M/+ 4
Stir for 1.5 hours at 5"C. Separately, add bromine [2,8E3
Diketene [1,5+71 and methylene chloride +7yl/l]
The mixture was added dropwise to a solution consisting of -40°C over 20 minutes, and then stirred at -60°C for 1 hour. This solution was added to the 4-amino-3-cephem-4-J sulfonic acid obtained earlier
It was added dropwise to a solution containing nitrobezolyl ester at -15°C, and stirred at the same temperature for 6°. 7x+50 to reaction solution
1) and extracted with ethyl acetate. Ethyl acetate extraction H'kyp Washing, drying with magnesium sulfate, and concentration under reduced pressure yielded oily 7-L2-[2-bromoacetyl 7
4-nitropencyl ester of L/l acetamido]-3-cephem-4-carboxylic acid + 6.15171
f('4ru. 1, R, v'7r": 1780.1740.1630m
"aX N, M, R, δ (DMSO-d6.p:pm+:3.6
2+2n. b r o a, σq + , 4.3712H, 81,
5,08+1H,6,J=5Hz+,5,4Q'12
H,Rl. 5.77-6.05 (m), 6.67 + IH,
t, J=5Hz l. 7.68, 8.04+ 4H, m, J=9H2l
, 9.07+ IH, d, J-8Hz 1 (2) 7-12-+2-bromoacetyl)ace1-
Ami) I-3-cephem-4-carvone 2y 4-nitrobendi1noeneutew+ 3.4[]Qlitetrahyfafun+150ge+ and 7K f3'
Dyn1]. Add acetic acid to this suspension.

[50
πl) and nitrate auxiliary I-IJum+1.2 [1171
An aqueous solution (15 πL) of
Stir for 15 hours. Pour the reaction solution into ice 7K (300 ml+) and stir for 20 minutes. Collect the precipitate, wash with water,
After drying, recrystallization from ethyl acetate IV yields 7-L2
- [2-Bromoacetyl 7V12-hydroxyiminoacetamide J-3-cephem-4-hydroxyiminoacetamide 4-nitrobenzyl ester of 7V12-hydroxyiminoacetamide (3.1 g) is obtained. mp153~162°C ■, R0ν""': 3250.1780.172[],
1705°ax 1650, 1610, 1600 [shoulder 1, 155
0, 1! 520cynN, M, R, δfDMso-
d, , pvrrN: 3.67 [2H, d, . , T=4Hz l, 4.63+ 1.5H, Fl
1, 4.88+Q, 5H1s1.5.13t IH,
d,,J=5Hz+. 5.45+ 2H, R+, 5.93+ 1n, dd,,
:r25Hz, 8H2l, 6.72T IH,t
, J=4Hz + . 7.73+ 2H, d, J=9Hz l, 8.28
(2H. d, J=9Hz, 1.9.33 [1n, d, J-=3H
zl. 11.27+ IH,R] (3) 7-[7-12-bromoacetyl)-2-hydroxyiminoacetamide)-3-cephem-4-/
'J IV 4-21'lobenzyl ester of fonic acid [Q
, 9 Q 1 and tetrahydrofuran + 30 r/+, a diethyl ether solution of diazomethane is added dropwise under water cooling little by little at 1, when the reaction is terminated. Acetic acid is added to the reaction solution to decompose excess diazomethane. When the reaction solution was concentrated under reduced pressure, a foamy 4-nitrobenzyl ester monoisomer of 7-[2-[2-bromoacetyl)V)-2-methoxyiminoacetamide]-6-cephem-4-carboxylic acid was obtained. 0.9 g) is obtained. (417-[2-12-bromoacetyl)-2-methoxyiminoacetamide]-4-nitrobenzylester of -6-cephem-4-carboxylic acid 71/(synisomer,
0.89+, ethanol+20y+l and X (5 scraps t
) in a solution consisting of naourea + [], 14. Add &1,
Stir at room temperature for 6.5 hours. After concentrating the reaction solution under reduced pressure,
Add water and ethyl acetate to the residue. The entire ethyl acetate layer was separated, washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to yield the crude compound I O,6Q.
+24ru. This product was subjected to silica gel column chromatography, and a mixture of benzene and ethyl acetate [8
:2], 7-L2-(2-amino-4-naazolino V)-2-methoxyiminoacetamide)-3
-cephem-4-carvone 6(Z) 4-nitrobenzyl ester 7tz (syn isomer, 0.21g+ obtained. mp165-170°C (decomposition) ■, R1 shift 'yo': 3350-ro2[] 0.177
[J, 1720°aX 1665.1615.15150x 1N, M, R, δ
[)MSO-d6. p'pml: 3,6Q+2H. 'broac181,3.8113H,Fll,5.1
2+IH, d, J=5Hz35.35+2n, S35.
83+ 1n, d, d,, J=5I (Z, BnZ l. 6.64+IH, -b, J=4Hz+, 6.70+ I
H. s+, 7.20+2n, s+, 7.65(2H, c+,
. J=9Hzl, 8.19f2H, cl, J=9Hz+. 9.6Q+ IH, d, J = 3Hz + (5) Thus obtained 7-[2-+2-amino-4-naazolyl)-2-nodoxyiminoacetamide F) -3-cephem-4- 4-nitrobendi)V ester of carboxylic acid to convert syn-U, sex form, 7.8171 to ethano-J+z+6
1h++? l and water [suspended in a mixture of 60 ml, IH
To 7, add potassium oxide aqueous solution + 45y + 11 under ice cooling with stirring [
After adding dropwise for 10 minutes, stir at 5°C for 15 minutes. The reaction solution was adjusted to pH 7.0 with concentrated hydrochloric acid, washed with ethyl acetate, and concentrated under reduced pressure in 1/2 volume. The total pH of the concentrate was adjusted to 5.0, and the porous nonionic adsorption resin Diaion HP-20 (trademark: manufactured by Mitsubishi Chemical Industries, Ltd. 1) was added.
180 m/] and eluted with 5% isopropyl alcohol-1. The fractions containing the target compound are combined and adjusted to pH 3.2 with 10% hydrochloric acid. When the precipitated crystals are collected and dried, 7-(2-(2-
Amino-4-thiazolyl-2-methoxyiminoacetamide]-3-cephem-4-olebonic acid (syn isomer, 26 g) is obtained. mp>290°C ■, hill, shift'yo'': ro470.3280.320
Skin 1780°aX 1695, 1655, 1622C+"1N, M, R
, δ+DMSO-d6. ppm1:3.6D[2H. 'broad Sl, 3.84 [3H, Fl 1.5.
12+ 1H, dd, J=5Hz 1.5.84+ 1
H. da, J=5.8Hz I, 6.52 F I
H, broadtl, 6.76f IH, s+, 7.
26+2H. broad 81,9.65+'lH,d,J=BHz
] Example 6 The following compounds are prepared in the same manner as in Example 5. (1) 7-14-[2-aminothiazo-)V-4-
2-ethoxyiminoacetamide, )-3-
4-nitrobenzyl ester C-syn isomer of cephem-4-carboxylic acid). 1, R, C: Broom-”: 3330.1780.1730.
1680° 1640 , 1610 cm 1 (2) 4-nitrobenzyl ester of 7-[2-+2-aminothiazo-tv 4-yl)-2-propoxyiminoacetamide]-5-cephem-4-carboxylic acid (
Shin different P4J+. 1, R, shift'yaw'': ro300.1780.1730
．． 1670. aX 164QCm 1 (3) 4-nitrobenzyl ester of 7-[1-+2-aminothiazole-4-ia1/ ]-]2-isopropoxyiminoacetamide]rosephem-4-carboxylic acid 71/ (syn isomer) . 1, R, ν''9-”': 3320, 3270, 1
775, 1730. ax 1670 , 163QC+++ 1 Furthermore, the above-obtained fl compound was subjected to free power! by the following method. Converted to a compound with a levoxy group. (4) 4-Nitropenzylene ethyl of 7-[2-12-amino-4-thiacylyl)-2-ethoxyiminoacetamide)-3-cephem-4-carboxylic acid (sin-1 biological, 2.39 +, tetrahydrofuran +30
m1+, methanol I 15+trl + and acetic acid t
0.5 ml) of palladium on carbon T1. moistened with water + 3 ml. 1 Oq was added and the mixture was subjected to catalytic reduction at room temperature and pressure for 2 hours. All catalyst P is removed from the reaction solution, and the filtrate is concentrated under reduced pressure. Add 1 part of ethyl acetate to the residue, boil the mushrooms,
After adjusting the pH of this to 7.5 with an aqueous sodium hydrogen carbonate solution, insoluble matter was removed. Separate the entire aqueous layer and add ethyl acetate! After washing with water and adjusting the pH to 5.5, it is treated with activated carbon. When this was adjusted to pH 3.2, insoluble matter +p was removed and dried, 7-[2-12-amino-4-thiazolyl]-2
-ethoxyiminoacetamide]-3-cephem-4-
Force 7 leponic acid (syn isomer, obtains 0.6+7+. 1, R, ν5′ yaw”: 3500.3300.200
．． 1785°ax 1625, 16DOo+ 1 (5) 7-(2-12-amino-4-thiacylyl 1V
1-2-Isopropoxyiminoacetamide J-3-cephem-4-force 7 Leponic acid 4-nitrobendi) V ester (syn isomer, 5.Of+ and a solution consisting of 150 ml of tetrahydrofuran with acetic acid (1πt) and 1
0% palladium accumulation (xtamz containing 2, Q Q +
Add a suspension of + and subject to catalytic reduction at room temperature and pressure. After removing the catalyst from the furnace, the furnace liquid is concentrated under reduced pressure. Add ethyl acetate to the residue
Add 80ml/l and add hydrogen ash).
Adjust to H7.5. Separate the organic layer and extract with an aqueous solution of hydrogen carbonate. Combine the aqueous layer and extract and add concentrated hydrochloric acid to pH 3.
, and then extracted with tetrahydrofuran. The extract is completely chlorinated) Washed with a solution of IJium saturated with chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Crystals that precipitate? When F is removed and dried, 7-(2-[2-amino-4
-thiazolyl l-2-isopropoxyiminoacetamide]-5-cephem-4-carboxylic acid (syn!A form,
Obtain 0.89 l k. 1, R, Shibon r'v: 3320.1780.1670.
1635ffi-1(6) 7-[2-12-amino-4-thiacyl-2-propoxyiminoacetamide]-6-cephem-4-carboxylic acid of 4-nitrobenzyl-restenone (synisomer, 5. 0g1 was treated in the same manner as in Example 6-(5) to obtain 742-(2-amino-4
-thiacylw]-2-propoxyiminoacetamito゛]-6-cephem-4-carboxylic acid (syn isomer, 0.
9/! Get +. ■, R8 shift'yaw": 3250.177D, 1650
．． 1660°ax 620ax Example 7 (1) Diketene (22.6g) and methylene chloride [3
A solution consisting of bromine [43,0171 and methylene chloride t30y+1 was added to a solution consisting of 0 ml at 60°C.
The mixture was added dropwise over a period of minutes, and stirred at the same temperature for 60 minutes. This solution was added to 7-amino-6-cephem-4-carboxylic acid.
-nitrobenzyl ester + 75.1 g +, binu(trimethylsilyl)acetamide + 63.4 g] and tetrahydrofuran [1,5 Stir for a minute. To the reaction solution, add 7 to 35 ml of sodium nitrite and 18. Add 135*li of +1+ aqueous solution. During this time, the liquid pH of the reaction solution was maintained at 2.0 VrC. After stirring this solution for 15 minutes at 1 Ll~15°C,
Adjust the pH of the IJium saturated bath solution to 4.5. Add a solution of 17.1!9+ (150 rainbow) to this, and adjust the pH to 7 with a solution of 7N sodium carbonate saturated.
6. After adjusting to IJ, stir for 20 minutes. The organic layer was separated, concentrated under reduced pressure, and the resulting solution was diluted with ethyl acetate + 1.5
1], and then washed 6 times with NONI. This is dried over magnesium sulfate, treated with activated carbon, and then concentrated under reduced pressure. The residue was crystallized with ethyl 7-reethenone + 2 ml of DO, and the precipitate was collected by the method of removing the precipitate. This was washed with total ethyl acetate [300*+Z+ and then heated at 60°C with tetrahydrofuran+5DOy+7+ and ethyl acetate)V(1
β), then acetic acid solution t-tv (100y+l
) six times and dried to give 7-[1-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamide]-6-cephem-4-carboni' saddleno-4-nitrobenzyl ester ( Syn isomer, 55.5j71 is obtained. 1, R, ν basin "": 176D, 171[1,166[1
1,16301-1N, M, R, δI DMSO-σ6
．． ppm1:3.60t2n,d. J=5Hz+, 5.12+IH,d, J=5nz35.
39t2H,s +, 5.88f IH,dd,, T=
8H2,5Hz], 6.63+ 1H,s 1,6.5
3~6.77+ 1H,m], 7,08(2H,'b
roadsl,7.68+2H,d,J=9Hz+,8
．． 22+2n, a, J=9Hz+, 9.47+1a, d
,. J=8Hz l, 11.33+ I H, s, +(
217-[2-12-amino-4-thiacylyl 1)-2
-Hydroxyiminoacetamide]-6-cephem-4
-Carboxylic acid 4-nitrobenzyl F-f 7L/
(Syn allofi, 0.79 l and methanol [70
A solution consisting of m1+ [10% palladium on carbon + [], 3
7II] and subjected to catalytic reduction at room temperature and pressure for 1.5 hours.・After filtering the anti-eyebrow liquid, reduce the liquid and concentrate under pressure. After adding a 7X solution of sodium carbonate to the residue, insoluble materials are removed. The furnace solution is washed sequentially with ethyl acetate and methylene chloride, and the organic solvent is removed by suctioning nitrogen gas, followed by freeze-drying. The resulting residue was 7K + 3
0 ml) and adjusted to pH 3.8 with 10% hydrochloric acid, porous non-ionic resin Padai ion n
p-2Q IJ (Trademark: Mitsubishi Chemical Corporation 1+
20m? Subject to column chromatography packed with +. After washing this with water, it is eluted with 40% aqueous acetone. Atenton was distilled off from the eluate under reduced pressure and the residue was lyophilized to give 7-52-+2-amino-4-thiazolyl)-2.
-Hydroxyiminoacetamide]-5-cephem-4
-carboxylic acid (syn isomer, 0.25 g+ is obtained. Engineering, R, Cy: rH": 3350-3200.1770.
1670°1630cnr 1 N, M, R, δlDMsO7d6. ppmM36Q[2
H. broad, q+, 5. I Q+ IH, a, J
=5H2+. 5.83 [1H, dd, , J=5Hz, 3Hz+. 6.47 (In, t, J=4Hz 1.6.6711H
. S l, 9.47 + 1H, a,, J=3Hz
Example 8 (1) 4-nitrobenzyl ester of 7-42=[2-bromoacetyl)-2-hydroxyiminoacetamide]-6-cephem-4-carphonic acid (syn isomer,
1.0! M'l, ethano-)V(25πl), tetrahydrofuran + 25yrl + and 7K + 5 ml
Add 0.18 g of thiourea to the turbid solution of ) and stir at room temperature for 4 hours. The reaction solution is concentrated under reduced pressure and then cooled. A mixture of tetrahydrofuran and ethyl acetate (V) was added to the residue and crystallized to give 7-[2-(2-amino-4-thiazolyl)-2-hydroxyiminoace1-amide]-3-cephemu-4-carboxylic acid. 4-nitrobendi7-reester of

[Syn isomer, 0.95 g+ colorless crystals were obtained. m9172~175°C (decomposition) 1, R, ν basin'-": 335 []-3200, 1770
,1725°1670 ,1625 ,1520C1x
1N, M, R, δ [DMsO-46, ppm 1:3.
68 [2H, d. J=4Hz+, 5.20+1a,d, J=5nz35.
43+2a, 835.90tIH, aa, J=8Hz,
5Hz 36.70+ 1H,t, J=4Hz l. 6.83[IH,s +,7.7Q+ 2H,d,,T
=9H2]. 8.23+2n, d, J===9Hz+, 9.63+I
n. d, J=8H2'1 (2) 7-[2-+2-amino-4-thiazolyl)
-2-hydroxyiminoacetamide]-4-nitrobenzyl ester of -3-cephem-4-leponic acid (syn isomer, 0.3f7+ and methanol [30M1)
Add a solution of diazomethane in diethyl ether little by little to Solution 1 consisting of the following: The reaction solution was concentrated under reduced pressure, and the residue was powdered with Jethy7-ether, filtered, and dried to give 7-[2-12-amino-4-thiazolyl)-2-methoxyiminoacetamide]-3-cephem- 4-nitrobenzyl ester of 4-carboxylic acid lV
+syn isomer, 0.2617+y obtained. This product is identified from the standard. Example 9 The following compounds are produced in the same manner as in Example 8-(2). (1) 7-[2-+2-aminothiazo-IV-4-
2-Ethoxyiminoacetamide] 4-nitrobenzyl ester (syn isomer) of 5-cephem-4-force7leponic acid. (2+712-12-aminothiazo-l-4-yl)
-2-propoxyiminoacetamide]-4-nitrobenzyl ester of -6-cephem-4-carboxylic acid (cy
i-mer 1゜(3) 4-nitrobenzyl ester of 7-12-[2-aminothiazo-1v-4-yl)-2-isopropoxyiminoacetamide]-6-cephem-4-canoponic acid) l/( syn isomer). Example 10 7-amino-5-cephem-4-carboxylic acid (2,51
'l'! z) Limethylsiri! Rareacetamide +11.
79'l, bis(trimethylsilyl)acetamide+
1" Nl+/) and 7 L/(50 liters) of dry ethyl acetate. Meanwhile, 12.43 g of bromine
A solution consisting of + and dry methylene chloride llh+1 is diketene +1.2811 and dry methylene chloride +25 m
It was added dropwise to a solution consisting of 1+ at -30'C over 10 minutes, and then stirred at the same temperature for 1.5 hours. 7-Amino-6-cephem-4 obtained from this solution first
- It was added dropwise to the solution containing the carboxylic acid at -15'C over 10 minutes, and then stirred at -15 to -10°C for 1.5 hours. Add yK+50m1+ to the reaction solution, separate the ethyl acetate layer, and extract with an aqueous solution of I-IJ in carbonate. The extract solution' was adjusted to pH 2.0 with 10% hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. 1, R-v'S)r'': 1760.166Da 'aX N, M, R, δIDMsO-a6.ppr+r+:3.
58+2H,d. J=4Hz +, 3.65+2H, s1.4.4ra2
H. s+, 5.06TIH1d, J=5Hz+, 5',
73f'I H,6,d,'J=8H2,5Hz l
, 6.50 ('IH,'t, J=4Hz +', 9
．． 08+ In, d. J-8H2) Example 11 (1) 7-[2-12-holemamide 4-thiacyly! )-2-methoxyiminoacetamide)-3-
Hydrogenation to a suspension consisting of 4-nitrobenzyl ester of hydroxy-6-cephem-4-carboxylic acid (syn & tetracarboxylic, I Q ), tetrahyfurofuran + 10πt'l, acetic acid + 3 m/l and water (1 ml). Add sodium 160+V+ for 1D min at O''C,
Stir for 55 minutes at "C". Add ice to the reaction solution and extract with ethyl #acid. The extract is diluted with a saturated aqueous solution of sodium chloride,
Sodium carbonate saturated solution and chloride) IJ
After successively washing the solution with magnesium saturated solution, the solution is dried over magnesium sulfate. After concentrating it under reduced pressure, the residue was powdered with diethyl ether to obtain 4-4-carboxylic acid of 7-2-+2-formamido-4-thiazolyl)-2-methoxyiminoacetamide]-6-hydroxycephalic acid. Nitrobenzyl ester (syn-14-mer, 0.77 g) is obtained. mp172-175°C (decomposition) ■, R0 shift'yaw': 3250.1775.1745
．． 1660Cyr"ax N, M, R, δ (DMSO-d6.ppm1:2.76
+ 1H, (1(1., r=14Hz,, 3az33.17t1a, aa. J=14Hz, 13Hz+, 3.92+3H, 81°4
, mouth + In, m +, 4.72 + 1H, d, r = 6
11Z l , 5.24+ In, d, J==4Hz
l. 5.37+2H, S +, 5.561■q, dd, J=
9Hz, 4H236,07+ IH, d, J=4Hz
＋. 7.44(IHlS +, 7.72+2H,d,, J=
8"z'-8,27 (2rr, d, :r=8H2+. 8.5411H,q 1.967+'lH,d,r=9
nz+(2+ 7-42-12-formamide-4-
Naazo IJ/shi)-2-methoxyiminoacetamide]
-4-nitrobezolyl ester of 5-hydroxycepham-4-carboxylic acid, 1g), N,N-
To a mixture of 110 liters of dimethylformamide and 0.732 g of potassium carbonate, add mediflechloride+[]
, 4406 g was stirred for 2 minutes at 0 to 5C, and stirred in a chamber for 2.5 hours after dropping. reaction solution rC
After adding ethyl acetate and 7K, extract with ethyl acetate. The remaining aqueous layer is extracted again with ethyl acetate. The ethyl acetate extracts are combined, washed with a solution of 7 ml of saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting solution was subjected to column chromatography packed with silica gel 430171 and eluted with a mixture of chloroform and ethyl acetate. The eluate was concentrated under reduced pressure to give 7-[2-1
4-nitrobenzyl ester of 2-formamide-4-thiacyl-2-methoxyiminoacetamide-6-cephem-4-leponic acid (syn isomer, 0.1
Get 2g+. m11224°C (decomposition 1 (3) 4-nitrobenzyl ester of 7-[2-+2-formamido-4-thiazolyl)-2-methoxyiminoacetamide]-5-cephem-4-carboxylic acid [
Syn-14 sex body, 1.259! y2 methanol (40
Mj) and tetrahydrofuran 15thy/+, and 10% palladium on carbon + [], 65I
7+ was added and then subjected to catalytic reduction at room temperature and pressure for 6.5 hours. After removing the catalyst from the reaction solution, the solution is concentrated under reduced pressure. Add 7Ju80*ff+all to the residue, add hydrogen carbonate) I
Adjust the pH to 7.5 with aqueous Jum solution. Insoluble matter was removed from this mixture in a furnace, and the furnace liquid was mixed with ethyl acetate (50%
After washing with 1 ml of ethyl acetate, dilute with 100 M/1 ml of ethyl acetate. After adjusting this solution to pH 1.5 with 10% hydrochloric acid,
Shake thoroughly. After separating the ethyl acetate layer, 7J'
The C layer was extracted twice with 181 J of ethyl acetate (7). Combine this extract with the ethyl acetate layer obtained earlier and salt it)
After washing with a solution of IJum 7, drying with magnesium sulfate, and concentrating under reduced pressure, 7-1! -+2-holemamido-4-nazolyl)-2-methoxyiminoacetamide)-3-cephem-4-carphonic acid (778
% isomer, 0.60 Q). mp176-183°C (decomposition) 1, R, v: 325 [1,1780,1690,
1660°155Dcn+1 N, M, R, δ [DMSO-d6. ppm1:3,63
[2H, d. J: 4Hzl, 3.93+3H,s), 5゜1DlIH
. a, J==5Hz), 5.90t IH,q, J=5.
3Hz+. 6.53ulH,t, J=4Hzl, 7.4711H. sl, 8.57+IH, sl, 9.7Ql 1H, (1
,. J=8H2l, 12.6311H, 81(4) 7-
[2-12-formamido-4-thiazolyl)-2-7
1-xyiminoacetamyl” J-3-cephem-
Suspend 4-carvone H (synthetic 1aE (L 95mQ I) in methanol-1 and 4π?1, add concentrated hydrochloric acid + 11
After adding 1 g+ of DI, the mixture was stirred at room temperature for 4 hours. Methanol-)V is distilled off from the reaction solution under reduced pressure. 7K+ for leftovers
30 vIl.
After sequentially washing with 10ml and menalene chloride + 15*t+, the remaining organic solvent was completely removed by blowing nitrogen gas, and then freeze-dried to obtain 7-42-(2-amino-4-thiazolyl)-2-methoxyimino. The hydrochloride salt (syn isomer, 63 mg) of acetamido]-ro-cefemu 4-power sulfonic acid is obtained. ml: 1180-190"C decomposed) ■, R1ν"'-": 3300.1770.1710.
1660°ax 1633Cm 1 N, M, R, δIDMsO-+16. ppm1:364
12H. broad R1,3,95+3H,s 1.5.14
+In,a,J==5nz35,32+In,t. , T=4Hz], 6.95(tq, s +
, 9.8011H,d,J=8Hzl Example 12 Phosphorus oxychloride+7 in a solution consisting of N,N dimethinone formamide f336+〃zo] and ethyl acetate'8 ml
04'lll was added dropwise at below 5°C and stirred at the same temperature for 60 minutes. Add 2-[2-pho7remamide naazol-4-i/L/1-2-meth-1-ximinoacetic acid t to this solution.
Add one syn isomer, 1Q, and stir at 5-10°C for 1 hour. This solution was mixed with 7-amino-6-hydroxycephalomu-4-carvone 6187277791, trimethylsilylacetamide [1. []! The mixture was added dropwise to a solution consisting of M+ and 20°C at -20°C over 5 minutes, and stirred at -2°C to -25'C for 1 hour. Add 7K I 5 CJtnlr to the reaction solution and adjust the vH to 7.0 with 7x sodium carbonate. The layers were separated in step 7, and the ethyl acetate layer was extracted with water (10jlt). After combining the two layers and adjusting the pH to 6, a porous non-ionic adsorption structure Diaion HP 2 Q 11 (trademark: manufactured by Mitsubishi Irgo Co., Ltd.) (column chromatography packed with 50 ml lr) was added. After washing with water + 50 yll+, it is eluted with 30% E1 [Jl- Soflovir 7y Recol. After adjusting the eluate containing all the target compounds to pH 6.5, it is concentrated under reduced pressure. When the residue is freeze-dried, 7- and 2-(2-hoI
V Muamidothiazo-7L/4-I-2-Methoxyiminoacetamide-3-Hydroxycepham-
Sodium salt of 4-carboxylic acid (syn isomer, 1.11
Get 71. N, M, R, δ1)2o, ppm l: 2.72-3.
18 + 2H, m). 4.0213I (, s l , 4.02-4.281
'1H, m +. 4.54+ 1H, cl, J=4Hz), 5.28F
IH. d, J=4Hz +, 5.53tIH, d, J=4H2
+.

Claims (1)

[Claims] 1. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is the formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, R^5 is an amino group or means a protected amino group), A is a methylene group or a formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, R^2 is a hydrogen atom or C_1-C_■alkyl group), R^3 is a hydrogen atom or the formula: -O-R^6 (where R^
6 means a hydrogen atom or an acyl group), R^4 is a carboxyl group or its ester, and the dotted line is 3-
It means Cefem nucleus or Cefam nucleus, respectively. However, 1) R^1 is a formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
Here, R^5 is the same as above) When it is a thiazolyl group, A is a formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
(Here, R^2 is the same as above), 2) When R^1 is a haloacetyl group, R^3 is a hydrogen atom, the dotted line is a 3-cephem nucleus, and 3) R ^1
is a formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (here R^
5 is a thiazolyl group represented by (same as above), and R^
When 3 is a hydrogen atom, A is a group represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and 4) R^3 is a group represented by the formula: -O-R^6 (here, R^6 is (means an acyl group), the dotted line means a cephalic nucleus] or a salt thereof. 2. (a) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^3 and R^4 have the same meanings as below) 7-amino-3-cephem (or cefame) compound or Carboxylic acids represented by the general formula R^1-A-COOH (wherein R^1 and A have the same meanings as below) or reactive derivatives thereof at the carboxy group to the reactive derivatives at the amino group or their salts. Or by acting on their salts, the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 is a formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, R^5 is an amino group or means a protected amino group), A is a methylene group or a formula: ▲ Numerical formula, chemical formula, table, etc. ▼ (Here, R^2 is a hydrogen atom or a C_1-C_8 alkyl group ), R^3 is a hydrogen atom or a group represented by the formula: -O-R^5 (where R^
5 means a hydrogen atom or an acyl group), R^4 is a carboxyl group or its ester, and the dotted line is 3-
It means Cefem nucleus or Cefam nucleus, respectively. However, 1) R^1 is a formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
Here, R^5 is the same as above) When it is a thiazolyl group, A is a formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
(Here, R^2 is the same as above), 2) When R^1 is a haloacetyl group, R^3 is a hydrogen atom, the dotted line is a 3-cephem nucleus, and 3) R ^1
is a formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (here R^5
is a thiazolyl group represented by (same as above), and R^3
When is a hydrogen atom, A is a group represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼, and 4) R^3 is a group represented by the formula: -O-R^6 (where R^6 is acyl In the case of a group represented by (meaning a group), the dotted line means a cephalic nucleus] or a salt thereof, or (b) General formula ▲ Numerical formula, chemical formula, table, etc. In the formula, R^1_a means a haloacetyl group, and R^4
is the same meaning as above)) A nitrosating agent is applied to the compound or its salt to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1_a and R^4 each have the same meaning as above) ), or (c) General formula▲There is a mathematical formula, chemical formula, table, etc.▼ (In the formula, R^1, R^3, R^4 and dotted lines are respectively the (same meaning as ) or its salt is treated with a C_1-C_8 alkylating agent to form the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^2_a means a C_1-C_8 alkyl group. (R^1, R^3, R^4 and dotted lines each have the same meaning as above) or (d) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1_a and R^4 each have the same meaning as above.) The compound represented by the formula or its salt has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^5 has the same meaning as above) (same meaning) is reacted with a thiourea compound represented by the general formula ▲ mathematical formula,
There are chemical formulas, tables, etc. ▼ (In the formula, R^4 and R^5 each have the same meaning as above.) Or, (e) General formula ▲ Numerical formula, chemical formula, table, etc. etc.▼ (In the formula, R^5_a means a protected amino group, and R
^2, R^3, R^4 and dotted lines each have the same meaning as above) A compound represented by or a salt thereof is subjected to an elimination reaction of the protecting group at the amino group of R^5_a, and the general formula ▲ mathematical formula, chemical formula , tables, etc. ▼ (In the formula, R^2, R^3, R^4 and dotted lines each have the same meaning as above.) Or, (f) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^2, R^4, and R^5 each have the same meaning as above.) By reducing the compound or its salt, the general formula ▲ mathematical formula, chemical formula, table, etc. etc. ▼ (In the formula, R^2, R^4 and R^5 each have the same meaning as above.) Or, (g) General formula ▲ Numerical formula, chemical formula, There are tables, etc. ▼ (In the formula, R^2, R^4 and R^5 each have the same meaning as above.) For the compound or its salt, the general formula, R^6_a
A compound represented by -OH (in the formula, R^6_a means an acyl group), its salt, or its reactive derivative is reacted with the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R^ 2, R^4, R^5 and R^6_a each have the same meaning as above) or produce a compound or its salt represented by (h) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ ( In the formula, R^4_a means an ester of a carboxy group, and R^1 and R^3 have the same meanings as above) or a salt thereof, by converting the ester of the carboxy group into a free carboxy group, General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1, R^3 and A each have the same meaning as above) , chemical formulas, tables, etc. ▼ (In the formula, R^1, R^3, R^4, A, and dotted lines each have the same meaning as above.) A method for producing cefem or a cefam compound or its salt. is the method of making the salt.