JPH0262556B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel cefem compounds, and more particularly to 7-substituted-3-cefem-4-carboxylic acids and salts thereof having antibacterial activity. The object of this invention is to develop a novel 7-substituted-3-cepheme-4 which has excellent antibacterial activity against a wide range of pathogenic bacteria, including Gram-negative and Gram-positive bacteria.
- To provide carboxylic acids and their salts. The novel cefem compound provided by this invention is represented by the following general formula (). K0353 [In the formula, R ¹ is an amino group or a protected amino group, R ² is a lower alkenyl group, a lower alkynyl group,
A halo(lower) alkyl group or a lower alkyl group substituted with carboxy or esterified carboxy, R ³ means a carboxy group or an esterified carboxy group, respectively] In the raw material compound and target compound of this invention, the formula

The thiazolyl group represented by [Formula] (where R ¹ is the same as above) is the formula

It is known that it has a tautomeric relationship with the thiazolinyl group represented by [Formula] (where R ¹ ' means an imino group or a protected imino group) as shown in the following balanced formula. There is. K0356 (wherein R ¹ and R ¹ ' are the same as above) Both of these tautomeric isomers are generally treated as substantially the same substance. Therefore, for convenience, in this specification, both isomers are referred to as "thiazolyl" and the formula

It is represented by the formula: (wherein R ¹ is the same as above), and both isomers based on the above tautomerism are included within the scope of the present invention. Next, regarding various definitions in the general formulas representing the raw material compound and target compound of this invention,
This will be explained in more detail. "Lower" means carbon number 1 unless otherwise specified.
It means a group of 6 to 6. As the protecting group for the "protected amino group" of R ¹ , common N-protecting groups such as benzyl,
Substituted or unsubstituted al(lower) alkyl groups such as benzhydryl, trityl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, halo(lower) alkyl groups such as trichloromethyl, trichloroethyl, trifluoromethyl, and tetrahydropyranyl groups , a substituted phenylthio group, a substituted alkylidene group, a substituted aralkylidene group, a substituted cycloalkylidene group, an acyl group, and the like. Acyl groups suitable as N-protecting groups include, for example, substituted or unsubstituted lower alkanoyl groups such as formyl, acetyl, chloroacetyl, trifluoroacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, iso Substituted or unsubstituted lower alkoxycarbonyl groups such as propoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, trichloroethoxycarbonyl, 2-pyridylmethoxycarbonyl, benzyloxycarbonyl, benzyl hydryloxycarbonyl, 4-
Substituted or unsubstituted alkoxycarbonyl groups such as nitrobenzyloxycarbonyl,
Lower cycloalkoxycarbonyl groups such as cyclopentyloxycarbonyl and cyclohexyloxycarbonyl, 8-quinolyloxycarbonyl groups,
Examples include succinyl group and phthaloyl group. Furthermore, reaction products of silicon, boron, aluminum or phosphorus compounds with amino groups are also included in N-protecting groups. Examples of such compounds include trimethylsilyl chloride, trimethoxysilyl chloride, boron trichloride, butoxyboron dichloride, aluminum trichloride, diethoxyaluminum chloride, phosphorus dibromide, and phenylphosphorus dibromide. The "lower alkenyl group" of R ¹ means a linear or branched lower alkene residue, and preferred examples thereof include vinyl, allyl, 1-propenyl, isopropenyl, butenyl, isobutenyl, and pentenyl. , hexenyl, and more preferable examples include alkenyl groups having 4 or less carbon atoms. The "lower alkynyl group" for ^R2 means a linear or branched lower alkyne residue, and preferable examples include ethynyl, propargyl,
1-propynyl, 3-butynyl, 2-butynyl,
Examples include groups such as 4-pentynyl, 3-pentynyl, 2-pentynyl, 1-pentynyl, and 5-hexynyl, and more preferable examples include alkynyl groups having 4 or less carbon atoms. Preferred examples of the "halo (lower) alkyl group" for ^R2 include chloromethyl, bromomethyl, iodomethyl, fluoromethyl, trichloromethyl,
Trifluoromethyl, 2-chloroethyl, 1,2
-dichloroethyl, 2,2,2-trifluoroethyl, 3-chloropropyl, 4-iodobutyl,
Examples include 5-fluoropentyl and 6-bromohexyl. Preferred examples of the "lower alkyl group substituted with carboxy" for ^R2 include carboxymethyl,
1-carboxyethyl, 2-carboxyethyl,
Examples include 1-carboxypropyl, 3-carboxypropyl, 4-carboxybutyl, 5-carboxypentyl, 6-carboxyhexyl, 1-carboxyisopropyl, 1-ethyl-1-carboxyethyl, 2-methyl-2-carboxypropyl, etc. It will be done. Preferred examples of the "lower alkyl group substituted with esterified carboxy" for ^R2 include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, t-
Butoxycarbonylmethyl, 2-ethoxycarbonylethyl, 2-ethoxycarbonylpropyl,
Lower groups such as 4-ethoxycarbonylbutyl, 1-t-butoxycarbonylisopropyl, 1-t-butoxycarbonyl-1-methylpropyl, 4-t-butoxycarbonylbutyl, 5-t-butoxycarbonylpentyl, 6-butoxycarbonylhexyl, etc. Examples include an alkoxycarbonyl (lower) alkyl group, and a more preferred example is a lower alkoxycarbonylmethyl group. Preferred examples of the ester moiety of the "esterified carboxy group" of ^R3 include methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, and t-pentyl ester. , hexyl ester,
Alkyl esters such as heptyl esters, octyl esters, and 1-cyclopropylethyl esters, alkenyl esters such as vinyl esters and allyl esters, alkynyl esters such as ethynyl esters and propynyl esters, methoxymethyl esters, ethoxymethyl esters, isopropoxymethyl esters, Alkoxyalkyl esters such as 1-methoxyethyl ester and 1-ethoxyethyl ester, methylthiomethyl ester,
Alkylthioalkyl esters such as ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, haloalkyl esters such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester, acetoxymethyl ester, propionyloxymethyl ester,
Alkanoyloxyalkyl esters such as butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, palmitoyloxymethyl ester, mesyl Alkanesulfonyl alkyl esters such as methyl ester and 2-methylethyl ester, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4
-Hydroxy-3,5-di-t-butylbenzyl ester, substituted or unsubstituted aralkyl ester, phenyl ester, tolyl ester, t-
Substituted or unsubstituted aryl esters such as butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, salicyl ester, trimethylsilyl ester, triethylsilyl ester, dimethylmethoxysilyl ester,
Examples thereof include trialkylsilyl compounds such as dimethylethoxysilyl ester, diethylmethoxysilyl ester, trimethoxysilyl ester, and triethoxysilyl ester, and esters with silyl compounds such as dialkylalkoxysilyl compounds and trialkoxysilyl compounds. In this invention, the "protected amino group" of R ¹ and the "esterified carboxy group" of R ³ specifically mean the groups described above, but these are In the production of the target compound by a chemical method, the amino group and the carboxy group are used to temporarily protect each other, and in the other case, the target compound is used to improve the physiological or pharmaceutical properties of the target compound itself. include. That is, the meaning of these groups in terms of production will become clear in the explanation of the production method described below, for example, when R ¹ is a free amino group and/or
If R ³ is a free carboxy group and there is a risk that such groups may cause undesirable side reactions during the reaction, a protected amino group and/or After converting each to an ester of carboxyl group,
In order to prevent such side reactions, and to convert the esters of protected amino groups and/or carboxy groups in the reaction product into free amino groups and/or free carboxy groups, respectively, as necessary, after the reaction. be. On the other hand, the use of these groups for the purpose of improving the physiological properties or pharmaceutical properties of the target compound means improving the solubility, stability, and absorption of active substances that have free amino and/or carboxyl groups. For the purpose of improving properties such as toxicity and toxicity, these free radicals are converted into esters of protected amino groups and/or carboxy groups. Salts of the target compound () include salts with inorganic bases or acids, such as alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, ammonium salts, hydrochlorides, and odorous salts. hydrochloride, sulfate, phosphate,
Inorganic acid salts such as carbonates and hydrogencarbonates, and salts with organic bases or organic acids, such as trimethylamine salts, triethylamine salts, pyridine salts, procaine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzyl ethylenediamine salt,
Amine salts such as N-methylglucamine salt, diethanolamine salt, triethanolamine salt, tris(hydroxymethylamino)methane salt, phenethylbenzylamine salt, acetate salt, maleate salt,
Organic carboxylic acids or sulfonates such as lactate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, basic or Examples include acidic amino acid salts. The object compound () of this invention can be produced by any of the following methods. K0358 K0359 K0360 K0361 K0362 K0363 (In the formula, R ¹ _a means a protected amino group, R ³ _a means an esterified carboxy group, and R ¹ , R ² and R ³ are all the same as above) Each method will be explained in detail below. Method A: N-acylation Compound () and its salts are 7-amino-3
- In the field of so-called β-lactam compounds such as penicillins and cephalosporins, a cefem compound () or a reactive derivative thereof at the amino group or a salt thereof is added to a carboxylic acid () or a reactive derivative thereof at the carboxy group or a salt thereof. It is prepared by working according to the conventional practice applied to well-known amidation reactions. Among the raw material compounds (), novel compounds can be produced according to the method described below. Reactive derivatives at the amino group of the compound () include various derivatives that can be used in so-called amidation reactions, and specifically, for example, isocyanato, isothiocyanato, or reaction with silyl compounds such as trimethylsilylacetamide and bis(trimethylsilyl)acetamide. Derivatives formed by the reaction, aldehyde compounds such as acetaldehyde, isopentaldehyde, benzaldehyde, salicylaldehyde, phenylacetaldehyde, p-nitrobenzaldehyde, m-chlorobenzaldehyde, hydroxynaphthaldehyde, furfural, thiophenecarbaldehyde, or these aldehyde compounds Derivatives formed by reaction with reactive derivatives such as hydrates, acetals, hemiacetals, and enolates, ketone compounds such as acetone, methyl ethyl ketone, methyl isobutyl ketone, acetylacetone, and ethyl acetoacetate, or their ketals, hemiketals, and enolates, etc. Examples include derivatives formed by reaction with reactive derivatives of , reaction products with phosphorus compounds such as phosphorus oxychloride and phosphorus trichloride, and reaction products with sulfur compounds such as thionyl chloride. As the salt of compound (), those exemplified as the salt of compound () are also exemplified here. Examples of reactive derivatives at the carboxy group of the compound () include acid halides, acid anhydrides, active amides, active esters, and 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,
Dibenzyl phosphoric acid mixed acid anhydride, substituted phosphoric acid mixed acid anhydride such as halogenated phosphoric acid mixed acid anhydride, dialkyl phosphorous acid mixed acid anhydride, sulfurous acid mixed acid anhydride, thiosulfuric acid mixed acid anhydride, sulfuric acid mixture Acid anhydrides, alkyl carbonic acid mixed acid anhydrides, aliphatic carboxylic acids (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutanoic acid, trichloroacetic acid)
Acid anhydrides such as mixed acid anhydrides, aromatic carboxylic acids (e.g. benzoic acid) mixed acid anhydrides, symmetrical acid anhydrides, acid amides with imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles, tetrazoles, etc., cyano Methyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ =CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester,
Trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl azophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester , 8-quinolylthioester, or N,N-dimethylhydroxylamine, 1-
Examples include esters such as esters with hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, 1-hydroxy-6-chloro-1H-benzotriazole, etc. It will be done. Compounds () and reactive derivatives of () are
Depending on the type of raw material compounds () and () and reaction conditions such as other reagents, solvents, and temperature,
Appropriately selected from the above. Salts of the compound () include alkali metal salts such as sodium salts and potassium salts, salts with inorganic bases such as alkaline earth metal salts such as calcium salts and magnesium salts, trimethylamine salts, triethylamine salts, N,N-dimethyl Examples include salts with organic bases such as tertiary amine salts such as aniline salts and pyridine salts, and salts with inorganic acids such as hydrochlorides and hydrobromides. This reaction usually involves water, acetone, dioxane, acetonitrile, chloroform, benzene,
The reaction is carried out in methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine, other solvents that do not adversely affect the reaction, or a mixed solvent thereof. When using the compound () in the form of a free acid or its salt in this reaction, for example, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,
N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3
-dimethylaminopropyl) carbodiimide, bisimidazolide compounds such as N,N'-carbonylbis(2-methylimidazole), and imine compounds such as pentamethyleneketene-N-cyclohexylimine and diphenylketene-N-cyclohexylimine. , ethoxyacetylene, olefinic or acetylenic ether compounds such as β-chlorovinylethyl ether, 1-(4-chlorobenzenesulfonyloxy)
-6-chloro-1H-benzotriazole, N-
Ethylbenzisoxazolium salt, N-ethyl-
5-Phenyl isoxazolium-3'-sulfonate, polyphosphoric acid, phosphorous trialkyl ester, polyphosphoric acid ethyl ester, polyphosphoric acid isopropyl ester, phosphorus oxychloride, phosphorus trichloride, diethylchlorophosphite, orthophenylene chloro Preferably, the reaction is carried out in the presence of a condensing agent such as a phosphorus compound such as a phosphite, a Vilsmeier reagent prepared by the reaction of dimethylformamide with thionyl chloride, phosphorus oxychloride or phosgene. In this reaction, if the reaction between the compound () and the syn isomer of the oxyiminoacylating agent () is carried out in the presence of the Vilsmeier reagent as described above under relatively mild conditions near neutrality, the oxyiminoacylating agent () is The syn isomer of compound () is obtained in high yield. Although the target compound () and its salts are useful as antibacterial agents in themselves, some are also useful as starting materials in the following methods. Method B: Removal of amino protecting group Compound (b) and its salts can be removed from compound (
It can be produced by subjecting a) or a salt thereof to an elimination reaction of the protecting group at the protected amino group of R ¹ _a . This elimination reaction is carried out according to conventional methods such as hydrolysis and reduction. These methods are appropriately selected depending on the type of protecting group to be removed. Hydrolysis is a method using acid (acidic hydrolysis),
This includes a method using a base (basic hydrolysis), a method using hydrazine, etc. Among these methods, hydrolysis using acid is
Among the N-protecting groups mentioned above, examples include substituted or unsubstituted lower alkanoyl, substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted alkoxycarbonyl, lower cycloalkoxycarbonyl, and other acyl groups, substituted phenylthio group, substituted alkylidene group,
Suitable for removing protective groups such as substituted aralkylidene groups and substituted cycloalkylidene groups. Examples of acids used in this acidic hydrolysis include inorganic or organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydrochloric acid, and cationic ion exchange resins. Among these, preferred acids are:
Examples include those that can be easily separated from the reaction product by conventional methods such as neutralization or distillation under reduced pressure, such as formic acid, trifluoroacetic acid, and hydrochloric acid. The acid suitable for this reaction is preferably selected as appropriate, taking into consideration the chemical properties of the starting compounds and reaction products and the type of protecting group to be removed. This acidic hydrolysis can be carried out in the presence or absence of water, a usual organic solvent, or a mixed solvent of these and water. Note that when trifluoroacetic acid is used as the acid, the reaction is promoted by adding anisole to the reaction system. Hydrolysis with a base is applied to remove protecting groups such as acyl groups, especially haloalkanoyl groups such as trifluoroacetyl. The bases used here include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide;
Alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, magnesium carbonate,
Alkaline earth metal carbonates such as calcium carbonate, alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate, hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate. Inorganic bases such as alkali metals, alkali metal acetates such as sodium acetate and potassium acetate, trialkylamines such as trimethylamine and triethylamine,
Picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,
0]-5-nonene, 1,4-diazabicyclo[2,
Examples include organic bases such as 2,2]octene, 1,5-diazabicyclo[5,4,0]-7-undecene, and anionic ion exchange resins. Hydrolysis using these bases is usually carried out in water, a commonly used organic solvent, or a mixed solvent thereof. Hydrolysis with hydrazine produces succinyl,
It is applied to the removal of protecting groups such as dibasic acyl groups such as phthaloyl. Elimination by reduction can be used to remove halo (lower) alkoxycarbonyls such as trichloroethoxycarbonyl,
Substituted or unsubstituted alkoxycarbonyl such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, acyl group such as 2-pyridylmethoxycarbonyl, benzyl,
It is applied to the removal of protecting groups such as aralkyl groups such as benzhidr and trityl. Examples of the reduction method include reduction using an alkali metal borohydride such as sodium borohydride, and catalytic reduction using a common catalyst. Furthermore, protective groups such as halo(lower) alkoxycarbonyl groups and 8-quinolyloxycarbonyl groups can be removed by treatment with heavy metals such as copper and zinc. The reaction temperature is not particularly limited and is selected taking into account the chemical properties of the starting compounds and reaction products, the type of N-protecting group, the application method, etc., but is usually under cooling, at room temperature, or under heating. Preferably, the reaction is carried out under mild conditions. If R ³ of the starting compound (a) is an esterified carboxy group, it may be converted to a free carboxy group during this reaction or post-treatment, and such cases are also included within the scope of this method. . The purpose of this method is to produce a compound that generally exhibits stronger antibacterial activity by removing the protecting group in the protected amino group of compound (a). Method C: Formation of carboxylic acid This method involves converting a compound (d) or a salt thereof having a free carboxyl group, which generally exhibits better antibacterial activity, to an ester of the corresponding carboxylic acid (
c). Therefore, the ester of the carboxy group in compound (c) is used for the purpose of temporarily protecting the free carboxy group during the production of the target compound by the chemical or biological method explained above. It is in the point of doing. This method is carried out by converting the ester of the carboxy group of the starting material (c) into a free carboxy group, and a preferred example of the esterified carboxy group represented by R ³ _a of the compound (c) is the compound Examples include esterified carboxy groups as exemplified in the explanation of the group R ³ in (). In this method, conventional methods such as hydrolysis and reduction are applied. Examples of the hydrolysis method include conventional methods using acids, bases, enzymes, enzyme preparations, and the like. Preferred examples of acids and bases include those exemplified in the method B above, and acidic or basic hydrolysis reactions can be carried out in the method B above.
This is done in the same way as in the case of . 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 tissue. The esterase used in enzymatic hydrolysis may be purified as well as crude. Such esterase activity can be obtained, for example, from microorganisms that are easily isolated from soil samples by conventional methods, or from deposited bacteria that can be obtained from microorganism depositories such as the ATCC and the Microbial Industry Research Institute. It has been confirmed that they are widely present in a variety of selected microorganisms, such as Bacillus, Corynebacterium, Micrococcus, Flavobacterium,
Salmonella, Staphylococcus, Vibrio, Microbacterium, Escherichia, Arthrobacter, Azotobacter, Alkaline, Rhizobium, Brevibacterium, Kluybella, Proteus, Sarcina,
Examples include microorganisms belonging to the genus Pseudomonas, Xanthomonas, Protaminobacter, Comamonas, and the like. Specific examples of these microorganisms include:
For example, Bacillus subtilis IAM-1069,
IAM-1107, IAM-1214, Bacillus sphaericus IAM-1286, Corynebacterium equi IAM-1308, Micrococcus variens
IAM−1314, Flavobacterium lygeus
IAM−1238, Salmonella teifuimurium
IAM-1406, Staphylococcus epidermides IAM-1296, Microbacterium flavum IAM-1642, Alcaligenes faecalis ATCC-8750, Arthrobacter simplex ATCC-6946, Azotobacter vinelandii IAM-1078, Escherichia coli IAM−
1101, Rhizobium japonicum IAM-0001, Vibrio mechnikovii IAM-1039, Brevibacterium herborum IAM-1637, Protaminobacter alboflavum IAM-1040, Comamonas terrigena IFO-12685, Sarcina lutea
Examples include IAM-1099, Pseudomonas syuriquiriensis IAM-1055, and Xanthomonas trifolii ATCC-12287. In enzymatic hydrolysis, 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. Cultivation of microorganisms can be carried out by conventional methods.
The medium used includes assimilable carbon and nitrogen sources and inorganic salts as nutritional sources. Examples of carbon sources include glucose, sucrose, lactose, sugar, glycerol, and starch. Nitrogen sources include meat extract, peptone, gluten, meal, corn meal, cottonseed meal, soybean flour, corn steep liquor, yeast extract, casein hydrolyzate, amino acids or ammonium sulfate, ammonium nitrite, Examples include ammonium salts such as ammonium phosphate, and inorganic or organic nitrogen compounds such as sodium nitrite. If desired, further calcium carbonate,
Metal salts such as sodium phosphate, potassium phosphate, magnesium salts, copper salts, or various vitamins may be added to the medium. The pH of the culture medium, temperature during culture, culture time, etc. are determined as appropriate depending on the type of microorganism, but usually pH5~
8 and incubated at a temperature of 20-35°C for 20-120 hours. The processed culture product obtained in this way is
It refers to various processed products obtained by conventional methods in order to increase esterase activity. The esterase activity of the culture exists within the bacterial cells and/or outside the bacterial cells. 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; separated 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 by conventional methods such as pulverizing the above-mentioned bacterial cells or dried bacterial cells with alumina, sea sand, etc., or treating them with ultrasonic waves. (4) Enzyme solution: Obtained by partially or fully preparing the above-mentioned sterile body extract by a conventional method. Furthermore, when the esterase activity is mainly present outside the bacterial cells, a processed product of the culture can be obtained in the following manner. (1) Supernatant or filtrate: Obtained from culture by conventional methods. (2) Enzyme solution: Obtained by partially or fully purifying the above supernatant or filtrate by a conventional method. Enzymatic hydrolysis involves contacting compound (c) with a culture of microorganisms or a treated product thereof in an aqueous solution such as water or a buffer such as a phosphate buffer, preferably in the presence of a conventional surfactant. This is done by That is, this reaction usually involves adding compound (c) to a microbial culture or a liquid treated product such as a supernatant, a filtrate, or an enzyme solution, or an aqueous solution or suspension of the culture or its treated product. This is done by 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 product, or the compound (c) used, but it is usually preferably pH 4 to 10, more preferably pH 4 to 10. is appropriately determined within the range of PH6 to 8, 20 to 50°C, more preferably 25 to 35°C, and 1 to 100 hours. Moreover, the concentration of compound (c) used as a substrate in the reaction mixture is
The amount is preferably about 0.1 to 100 mg/ml, preferably about 1 to 20 mg/ml. The reduction method is carried out in the same manner as the reduction method in method B above. In addition, if the protecting group in the protected amino group of R ¹ of compound (c) is removed during this reaction or post-treatment, and (or) if the protecting group in the protected amino group of R ² is removed, A case where an esterified carboxy group of a lower alkyl group is converted into a free carboxy group is also included within the scope of this method. The target compounds obtained by the various methods of this invention are isolated and purified by conventional methods. When R ³ of the target compound () is a free carboxy group and/or when R ¹ is a free amino group, this can be converted into a salt by a conventional method. The target compound (2) and its salts have excellent antibacterial activity that inhibits the growth of a wide range of pathogenic bacteria, including gram-negative and gram-positive bacteria, and are useful as antibacterial agents. Typical specific examples of the target compounds obtained by the method of the present invention are shown below. 7-[2-(2-amino-4-thiazolyl)-2
-propargyloxyiminoacetamide]-3
-Cefem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2
-ethoxycarbonylmethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2
-carboxymethoxyiminoacetamide]-3
-Cefem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2
-(2,2,2-trifluoroethoxyimino)
Acetamide]-3-cephem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2
-(2-chloroethoxyimino)acetamide]-
3-Cefem-4-carboxylic acid (syn isomer) 7-[2-(2-amino-4-thiazolyl)-2
-trifluoroethoxyiminoacetamide]-
3-Cefem-4-carboxylic acid (syn isomer) In order to demonstrate the usefulness of the compound () having antibacterial activity, test results for representative compounds () are shown below. 1 In vitro antibacterial activity test (1) Test method: Antibacterial activity was measured by the usual agar plate dilution method. One platinum loopful of a 100-fold dilution of each test strain cultured overnight in trypticase-soy broth was added to heart tubes containing the test compound at graded concentrations.
Infusion agar (HI-agar) was inoculated and cultured at 37°C for 20 hours. The minimum inhibitory concentration (MIC) is determined and expressed in μg/ml. (2) Test compound: 7-[2-(2-amino-4-thiazolyl)-2
-propargyloxyiminoacetamide]-3
-Cefem-4-carboxylic acid (syn isomer) (hereinafter referred to as compound 1) 7-[2-(2-amino-4-thiazolyl)-2
-(2-chloroethoxyimino)acetamide]-
3-cephem-4-carboxylic acid (syn isomer)
(Hereinafter referred to as compound 2) 7-[2-(2-amino-4-thiazolyl)-2
-(2,2,2-trifluoroethoxyimino)
Acetamide]-3-cephem-4-carboxylic acid (syn isomer) (hereinafter referred to as compound 3) (3) Test results:

[Table] The object compound of the present invention () can be used in the form of solid preparations such as capsules, tablets, granules, troches, and suppositories, as well as liquid preparations such as ointments, solutions, suspensions, and emulsions, together with ordinary carriers. It is administered to patients by oral administration, rectal administration, or parenteral administration such as injection. Various formulations such as those exemplified above include excipients, binders, stabilizers,
Conventional additives such as suspending agents, emulsifying agents, solubilizing agents, flavoring agents, and buffering agents may be added. The dosage depends on the patient's age, weight, etc., the type of disease,
It is determined as appropriate depending on the severity and type of drug, but usually 10mg, 50mg, 100mg, 250mg, 500mg
It is administered as a preparation containing etc. Generally, the dose is administered in the range of 1 mg/Kg to 100 mg/Kg, preferably in the range of 5 mg/Kg to 50 mg/Kg. The raw material compound () used in the above method A is:
It can be manufactured by the following method. K0364 K0365 (In the formula, R ² and R ¹ _a have the same meanings as above,
(X means halogen, Z means lower alkyl group) Next, this invention will be explained with reference to Examples. Example A for the production of raw material compounds (1) Mixture of ethyl ester of 2-hydroxyimino-3-oxobutyric acid (syn isomer, 56.7 g), potassium carbonate (72.3 g) and N,N-dimethylformamide (280 ml) Propargyl bromide (43 g) was added dropwise to the mixture, and the mixture was allowed to react at room temperature for 4 hours. The reaction solution was poured into water and extracted with methylene chloride. The extract is washed with an aqueous sodium chloride solution and then dried. When the solvent was distilled off, ethyl ester of 2-propargyloxyimino-3-oxobutyric acid (syn isomer, 71.2 g) was obtained. IRν film max: 3280, 3220, 2120, 1735,
1670cm ^-1 (2) Ethyl ester of 2-propargyloxyimino-3-oxobutyric acid (syn isomer, 71.2g)
of sulfuryl chloride (50.2 ml) in acetic acid (81 ml)
g) dropwise at 35-40℃ for 10 minutes and then at room temperature for 6.5 minutes.
time, then allowed to stir at 60 °C for 2.5 h. The reaction solution was poured into water and extracted with methylene chloride. The extract is washed with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, and then dried over magnesium sulfate. When the solvent is distilled off, oily 4-
Ethyl ester of chloro-3-oxo-2-propargyloxyiminobutyric acid (syn isomer,
61.6g). IRν film max: 3300, 2130, 1745, 1720,
1675cm ^-1 NMRδ (CCl ₄ , ppm): 1.39 (3H, t, J = 7
Hz), 2.57 (1H, t, J=2Hz), 4.36 (2H,
q, J=7Hz), 4.56 (2H, s), 4.86 (2H,
d, J = 2 Hz) (3) Ethyl ester of 4-chloro-3-oxo-2-propargyloxyiminobutyric acid (syn isomer, 61 g), thiourea (20 g), trihydrate of sodium acetate (35.8 g) ), water (150 ml) and ethanol (180 ml) is stirred at 40°C for 1 hour. The reaction solution was concentrated, water was added, and then extracted with ethyl acetate. The extract is washed with an aqueous sodium chloride solution and then dried. The solvent was distilled off and the resulting oil was crystallized from diisopropyl ether to give 2-(2-aminothiazol-4-yl).
Ethyl ester of -2-propargyloxyiminoacetic acid (syn isomer, 35.6 g) is obtained. IRν Nudiol max: 3290, 2220, 1729 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.28 (3H, t,
J = 7Hz), 3.49 (1H, t, J = 3Hz),
4.31 (2H, q, J = 7Hz), 4.76 (2H, d,
J = 3Hz), 6.95 (1H, s) 7.29 (2H, s) (4) 2-(2-aminothiazol-4-yl)-2
- A mixture of ethyl ester of propargyloxyiminoacetic acid (syn isomer, 2.8 g), 1N aqueous sodium hydroxide solution (22.17 ml), methanol (23 ml) and tetrahydrofuran (20 ml) was added at 35°C.
Let it react for 6 hours. The reaction solution was adjusted to pH 7, concentrated, and the residue was adjusted to pH 7 with 10% hydrochloric acid.
After charcoal treatment, the pH was adjusted to 3.0 with 10% hydrochloric acid, and the precipitated solid was collected by filtration, yielding 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetic acid (syn isomer, 1.924 g). ). IRνnudjol max: 2190, 1740cm ^-1 NMRδ ((DMSO−d ₆ , ppm): 3.47 (1H,
t, J = 1.5Hz), 4.74 (2H, d, J = 1.5
Hz), 6.90 (1H, s) Example B (1) 2-(2-tritylaminothiazole-4-
Allyl bromide (2.91 g) was added to a suspension of ethyl ester (syn isomer, 10 g) of yl)-2-hydroxyiminoacetic acid, N,N-dimethylformamide (100 ml) and potassium carbonate (4.54 g) on ice. It was added dropwise over a period of 5 minutes and stirred at the same temperature for 4 hours. Water (200 ml) was added to the reaction solution, and this was extracted twice with diethyl ether. The extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was powdered with a mixture of n-hexane and ethyl ether and collected by filtration to give 2-(2
-tritylaminothiazol-4-yl)-2
- Ethyl ester of allyloxyiminoacetic acid (syn isomer, 9.4 g) is obtained. mp 130~132℃ IRνnujiol max: 3380, 1735, 1520, 1500cm
^-1 NMRδ (DMSO-d ₆ , ppm): 1.08 (3H, t,
J = 7Hz), 3.96 (2H, q, J = 7Hz),
4.54 (2H, broad d, J=5Hz), 5.0−5.5
(2H, m), 5.6-6.3 (1H, m), 6.90 (15H,
broad s), 7.74 (1H, s) (2) 2-(2-tritylaminothiazole-4-
yl)-2-allyloxyiminoacetic acid ethyl ester (syn isomer, 8.7 g), 50% formic acid (42.5 ml) and tetrahydrofuran (42.5 ml)
Stir the solution consisting of at 60 °C for 40 min. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate, washed successively with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and sequentially eluted with benzene and ethyl acetate to obtain 2-(2-aminothiazol-4-yl)-2.
- Ethyl ester of allyloxyiminoacetic acid (syn isomer, 3.7 g) is obtained. mp 102-104℃ IRνnujiol max: 3460, 3260, 3130, 1725,
1620, 1540, 1460 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.25 (3H, t,
J = 7Hz), 4.30 (2H, q, J = 7Hz),
4.61 (2H, dd, J=5Hz, 1Hz), 5.0−5.5
(2H, m), 5.6-6.5 (1H, m), 6.95 (1H,
s), 7.28(2H,s) (3) 2-(2-aminothiazol-4-yl)-2
- Ethyl ester of allyloxyiminoacetic acid (syn isomer, 3.6 g), 2N aqueous sodium hydroxide solution (14.1 ml), tetrahydrofuran (14.1 ml)
and methanol (15 ml) at 40°C.
Stir for 1.5 hours. After concentrating the reaction solution under reduced pressure,
Dissolve the residue in water and add 10% hydrochloric acid to it under ice cooling.
Adjust to PH2.8. The precipitate was collected by filtration, washed successively with water and acetone, and dried to give 2-
(2-Aminothiazol-4-yl)-2-allyloxyiminoacetic acid (syn isomer, 1.91 g) is obtained. mp 187℃ (decomposition) IRνnujiol max: 3350, 1630, 1580, 1460cm
^-1 NMRδ (DMSO−d ₆ , ppm): 4.61 (2H, d,
J=6Hz), 5.1-5.5 (2H, m), 5.7-6.2
(1H, m), 6.84 (1H, s), 7.25 (2H, broad s) Example C (1) 2-(2-tritylaminothiazole-4-
Propargyl bromide (4.16 g) was added to a suspension of ethyl ester of 2-hydroxyiminoacetic acid (syn isomer, 10 g), potassium carbonate (4.84 g) and N,N-dimethylformamide (22 ml) under nitrogen. Add while blowing gas,
Then stir for 100 minutes at room temperature. Insoluble matter is filtered and washed with a small amount of N,N-dimethylformamide. The filtrate and washing liquid are combined, water (400 ml) is added, and then extracted with ethyl acetate (400 ml). The extract is washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, and concentrated under reduced pressure. The residue was powdered with diisopropyl ether, collected by filtration, and washed with diisopropyl ether, resulting in 2
-(2-tritylaminothiazol-4-yl)
Ethyl ester of -2-propargyloxyiminoacetic acid (syn isomer, 8.34 g) is obtained. IRνnudjol max: 3290, 2225, 1735 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.12 (3H, t,
J = 7Hz), 3.47 (1H, t, J = 3Hz),
3.97 (2H, q, J = 7Hz), 4.67 (2H, d,
J=3Hz), 6.95 (1H, s), 7.26 (15H,
s), 8.77 (1H, s) (2) 2-(2-tritylaminothiazole-4-
2-propargyloxyiminoacetic acid (syn isomer, 8.2 g) and tetrahydrofuran (41 ml).
% formic acid (41 ml) and stirred at 60°C for 1 hour. After concentrating the reaction solution under reduced pressure to 1/2 volume,
The precipitate is filtered and washed with diisopropyl ether. The filtrate and washing liquid are combined and concentrated under reduced pressure. Ethyl acetate (200 ml) was added to the residue with stirring, and the insoluble matter was filtered out, and this was washed with diethyl ether to obtain ethyl 2-(2-aminothiazol-4-yl)-2-propargyloxyiminoacetate. Ester (syn isomer, 0.3g)
get. The filtrate and diethyl ether washings were combined, and this was diluted with a saturated aqueous solution of sodium bicarbonate.
It is then washed twice with a saturated aqueous sodium chloride solution and then dried over magnesium sulfate. This is then treated with activated carbon and concentrated under reduced pressure. After adding benzene to the residue and drying under reduced pressure, the residue is subjected to silica gel column chromatography and sequentially eluted with benzene and ethyl acetate. The eluate is concentrated under reduced pressure, and the residue is triturated with diisopropyl ether. The resulting precipitate is collected by filtration and washed with diisopropyl ether to obtain the same compound as previously obtained (syn isomer, 2.658 g). I.
R. Spectrum and NMR spectrum data show that the compound obtained here is Example A-
This shows that it is the same compound as that obtained in (3). Example D 2-(2-formamidothiazol-4-yl)
After adding and dissolving sodium bicarbonate (0.84 g) in a suspension consisting of oxalic acid (2 g) and water (120 ml), to this was added hydrochloride of ethyl ester of 2-aminooxyacetic acid (4.56 g). , stir at room temperature for 3 hours. During this time, add sodium bicarbonate to the solution to keep the liquid pH at 6. The reaction solution was adjusted to PH1.5 with hydrochloric acid.
After adjusting to the desired temperature, salting out is performed, and then extraction is performed three times with ethyl acetate. The extract is dried over magnesium sulfate and concentrated under reduced pressure. The residue was triturated with diethyl ether, and the precipitate was collected by filtration and dried to give 2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid (syn isomer,
1.44g). mp 112℃ (decomposition) IRνnujiol max: 3150, 1740, 1670, 1550cm
^-1 NMRδ (DMSO-d ₆ , ppm): 1.23 (3H, t,
J = 7Hz), 4.16 (2H, q, J = 7Hz),
4.77 (2H, s), 7.56 (1H, s), 8.54 (1H,
s) Example E (1) Ethyl ester of 2-hydroxyimino-3-oxobutyric acid (syn isomer, 60 g), potassium carbonate (78 g), 1-bromo-2-chloroethane (54.1 g) and N,N- When dimethylformamide (200 ml) was treated in the same manner as in Example A-(1), an oily 2-(2-chloroethoxyimino)-
Ethyl ester of 3-oxobutyric acid (syn isomer, 83.6 g) is obtained. IRν film max: 1740, 1680, 1430 cm ^-1 NMR δ (CCl ₄ , ppm): 1.34 (3H, t, J=
7Hz), 2.34 (3H, s), 3.72 (2H, t, J
= 6Hz), 4.28 (2H, q, J = 7Hz), 4.46
(2H, t, J = 6 Hz) (2) Ethyl ester of 2-(2-chloroethoxyimino)-3-oxobutyric acid (syn isomer, 83.6
g), sulfuryl chloride (52.4 g) and acetic acid (83.6 ml) were treated in the same manner as in Example A-(2),
Oily ethyl ester of 4-chloro-3-oxo-2-(chloroethoxyimino)butyric acid (syn isomer, 68 g) is obtained. IRν film max: 1740, 1720cm ^-1 NMRδ (CCl ₄ , ppm): 1.32 (3H, t, J=
7Hz), 3.70 (2H, t, J=6Hz), 4.29
(2H, q, J=7Hz), 4.47 (2H, s),
4.48 (2H, t, J = 6 Hz) (3) Ethyl ester of 4-chloro-2-oxo-2-(2-chloroethoxyimino)butyric acid (syn isomer, 68 g), thiourea (20.2 g), acetic acid When sodium trihydrate (36.2 g), water (170 ml) and ethanol (270 ml) were treated in the same manner as in Example A-(3), 2-(2-aminothiazole-
4-yl)-2-(2-chloroethoxyimino)
Ethyl ester of acetic acid (syn isomer, 33.7g)
get. mp 126-128℃ IRνnujiol max: 3440, 3260, 3140, 1725,
1620, 1540 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.30 (3H, t,
J=7Hz), 3.78 (2H, t, J=6Hz), 4.1
−4.6 (4H, m), 6.96 (1H, s), 7.27 (2H,
s) (4) 2-(2-aminothiazol-4-yl)-2
-(2-chloroethoxyimino)acetic acid ethyl ester (syn isomer, 30.5 g), 1N aqueous sodium hydroxide solution (220 ml), methanol (110 ml)
and tetrahydrofuran (140 ml) were treated as in Example A-(4) to yield 2-(2-aminothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 23.4 g). get. mp 201℃ (decomposition) IRνNujiol max: 3210, 3100, 1640, 1620,
1580cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.83 (2H, t,
J = 6Hz), 4.36 (2H, t, J = 6Hz),
6.92 (1H, s), 7.30 (2H, s) (5) 2-(2-aminothiazol-4-yl)-2
A solution of formic acid (11.0 g) and acetic anhydride (24.5 g) in -(2-chloroethoxyimino)acetic acid (syn isomer, 15 g), stirred at 50°C for 1 hour was added under ice cooling, and the mixture was heated to room temperature. Stir for 3 hours. The solvent was distilled off from the reaction solution, tetrahydrofuran (50 ml) was added to the residue, and the solvent was then distilled off. The resulting residue is suspended in an aqueous sodium hydrogen carbonate solution, and the pH is adjusted to 3.5 with 10% hydrochloric acid. When the precipitate is collected by filtration, washed with water, and dried, 2-
(2-formamidothiazol-4-yl)-2
-(2-chloroethoxyimino)acetic acid (syn isomer, 13.4 g) is obtained. mp 155℃ (decomposition) IRνnujiol max: 3100, 1740, 1690, 1660cm
^-1 NMRδ (DMSO-d ₆ , ppm): 3,87 (2H,
t, J = 6Hz), 4.40 (2H, t, J = 6
Hz), 7.60 (1H, s), 8.56 (1H, s),
12.62 (1H, broad s) Example F 2-(2-formamidothiazol-4-yl)
A 1N aqueous sodium hydroxide solution was added to a suspension consisting of oxalic acid (3.0 g), methanol (60 ml), and water (60 ml) under stirring to adjust the pH to 8. 2,2,2-trifluoroethoxyamine hydrochloride (2.24 g) was added to this solution, the pH was adjusted to 2.5 to 3 with a 1N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 1.5 hours. Methanol is distilled off from the reaction solution under reduced pressure, and the residue is adjusted to pH 7 with a 1N aqueous sodium hydroxide solution, and then washed with ethyl acetate. After adding ethyl acetate to this and adjusting the pH to 1.5 with 10% hydrochloric acid,
Extract with ethyl acetate. The remaining aqueous layer is extracted again with ethyl acetate, and both extracts are combined and washed with saturated aqueous sodium chloride solution. This was dried over magnesium sulfate and then concentrated under reduced pressure.
formamidothiazol-4-yl)-2-(2,
2,2-trifluoroethoxyimino)acetic acid (syn isomer, 2.4 g) is obtained. mp 162-163℃ (decomposition) IRν Nudiol max: 3200, 1700, 1600, 150cm ^-1 NMRδ (DMSO-d ₆ , ppm): 4.83 (2H, q,
J=8.5Hz), 7.65 (1H, s), 8.58 (1H,
s), 12.60 (1H, broad s) Example G 2-(2-formamidothiazol-4-yl)
Oxalic acid (10g), sodium bicarbonate (4.2g)
and tertiary butyl ester of 2-aminooxyacetic acid (8.1 g) were treated in the same manner as in Example D, the resulting oil was powdered with n-hexane, and the resulting precipitate was collected by filtration. Drying yields 2-(2-formamidothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer, 11.3 g). mp 117℃ (decomposition) IRνNujiol max: 3180, 3140, 1750, 1690,
1630cm ^-1 NMRδ (DMSO−d ₆ , ppm): 1.46 (9H,
s), 4.66 (2H, s), 7.56 (1H, s), 8.56
(1H, s), 12.67 (1H, broad s) Example 1 of the method for producing the target compound () 2-(2-aminothiazol-4-yl)-2-
Allyloxyiminoacetic acid (syn isomer, 1.0g),
Tetrahydrofuran (10ml) and water (0.05ml)
Phosphorus oxychloride (0.84 g) was added dropwise to the suspension at 5°C, and the mixture was stirred at the same temperature for 20 minutes. After adding trimethylsilylacetamide (0.66 g), phosphorus oxychloride (0.84 g) and N,N-dimethylformamide (0.45 g) to this, stirring at 5 ° C. for 1 hour,
Obtain a solution of activated acid. Meanwhile, trimethylsilylacetamide (4.0 g) was added to a suspension of 7-amino-3-cephem-4-carboxylic acid (0.88 g) and tetrahydrofuran (10 ml) at 40°C, and the mixture was stirred for 30 minutes. To this solution, the previously obtained activated acid solution was added all at once at -20°C.
Stir at ℃ for 2 hours. Add water (20ml) to the reaction solution at -20%
℃, adjust the pH to 7.5 with an aqueous sodium bicarbonate solution, and then add ethyl acetate. The aqueous layer is separated, washed sequentially with ethyl acetate and diisopropyl ether, adjusted to pH 5.0, and then treated with activated carbon. After adjusting the pH of the solution to 3.0, the precipitate was collected by filtration, washed with water, and dried with phosphorus pentoxide.
[-2-(2-aminothiazol-4-yl)-2
-allyloxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.8 g). IRν Nujiol max 3300, 1780, 1660, 1630cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.67 (2H, d,
J=4Hz), 4.67 (2H, m), 5.17 (1H, d,
J=5Hz), 5.25 (1H, m), 5.50 (1H,
m), 5.90 (1H, dd, J=5Hz, 8Hz),
6.03 (1H, m), 6.55 (1H, m), 6.80 (1H,
s), 7.50 (2H, m), 9.68 (1H, d, J=
8Hz) Example 2 2-(2-aminothiazol-4-yl)-2-
Propargyloxyiminoacetic acid (syn isomer,
Phosphorus oxychloride (1.4 g) was added dropwise to a suspension of 1.7 g) and tetrahydrofuran (15 ml) at 7°C or lower, and the mixture was stirred at the same temperature for 10 minutes. Phosphorous oxychloride (1.4 g), trimethylsilylacetamide (1.3 g) and N,N-dimethylformamide (0.76 g) are added to this solution and stirred for 20 minutes to obtain a solution of activated acid. Meanwhile, trimethylsilylacetamide (7.8 g) was added to a suspension of 7-amino-3-cephem-4-carboxylic acid (1.5 g) and tetrahydrofuran (20 ml), and the mixture was stirred at 40°C for 30 minutes. The previously obtained activated acid solution was added at once to this solution at -20°C, and the mixture was stirred at 0°C for 30 minutes. Add water (20 ml) to the reaction solution at -20°C, and adjust the pH to 7.5 with an aqueous sodium hydrogen carbonate solution. The aqueous layer is separated, washed sequentially with ethyl acetate and diisopropyl ether, and then treated with activated carbon at pH 5.5. After adjusting the pH to 3.0 and collecting the precipitate by filtration, it was dried with phosphorus pentoxide under reduced pressure.
-aminothiazol-4-yl)-2-propargyloxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 1.47 g). IRνnujiol max3500, 3300, 1780, 1720,
1660, 1630 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.48 (1H,
m), 3.67 (2H, m), 4.80 (2H, d, J=
2Hz), 5.17 (1H, d, J = 5Hz), 5.88
(1H, dd, J = 5Hz, 8Hz), 6.55 (1H,
m), 6.85 (1H, s), 7.33 (2H, m), 9.73
(1H, d, J = 8 Hz) Example 3 (1) Phosphorus oxychloride (825 mg) was added dropwise to a mixed solution of N,N-dimethylformamide (393 mg) and tetrahydrofuran (3.5 ml) at -5°C with stirring. Stir at the same temperature for 30 minutes. This was added to tetrahydrofuran (10 ml) and 2-(2-formamidothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetic acid (syn isomer,
1.35g) was added at -5°C and stirred at the same temperature for 30 minutes. This solution was added to 7-amino-3-cephem-
A suspension consisting of 4-nitrobenzyl ester of 4-carboxylic acid (1.54 g), tetrahydrofuran (7.7 ml), acetone (3.9 ml) and water (3.9 ml) was prepared at -5°C to 5°C for 15 minutes. Add dropwise while stirring. During this time, add a 20% aqueous sodium carbonate solution to maintain the pH of the reaction solution at 7 to 7.5. This solution is then stirred for 30 minutes. After removing insoluble matter by filtration, a saturated aqueous sodium chloride solution was added to the filtrate, and the mixture was extracted twice with tetrahydrofuran. The extract is washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated under reduced pressure. When diisopropyl ether is added to the residue and crystallized, 7-[2-(2-formamidothiazole-
4-nitrobenzyl ester of 4-yl)-2-ethoxycarbonylmethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 2.52 g) is obtained. IRνnujiol max: 3250, 1790, 1730, 1690,
1640cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.23 (3H, t,
J=7Hz), 3.66 (2H, s), 4.13 (2H, q,
J=7Hz), 4.74 (2H, s), 5.22 (1H, d,
J=5Hz), 5.42 (2H, s), 5.98 (1H, dd,
J=5Hz, 9Hz), 6.49 (1H, broad s),
7.43 (1H, s), 7.71 (2H, d, J=9Hz),
8.23 (2H, d, J=9Hz), 8.52 (1H, s),
9.68 (1H, d, J = 9Hz), 12.66 (1H, s) (2) 7-[2-(2-formamidothiazole-4
4-nitrobenzyl ester of -yl)-2-ethoxycarbonylmethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 2.52 g), tetrahydrofuran (25 ml),
10% palladium on carbon (1.3g), ethanol (13
ml), acetic acid (0.22 ml), and water (2.2 ml) are subjected to catalytic reduction at room temperature and pressure. The reaction solution is filtered, and the filtered insoluble matter is washed with tetrahydrofuran. Combine the filtrate and washing liquid and concentrate under reduced pressure. After dissolving the residue in a mixture of ethyl acetate and an aqueous sodium hydrogen carbonate solution, insoluble matter was filtered off. The ethyl acetate layer is separated and extracted with an aqueous sodium hydrogen carbonate solution. The aqueous layer and extract are combined, washed sequentially with ethyl acetate and diethyl ether, adjusted to pH 2.0 with 10% chlorine, and then stirred for 30 minutes. The precipitate was collected by filtration, washed with water, and dried over magnesium sulfate to give 7-[2
-(2-formamidothiazol-4-yl)-
2-Ethoxycarbonylmethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.4 g) is obtained. IRνnujiol max: 3250, 3060, 1780, 1750,
1690, 1660 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.23 (3H, t,
J=7Hz), 3.61 (2H, broad s), 4.15
(2H, q, J=7Hz), 4.73 (2H, s),
5.13 (1H, d, J=5Hz), 5.87 (1H, dd,
J=5Hz, 9Hz), 6.48 (1H, broad s),
7.43 (1H, s), 8.50 (1H, s), 9.62 (1H,
d, J = 9Hz), 12.58 (1H, s) (3) 7-[2-(2-formamidothiazole-4
-yl)-2-ethoxycarbonylmethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 0.35 g), concentrated hydrochloric acid (0.39
g), tetrahydrofuran (8 ml) and ethanol (5.3 ml) is stirred at room temperature for 4.5 hours. The reaction solution is concentrated under reduced pressure, the residue is dissolved in an aqueous sodium bicarbonate solution, treated with activated carbon, and then filtered. PH the filtrate with 10% hydrochloric acid under ice cooling.
Adjust to 3.5. After filtering the precipitate and washing with water,
When dried, 7-[2-(2-aminothiazol-4-yl)-2-ethoxycarbonylmethoxyiminoacetamide]-3-cephem-4-
Carboxylic acid (syn isomer, 0.1 g) is obtained. IRνnujiol max: 3250, 3050, 1775, 1720,
1660, 1630, 1550 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 1.21 (3H, t,
J=7Hz), 3.59 (2H, s), 4.14 (3H, q,
J=7Hz), 4.66 (2H, s), 5.10 (1H, d,
J = 5Hz), 5.83 (1H, dd, J = 5Hz, 8
Hz), 6.47 (1H, broad s), 6.78 (1H,
s), 7.23 (2H, s), 9.52 (1H, d, J=
8 Hz) Example 4 (1) Vilsmeier reagent was prepared from N,N-dimethylformamide (0.32 g) and phosphorus oxychloride (0.67 g) according to a conventional method, and ethyl acetate (10
ml). This suspension was added to 2-(2-formamidothiazol-4-yl)-2-(2,
Add 2,2-trifluoroethoxyimino)acetic acid (syn isomer, 1.2 g) to the ice-cooled stirrer and stir at the same temperature for 30 minutes. Add this solution to 7-amino-
Add to a solution of 3-cephem-4-carboxylic acid (0.8 g), trimethylsilylacetamide (4.2 g) and ethyl acetate (20 ml) at -25°C,
Stir for 1 hour at ~-10°C. After adding water and ethyl acetate to the reaction solution, the ethyl acetate layer is separated. The aqueous layer is extracted with ethyl acetate, both ethyl acetate layers are combined, water is added, and the pH is adjusted to 7.5 with a saturated aqueous sodium bicarbonate solution. Separate the aqueous layer,
After adding ethyl acetate and adjusting the pH to 1.5 with hydrochloric acid,
Separate the ethyl acetate layer. The aqueous layer is extracted with ethyl acetate, and both ethyl acetate layers are combined, washed with a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. After concentrating this under reduced pressure and crystallizing the residue with diethyl ether, the precipitate was collected by filtration and dried. trifluoroethoxyimino)acetamide]-3-cephem-4-carboxylic acid (syn isomer, 1.55 g)
get. IRνnujiol max: 3250, 1790, 1690, 1660,
1630, 1605, 1580, 1550 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.67 (2H,
broad s), 4.78 (2H, q, J=5Hz),
5.17 (1H, d, J=5Hz), 5.92 (1H, dd,
J = 5Hz, 8Hz), 6.53 (1H, t, J = 4
Hz), 7.52 (1H, s), 8.57 (1H, s), 9.83
(1H, d, J = 8Hz), 12.67 (1H, broad
s) (2) 7-[2-(2-formamidothiazole-4
-yl)-2-(2,2,2-trifluoroethoxyimino)acetamide]-3-cephem-
A mixture of 4-carboxylic acid (syn isomer, 1.5 g), concentrated hydrochloric acid (1.3 ml), tetrahydrofuran (10 ml) and methanol (30 ml) is stirred at room temperature for 2 hours. After distilling off the solvent from the reaction solution, water (50 ml) is added, and the pH is adjusted to 7.5-8.0 with an aqueous sodium hydrogen carbonate solution. After the charcoal powder treatment, the filtrate was adjusted to pH 3.4 under ice cooling, and the precipitated solid was collected by filtration, resulting in 7-[2-
(2-aminothiazol-4-yl)-2-(2,
2,2-trifluoroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.1 g) is obtained. IRνnujiol max: 3450, 3300, 1780, 1660,
1625, 1590, 1550 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 6.60 (2H,
broad s), 4.70 (2H, q, J=8.5Hz),
5.13 (1H, d, J=5Hz), 5.87 (1H, dd,
J = 5Hz, 8Hz), 6.52 (1H, t, J = 4
Hz), 6.87 (1H, s), 9.80 (1H, d, J=
8 Hz) Example 5 (1) 2-(2-formamidothiazol-4-yl)-2-(2-chloroethoxyimino)acetic acid (syn isomer, 3.47 g), N,N-dimethylformamide (1.1 g) , phosphorus oxychloride (2.3 g) and ethyl acetate (35 ml) and 7-
Amino-3-cefem-4-carboxylic acid (2.5
g) and bis(trimethylsilyl)acetamide (12.7 g) in ethyl acetate (25 ml) in the same manner as in Example 3-(1) to obtain 7-[2
-(2-formamidothiazol-4-yl)-
2-(2-chloroethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.85 g) is obtained. IRνnujiol max: 3250, 3050, 1780, 1695,
1685, 1655, 1625 cm ^-1 NMRδ (DMSO-d ₆ , ppm): 3.62 (2H, d,
J = 4Hz), 3.86 (2H, t, J = 6Hz),
4.37 (2H, t, J=6Hz), 5.16 (1H, d,
J = 5Hz), 5.90 (1H, dd, J = 5Hz, 9
Hz), 6.52 (1H, t, J=4Hz), 7.50 (1H,
s), 8.53 (1H, s), 9.68 (1H, d, J=
9Hz), 12.72 (1H, broad s) (2) 7-[2-(2-formamidothiazole-4
-yl)-2-(2-chloroethoxyimino)acetamide]-3-cephem-4-carboxylic acid (syn isomer, 1.8 g), concentrated hydrochloric acid (1.6 g), tetrahydrofuran (40 ml) and methanol (27
ml) in the same manner as in Example 3-(3) to obtain 7-
[2-(2-aminothiazol-4-yl)-2
-(2-chloroethoxyimino)acetamide]
-3-cephem-4-carboxylic acid (syn isomer, 1.4 g) is obtained. IRνnujiol max: 3440, 3300, 3070, 1780,
1660, 1625, 1555 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.60 (2H,
s), 3.80 (2H, t, J=6Hz), 4.30 (2H,
t, J = 6Hz), 5.10 (1H, d, J = 5
Hz), 5.83 (1H, dd, J=5Hz, 9Hz),
6.47 (1H, s), 6.78 (1H, s), 7.24 (2H,
s), 9.58 (1H, d, J = 9Hz) Example 6 (1) 2-(2-formamidothiazol-4-yl)-2-(tert-butoxycarbonylmethoxyimino)acetic acid (syn isomer 3.2g ), N, N-
A solution consisting of dimethylformamide (0.852 g), phosphorous oxychloride (1.79 g) and ethyl acetate (34 ml) with 7-amino-3-cephem-4-carboxylic acid (1.95 g), bis(trimethylsilyl)
A solution consisting of acetamide (9.9 ml) and ethyl acetate (19.5 ml) was treated in the same manner as in Example 3-(1) to obtain 7-[2-(2-formamidothiazol-4-yl)-2-(tertiary butoxycarbonylmethoxyimino)acetamide]-3-cephem-4-carboxylic acid (syn isomer, 2.9 g)
get. IRνnujiol max: 3260, 3180, 3060, 1785,
1730, 1690, 1640 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 1.44 (9H,
s), 3.63 (2H, s), 4.62 (2H, s), 5.12
(1H, d, J = 5Hz), 5.87 (1H, dd, J
=5Hz), 9Hz), 6.48 (1H, broad s),
7.42 (1H, s), 8.50 (1H, s), 9.57 (1H,
d, J = 9Hz), 12.62 (1H, broad s) (2) 7-[2-(2-formamidothiazole-4
-yl)-2-(tert-butoxycarbonylmethoxyimino)acetamide]-3-cephem-
4-carboxylic acid (syn isomer, 2.8 g), anisole (2.8 ml) and trifluoroacetic acid (11.2
ml) is stirred at room temperature for 1 hour. After adding ethyl acetate and water to the reaction solution, adjust the pH to 7.0 with sodium hydrogen carbonate. Separate the aqueous layer and extract the ethyl acetate layer with water. Both aqueous layers are combined, washed sequentially with ethyl acetate and diethyl ether, and then adjusted to pH 2.0 with 10% hydrochloric acid under ice cooling. The precipitate is collected by filtration, washed with water, and dried to give 7-[2-(2-formamidothiazole-
4-yl)-2-carboxymethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 1.43 g) is obtained. IRνnujiol max: 3270, 3120, 3070, 1760,
1720, 1690, 1660, 1620 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.60 (2H,
s), 4.63 (2H, s), 5.11 (1H, d, J=
5Hz), 5.88 (1H, dd, J=5Hz, 9Hz),
6.48 (1H, t, 4Hz), 7.44 (1H, s),
8.52 (1H, s), 9.59 (1h, d, J=9Hz),
12.64 (1H, broad s) (3) 7-[2-(2-formamidothiazole-4
-yl)-2-carboxymethoxyiminoacetamide]-3-cephem-4-carboxylic acid (syn isomer, 1.35 g), concentrated hydrochloric acid (3.926 g), methanol (20 ml), water (10 ml) and tetrahydrofuran (40 ml). Stir the mixture at 30°C for 6 hours. Methanol is distilled off from the reaction solution under reduced pressure, and the remaining aqueous solution is adjusted to pH 4.2 with a 10% aqueous sodium hydroxide solution. PH this with 10% hydrochloric acid.
3.0, filtered the precipitate, and dried it to give 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamide]-3-cephem-4-carboxylic acid (synthetic acid). isomer, 0.8 g). IRνnujiol max: 3300 (broad), 3200
(broad), 1775, 1670, 1635 cm ^-1 NMRδ (DMSO−d ₆ , ppm): 3.64 (2H,
s), 4.64 (2H, s), 5.13 (1H, d, J=
5Hz), 5.86 (1H, dd, J=5Hz, 7Hz),
6.49 (1H, t, J=4Hz), 6.82 (1H, s),
7.33 (2H, s), 9.57 (1H, d, J=9Hz)

Claims (1)

[Claims] 1 General formula K0352 [wherein R ¹ is an amino group or a protected amino group, R ² is a lower alkenyl group, a lower alkynyl group,
a halo(lower) alkyl group or a lower alkyl group substituted with carboxy or esterified carboxy, R ³ means a carboxy group or an esterified carboxy group, respectively] or a salt thereof.