JPH039116B2 - - Google Patents

Description

[Detailed description of the invention]

This invention describes the general formula () useful as an antibacterial substance: [Wherein, R ¹ is an amino group or a protected amino group; R ² is a cyclo-lower alkenyl group; R ³ is a carboxy group or a protected carboxy group; R ⁴ is hydrogen or the formula: -CH ₂ - R ^4a ( In the formula, R ^4a is an acyloxy group; an amino lower alkylthio group; a protected amino lower alkylthio group; a pyridinium group which may have a hydroxy lower alkyl group or a carbamoyl group; or a lower alkyl group, a lower alkenyl group, or a carboxy group , carboxy lower alkyl group, hydroxy lower alkyl group,
a thiadiazolylthio group, a tetrazolylthio group, a pyridylthio group, a triazolylthio group or a tetrazolopyridazinylthio group which may have an amino lower alkyl group or a protected amino lower alkyl group; R ⁵ means hydrogen or a lower alkyl group, respectively; provided, however, that when R ^4a means a pyridinium group which may have a hydroxy lower alkyl group or a carbamoyl group, R ³ means a COO ^- group ] The present invention relates to novel cefem compounds, their salts, and their production methods and uses. According to this invention, the above-mentioned novel cefem compound () can be produced by various methods shown below. [In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as above, R ^1a is a protected amino group, R ^4b is amino lower alkylthiol; protected amino lower alkyl Thiol; pyridine which may have a hydroxy lower alkyl group or carbamoyl group; or lower alkyl group, lower alkenyl group, carboxy group, carboxy lower alkyl group, hydroxy lower alkyl group, amino lower alkyl group or protected amino lower Thiadiazolylthiol, tetrazolylthiol, pyridylthiol, which may have an alkyl group,
triazolylthiol or tetrazolopyridazinylthiol, Y has the formula: -R ^4c (wherein R ^4c has an amino lower alkylthio group; a protected amino lower alkylthio group; a hydroxy lower alkyl group or a carbamoyl group); a pyridinium group which may have a lower alkyl group, a lower alkenyl group, a carboxy group, a carboxy lower alkyl group, a hydroxy lower alkyl group, an amino lower alkyl group or a protected amino lower alkyl group; Zolylthio group, tetrazolylthio group,
pyridylthio group, triazolylthio group or tetrazolopyridazinylthio group), R ^4c has the same meaning as above, R ^3a is a protected carboxy group, R ^4d is a protected Thiadiazolylthio group, tetrazolylthio group having an amino lower alkyl group,
Pyridylthio group, triazolylthio group or tetrazolopyridazinylthio group; protected amino lower alkylthio group; or protected carbamoyloxy group, R ^4e is a thiadiazolylthio group, tetrazolylthio group, pyridylthio group having an amino lower alkyl group , triazolylthio group or tetrazolopyridazinylthio group; amino lower alkylthio group;
or a carbamoyloxy group. ) Among the raw material compounds of this invention, compound () is new and can be produced, for example, by the method shown below. Further, the compound () also includes a new compound, and this new compound can be produced by the method shown below. (In the formula, R ₁ , R ^1a , R ₂ , R ₃ and R ₅ have the same meanings as above, and Y ^a is the formula:

A group that can be substituted by a group represented by the formula: X means a hydroxy group or a reactive derivative group thereof, and R ⁶ means an amino group having a protecting group. ) Target compound (), (a), (b), (c),
(d), (e), (f), (g) and (h
)
and the starting compounds (), (a), (b) and () each include tautomers. That is, the formula: (wherein R ¹ has the same meaning as before), this group is defined by its tautomeric formula

It can also be represented by the formula: (wherein R ¹ ' means an imino group or a protected imino group). That is, these two types of groups are in a balanced relationship with each other, and such tautomerism can be shown by the balanced formula below. (In the formula, R ¹ and R ¹ ′ each have the same meaning as before). The tautomerism between the above types of amino compounds and the corresponding imino compounds is well known, and although both can be converted into each other, they are generally treated by those skilled in the art as substantially the same compound. In the explanation of this specification and claims, these target compounds are conveniently expressed by the formula which is one of the tautomers. (In the formula, R ¹ has the same meaning as before.) However, the invention is not limited thereto, and both tautomers are included within the scope of the present invention. In addition, the target compounds (), (a), (b), (
c), (d), (e), (f), (g) and (h) and starting compounds (), (a) and (b) include syn isomers, anti-isomers and these compounds. do. For example, for the target compound (), the syn isomer has the formula: (wherein R ¹ and R ² have the same meanings as before), and anti-isomer means a geometric isomer having the partial structure of the formula: (In the formula, R ¹ and R ² have the same meanings as before). Regarding the remaining target compounds and starting compounds listed above, the syn and anti isomers respectively mean the same geometric isomeric forms corresponding to the formulas shown for the target compound (). Suitable pharmaceutically acceptable salts of the target compound () are commonly used non-toxic salts, such as alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. Metal salts including salts, salts with organic bases such as ammonium salts, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, acetate salts, maleate salts, tartaric acid salts salts with organic acids such as methanesulfonates, benzenesulfonates, formates, toluenesulfonates; salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, phosphates; Examples include salts with amino acids such as arginine salt, aspartate, and glutamate. Next, various definitions in the above general formula will be explained in detail. In this specification, "lower" means carbon atoms of 1 to 6 unless otherwise specified. Suitable examples of the protected amino group and the protected amino group moiety in the "protected amino lower alkylthio group", "protected amino lower alkylthiol" and "protected amino lower alkyl group" include: In addition to the acylamino group,
Also included are amino groups substituted with conventional protecting groups such as aryl lower alkyl groups (eg, benzyl group, trityl group, etc.) which may have at least one suitable substituent. Suitable examples of the acyl group moiety of “acylamino” and “acyloxy” in R ^4a include:
Examples include a lower carbamoyl group, an aliphatic acyl group, and an acyl group containing an aromatic ring or a heterocycle. More specifically, formyl, acetyl, propionyl,
Lower alkanoyl groups such as butyryl, isobutyryl, valeryl, isovaleryl, oxalyl, succinyl, pivaloyl; methoxycarbonyl, nitoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, pentyl Lower alkoxycarbonyl groups such as oxycarbonyl and hexyloxycarbonyl; lower alkanesulfonyl groups such as mesyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl; arenesulfonyl groups such as benzenesulfonyl and tosyl;
Examples include aroyl groups such as benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, and indancarbonyl; aryl lower alkanoyl groups such as phenyl acetyl and phenylpropionyl; aryl lower alkoxycarbonyl groups such as benzyloxycarbonyl and phenethyloxycarbonyl; It will be done. The above acyl moieties may have one or more suitable substituents such as halogen (chlorine, bromine, fluorine and iodine). Preferred examples of the acylamino group and the acyloxy group include a lower alkanoylamino group, a halogen-substituted lower alkanoylamino group, a lower alkoxycarbonylamino group, a lower alkanoyloxy group, and a carbamoyloxy group, respectively. Suitable examples of the cyclo lower alkenyl group for R ² include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. Preferred examples of the protected carboxy group in R ³ include esterified carboxy groups, and preferred examples of the ester moiety of this esterified carboxy group include methyl ester, ethyl ester, propyl ester, etc. Lower alkyl esters such as ester, isopropyl ester, butyl ester, isobutyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester; acetoxymethyl ester,
Alkanoyloxy lower alkyl esters such as propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, One or more lower alkanesulfonyl lower alkyl esters such as 2-mesylethyl ester, mono (or di or tri) halo lower alkyl esters such as 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc. Alkyl esters having suitable substituents; lower alkenyl esters such as vinyl esters and allyl esters; lower alkynyl esters such as ethynyl esters and propynyl esters; benzyl esters, 4-methoxybenzyl esters, 4-nitrobenzyl esters, phenethyl esters , trityl ester, diphenyl methyl ester, bis(methoxyphenyl) methyl ester, 3,4-
dimethoxybenzyl ester, 4-hydroxy-
Aryl lower alkyl esters which may have one or more suitable substituents, such as 3,5-di(tertiary butyl)benzyl esters; phenyl esters, 4-chlorophenyl esters, tolyl esters , tertiary butyl phenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc., which may have one or more suitable substituents. Preferred examples of the above esterified carboxy groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl, and tertiary pentyloxycarbonyl. , hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl and other lower alkoxycarbonyl groups, and phenyl lower alkoxycarbonyl groups such as benzyloxycarbonyl and diphenylmethoxycarbonyl. The "thiadiazolyl" moiety in "thiadiazolylthio group" and "thiadiazolylthiol" includes 1,2,3-thiadiazolyl, 1,
Examples include 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, and the like. Examples of the "tetrazolyl" moiety in "tetrazolylthio group" and "tetrazolylthiol" include 1H-tetrazolyl, 2H-tetrazolyl, and the like. The "triazole" moiety in "triazolylthio group" and "triazolylthiol" includes 4H-1,2,4-triazolyl, 1H-1,
Examples include 2,3-triazolyl and 2H-1,2,3-triazolyl. Examples of the "lower alkenyl group" include vinyl, allyl, butenyl, and the like. Examples of the "carboxy lower alkyl group" include carboxymethyl, carboxyethyl, carboxypropyl, and the like. Examples of the "hydroxy lower alkyl group" include hydroxymethyl, hydroxyethyl, hydroxypropyl, and the like. Examples of the "amino lower alkyl group" include aminomethyl, aminoethyl, aminopropyl, aminobutyl, and the like. Examples of the "protected amino lower alkyl group" include acylaminomethyl, acylaminoethyl,
Examples thereof include acylaminopropyl, acylaminobutyl (here, the acyl moiety has the same meaning as before), and the like. The lower alkyl group and the lower alkyl moiety in "amino lower alkylthio group", "protected amino lower alkylthio group", "amino lower alkylthiol" and "protected amino lower alkylthiol" can be straight chain or branched chain. Both are meant and include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. Preferred examples of the amino lower alkylthio group include aminomethylthio, aminoethylthio, aminopropylthio, and the like. Suitable protected carbamoyl groups include acylcarbamoyl groups (wherein the meaning of acyl group is the same as before). Preferred examples of Y and Y ^a include azide,
Examples include the above-mentioned halogens and acid residues such as the above-mentioned acyloxy. Suitable examples of reactive derivatives of hydroxy groups in X include acid residues such as halogens (eg chlorine, bromine, fluorine or iodine). Examples of the amino group having a suitable protecting group in R ⁶ include phthalimide, succinimide, ethoxycarbonylamino, and the like, with phthalimide being particularly preferred. Preferred examples of the target compound () are listed below. Preferred examples of R ¹ are an amino group, a lower alkanoylamino group, or a halogen-substituted lower alkanoylamino group; R ² is a cyclopentenyl group or a cyclohexenyl group; R ³ is a carboxy group or an aryl lower alkoxycarbonyl group (more preferably is a diphenyl lower alkoxycarbonyl group); R ⁴ is hydrogen or has the formula: -CH ₂ -R ^4a (wherein, preferred examples of R ^4a are a lower alkanoyloxy group, a carbamoyloxy group, and a lower alkyl group as a substituent); a thiadiazolylthio group which may have an amino lower alkyl group as a substituent, a thiadiazolylthio group which has a lower alkoxycarbonylamino lower alkyl group as a substituent, a lower A tetrazolylthio group which may have an alkyl group, a tetrazolylthio group having a lower alkenyl group as a substituent,
A tetrazolylthio group having a carbonyl lower alkyl group as a substituent, a tetrazolylthio group having a hydroxy lower alkyl group as a substituent, a pyridylthio group having a carboxy group as a substituent,
Amino lower alkylthio group, alkoxycarbonylamino lower alkylthio group, tetrazolylthio group having amino lower alkyl group as a substituent,
Tetrazolylthio group, triazolylthio group, tetrazolopyridazinylthio group, pyridinium group having a lower alkoxycarbonylamino lower alkyl group as a substituent, pyridinium group having a hydroxy lower alkyl group as a substituent, and pyridinium having a carbamoyl group as a substituent R ⁵ is hydrogen or a lower alkyl group. Next, a method for producing the object compound of the present invention will be explained in detail. Method 1 The object compound of this invention or its salts can be obtained by reacting the compound () or its reactive derivative at the amino group or a salt thereof with the compound () or its reactive derivative at the carboxyl group or its salt. can be manufactured. Examples of reactive derivatives at the amino group of the compound () include Schiff's base (imino type or its enamine type isomer) produced by the reaction of the compound () with a carbonyl compound such as an aldehyde or ketone; Silyl derivatives produced by reaction with silyl compounds such as bis(trimethylsilyl)acedeamide; compounds () and 3
Examples include derivatives produced by reaction with phosphorus chloride, phosgene, and the like. Examples of suitable salts of compounds () and () include salts with organic acids such as acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate; hydrochloride, hydrobromic acid; Acid addition salts including salts with inorganic acids such as salts, sulfates and phosphates; metal salts such as sodium, potassium, calcium and magnesium salts; ammonium salts; organic amines such as triethylamine salts and dicyclohexylamine salts. Examples include salt. Reactive derivatives at the carboxy group of compound () include acid halides, acid anhydrides, activated amides, activated esters, and the like. Suitable examples include acid chlorides, acid azides; mixed acid anhydrides, such as dialkyl phosphoric acids, phenyl phosphoric acids, diphenyl phosphoric acids, dibenzyl phosphoric acids, substituted phosphoric acids such as halogenated phosphoric acids, dialkyl phosphorous acids, sulfites; Mixed acid anhydrides with acids such as aliphatic carboxylic acids such as thiosulfate, sulfuric acid, alkyl carbonates, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid; symmetrical acid anhydrides; imidazole, 4 - substituted imidazole,
Activated amides with dimethylpyrazole, triazole, tetrazole, etc.; cyanomethyl 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 thio ester, P-nitrophenyl thio ester, P-cresyl thio ester, carboxymethyl thio Activated esters such as ester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester; or N,N-dimethylhydroxyamine, 1-hydroxy-2-(1H)-
Pyridone, N-hydroxysuccinimide, N-
Hydroxyphthalimide, 1-hydroxy-6-
Examples include esters with N-hydroxy compounds such as chloro-1H-benzotriazole, and these are appropriately selected depending on the type of compound () used. This reaction typically involves water, acetone, dioxane,
Acetonitrile, chloroform, methylene chloride,
The reaction is carried out in a common solvent such as ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or other organic solvents that do not adversely affect the reaction. These general solvents can also be used in combination with water. When the compound () is used in the form of the free acid or its salt in this reaction, it is advantageous to carry out the reaction in the presence of a customary condensing agent. Examples of the condensing agent include N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarboimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, N,N'-carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1 -Alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-
Ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)
Isoxazolium hydroxide inner salt, 1-
(p-chlorobenzenesulfonyloxy)-6-
Examples include chloro-1H-benzotriazole; the so-called Vilsmeier reagent produced from dimethylformamide and thionyl chloride, phosgene, phosphorus oxychloride, and the like. The reaction can also be carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate, tri-lower alkylamine, pyridine, N-lower alkylmorpholine, N,N-di-lower alkylbenzylamine. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or at room temperature. In this reaction, the syn isomer of the target compound () is preferably reacted with the syn isomer of the corresponding starting compound () in the presence of the above-mentioned Vilsmeier reagent, etc., at a temperature near neutrality. It can be obtained by carrying out the reaction under the following reaction conditions. Method 2 The target compound (b) or its salts can be produced by subjecting compound (a) or its salts to an amino-protecting group elimination reaction. As salts of compound (a), compound ()
Examples include metal salts, ammonium salts, and organic amine salts. This amino-protecting group elimination reaction is hydrolysis; reduction; for compounds (a) in which R ^1a is an acylamino group;
This is carried out by a conventional method such as treating the product with an iminohalogenating agent and an iminoetherifying agent and then hydrolyzing the product as necessary. Hydrolysis includes methods using acids or bases, hydrazine, and the like. These methods can be selected depending on the type of protecting group to be removed. Among these methods, hydrolysis with acids is
For example, substituted or unsubstituted alkoxycarbonyl groups such as tertiary-pentyloxycarbonyl, lower alkanoyl groups such as formyl and acetyl, cycloalkoxycarbonyl groups, substituted or unsubstituted aralkoxycarbonyl groups, aralkyl groups such as trityl, substituted phenylthio This is the most common and preferable method for removing protective groups such as a substituted aralkylidene group, a substituted aralkylidene group, a substituted alkylidene group, a substituted cycloalkylidene group, etc. Suitable acids used for this purpose include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the most suitable acids are those prepared by conventional methods such as vacuum distillation. Acids that can be easily removed from the reaction mixture, such as formic acid, trifluoroacetic acid, hydrochloric acid, and the like.
The acid can be selected depending on the type of protecting group to be removed. Elimination reactions using acids can be carried out either in the absence or presence of a solvent. Suitable solvents include water, common organic solvents or mixtures thereof. The elimination reaction using trifluoroacetic acid may be carried out in the presence of anisole. Hydrolysis with hydrazine is commonly used to remove phthaloyl, succinyl type amino protecting groups. Elimination with a base is utilized to eliminate acyl groups such as trifluoroacetyl. Suitable bases include both inorganic and organic bases. Elimination by reduction is generally applied to the elimination of protecting groups such as haloalkoxycarbonyl groups such as trichloroethoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, and 2-pyridylmethoxycarbonyl. Suitable reduction methods include, for example, reduction with alkali metal borohydrides such as sodium borohydride; reduction by combinations of organic or inorganic acids (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); as well as catalytic reduction. Suitable catalysts include the conventional ones such as Raney nickel, platinum oxide, palladium on carbon, and the like. Among protecting groups, acyl groups can generally be removed by hydrolysis. In particular, halogen-substituted alkoxycarbonyl groups and 8-quinolyloxycarbonyl groups are usually eliminated by treatment with heavy metals such as copper and zinc. Acyl groups as amino protecting groups can also be treated with iminohalogenating agents (e.g., phosphorous oxychloride, etc.) and iminoetherifying agents (e.g., lower alkanols such as methanol, ethanol, etc.), followed by optional hydrolysis. It can also be removed by The reaction temperature in the amino-protecting group elimination reaction is not particularly limited, and is appropriately selected depending on the type of amino-protecting group mentioned above, the type of elimination method, etc.; It is desirable that the test be carried out under suitable conditions. The invention provides within its scope that another protected amino group and/or a protected carboxy group is converted into a corresponding free amino group and/or free carboxy group during the work-up step of this reaction or of this process. It also includes cases. Method 3 The target compound (a) or its salts can be produced by reacting the compound (c) or its salts with the compound () or its reactive derivative. Suitable salts for compound (c) include those exemplified for compound (). Suitable reactive derivatives of compound () include alkali metal salts such as sodium salts, potassium salts, alkaline earth metal salts such as magnesium salts. This reaction can be carried out in the presence of sodium iodide, sodium thiocyanate, and the like. The reaction usually involves water, acetone, chloroform,
Nitrobenzene, methylene chloride, ethylene chloride,
The reaction is carried out in dimethylformamide, methanol, ethanol, ether, tetrahydrofuran or other common solvents that do not adversely affect the reaction. Preferred solvents are highly polar and
It may be used as a mixture with water. When compound (c) and/or compound () is used in the reaction in free form, organic or inorganic compounds such as alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, trialkylamines, pyridine, etc. Preferably, the reaction is carried out in the presence of a base, and preferably near neutral conditions. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature or under heating. The invention includes within its scope the case in which protected amino groups and/or protected carboxy groups are converted into the corresponding free amino and/or free carboxy groups during the reaction or work-up steps of the process. Method 4 The target compound (f) or its salts can be produced by subjecting compound (e) or its salts to an elimination reaction of the carboxy protecting group. Suitable salts of compound (e) include the acid addition salts exemplified for compound (). For this elimination reaction, all conventional methods used for elimination reactions of carboxy-protecting groups, such as hydrolysis, reduction, and elimination using Lewis acids, can be used. If the carboxy protecting group is an ester, it can be removed by hydrolysis or elimination using a Lewis acid. Hydrolysis is preferably carried out in the presence of a base or an acid. Suitable bases include inorganic bases and organic bases as described above. Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid. This hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof. The reaction temperature is not particularly limited and can be appropriately selected depending on the type of carboxy-protecting group and the elimination method. Elimination using a Lewis acid is preferably used to eliminate substituted or unsubstituted aryl lower alkyl esters, and is carried out by reacting compound (e) or a salt thereof with a Lewis acid.
Examples of Lewis acids include boron trihalides such as boron trichloride and boron trifluoride, titanium tetrahalides such as titanium tetrachloride and titanium tetrabromide, and tetrahalides such as tin tetrachloride and tin tetrabromide. tin,
Examples include aluminum halides such as aluminum chloride and aluminum bromide, and trihaloacetic acids such as trichloroacetic acid and trifluoroacetic acid.
This elimination reaction is preferably carried out in the presence of a cation scavenger (e.g., anisole, phenol, etc.), and is usually carried out with nitroalkanes such as nitromethane and nitroethane, alkylene halides such as methylene chloride and ethylene chloride, and diethyl ether. , carried out in carbon disulfide or other solvents that do not adversely affect the reaction. These solvents can also be used in a mixed state. Although there is no particular restriction on the reaction temperature, the reaction is usually carried out under cooling, at room temperature, or under heating. Reductive elimination is 2-iodoethyl, 2,2,2
It is preferable to use it for removing protecting groups such as halo lower alkyl esters such as -trichloroethyl and aryl lower alkyl esters such as benzyl. This reduction method, which can be applied to elimination reactions, includes, for example, metals (e.g. zinc, zinc amalgam, etc.) or chromium compounds (e.g. chromous chloride, chromous acetate, etc.) and organic or inorganic acids (e.g. acetic acid, propionic acid, hydrochloric acid, etc.); as well as conventional catalytic reductions in the presence of conventional metal catalysts (eg, palladium on carbon, Raney nickel, etc.). This carboxy-protecting group elimination reaction also includes cases where the protected amino group of compound (a) is converted to a free amino group depending on the reaction conditions and the type of protecting group during the reaction and/or post-treatment of the reaction. Include within the scope. Method 5 The target compound (h) or a salt thereof can be produced by subjecting the compound (g) or a salt thereof to an amino-protecting group elimination reaction. Suitable salts for compound (g) include those exemplified for compound (). This elimination reaction of the amino protecting group of compound (g) can be carried out in the same manner as Method 2 above. Next, the raw material compound () and the method for producing () will be explained in detail. Production method 1 () + () → (): [Method (A)] Compound () is compound ()
It can be produced by reacting with This reaction is preferably carried out in the presence of a base as exemplified in method 1 when X is an acid residue, and when X is a hydroxy group a condensing agent such as triphenylphosphine is used. Preferably it is carried out in the presence of one formed from yne and diethyl azoformate. This reaction is usually carried out in the presence of a solvent, which includes acetonitrile, dimethylformamide, and other solvents that do not adversely affect this reaction. The reaction temperature is not particularly limited,
It is usually carried out at a wide range of temperatures, from cooling to heating to near the boiling point of the solvent used. Production method 2 ()→(): [Method (A)] Compound () or a salt thereof can be produced by subjecting compound () to an amino-protecting group elimination reaction. The elimination reaction of the amino protecting group of compound () can be carried out in the same manner as explained in Method 2 above. Suitable solvents include water, ethanol, chloroform, diethyl ether, and the like. Although the reaction temperature is not particularly limited, the reaction is usually carried out with or under heating. Production method 3 ()+()→(): [Method (A)] Compound () or a salt thereof can be produced by reacting compound () or a salt thereof with compound (). Examples of the salts of the compound () include inorganic acid salts such as hydrochloride, hydrobromide, and sulfate, and organic acid salts such as acetate and p-toluenesulfonate. This reaction is usually carried out in a solvent, and in addition to water, alcohols such as methanol and ethanol, and mixed solvents thereof, any conventional solvent that does not adversely affect this reaction can be used. When the compound () is used in the form of its salt, this reaction is preferably carried out in the presence of an organic or inorganic base such as those mentioned above. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling or heating. In order to obtain the syn isomer of compound () by this reaction, it is preferable to carry out this reaction under conditions around neutrality. Production method 4. (a) → (b): [Method (B)] Compound (b) or its salts is a compound (
It can be produced by subjecting a) or a salt thereof to a reaction of introducing an amino protecting group. This reaction can be carried out in the same manner as Method 1 above. Manufacturing method 5 (b) + (a) → (a): [Method
(C)] Compound (a) or its salts are compound (
b) or a salt thereof with compound (a) or a reactive derivative thereof at the mercapto group or a salt thereof. This reaction can be carried out similarly to Method 3 above. The invention also includes within its scope the cases where one type of tautomer is converted to the other type of isomer during the reaction and/or work-up steps of each process. If the target compound () is obtained in a free form at the 4-position and/or if the compound () has a free amino group, it is converted into its pharmaceutically acceptable salt by conventional methods as described above. Can be converted. The object compound of this invention () and its salts are all new compounds and have high antibacterial activity and are useful as medicines, but the syn isomer has particularly high antibacterial activity compared to the corresponding anti-isomer. It has power. Next, data on the in vitro antibacterial activity of the following test compounds among the target compounds () of this invention are shown. Test compound (1) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-cephem-4
-Carboxylic acid (syn isomer). (2) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(1,3,4-
Thiadiazol-2-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer). (3) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-allyl-
1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer). (4) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-cephem-4
-Carboxylic acid (syn isomer). (5) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido}-3-cephem-3
-ylmethyl]pyridinium-4-carboxylate (syn isomer). (6) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer). Test method The test is agar plate dilution method (inoculum amount: ¹⁰⁸ cells/ml)
The minimum inhibitory concentration (MIC) at which growth of each test bacterium no longer occurs was observed and recorded.

【table】 Manufacturing example 1 (1) 3-chlorosilane in acetonitrile (370ml)
Clopentene (36.9g) and N-hydroxyphthalate
Ruimide (58.2g) and triethylamine (53.9g)
The mixture with g) was refluxed for 2 hours. reaction mixture
was poured into ice water. Separate the precipitated crystals and add water
Washed, dried over phosphorus pentoxide and
Clopenten-1-yl)oxyphthalimide
(56.5g) was obtained. I.R. (Nujiyor): 1780, 1730, 1610cm^-1 N.M.R. (DMSO−d₆, δ) 1.98-2.9 (4H, m), 5.42 (1H, S), 6.00
(1H, m), 6.28 (1H, m), 7.92 (4H, S) (2) 3-hydro in tetrahydrofuran (200ml)
Roxycyclohexene (4.0g), N-hydroxy
Shiftlimide (6.7g) and triphenyl
A mixture of phosphine (9.2 g) was stirred at room temperature.
Ta. After adding diethyl azoformate (7.9 g),
The resulting mixture was stirred at room temperature for 20 hours. reaction
Evaporate the mixture and elute the residue with chloroform
Column chromatography using silica gel (80g) as a reagent.
Graphically processed. Fractions containing the target compound
Collected and evaporated to give N-(2-cyclohexene
-1-yl)oxyphthalimide (6.5g)
Obtained. I.R. (Nuzhiyor): 1780, 1720cm^-1 N.M.R. (DMSO−d₆, δ) 1.43-2.2 (6H, m), 4.5-4.8 (1H, m),
5.68−6.25 (2H, m), 7.48 (4H, S) Manufacturing example 2 (1) N-(2-Cyclope in ethanol (300ml)
1-1-yl)oxyphthalimide (30.0
g) and hydrazine hydrate (14.5 g).
Stirred at 60°C for 1.5 hours. Add concentrated hydrochloric acid to the reaction mixture.
(30ml) and water (300ml), the resulting mixture
The mixture was filtered and the solvent was then distilled off from the liquid.
Ta. The remaining mixture was filtered and
Contains (ten-1-yl)oxyamine hydrochloride
Ethanol (400 ml) was added to the solution. child
The mixture was adjusted to pH7.0 with 4N aqueous sodium hydroxide solution.
To this, 2-(2-formamide thia
sol-4-yl)glyoxylic acid (21.9g)
added. The resulting mixture was adjusted to pH4~ with 10% hydrochloric acid.
The temperature was adjusted to 4.5 and stirred for 3 hours. reaction mixture?
Distill the solvent and add 4N aqueous sodium hydroxide solution.
After adjusting the pH to 7.5 and washing with ethyl acetate,
A mixture of ethyl acetate and tetrahydrofuran was added to the aqueous layer.
compound was added. PH the resulting mixture with 10% hydrochloric acid
2.0 and washed with saturated sodium chloride aqueous solution.
purified, dried over magnesium sulfate and concentrated.
Ta. Separate the precipitated crystals and dilute with diethyl ether.
2-(2-cyclopentene)
-1-yl)oximino-2-(2-form
amidothiazol-4-yl)acetic acid (syn isomer
body) (19.0 g) was obtained. I.R. (Nuzhiyor): 3200, 1740, 1710, 1600,
1560cm^-1 N.M.R. (DMSO−d₆, δ) 1.52−2.67 (4H, m), 5.45 (1H, m), 6.00
(1H, m), 6.28 (1H, m), 7.67 (1H, m),
8.73 (1H, s), 1.30 (1H, broad s) (2) N-(2-cyclohexen-1-yl)oxy
Mixture of siphthalimide (6.5g) and ethanol
Heat the mixture to 60℃ while stirring, and add water to it.
Add hydrazine (2.6g) at the same temperature and stir
continued for 1.5 hours. Concentrated hydrochloric acid (8ml) and water (80ml)
is added to the reaction mixture, the mixture is filtered,
The solvent was distilled off from the solution under reduced pressure. remove the precipitate
and (2-cyclohexen-1-yl)oxy
Wash the solution containing amine hydrochloride with ethyl acetate.
After cleaning, adjust the pH to 7.0 with 4N sodium hydroxide aqueous solution.
I arranged it. 2-(2-forma) was added to the resulting mixture.
Midothiazol-4-yl)glyoxylic acid
(4.6 g) and ethanol (120 ml) were added. child
Adjust the mixture to PH4~4.5 with 10% hydrochloric acid and store in the room.
Stir at room temperature for 2 hours. 4N hydroxylation of the reaction mixture
Adjust the pH to 7.5 with aqueous sodium solution and reduce the solvent.
It was distilled off under pressure. Wash the residue with ethyl acetate
Ta. Add ethyl acetate to the aqueous layer, then PH with hydrochloric acid.
Adjusted to 2.0. Separate the organic layer and saturated chloride
Wash with sodium aqueous solution and magnesium sulfate
and evaporate the solvent to give 2-(2-cyclo
lohexen-1-yl)oxyimino-2-
(2-formamidothiazol-4-yl) vinegar
Acid (syn isomer) (2.3g) was obtained. I.R. (Nujiyor): 3200, 1700, 1550cm^-1 N.M.R. (DMSO−d₆, δ) 1.35-2.32 (6H, m), 4.52-4.9 (1H, m),
5.62−6.2 (2H, m), 7.55 (1H, s), 8.57
(1H, s), 12.7 (1H, broad s) (3) N-(2-cyclohexane) in ethanol (180ml)
xen-1-yl)oxyphthalimide (17.6
g) and hydrazine hydrate (7.2 g).
Stirred at 60°C for 1.5 hours. Add water (100
ml) and concentrated hydrochloric acid (20 ml), the resulting mixture
The mixture was filtered and the solvent was distilled off from the liquid. residual
(2-cyclohexene
-1-yl)oxyamine hydrochloride
A liquid (liquid A) was obtained. 2-(2-formamide
Thiazol-4-yl)glyoxylic acid (10.0
g) in water (50 ml), add sodium hydroxide.
A solution of Limum (4.4 g) in water (50 ml) was added.
The resulting mixture was stirred at room temperature for 2.5 hours, and 2-
(2-aminothiazol-4-yl)glyoki
The mixture containing silicic acid was brought to pH 7.0 with 10% hydrochloric acid.
After adjustment, the solution A obtained above was added to this.
This mixture was stirred at room temperature for 2 hours. reaction mixture
Adjust the pH to 7.5 with 4N sodium hydroxide solution.
After that, the solvent was distilled off. The residue was dissolved in ethyl acetate.
After washing, the pH was adjusted to 2.0 with 10% hydrochloric acid. Shen
Separate the lees, wash with water and dry over phosphorus pentoxide.
2-(2-cyclohexen-1-yl)o
xiimino-2-(2-aminothiazole-4
-yl)acetic acid (syn isomer) (2.0 g) was obtained. I.R. (Nuzhiyor): 3400-3100, 1660-1600cm^-1 N.M.R. (DMSO−d₆, δ) 1.06−2.28 (6H, m), 4.60 (1H, s), 5.56−
6.10 (2H, m), 6.82 (1H, s) (4) 2-
(2-cyclopenten-1-yl)oxyimie
Nor-2-(2-aminothiazol-4-yl)
Acetic acid (syn isomer) was produced. N.M.R. (DMSO−d₆, δ) 1.47−2.88 (4H, m), 5.28 (1H, m), 5.32−
5.7 (2H, m), 6.85 (1H, s) Manufacturing example 3 2-(2-cyclopenten-1-yl)oxy
imino-2-(2-aminothiazol-4-yl)
Acetic acid (syn isomer) (2.8g) in ethyl acetate (30ml)
Add bis(trimethylate) to the solution while stirring on ice.
(5.0 g) was added. child
The mixture was stirred at room temperature for 10 min, then cooled to −10°C.
Rejected. This contains no 2,2,2-trifluoroacetic acid.
water (7.5g) while maintaining the temperature at -10℃.
dripped. The resulting mixture was heated at the same temperature for 20 minutes.
Next, stir at 0-5℃ for 2 hours, then cool to -10℃.
did. Water (30 ml) and ethyl acetate (20 ml) were added to the reaction mixture.
ml), then saturated aqueous sodium bicarbonate solution
The pH was adjusted to 1.5. Separate the ethyl acetate layer;
Wash with saturated aqueous sodium chloride solution and soak in magnesium sulfate.
The solvent was evaporated. remove the residue
Wash with a mixture of sopropyl ether and hexane
, 2-(2-cyclopenten-1-yl)oxy
Shiimino-2-[2-(2,2,2-trifluoro
acetamido)thiazol-4-yl]acetic acid
(syn isomer) (1.8 g) was obtained. I.R. (Nujiyor): 3400-3100, 1720, 1590cm^-1 N.M.R. (DMSO−d₆, δ) 1.4−2.9 (4H, m), 5.35 (1H, m), 5.7−
6.37 (2H, m), 7.65 (1H, s), 10.2 (1H, block)
load s) Manufacturing example 4 (1) Tetrahydrofuran (60ml) and methanol
(60 ml) of 2-mercapto-4-pi
In a suspension of lysine carboxylic acid (7.65 g), 2-
Isopropyla of sodium ethylhexanoate
Add alcohol solution (27.5%) and mix this mixture with
Stirred at room temperature for 2 days. Remove solvent from reaction mixture
Distill the residue into a mixture of acetone and ethanol.
Washed with. Separate this crystal and place it on phosphorus pentoxide.
2-sulfide-4-pyridine
Disodium rubonate (8.5 g) was obtained. I.R. (Nujiyor): 1570, 1390cm^-1 N.M.R. (D₂O-, δ): 7.27-8.63 (3H, m) (2) 7-aminocephalosporanic acid (9.30g) and
2-sulfide-4-pyridinecarboxylic acid nina
Thorium (6.80g) was suspended in water (160ml)
Add sodium hydrogen carbonate (5.73g) to the solution at room temperature.
dripped. Add sodium bicarbonate to the resulting mixture.
Adjust the pH to 6.8 by adding a saturated aqueous solution of
Ta. Warm the mixture to 65°C and stir for 1.5 hours.
During that time, the temperature was increased from 65℃ to 75℃.
Ta. After cooling the reaction mixture, adjust the pH to 3.6 with 10% hydrochloric acid.
It was adjusted. Separate the precipitate, add water (twice), and acetate.
(twice) and diethyl ether.
7-amino-3-(4-carbohydrate)
xypyridin-2-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (6.61 g) was obtained. I.R. (Nuzhiyor): 1800, 1700, 1610, 1540,
1410cm^-1 N.M.R. (DMSO−d₆, δ) 3.60 (2H, ABq, J=16Hz), 4.33 (2H,
ABq, J=13Hz), 4.70−5.03 (2H, m),
7.50-7.90 (2H, m), 8.57-8.77 (1H, m) Example 1 Dry N,N-dimethane in dry ethyl acetate (16 ml)
Chilformamide (0.62g) and phosphorus oxychloride
(1.3g) and Vilsmeier test
A drug solution was prepared using a conventional method. This Bill Smyth
Add 2-(2-cyclopetrope) to the solution of Ar reagent under ice-cooling and stirring.
(ten-1-yl)oxyimino-2-(2-pho
lumamidothiazol-4-yl)acetic acid (syn
(2.0 g) of dry tetrahydrofuran (5
ml) solution was added. The resulting mixture was mixed with 7-amino
Nor-3-cefem-4-carboxylic acid (1.4g) and
Vinegar with trimethylsilylacetamide (5.5g)
Add to ethyl acid (14 ml) solution at -10℃ and mix.
The mixture was stirred at -5 to -10°C for 30 minutes. After adding ethyl acetate and water to the reaction mixture, the organic
Separate the layers and add to this an aqueous solution of sodium bicarbonate.
added. Separate this aqueous solution and add ethyl acetate to it.
Added ru. Adjust this mixture to PH3.0 with 10% hydrochloric acid.
I arranged it. Separate the organic layer and add saturated sodium chloride water
solution, dry over magnesium sulfate, and evaporate.
7-[2-(2-cyclopentene-1-i)
)oximino-2-(2-formamidothia)
sol-4-yl)acetamide]-3-cephe
Mu-4-carboxylic acid (syn isomer) (1.75g) was obtained.
Ta. Melting point 145-170℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1780, 1680,
1650, 1540cm^-1 N.M.R. (DMSO−d₆, δ) 12.6 (1H, broad s), 9.55 (1H, d, J=
8Hz), 8.5 (1H, s), 7.35 (1H, s), 6.47
(1H, m), 6.07 (1H, m), 6.25−5.68 (3H,
m), 5.32 (1H, m), 5.08 (1H, d, J=5
Hz), 3.58 (2H, m), 2.67-1.57 (4H, m). Example 2 Dry N,N-dimethane in dry ethyl acetate (3 ml)
Chilformamide (0.48g) and phosphorus oxychloride
(0.98g) to a solution of Vilsmeier reagent using the standard method.
Adjusted by. This Vilsmeier reagent solution
While stirring under ice-cooling, add 2-(2-shield) to this.
Clopenten-1-yl)oxyimino-2-
(2-formamidothiazol-4-yl)acetic acid
(syn isomer) (1.5 g) in dry tetrahydrofuran
(12ml) solution was added. The resulting mixture was 7-
Amino-2-methyl-3-cephem-4-carbo
acid (1.37g) and trimethylsilylacetamide
(5.04g) in ethyl acetate (14ml) -30~-
Add at 20°C and keep the mixture at -5 to -10°C for 2 hours.
Stirred. Water and ethyl acetate were added to the reaction mixture.
After that, separate the ethyl acetate layer and add sodium bicarbonate.
The pH was adjusted to 7 with an aqueous solution. Separate the aqueous layer and add
Ethyl acetate was added. Mixture to PH2.5 with 10% hydrochloric acid
Adjusted to. Separate the ethyl acetate layer and add sodium chloride.
Wash with magnesium sulfate solution and dry over magnesium sulfate.
After that, the solvent was distilled off. Diisopropyl residue
Powdered in ether to give 7-[2-(2-cyclo
penten-1-yl)oxyimino-2-(2-
Formamidothiazol-4-yl)acetamide
[do]-2-methyl-3-cephem-4-carvone
Acid (syn isomer) (1.98g) was obtained. I.R. (Nujiyor): 3260, 1780, 1680, 1660cm^-1 N.M.R. (DMSO−d₆, δ) 1.45 (3H, d, J = 8Hz), 1.72-1.75 (4H,
m), 3.55-4.15 (1H, m), 5.15 (1H, d,
J=5Hz), 5.18-5.55 (1H, m), 5.92 (1H,
dd, J = 5 and 8Hz), 5.93−6.38 (2H,
m), 6.58 (1H, d, J=5Hz), 7.4 (1H,
s), 8.55 (1H, s), 9.62 (1H, d, J=8
Hz), 12.72 (1H, broad s). Example 3 Dry N,N-dimethane in dry ethyl acetate (15 ml)
Chilformamide (0.38g) and phosphorus oxychloride
(0.79g) to Vilsmeier reagent using a conventional method.
A solution was prepared. This Vilsmeier reagent solution
Add 2-(2-si) to this while stirring under ice-cooling.
Clopenten-1-yl)oxyimino-2-
[2-(2,2,2-trifluoroacetamide)
Thiazol-4-yl]acetic acid (syn isomer) (1.5
g) was added. The resulting mixture was diluted with 7-aminocetate.
Phalosporanic acid (1.2g) and trimethylsilyl
Ethyl acetate (12ml) with acetamide (3.4g)
solution at -10°C and the mixture at -5 to -10°C.
The mixture was stirred for 30 minutes. After adding water and ethyl acetate to the reaction mixture, acetic acid
Separate the ethyl layer and add it to sodium bicarbonate solution.
solution was added. Separate the aqueous layer and add to it ethyl acetate.
added. Adjust this mixture to PH3.0 with 10g hydrochloric acid.
did. Separate the ethyl acetate layer and add saturated sodium chloride.
Wash with aqueous solution and dry over magnesium sulfate.
Then, the solvent was distilled off to obtain 7-[2-((2-cyclopene)
(ten-1-yl)oxyimino-2-{2-
(2,2,2-trifluoroacetamide)thia
sol-4-yl)acetamide] Cephalospo
Lanic acid (syn isomer) (1.8 g) was obtained. I.R. (Nuzhiyor): 3400-3100, 1780, 1730,
1660, 1580, 1510cm^-1 N.M.R. (DMSO−d₆, δ) 1.5−2.73 (4H, m), 3.62 (2H, broad
s), 4.9 (2H, q, J = 13Hz), 5.2 (1H, d,
J = 5Hz), 5.38 (1H, m), 6.3-5.7 (3H,
m), 7.53 (1H, s), 9.7 (1H, d, J=8
Hz). Example 4 Dry N,N-di in dry ethyl acetate (1.72ml)
Methylformamide (0.43g) and phosphorus oxychloride
(0.90g) to Vilsmeier reagent using a conventional method.
A solution was prepared. Suspend this Vilsmeier reagent solution under ice cooling.
While stirring the solution, add 2-(2-cyclopene) to it.
then-1-yl)oxyimino-2-(2-hor
muamidothiazol-4-yl)acetic acid (syn isomer
Add a solution of dry ethyl acetate (20 ml) of
I got it. The resulting mixture was mixed with 7-amino-3-(1,
3,4-thiadiazol-2-yl)thiomethyl
-3-cefem-4-carboxylic acid (1.5g)
Drying with lymethylsilylacetamide (4.2g)
Added to tetrahydrofuran (30ml) solution at -10℃.
Then, stir this mixture for 30 minutes at -5 to -10℃.
Ta. After adding water to the reaction mixture, bring the temperature of the mixture to room temperature.
It was allowed to warm up and then the organic layer was separated. This organic layer
The pH was adjusted to 7.5 with an aqueous sodium hydrogen carbonate solution.
The aqueous layer was separated, washed with ethyl acetate, and then added with acetic acid.
Ethyl and tetrahydrofuran were added. This mixture
The pH was adjusted to 2.0 with 10% hydrochloric acid. Separate the organic layer
washed with water, dried over magnesium sulfate, and activated
Treated with charcoal and evaporated. Dilute the residue with diethyl ether
Powder in a vacuum chamber, separate and wash with diethyl ether.
7-[2-(2-Cyclope)
(ten-1-yl)oxyimino-2-(2-pho
lumamidothiazol-4-yl)acetamide
]-3-(1,3,4-thiadiazole-2-y)
)thiomethyl-3-cephem-4-carboxylic acid
(syn isomer) (2.63 g) was obtained. I.R. (Nujiyor): 3150, 1770, 1670cm^-1 N.M.R. (DMSO−d₆, δ) 1.80−2.90 (4H, m), 3.74 (2H, m) 4.49
(2H, q, J = 14.0Hz), 5.20 (1H, d, J =
5.0Hz), 5.36 (1H, m), 5.68-6.30 (3H,
m), 7.43 (1H, s), 8.53 (1H, s), 9.60
(1H, s), 9.65 (1H, d, J = 8.0Hz) Example 5 N,N-dimethyl in dry ethyl acetate (16ml)
Formamide (0.62g) and phosphorus oxychloride (1.3g)
Prepare a solution of Vilsmeier reagent by a conventional method from
did. A suspension of this Vilsmeier solution under ice cooling.
Add 2-(2-cyclopentene) to this while stirring.
-1-yl)oximino-2-(2-formua
Midothiazol-4-yl)acetic acid (syn isomer)
(2.0g) in dry tetrahydrofuran (5ml)
added. The resulting mixture was converted into 7-amino-3-
(1-allyl-1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid (2.5
g) and trimethylsilylacetamide (5.5g)
Add this to a solution of ethyl acetate (25 ml) at -10°C.
The mixture was stirred at -5 to -10°C for 30 minutes. Add water, ethyl acetate and tetrahydride to the reaction mixture.
After adding Lofuran, separate the organic layer and add to it charcoal.
An aqueous solution of sodium oxyhydrogen was added. Separate the aqueous layer
Then, ethyl acetate was added to this. Add this mixture to 10
The pH was adjusted to 3.0 with % hydrochloric acid. Separate the organic layer and
Wash with aqueous sodium chloride solution and soak with magnesium sulfate.
7-[2-
(2-cyclopenten-1-yl)oxyimino
-2-(2-formamidothiazol-4-yl)
Acetamide]-3-(1-allyl-1H-tetra
sol-5-yl)thiomethyl-3-cephem-
4-carboxylic acid (syn isomer) (3.25 g) was obtained.
Melting point 120-139°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.57−2.73 (4H, m), 3.73 (2H, broad
s), 4.4 (2H, m), 4.88-5.52 (6H, m),
5.7−6.58 (4H, m), 7.42 (1H, s), 8.57
(1H, s), 9.63 (1H, d, J=8Hz), 12.4
(1H, Broads). Example 6 dry N in dry tetrahydrofuran (1 ml),
N-dimethylformamide (0.475g) and oxy
Vilsmeier from phosphorus chloride (0.997g) by the usual method.
- Prepared reagent solutions. This stirred suspension of Vilsmeier reagent
2-(2-cyclopentene-1-
yl)oximino-2-(2-formamidothi
azol-4-yl)acetic acid (syn isomer) (1.91
Add a solution of g) in dry tetrahydrofuran (12 ml).
Then, the mixture was stirred for 20 minutes. the resulting mixture
A mixed solvent of acetone (12 ml) and water (12 ml)
7-amino-3-(4-carboxypyridine-
2-yl)thiomethyl-3-cephem-4-cal
Bonic acid (1.84g) and sodium bicarbonate (0.84g)
Add g) to the dissolved solution at -3 to 0°C, and add this mixture.
The mixture was stirred at the same temperature for 40 minutes. The solvent was distilled off from the reaction mixture under reduced pressure. residue
Adjust to PH6.5 with 10% hydrochloric acid and wash with ethyl acetate.
After concentrating to a small amount, adjust the pH to 2.9 with 10% hydrochloric acid.
did. Separate the precipitate, wash with water, and add pentaacid.
7-[2-(2-cyclopene)
then-1-yl)oxyimino-2-(2-hor
Muamidothiazol-4-yl)acetamide]
-3-(4-carboxypyridin-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid (syn
isomer) (2.74 g) was obtained. I.R. (Nuzhiyor): 1770, 1690-1650, 1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.73−2.50 (4H, m), 3.60 (2H, m), 4.30
(2H, ABq, J=12Hz), 5.07−5.43 (2H,
m), 5.77-6.20 (3H, m), 7.40-7.97 (4H,
m), 8.53 (1H, s), 9.63 (1H, d, J=8
Hz), 12.70 (1H, broad s). Example 7 Dry N,N-dimethane in dry ethyl acetate (16 ml)
Chilformamide (0.6g) and phosphorus oxychloride
(1.25g) to Vilsmeier reagent using a conventional method.
A solution was prepared. This Vilsmeier being stirred under ice cooling
Add 2-(2-cyclohexene to the suspension of reagent solution)
-1-yl)oximino-2-(2-formua
Midothiazol-4-yl)acetic acid (syn isomer)
(2.0g) was added. The resulting mixture was diluted with acetone.
(25 ml) and water (25 ml) in a mixed solvent of 7-amino-
3-(1-carboxymethyl-1H-tetrazole
-5-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (2.5g) and sodium bicarbonate (2.2g)
g) to the dissolved solution at -10℃, and this mixture
was stirred at -5 to -10°C for 30 minutes. After adding ethyl acetate to the reaction mixture, separate the aqueous layer.
To this was added ethyl acetate. this mixture
The pH was adjusted to 3.0 with 10% hydrochloric acid. Separate the organic layer;
Wash with saturated aqueous sodium chloride solution and soak with magnetic sulfate.
7-[2-(2
-cyclohexen-1-yl)oxyimino-2
-(2-formamidothiazol-4-yl)a
Cetamido]-3-(1-carboxymethyl-1H
-tetrazol-5-yl)thiomethyl-3-se
Fem-4-carboxylic acid (syn isomer) (2.0g)
I got it. I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 N.M.R. (DMSO−d₆, δ) 12.7 (1H, broad s), 9.65 (1H, d, J=
8Hz), 8.53 (1H, s), 7.38 (1H, s), 6.17
−5.58 (3H, m), 5.3 (2H, s), 5.12 (1H,
d, J=5Hz), 4.63 (1H, m), 4.35 (2H,
q, J=13Hz), 3.67 (2H, m), 2.42−1.13
(6H, m). Example 8 Dry N,N-dimethane in dry ethyl acetate (15 ml)
Chilformamide (0.48g) and phosphorus oxychloride
(1.0g) to dissolve Vilsmeier reagent using the usual method.
A liquid was prepared. This Vilsmeier reagent was stirred under ice cooling.
In the suspension of the solution, 2-(2-cyclohexene-1
-yl)oximino-2-(2-formamide
Thiazol-4-yl)acetic acid (syn isomer) (1.5
g) was added. The resulting mixture was incubated at -10°C for 7-
Amino-3-(1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid (1.6
g) and trimethylsilylacetamide (4.6g)
and bis(trimethylsilyl)acetamide (3.1
g) in ethyl acetate (32 ml), add this mixture to
The mixture was stirred at -5 to -10°C for 30 minutes. After adding water and ethyl acetate to the reaction mixture, the organic
Separate the layers and add to this an aqueous solution of sodium bicarbonate.
added. Separate the aqueous layer and add ethyl acetate to it.
I got it. This mixture was adjusted to pH 3.0 with 10% hydrochloric acid.
Separate the organic layer and wash with saturated aqueous sodium chloride solution.
dried over magnesium sulfate and evaporated.
Then, 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothia)
sol-4-yl)acetamide]-3-(1H-
Tetrazol-5-yl)thiomethyl-3-cef
Em-4-carboxylic acid (syn isomer) (1.7g)
Obtained. I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1540cm^-1 N.M.R. (DMSO−d₆, δ) 9.63 (1H, d, J=8Hz), 8.55 (1H, s),
7.4 (1H, s), 6.17-5.6 (3H, m), 5.18
(1H, d, J=5Hz), 4.68 (1H, m), 4.37
(2H, m), 3.73 (2H, broad s), 2.33−
1.17 (6H, m). Example 9 2-(2-cyclohexen-1-yl)oxy
imino-2-(2-aminothiazol-4-yl)
Acetic acid (syn isomer) (1.91g: This stuff is 8% water
) in tetrahydrofuran (20 ml)
The mixture was stirred at a temperature lower than 5°C. Oxychloride in this solution
Add phosphorus (1.4 g) and continue stirring for 20 minutes below 5°C.
I got it. This solution was then followed by trimethylsilylacetate.
Amide (1.11g; this reagent also contains 8% water)
was added and stirring continued for 20 minutes at the same temperature. moreover
Add phosphorus oxychloride (1.4g) to this solution and stir.
Stirring was continued for 20 minutes at the same temperature. In the resulting solution
Add N,N-dimethylformamide (0.65g)
Then, stirring was continued for another 30 minutes to obtain solution A.
Separately, 7-aminocephalosporanic acid (1.9 g)
and trimethylsilylacetamide (5.6g)
Ethyl acetate (40ml) solution was stirred at 40°C for 15 minutes.
After that, it was cooled to -25°C. into the resulting solution obtained above
Solution A was added and the mixture was stirred at -15°C for 1 hour.
did. After adding ethyl acetate and water to the reaction mixture,
Separate the organic layer and wash with saturated aqueous sodium chloride solution.
dried over magnesium sulfate and evaporated.
did. PH the residue with saturated aqueous sodium bicarbonate solution.
6.5 and 5% sodium acetate as eluent.
Column chromatography treatment with alumina
7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-aminothiazole-4
-yl)acetamido]cephalosporanic acid
(syn isomer) (0.5 g) was obtained. I.R. (Nuzhiyor): 3400-3100, 1770, 1740,
1660, 1630, 1520cm^-1 N.M.R. (DMSO−d₆, δ) 1.28−2.25 (6H, m), 2.05 (3H, s), 3.60
(2H, broad s), 4.71 (1H, m), 4.88
(2H, m), 5.17 (1H, d, J=5Hz), 5.65
−6.22 (3H, m), 6.75 (1H, s), 9.58 (1H,
d, J=8Hz) Example 10 dry N,N-dimethylformamide (0.4g),
Phosphorous oxychloride (0.8g) and dry ethyl acetate
(1.6 ml) and dissolve Vilsmeier reagent in the usual manner.
A liquid was prepared. Add dry tetrahydrofura to this solution.
(18 ml) and 2-(2-cyclopentene-1-y)
)oximino-2-(2-formamidothia)
sol-4-yl)acetic acid (syn isomer) (1.2g)
was added and stirred at -3 to 3°C (Solution A). Separately 7
-amino-3(tetrazolo[1,5-b]pyrida
Zin-6-yl)thiomethyl-3-cephem-4
-Carboxylic acid (1.5g) and sodium carbonate (0.9g)
Stir the mixture of g) and water (9.0ml) until it is homogeneous.
A solution was obtained. After adding acetone (9.0ml),
The solution was cooled to -3°C, and the temperature was increased from -3 to 3°C.
℃ and keep the pH between 7.5 and 8.5 with triethylamine.
Meanwhile, solution A obtained above was added over 4 minutes.
The resulting mixture was stirred for 30 min at the same temperature and pH.
Ta. Add water, ethyl acetate and tetrahydrogen to the reaction mixture.
After adding Dorofuran, salt the resulting mixture 10%
The pH was adjusted to 2.0 with acid and filtered. organic layer from liquid
Separate, wash three times with water, and dry over magnesium sulfate.
It was dried, treated with activated carbon and the solvent was evaporated. residue
Triturated in isopropyl ether. precipitated
Separate the powder, wash with isopropyl ether,
After drying, 7-[2-(2-cyclopentene-1-
yl)oximino-2-(2-formamidothi
azol-4-yl)acetamide]-3-(tet)
lazolo[1,5-b]pyridazin-6-yl)thi
Omethyl-3-cephem-4-carboxylic acid (syn
isomer) (1.83 g) was obtained. I.R. (Nujiyor): 3180, 1780, 1670cm^-1 N.M.R. (DMSO−d₆, δ) 1.60−2.68 (4H, m), 3.75 (2H, ABq, J=
18.0Hz), 4.43 (2H, ABq, J=14.0Hz),
5.17 (1H, d, J = 5.0Hz), 5.28 (1H, m),
5.72−6.22 (3H, m), 7.37 (1H, s), 7.70
(1H, d, J=9.0Hz), 8.48 (1H, s), 8.52
(1H, d, J = 9.0Hz), 9.58 (1H, d, J =
8.0Hz), 12.57 (1H, broad s). Example 11 dry N,N-dimethylformamide (0.48g),
Phosphorous oxychloride (1.0g), ethyl acetate (4ml) and
and tetrahydrofuran (15 ml) in a conventional manner.
A solution of Lussmeier's reagent was prepared. in this solution
2-(2-cyclopenten-1-yl) under ice cooling.
Oximino-2-[2-(2,22-trifluoro
acetamido)thiazol-4-yl]acetic acid
(syn isomer) (1.9 g) and the resulting solution
Stirred for a minute (solution A). Separately, N-[7-amino
-3-cephem-3-ylmethyl]pyridinium
-4-carboxylate dihydrochloride (2.0g) and
Limethylsilylacetamide (5.7g) and tetra
Heat the mixture with hydrofuran (40ml) to 40℃ and stir.
After stirring to obtain a homogeneous solution, this was cooled to -25℃.
Ta. Solution A obtained above was added to this. The resulting mixture
The mixture was stirred at approximately -10°C for 30 minutes. The obtained N-
[7-[2-(2-cyclopenten-1-yl)o
xiimino 2-{2-(2,2,2-trifluoro
acetamido)thiazol-4-yl}acetoa
mido]-3-cephem-3-ylmethyl]pyridi
nium-4-carboxylate (syn isomer)
Add ethyl acetate (50 ml) and water to the reaction mixture containing
(100ml) was added. Separate the ethyl acetate layer and saturate
Extracted with aqueous sodium hydrogen carbonate solution (50ml).
Combine this extract and the remaining aqueous layer and add 4N hydroxide.
After adjusting the pH to 6.0 with an aqueous sodium solution, this
Sodium acetate (7.5 g) was added to the solution. This mixture
Stir the mixture at room temperature for 41 hours and adjust the pH to 2.0 with 10% hydrochloric acid.
Arranged and passed. Transfer the liquid to a nonionic adsorption resin
Iaion HP20, manufactured by Mitsubishi Chemical Industries) (60ml)
After washing the column with water, add 10%
Elute with sopropyl alcohol and 30% methanol
Ta. Collect the eluate of the fraction containing the target compound,
The solvent was distilled off and the product was freeze-dried. Reduce the resulting powder
Dry under pressure over phosphorus pentoxide to give N-[7-{2-
(2-cyclopenten-1-yl)oxyimino
-2-(2-aminothiazol-4-yl)acetate
toamido}-3-cephem-3-ylmethyl]pi
Lysinium-4-carboxylate (syn isomer
(0.3 g) was obtained. Melting point 171-180℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1610, 1530cm^-1 N.M.R. (D₂O, δ): 1.5−2.67 (4H, m), 3.42
(2H, ABq, J=18Hz), 5.12−5.7 (1H,
m), 5.25 (1H, d, J=5Hz), 5.5 (2H,
m), 5.85 (1H, d, J=5Hz), 6.05 (2H,
m), 6.93 (1H, s), 7.8-8.82 (3H, m),
8.98 (2H, m). Example 12 The following compounds were produced in the same manner as Examples 1 to 11.
did. (1) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamido]-3-carba
Moyloxymethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3450, 3260, 1770, 1660,
1640, 1700, 1610, 1550cm^-1 N.M.R. (DMSO−d₆, δ) 1.64−2.44 (4H, m), 3.48 (2H, q, J=17
Hz), 4.72 (2H, q, J = 13Hz), 5.12 (1H,
d, J=5Hz), 5.30 (1H, m), 6.2−5.58
(3H, m), 6.54 (2H, s), 7.36 (1H, s),
8.48 (1H, s), 9.54 (1H, d, J=8Hz),
11.5 (1H, Broads) (2) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(2-
tert-butoxycarboxamide ethyl)thiome
Chil-3-cephem-4-carboxylic acid benzene
Drill (syn isomer). I.R. (Nujiyor): 3270, 3150, 1780, 1710,
1680, 1660, 1570, 1225cm^-1 N.M.R. (DMSO−d₆, δ) 1.37 (9H, s), 1.07-2.67 (4H, m), 3.03
(2H, m), 3.33-3.87 (4H, m), 5.27 (1H,
d, J=5Hz), 5.33 (1H, m), 5.70−6.33
(5H, m), 6.97 (1H, s), 7.07−7.67 (11H,
m), 8.53 (1H, s), 9.63 (1H, d, J=8
Hz), 12.72 (1H, broad s) (3) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(5-methyl)
Chil-1,3,4-thiadiazol-2-y
)thiomethyl-3-cephem-4-carvone
Acid (syn isomer). I.R. (Nujiyor): 3240, 1765, 1660cm^-1 N.M.R. (DMSO−d₆, δ) 1.74−2.88 (4H, m), 2.70 (3H, s), 3.70
(2H, m), 4.40 (2H, q, J=14Hz), 5.17
(1H, d, J=5Hz), 5.2−5.7 (1H, m),
5.82 (1H, dd, J=5 and 8Hz), 5.87−
6.3 (2H, m), 7.4 (1H, s), 8.54 (1H, s),
9.57 (1H, d, J = 8Hz), 12.71 (1H, block
code) (4) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(1-mer)
thyl-1H-tetrazol-5-yl)thiome
Chil-3-cefem-4-carboxylic acid (syn
gender). I.R. (Nujiyor): 3240, 1760, 1670cm^-1 N.M.R. (DMSO−d₆, δ) 1.6−2.93 (4H, m), 3.70 (2H, m), 3.93
(3H, s), 4.33 (2H, m), 5.15 (1H, d,
J=5Hz), 5.13-5.7 (1H, m), 5.81 (1H,
dd, J=5and8Hz), 5.9-6.31 (2H, m), 7.4
(1H, s), 8.5 (1H, s), 9.58 (1H, d, J
=8Hz), 12.7 (1H, broad s) (5) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(1-ka
Ruboxymethyl-1H-tetrazol-5-y
)thiomethyl-3-cephem-4-carvone
Acid (syn isomer). I.R. (Nujiyor): 3150, 1770, 1660cm^-1 N.M.R. (DMSO−d₆, δ) 1.57−2.75 (4H, m), 3.72 (2H, m), 4.40
(2H, q, J=14Hz), 5.03−5.62 (4H, m),
5.66−6.40 (3H, m), 7.41 (1H, s), 8.54
(1H, s), 9.63 (1H, d, J = 8.0Hz) (6) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(1H-
Tetrazol-5-yl)thiomethyl-3-se
Fem-4-carboxylic acid (syn isomer). I.R. (Nujiyor): 1770, 1660cm^-1 N.M.R. (DMSO−d₆, δ) 1.60−2.70 (4H, m), 3.67 (2H, m), 4.31
(2H, q, J = 13.0Hz), 5.02−5.53 (2H,
m), 5.69-6.29 (3H, m), 7.39 (1H, s),
8.53 (1H, s), 9.62 (1H, d, J = 8.0Hz) (7) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(5-
tert-butoxycarboxamidomethyl-1,
3,4-thiadiazol-2-yl)thiomethy
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 195-220℃ (decomposition). I.R. (Nujiyor): 3270, 1780, 1700, 1680,
1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.55 (9H, s), 1.93-2.57 (4H, m), 3.67
(2H, m), 4.2-4.67 (4H, m), 5.13 (1H,
d, J=5Hz), 5.3 (1H, m), 5.63−6.20
(3H, m), 7.37 (1H, s), 8.5 (1H, s),
9.62 (1H, d, J = 8Hz), 12.67 (1H, block
code) (8) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamido]-3-cephe
Mu-4-carboxylic acid (syn isomer). Melting point 155~
185℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1780, 1690,
1660, 1630, 1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.27−2.33 (6H, m), 3.62 (2H, m), 4.48−
4.98 (1H, m), 5.12 (1H, d, J=5Hz),
5.62−6.23 (3H, m), 6.48 (1H, m), 7.37
(1H, s), 8.5 (1H, s), 9.58 (1H, d, J
=8Hz), 12.6 (1H, broad s) (9) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamido]-2-methyl
-3-cefem-4-carboxylic acid (syn isomer
body). I.R. (Nujiyor): 3275, 3175, 1780, 1690,
1660, 1620, 1570, 1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.45 (3H, d, J=7Hz), 1.15−2.38 (6H,
m), 3.5-4.23 (1H, m), 4.67 (1H, m),
5.12 (1H, d, J = 5Hz), 6.33-5.45 (3H,
m), 6.53 (1H, d, J=6Hz), 7.33 (1H,
s), 8.48 (1H, s), 9.55 (1H, d, J=8
Hz), 12.5 (1H, broad s) (10) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(1,
3,4-thiadiazol-2-yl)thiomethy
-3-cephem-4-carboxylic acid (syn isomer
body). I.R. (Nuzhiyor): 3300-3100, 1780, 1670,
1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.4-2.26 (6H, m), 3.7 (2H, broad s),
4.43 (2H, q, J = 13Hz), 4.43−4.83 (1H,
m), 5.17 (1H, d, J = 5Hz), 5.33−6.23
(3H, m), 7.37 (1H, s), 8.5 (1H, s),
9.53 (1H, s), 9.57 (1H, d, J=8Hz),
12.6 (1H, Broads) (11) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(1-mer)
thyl-1H-tetrazol-5-yl)thiome
Chil-3-cephem-4-carboxylic acid (syn
gender). I.R. (Nuzhiyor): 3400-3100, 1780, 1660,
1550cm^-1 N.M.R. (DMSO−d₆, δ) 1.12−2.28 (6H, m), 3.73 (2H, broad
s), 3.97 (3H, s), 4.35 (2H, m), 4.7
(1H, broad s), 5.18 (1H, d, J=5
Hz), 6.2-5.55 (3H, m), 7.42 (1H, s),
8.55 (1H, s), 9.65 (1H, d, J=8Hz),
12.7 (1H, Broads) (12) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamide]-3-(1-a
Lyle-1H-tetrazol-5-yl)thiome
Chil-3-cefem-4-carboxylic acid (syn
gender body). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.12-2.3 (6H, m), 3.6 (2H, broad s),
4.42 (2H, m), 4.65 (1H, m), 4.82−5.48
(5H, m), 5.57-6.47 (4H, m), 7.38 (1H,
s), 8.53 (1H, s), 9.6 (1H, d, J=8
Hz), 12.4 (1H, broad s) (13) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-cephem
-4-carboxylic acid (syn isomer). Melting point 201~
213℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1650,
1620, 1540cm^-1 (14) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
(l-4-yl)acetamido]-2-methyl-
3-cephem-4-carboxylic acid (syn isomer). I.R. (Nujiyor): 3300, 1770, 1660, 1630cm^-1 (15) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
(4-yl)acetamide] Cephalospora
acid (syn isomer). Melting point 141-150℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1730,
1650, 1530cm^-1 (16) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
(l-4-yl)acetamide]-3-carbamo
yloxymethyl-3-cephem-4-carbo
acid (syn isomer). Melting point 182-195°C (decomposition). I.R. (Nuzhiyor): 3250, 1760, 1700, 1650,
1540cm^-1 (17) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(2-tertiary
(butoxycarboxamide ethyl)thiomethane
Le-3-cephem-4-carboxylic acid benzhydride
Lil (syn isomer). I.R. (Nuzhiyor): 3500-3200, 1780, 1680,
1620, 1530cm^-1 (18) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(2-amido)
(noethyl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer). I.R. (Nuzhiyor): 3350-3100, 1760, 1660,
1610, 1515cm^-1 (19) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1,3,
4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 152-157°C (decomposition). I.R. (Nujiyor): 3340, 1775, 1655cm^-1 (20) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(5-methy
(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 148-152℃. I.R. (Nujiyor): 3260, 1770, 1650cm^-1 (21) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-methy
-1H-tetrazol-5-yl)thiomethy
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 147-150℃. I.R. (Nujiyor): 3300, 1770, 1660cm^-1 (22) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-aryl)
-1H-tetrazol-5-yl)thiomethylene
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 145-153°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1620, 1520cm^-1 (23) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-cal)
boxymethyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 164-170℃ (decomposition). I.R. (Nujiyor): 3280, 1765, 1655cm^-1 (24) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(4-cal)
boxypyridin-2-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer). Melt
Point 174-205℃ (decomposition). I.R. (Nuzhiyor): 1760, 1670, 1620, 1450,
1370, 1360cm^-1 (25) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1H-te
Torazol-5-yl)thiomethyl-3-cef
Em-4-carboxylic acid (syn isomer). Melting point 165
~172℃ (decomposition). I.R. (Nujiyor): 3300, 1770, 1660, 1630cm^-1 (26) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(5-amido)
Nomethyl-1,3,4-thiadiazole-2-
yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer). Melting point 145-170℃ (decomposition). I.R. (Nujiyor): 3150, 1760, 1650, 1610,
1520cm^-1 (27) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-cephem
-4-carboxylic acid (syn isomer). Melting point 220~
241℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1650,
1630, 1530cm^-1 (28) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
(l-4-yl)acetamido]-2-methyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 159-166°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1630, 1520cm^-1 (29) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1,3,
4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1530cm^-1 (30) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-methy
-1H-tetrazol-5-yl)thiomethylene
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 156-160℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1520cm^-1 (31) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-aryl)
-1H-tetrazol-5-yl)thiomethylene
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 148-157°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1620, 1520cm^-1 (32) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-cal)
boxymethyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 166-182°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1530cm^-1 (33) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1H-te
Torazol-5-yl)thiomethyl-3-ceph
Em-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1630, 1520cm^-1 (34) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-hydroxyethyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephemka
Rubonic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1780, 1670,
1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.47-2.65 (4H, m), 3.33-3.97 (4H, m),
4.03−4.65 (4H, m), 5.13 (1H, d, J=5
Hz), 5.35 (1H, m), 5.72-6.28 (3H, m),
7.4 (1H, s), 9.60 (1H, d, J=8Hz),
12.7 (1H, Broads) (35) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-hydroxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). Melting point 162-168℃ (min.
solution). I.R. (Nuzhiyor): 3400-3100, 1770, 1720,
1650, 1540cm^-1 (36) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-carboxyethyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
- Carboxylic acids (syn isomers). I.R. (Nujiyor): 3160, 1770, 1660cm^-1 N.M.R. (DMSO−d₆, δ) 1.58−2.73 (4H, m), 2.96 (2H, t, J = 7.0
Hz), 3.74 (2H, ABq, J=15.0Hz), 4.05−
4.75 (4H, m), 5.16 (1H, d, J = 5.0Hz),
5.35 (1H, m), 5.66-6.30 (3H, m), 7.42
(1H, s), 8.55 (1H, s), 9.62 (1H, d,
J=8.0Hz) (37) 7-[2-(2-cyclopentene-1-i
)oximino-2-{2-(2,2,2-t)
(rifluoroacetamide) thiazole-4-y
}-acetamide]-3-(1H-1,2,3-
triazol-5-yl)thiomethyl-3-se
Fem-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3250, 1780, 1730, 1660,
1590, 1540cm^-1 N.M.R. (DMSO−d₆, δ) 2.10 (2H, m), 2.33 (2H, m), 3.67 (2H,
m), 3.97 (2H, m), 5.17 (1H, d, J=5
Hz), 5.33 (1H, m), 5.57-6.23 (2H, m),
7.50 (1H, s), 7.90 (1H, s), 9.73 (1H,
d, J=8Hz) (38) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-{3-(N-tertiary-butoxycarbonylamine
d)propyl}-1H-tetrazole-5-y
]thiomethyl-3-cephem-4-carvone
Acid (syn isomer). I.R. (Nujiyor): 3180, 1780, 1680cm^-1 N.M.R. (DMSO−d₆, δ) 1.42 (9H, s), 1.67-2.69 (6H, m), 3.01
(2H, m), 3.73 (2H, m), 4.08−4.73 (4H,
m), 5.18 (1H, d, J = 5.0Hz), 5.32 (1H,
m), 5.69-6.32 (3H, m), 7.42 (1H, s),
8.55 (1H, s), 9.62 (1H, d, J = 8.0Hz) (39) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-ka
rubamoyloxymethyl-3-cephem-4-
Carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3260, 1780, 1680 (Bro
), 1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.3-2.3 (6H, m), 3.55 (2H, broad s),
4.50−5.10 (3H, m), 5.20 (1H, d, J=5
Hz), 5.67-6.17 (3H, m), 6.57 (2H, block
code s), 7.38 (1H, s), 8.52 (1H, s),
9.60 (1H, d, J = 8Hz), 12.60 (1H, block
code) (40) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-carboxyethyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
- Carboxylic acids (syn isomers). I.R. (Nujiyor): 3180, 1770, 1660cm^-1 N.M.R. (DMSO−d₆, δ) 1.28−2.30 (6H, m), 2.97 (2H, m), 3.75
(2H, m), 4.22-4.95 (5H, m), 5.17 (1H,
d, J = 5.0Hz), 5.66-6.23 (3H, m), 7.43
(1H, s), 8.56 (1H, s), 9.66 (1H, d,
J=8.0Hz) (41) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-carboxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3270, 1765, 1660, 1630cm^-1 (42) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1H-1,
2,3-triazol-5-yl)thiomethyl
-3-cefem-4-carboxylic acid (syn isomer
body). Melting point 175-185℃ (decomposition). I.R. (Nujiyor): 3420, 3250, 1760, 1650,
1530cm^-1 (43) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(3
-aminopropyl)-1H-tetrazole-5-
yl]thiomethyl-3-cephem-4-carbo
acid (syn isomer). I.R. (Nujiyor): 3180, 1760, 1660, 1620cm^-1 (44) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(tetrazo
b[1,5-b]pyridazin-6-yl)thio
Methyl-3-cephem-4-carboxylic acid (syn
isomers). Melting point 178-180℃ (decomposition). I.R. (Nujiyor): 3280, 3180, 1770, 1650,
1620cm^-1 (45) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
(l-4-yl)acetamide]-3-carbamo
yloxymethyl-3-cephem-4-carbo
acid (syn isomer). Melting point 230-235°C (decomposition). I.R. (Nujiyor): 3440, 3330, 3270, 1750,
1690, 1630, 1530cm^-1 (46) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-carboxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nuzhiyor): 3300, 3200, 1770, 1660,
1630cm^-1 (47) N-[7-[2-(2-cyclopentene-1
-yl)oximino-2-(2-aminothia
sol-4-yl)acetamide]-3-ceph
Em-3-ylmethyl]-3'-hydroxymethy
Lupyridinium-4-carboxylate (syn
isomers). I.R. (Nuzhiyor): 3400-3150, 1770, 1660,
1610, 1530cm^-1 (48) N-[7-[2-(2-cyclopentene-1
-yl)oximino-2-(2-aminothia
sol-4-yl)acetamide]-3-cef
Em-3-ylmethyl]-3'-carbamoylpi
Lysinium-4-carboxylate (syn isomer
body). I.R. (Nuzhiyor): 3400-3200, 1780, 1680,
1615, 1530cm^-1 Example 13 7-[2-(2-cyclopenten-1-yl)o
Kixiimino-2-(2-formamidothiazole
-4-yl)acetamide]-3-cephem-4
-Carboxylic acid (syn isomer) (1.6g), concentrated hydrochloric acid
(1.1g), methanol (20ml) and tetrahydride
A mixture consisting of Lofuran (15 ml) was heated at room temperature for 2 hours.
Stirred. The solvent was distilled off from the reaction mixture. residue
was dissolved in an aqueous sodium hydrogen carbonate solution, and the obtained
The solution was adjusted to pH 3.0 with hydrochloric acid. The precipitate that has separated out
Filtered off, washed with water, dried over phosphorus pentoxide, 7-
[2-(2-cyclopenten-1-yl)oxy
Mino-2-(2-aminothiazol-4-yl)
Acetamide]-3-cephem-4-carboxylic acid
(syn isomer) (1.3 g) was obtained. Melting point 201~213℃
(Disassembly). I.R. (Nuzhiyor): 3400-3100, 1770, 1650,
1620, 1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.56−2.68 (4H, m), 3.56 (2H, broad
s), 5.08 (1H, d, J=5Hz), 5.26 (1H,
m), 5.44-5.98 (2H, m), 6.18 (1H, m),
6.46 (1H, m), 6.7 (1H, s), 9.50 (1H, d,
J=8Hz) Example 14 7-[2-(2-cyclopenten-1-yl)o
Kixiimino-2-{2-(2,2,2-trifluoro
roacetamido)thiazol-4-yl}aceto
Amide] Cephalosporanic acid (syn isomer) (1.8
g), sodium acetate trihydrate (4.1g), water
(50ml) and tetrahydrofuran (2ml)
The mixture was stirred at room temperature for 20 hours. Ethyl acetate
was added, the aqueous layer was separated and the solvent was distilled off. Residue
Adjust the residue to PH3.0 with 10% hydrochloric acid, and remove the precipitate.
Filtered off, washed with water, dried over phosphorus pentoxide, 7-
[2-(2-cyclopenten-1-yl)oxy
Mino-2-(2-aminothiazol-4-yl)
Acetamide] Cephalosporanic acid (syn isomer
(1.1 g) was obtained. Melting point 141-150℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1730,
1650, 1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.32−2.78 (4H, m), 3.58 (2H, broad
s), 4.87 (2H, q, J = 13Hz), 5.17 (1H,
d, J=5Hz), 5.32 (1H, m), 6.3-5.6
(3H, m), 6.76 (1H, s), 9.58 (1H, d,
J==8Hz) Example 15 7-[2-(2-cyclopenten-1-yl)o
Kixiimino-2-(2-formamidothiazole
-4-yl)acetamide]-3-(1,3,4-
Thiadiazol-2-yl)thiomethyl-3-ce
Fem-4-carboxylic acid (syn isomer) (2.5g),
Methanol (17.5ml), concentrated hydrochloric acid (0.88g) and
A mixture consisting of tetrahydrofuran (5.0 ml)
Stirred at room temperature for 1.5 hours. This reaction mixture has a pH of
water and saturated sodium bicarbonate to adjust to 5.0.
um aqueous solution was added. Remove the solvent from the resulting mixture.
The residue was evaporated and ethyl acetate was added to the residue. this mixture
Adjust the pH to 7.5 with saturated aqueous sodium bicarbonate solution.
did. Separate the aqueous layer, wash with ethyl acetate, and remove the remaining
The solvent was distilled off, and the residue was adjusted to pH 3.0 with 10% hydrochloric acid.
I arranged it. Separate the precipitate by filtration, wash with water, and add pentoxide.
Dry under reduced pressure over phosphorus to obtain 7-[2-(2-cyclo
Lopenten-1-yl)oxyimino-2-(2
-aminothiazol-4-yl)acetamide]
-3-(1,3,4-thiadiazol-2-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer) (2.00 g) was obtained. Melting point 152-157℃
(Disassembly). I.R. (Nujiyor): 3340, 1775, 1655cm^-1 N.M.R. (DMSO−d₆, δ) 1.66−2.81 (4H, m), 3.71 (2H, m), 4.47
(2H, q, J=14Hz), 4.99−5.57 (2H, m),
5.57−6.38 (3H, m), 6.76 (1H, s), 9.55
(1H, d, J=8.0Hz), 9.59 (1H, s) Example 16 7-[2-(2-cyclopenten-1-yl)o
Kixiimino-2-(2-formamidothiazole
-4-yl)acetamide]-3-(5-tertiary-
butoxycarboxamidomethyl-1,3,4-thi
adiazol-2-yl)thiomethyl-3-cef
Em-4-carboxylic acid (syn isomer) (2.3g), concentrated
From hydrochloric acid (1.35g) and methanol (30ml)
The mixture was stirred at room temperature for 2 hours. reaction mixture?
The solvent was distilled off, and the residue was dissolved in sodium hydrogen carbonate.
The solution was dissolved in a liquid, and insoluble matter was filtered off. Salt the filtrate with 10%
After adjusting the pH to 3.5 with acid, add 40% isopropyl alcohol.
Column chromatography using coal as eluent
Treatment (Nonionic adsorption resin manufactured by Mitsubishi Chemical Industries,
7-[2-(2-
cyclopenten-1-yl)oxyimino-2-
(2-aminothiazol-4-yl)acetamide
]-3-(5-aminomethyl-1,3,4-thia
diazol-2-yl)thiomethyl-3-cefe
Mu-4-carboxylic acid (syn isomer) (0.48g) was obtained.
Ta. Melting point 145-170℃ (decomposition). I.R. (Nujiyor): 3150, 1760, 1650, 1610,
1520cm^-1 N.M.R. (DMSO−d₆, δ) 1.87−2.57 (4H, m), 3.60 (2H, m), 4.3−
4.03 (2H, m), 4.47 (2H, broad s), 5.0
-5.27 (2H, m), 5.53 - 6.63 (3H, m), 6.63
(1H, s), 9.43 (1H, d, J=8Hz) Example 17 Methanol (12.0ml) and concentrated hydrochloric acid (0.56g)
7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamidothiazole)
-4-yl)acetamide]-3-(tetrazolo)
[1.5-b]pyridazin-6-yl)thiomethyl-
3-Cefem-4-carboxylic acid (syn isomer)
After stirring the suspension of (1.7 g), add
Add Dorofuran (12.0ml) to obtain a homogeneous solution;
The mixture was stirred at room temperature for 2 hours and 50 minutes. This reaction mixture
Add water and sodium bicarbonate to a pH of 5.0.
added to. After concentrating the mixture, add vinegar to this concentrate.
Ethyl acid, water and sodium hydrogen carbonate to pH 7.5
I added it so that it would be. Separate the aqueous layer and add ethyl acetate to
Wash twice, concentrate, and adjust to PH3.0 with 10% hydrochloric acid.
Ta. The deposited precipitate was filtered, washed with water, and dried under reduced pressure.
Dry over phosphorus oxide to obtain 7-[2-(2-cyclopene)
(ten-1-yl)oxyimino-2-(2-a
minothiazol-4-yl)acetamide]-3
-(tetrazolo[1,5-b]pyridazine-6-
yl)thiomethyl-3-cephem-4-carvone
Acid (syn isomer) (1.00g) was obtained. Melting point 178-180
°C (decomposition). I.R. (Nujiyor): 3280, 3180, 1770, 1650,
1620cm^-1 N.M.R. (DMSO−d₆, δ) 1.66−2.72 (4H, m), 3.71 (2H, m), 4.42
(2H, ABq, J=13.0Hz), 4.98−5.42 (2H,
m), 5.62-6.23 (3H, m), 6.67 (1H, s),
7.69 (1H, d, J = 10.0Hz), 8.52 (1H, d,
J = 10.0Hz), 9.44 (1H, d, J = 8.0Hz) Example 18 7-[2-(2-cyclopenten-1-yl)o
Kixiimino-2-{2-(2,2,2-trifluoro
roacetamido)thiazol-4-yl}aceto
amide]-3-(1H-1,2,3-triazole
-5-yl)thiomethyl-3-cephem-4-ka
Rubonic acid (syn isomer) (1.4g), sodium acetate
(1.78g) and water (60ml) in a chamber.
Stir overnight at room temperature. Separate the aqueous layer from the reaction mixture
The pH was then adjusted to 3.0 with 10% hydrochloric acid. formed precipitate
was filtered and washed with water to obtain 7-[2-(2-cyclopene).
then-1-yl)oxyimino-2-(2-amino)
Nothiazol-4-yl)acetamide]-3-
(1H-1,2,3-triazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid (syn
isomer) (0.8 g) was obtained. Melting point 175-185℃ (min.
solution). I.R. (Nujiyor): 3420, 3250, 1760, 1650,
1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.63−2.50 (4H, m), 3.60 (2H, m), 3.93
(2H, m), 5.07 (1H, d, J=5Hz), 5.13
−5.43 (1H, m), 5.50−6.23 (2H, m), 6.67
(1H, s), 7.90 (1H, s), 9.52 (1H, d,
J=8Hz) Example 19 By a method similar to that described in Examples 13-18
The following compounds were prepared. (1) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-2-methyl-3-
Cefem-4-carboxylic acid (syn isomer). I.R. (Nujiyor): 3300, 1770, 1660, 1630cm^-1 N.M.R. (DMSO−d₆, δ) 1.42 (3H, d, J = 7Hz), 1.74-2.7 (4H,
m), 3.57-4.04 (1H, m), 5.12 (1H, d,
J=5Hz), 5.14-5.64 (1H, m), 5.85 (1H,
dd, J=5 and 8Hz), 5.87−6.24 (2H, m),
6.55 (1H, d, J=6Hz), 6.7 (1H, s),
7.24 (2H, broad s), 9.50 (1H, d, J=
8Hz) (2) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-carbamoyl
Oxymethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 182-195°C (decomposition). I.R. (Nujiyor): 3250, 1760, 1700, 1650,
1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.78−2.53 (4H, m), 3.53 (2H, broad
s), 4.78 (2H, q, J = 13Hz), 5.17 (1H,
d, J=5Hz), 5.30 (1H, m), 5.60−6.33
(3H, s), 6.60 (2H, broad s), 6.77
(1H, s), 9.57 (1H, d, J=8Hz) (3) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(2-tertiary-
Butoxycarboxamidoethyl)thiomethyl-
Benzhydryl 3-cephem-4-carboxylate
(syn isomer). I.R. (Nuzhiyor): 3500-3200, 1780, 1680,
1620, 1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.33 (9H, s), 1.90−2.50 (4H, m), 2.93
(2H, m), 3.43-3.77 (4H, m), 5.20 (1H,
d, J=5Hz), 5.27 (1H, m), 5.60−6.17
(5H, m), 6.70 (1H, s), 6.88 (1H, s),
7.00−7.67 (10H, m), 9.52 (1H, d, J=
8Hz) (4) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(2-aminoe)
thiomethyl-3-cephem-4-carbo
acid (syn isomer). I.R. (Nuzhiyor): 3350-3100, 1760, 1660,
1610, 1515cm^-1 (5) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(5-methyl-
1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid (syn
isomers). Melting point 148-152℃. I.R. (Nujiyor): 3260, 1870, 1650cm^-1 N.M.R. (DMSO−d₆, δ) 1.5−2.87 (4H, m), 2.87 (3H, s), 3.68
(2H, m), 4.40 (2H, dd, J=15 and 21Hz),
5.13 (1H, d, J = 5Hz), 5.1-5.5 (1H,
m), 5.77 (1H, dd, J=5 and 8Hz), 5.83−
6.29 (2H, m), 6.72 (1H, s), 7.2 (2H,
m), 9.5 (1H, d, J=8Hz) (6) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 147-150℃. I.R. (Nujiyor): 3300, 1770, 1660cm^-1 N.M.R. (DMSO−d₆, δ) 1.67−2.69 (4H, m), 3.68 (2H, m), 3.93
(3H, s), 4.32 (2H, m), 5.12 (1H, d,
J = 5Hz), 5.1-5.43 (1H, m), 5.78 (1H,
dd, J=5 and 8Hz), 5.9−6.32 (2H, m),
6.7 (1H, s), 7.2 (2H, m), 9.5 (1H, d,
J=8Hz) (7) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-allyl-
1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 145-153°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1620, 1520cm^-1 N.M.R. (DMSO−d₆, δ) 1.52−2.8 (4H, m) 3.7 (2H, broad s),
4.37 (2H, q, J = 13Hz), 4.83−5.48 (6H,
m), 5.63-6.53 (4H, m), 6.72 (1H, s),
9.48 (1H, d, J=8Hz) (8) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(1-carboxy
dimethyl-1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 164-170℃ (decomposition). I.R. (Nujiyor): 3280, 1765, 1655cm^-1 N.M.R. (DMSO−d₆, δ) 1.76−2.79 (4H, m), 3.70 (2H, m), 4.39
(2H, q, J = 14.0Hz), 5.13 (1H, d, J =
5.0Hz), 5.03-5.56 (3H, m), 5.65-6.35
(3H, m), 6.74 (1H, s), 9.56 (1H, d,
J=7.0Hz) (9) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(4-carboxy
cypyridin-2-yl)thiomethyl-3-cef
Em-4-carboxylic acid (syn isomer). Melting point 174
~205℃ (decomposition). I.R. (Nuzhiyor): 1760, 1670, 1620, 1450,
1370, 1360cm^-1 N.M.R. (DMSO−d₆, δ) 1.77-2.50 (4H, m), 3.50-3.77 (2H, m),
4.30 (2H, ABq, J=15Hz), 5.10−5.43
(2H, m), 5.57-6.37 (3H, m), 6.73 (1H,
s), 7.50-7.77 (2H, m), 8.60-8.67 (1H,
m), 9・53 (1H, d, J=8Hz) (10) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1H-tetra
sol-5-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer). Melting point 165-172°C (decomposition). I.R. (Nujiyor): 3300, 1770, 1660, 1630cm^-1 N.M.R. (DMSO−d₆, δ) 1.56−2.68 (4H, m), 3.70 (2H, m), 4.34
(2H, q, J = 13.0Hz), 5.03−5.54 (2H,
m), 5.61-6.30 (3H, m), 6.76 (1H,
s), 9.56 (1H, d, J = 8.0Hz) (11) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-cephem-4
- Carboxylic acids (syn isomers). Melting point 220-241℃
(Disassembly). I.R. (Nuzhiyor): 3400-3100, 1770, 1650,
1630, 1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.37−2.4 (6H, m), 3.65 (2H, m), 4.67
(1H, m), 5.13 (1H, d, J=5Hz), 5.62
−6.31 (3H, m), 6.53 (1H, m), 6.75 (1H,
s), 9.56 (1H, d, J = 8Hz) (12) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-2-methyl-3-
Cefem-4-carboxylic acid (syn isomer). Melting point 159-166°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1630, 1520cm^-1 N.M.R. (DMSO−d₆, δ) 1.47 (3H, d, J = 7Hz), 1.08−2.3 (6H,
m), 4.18-3.48 (1H, m), 5.13 (1H, d,
J = 5Hz), 4.67 (1H, m), 5.5-6.25 (3H,
m), 6.77 (1H, d, J=6Hz), 9.57 (1H,
d, J=8Hz) (13) 7-[2-(2-cyclohexene-1-y
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1,3,
4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.07−2.25 (6H, m), 3.7 (2H, broad
s), 4.45 (2H, q, J = 12Hz), 4.23−4.92
(1H, m), 5.15 (1H, d, J=5Hz), 5.87
−6.17 (3H, m), 6.77 (1H, s), 9.58 (1H,
d, J=8Hz), 9.58 (1H, s) (14) 7-[2-(2-cyclohexene-1-y
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-methy
-1H-tetrazol-5-yl)thiomethy
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 156-160℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1520cm^-1 N.M.R. (DMSO−d₆, δ) 1.18−2.22 (6H, m), 3.67 (2H, broad
s), 3.93 (3H, s), 4.3 (2H, m), 4.57
(1H, m), 5.12 (1H, d, J=5Hz), 5.35
−6.17 (3H, m), 6.73 (1H, s), 9.58 (1H,
d, J=8Hz) (15) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-aryl)
-1H-tetrazol-5-yl)thiomethy
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 148-157°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1620, 1520cm^-1 N.M.R. (DMSO−d₆, δ) 1.05−2.38 (6H, m), 3.68 (2H, broad
s), 4.38 (2H, m), 4.65 (1H, m), 4.8−
5.53 (5H, m), 5.6-6.42 (4H, m), 6.73
(1H, s), 9.53 (1H, d, J=8Hz) (16) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-cal)
boxymethyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 166-182°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.1−2.25 (6H, m), 3.68 (2H, m), 4.37
(2H, m), 4.63 (1H, m), 5.12 (1H, d,
J=5Hz), 5.3 (2H, s), 5.07 (3H, m),
6.7 (1H, s), 9.52 (1H, d, J=8Hz) (17) 7-[2-(2-cyclohexene-1-y
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1H-te
Torazol-5-yl)thiomethyl-3-ceph
Em-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1630, 1520cm^-1 N.M.R. (DMSO−d₆, δ) 1.17−2.32 (6H, m), 3.68 (2H, broad
s), 4.33 (2H, m), 4.6 (1H, m), 5.12
(1H, d, J=5Hz), 6.13−5.57 (3H, m),
6.73 (1H, s), 9.52 (1H, d, J=8Hz) (18) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-hydroxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). Melting point 162-168℃ (min.
solution). I.R. (Nuzhiyor): 3400-3100, 1770, 1720,
1650, 1540cm^-1 N.M.R. (DMSO−d₆, δ) 1.45-2.68 (4H, m), 3.53-4.00 (2H, m),
4.08−4.67 (4H, m), 5.15 (1H, d, J=5
Hz), 5.35 (1H, m), 5.65-6.3 (3H, m),
6.87 (1H, s), 9.67 (1H, d, J=8Hz) (19) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
(4-yl)acetamide] Cephalospora
acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1740,
1660, 1630, 1520cm^-1 (20) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-carboxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3270, 1765, 1660, 1630cm^-1 N.M.R. (DMSO−d₆, δ) 1.67−1.73 (4H, m), 2.90 (2H, t, J = 6.0
Hz), 3.67 (2H, m), 4.01-4.70 (4H, m),
5.06 (1H, d, J = 5.0Hz), 5.20 (1H, m),
5.50−6.18 (3H, m), 6.63 (1H, s), 9.40
(1H, d, J=8.0Hz) (21) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(3
-aminopropyl)-1H-tetrazole-5-
yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer). I.R. (Nujiyor): 3180, 1760, 1660, 1620cm^-1 N.M.R. (DMSO−d₆, δ) 1.68−2.60 (4H, m), 2.96 (2H, m), 3.51
(2H, m), 4.06-4.67 (4H, m), 5.01 (1H,
d, J=5Hz), 5.26 (1H, m), 5.47−6.28
(3H, m), 6.70 (1H, s), 9.45 (1H, d,
J=8Hz) (22) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
(l-4-yl)acetamide]-3-carbamo
yloxymethyl-3-cephem-4-carbo
acid (syn isomer). Melting point 230-235°C (decomposition). I.R. (Nujiyor): 3440, 3330, 3270, 1750,
1690, 1630, 1530cm^-1 N.M.R. (DMSO−d₆, δ) 1.13−2.27 (6H, m), 3.50 (2H, broad
s), 4.43-4.93 (3H, m), 5.15 (1H, d,
J = 5Hz), 5.57-6.07 (3H, m), 6.57 (1H,
broad s), 6.70 (1H, s), 9.53 (1H, d,
J=8Hz) (23) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-carboxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nuzhiyor): 3300, 3200, 1770, 1660,
1630cm^-1 N.M.R. (DMSO−d₆, δ) 1.30−2.26 (6H, m), 2.95 (2H, t, J = 6.0
Hz), 3.72 (2H, m), 4.08-4.84 (5H, m),
5.13 (1H, d, J = 4.0Hz), 5.61−6.11 (3H,
m), 6.73 (1H, s), 9.54 (1H, d, J = 8.0
Hz) (24) N-[7-{2-(2-cyclopentene-1
-yl)oximino-2-(2-aminothia
sol-4-yl)acetamide}-3-cef
Em-3-ylmethyl]pyridinium-4-ka
Ruboxylate (syn isomer). Melting point 171-180
°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1610, 1530cm^-1 (25) N-[7-[2-(2-cyclopentene-1
-yl)oximino-2-(2-aminothia
sol-4-yl)acetamide]-3-ceph
Em-3-ylmethyl]-3'-hydroxymethy
Lupyridinium-4-carboxylate (syn
isomers). I.R. (Nuzhiyor): 3400-3150, 1770, 1660,
1610, 1530cm^-1 (26) N-[7-[2-(2-cyclopentene-1
-yl)oximino-2-(2-aminothia
sol-4-yl)acetamide]-3-ceph
Em-3-ylmethyl]-3'-carbamoylpi
Lysinium-4-carboxytote (syn isomer
body). I.R. (Nuzhiyor): 3400-3200, 1780, 1680,
1615, 1530cm^-1 Example 20 7-[2- in phosphate buffer (PH6.4) (150ml)
(2-cyclopenten-1-yl)oxyimino
-2-(2-aminothiazol-4-yl)acetate
Toamide] Cephalosporanic acid (syn isomer)
(1.52 g) of 1,3,4-thiadiazole
Ru-2-thiol (0.53g) was added. This mixture
The mixture was stirred at 55-60°C for 3 hours. Cool the reaction mixture
After cooling, the pH was adjusted to 3 with 10% hydrochloric acid. precipitated
The precipitate was filtered, washed with water, and dried to give 7-[2-(2
-cyclopenten-1-yl)oxyimino-2
-(2-aminothiazol-4-yl)acetoa
mido]-3-(1,3,4-thiadiazole-2-
yl)thiomethyl-3-cephem-4-carvone
Acid (syn isomer) (0.73g) was obtained. I.R.
): 3340, 1775, 1655cm^-1 Example 21 7-[2-(2-cyclopenten-1-yl)o
xiimino-2-(2-aminothiazole-4-
yl) acetamide] cephalosporanic acid (syn
isomer) (3.0g) and sodium bicarbonate (0.5g)
Pyridine (1.2 g) in water (30 ml) solution at 50 °C with
added. Furthermore, sodium iodide (9
After adding g), stir the mixture at the same temperature for 40 minutes.
did. The reaction mixture was cooled to 5°C and the pH was adjusted with 10% hydrochloric acid.
After adjusting to 2.0, it was filtered. The filtrate is transferred to Mitsubishi Chemical
Industrial non-ionic adsorption resin, Diaion
Chromatographed on a column of Hp20,
% methanol aqueous solution. Contains the target compound
The fractions containing N-
[7-{2-(2-cyclopenten-1-yl)o
xiimino-2-(2-aminothiazole-4-
yl) acetamido}-3-cephem-3-yl
Methyl]pyridinium-4-carboxylate
(syn isomer) (0.35 g) was obtained. This product is true
It was the same as the original sample. Example 22 7-[2-(2-cyclopentene) in water (6 ml)
-1-yl)oximino-2-(2-aminothi
Azol-4-yl)acetamide] Cephalos
Polanic acid (syn isomer) (4.92g), sodium bicarbonate
(0.84g), 3-hydroxymethylpyridine
(5.5g) and sodium iodide (21g).
The mixture was stirred at 80-81°C for 1 hour. reaction mixture
Dissolve the material in water (300 ml) and wash with ethyl acetate.
Ta. Separate the aqueous layer and adjust the pH to 1.0 with 10% hydrochloric acid.
The precipitate was removed. 10% sodium hydroxide solution
The pH was adjusted to 5.5 with a solution. After removing the solvent under reduced pressure,
The remaining aqueous solution was brought to pH3.6 with an aqueous hydrochloric acid solution under ice cooling.
It was adjusted. This solution was added to the nonionic adsorption resin
Aion HP20” (trademark: manufactured by Mitsubishi Chemical Industries)
Lamb chromatography treated, 40% isopropylene
Elution was performed with an aqueous alcohol solution. Contains the target compound
Collect the fractions, concentrate in vacuo, and lyophilize.
, N-[7-[2-(2-cyclopentene-1-
yl)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-cephem-
3-ylmethyl]-3'-hydroxymethylpyridi
Ni-4-carboxylate (syn isomer)
(0.7g) was obtained. I.R. (Nuzhiyor): 3400-3150, 1770, 1660,
1610, 1530cm^-1 N.M.R. (D₂O+DCL, δ): 1.5−3.00 (4H, m), 3.7 (2H, m), 5.27−
6.5 (7H, m), 5.40 (1H, d, J=5Hz),
6.00 (1H, d, J=5Hz), 7.22 (1H, s),
8.25 (1H, m), 8.5-9.17 (3H, m) Example 23 By a method similar to that described in Examples 20-22
The following compounds were prepared. (1) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(2-tertiary-
Butoxycarboxamidoethyl)thiomethyl-
Benzhydryl 3-cephem-4-carboxylate
(syn isomer). I.R. (Nuzhiyor): 3500-3200, 1780, 1620,
1530cm^-1 (2) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(2-aminoe)
thiomethyl-3-cephem-4-carbo
acid (syn isomer). I.R. (Nuzhiyor): 3350-3100, 1760, 1660,
1610, 1515cm^-1 (3) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(5-methyl-
1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid (syn
isomers). Melting point 148-152℃. I.R. (Nujiyor): 3260, 1770, 1650cm^-1 (4) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 147-150℃. I.R. (Nujiyor): 3300, 1770, 1660cm^-1 (5) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-allyl-
1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 145-153°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1620, 1520cm^-1 (6) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(1-carboxy
dimethyl-1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 164-170℃ (decomposition). I.R. (Nujiyor): 3280, 1765, 1655cm^-1 (7) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(4-carboxy
cypyridin-2-yl)thiomethyl-3-ceph
Em-4-carboxylic acid (syn isomer). Melting point 174
~205℃ (decomposition). I.R. (Nuzhiyor): 1760, 1670, 1620, 1450,
1370, 1360cm^-1 (8) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(1H-tetra
sol-5-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer). Melting point 165~
172℃ (decomposition). I.R. (Nujiyor): 3300, 1770, 1660, 1630cm^-1 (9) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(5-aminome)
Chil-1,3,4-thiadiazol-2-y
)thiomethyl-3-cephem-4-carvone
Acid (syn isomer). Melting point 145-170℃ (decomposition). I.R. (Nujiyor): 3150, 1760, 1650, 1610,
1520cm^-1 (10) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(1,3,4-
Thiadiazol-2-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1530cm^-1 (11) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-methyl-
IH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 156-160℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1520cm^-1 (12) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-allyl-
IH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 148-157°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1620, 1520cm^-1 (13) 7-[2-(2-cyclohexene-1-y
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-cal)
boxymethyl-IH-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 166-182°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1530cm^-1 (14) 7-[2-(2-cyclohexene-1-y
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(IH-te)
Torazol-5-yl)thiomethyl-3-ceph
Em-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1630, 1520cm^-1 (15) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(2
-tertiary-butoxycarboxamide ethyl)thi
Ben omethyl-3-cephem-4-carboxylate
Zuhydryl (syn isomer). I.R. (Nujiyor): 3270, 3150, 1780, 1710,
1680, 1660, 1570, 1225cm^-1 (16) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nujiyor): 3150, 1770, 1670cm^-1 (17) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(5
-Methyl-1,3,4-thiadiazole-2-
yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer). I.R. (Nujiyor): 3240, 1765, 1660cm^-1 (18) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-Methyl-IH-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nujiyor): 3240, 1760, 1670cm^-1 (19) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-Allyl-IH-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 120-139°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 (20) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-carboxymethyl-IH-tetrazole-5
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3150, 1770, 1660cm^-1 (21) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(4
-carboxypyridin-2-yl)thiomethyl
-3-cefem-4-carboxylic acid (syn isomer
body). I.R. (Nuzhiyor): 1770, 1690-1650, 1540cm
^-1 (22) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-
(IH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer). I.R. (Nujiyor): 1770, 1660cm^-1 (23) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(5
-Tertiary-butoxycarboxamidomethyl-
1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid (syn
isomers). I.R. (Nujiyor): 3270, 1780, 1700, 1680,
1530cm^-1 (24) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer) I.R. (Nuzhiyor): 3300-3100, 1780, 1670,
1540cm^-1 (25) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-Methyl-IH-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nuzhiyor): 3400-3100, 1780, 1660,
1550cm^-1 (26) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-Allyl-IH-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 (27) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-carboxymethyl-IH-tetrazole-5
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 (28) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-
(IH-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1540cm^-1 (29) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-Hydroxyethyl)-IH-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). Melting point 162-168℃ (min.
solution). I.R. (Nuzhiyor): 3400-3100, 1770, 1720,
1650, 1540cm^-1 (30) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-hydroxyethyl)IH-tetrazole
-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1780, 1670,
1540cm^-1 (31) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-carboxyethyl)-IH-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
- Carboxylic acids (syn isomers). I.R. (Nujiyor): 3160, 1770, 1660cm^-1 (32) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-carboxyethyl)-IH-tetrazole-5
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3270, 1765, 1660, 1630cm^-1 (33) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1H-1,
2,3-triazol-5-yl)thiomethyl
-3-cefem-4-carboxylic acid (syn isomer
body). Melting point 175-185℃ (decomposition). I.R. (Nujiyor): 3420, 3250, 1760, 1650,
1530cm^-1 (34) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-[3-(N-tertiary-butoxycarbonylamine
) Propyl]-IH-tetrazole-5-y
]thiomethyl-3-cephem-4-carvone
Acid (syn isomer). I.R. (Nujiyor): 3180, 1780, 1680cm^-1 (35) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(3
-aminopropyl)-IH-tetrazole-5-
yl]thiomethyl-3-cephem-4-carbo
acid (syn isomer). I.R. (Nujiyor): 3180, 1760, 1660, 1620cm^-1 (36) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(te)
Torazolo[1,5-b]pyridazine-6-y
)thiomethyl-3-cephem-4-carvone
Acid (syn isomer). I.R. (Nujiyor): 3180, 1780, 1670cm^-1 (37) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(tetrazo
b[1,5-b]pyridazin-6-yl)thio
Methyl-3-cephem-4-carboxylic acid (syn
isomers). Melting point 178-180℃ (decomposition). I.R. (Nujiyor): 3280, 3180, 1770, 1650,
1620cm^-1 (38) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-carboxyethyl)-IH-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
-carboxylic acids (syn isomers). I.R. (Nujiyor): 3180, 1770, 1660cm^-1 (39) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-carboxyethyl)-IH-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nuzhiyor): 3300, 3200, 1770, 1660,
1630cm^-1 (40) N-[7-[2-(2-cyclopentene-1
-yl)oximino-2-(2-aminothia
sol-4-yl)acetamide]-3-cef
Em-3-ylmethyl]-3'-carbamoylpi
Lysinium-4-carboxylate (syn isomer
body). I.R. (Nuzhiyor): 3400-3200, 1780, 1680,
1615, 1530cm^-1 N.M.R. (D₂O+DCL, δ): 1.5−2.72 (4H, m), 3.53, 4.00 (2H, q, J
= 18Hz), 5.33-6.50 (5H, m), 5.43 (1H,
d, J=5Hz), 6.00 (1H, d, J=5Hz),
7.20 ((1H, s), 8.40 (1H, dd, J=6and6
Hz), 9.00-9.47 (2H, m), 9.53 (1H, s) Example 24 7-[2-(2-cyclopenten-1-yl)o
xiimino-2-(2-aminothiazole-4-
yl)acetamido]-3-(2-tertiary-butoxy)
cycarboxamide ethyl)thiomethyl-3-cef
Benzhydryl Em-4-carboxylate (syn isomer
(2.7 g) in methylene chloride (20 ml), cooled on ice.
Discard trifluoroacetic acid (7.8g) and anisole
(2.2g) was added. Stir this mixture for 50 minutes at room temperature.
Stirred. The solvent was distilled off from the reaction mixture and the residue was cooled.
A mixture of water and ethyl acetate was added. this mixture
Adjust the pH to 7.5 with 20% sodium bicarbonate aqueous solution.
Ta. Separate the aqueous layer, wash with ethyl acetate, and add to this
Ethyl acetate was added. PH this mixture with 10% hydrochloric acid.
Adjusted to 2. Separate the aqueous layer and add saturated sodium bicarbonate.
After adjusting the pH to 6 with aqueous lithium solution, the solvent was distilled off.
After adjusting the residue to PH3.8 with 10% hydrochloric acid, add 30% isopropylene.
Column chromatography using pill alcohol as eluent
Roughy treatment (Nonionic adsorption manufactured by Mitsubishi Chemical Corporation)
(using resin, Diaion HP20). objectification
Fractions containing the compound were collected and the solvent was distilled off. Residue
The residue was lyophilized to give 7-[2-(2-cyclopente
(1-yl)oxyimino-2-(2-amino
thiazol-4-yl)acetamide]-3-(2
-aminoethyl)thiomethyl-3-cephem-4
-carboxylic acid (syn isomer) (1.0 g) was obtained. I.R. (Nuzhiyor): 3350-3100, 1760, 1660,
1610, 1515cm^-1 N.M.R. (DMSO−d₆, δ) 1.60−3.24 (6H, m), 3.24−3.90 (6H, m),
5.08 (1H, d, J=5Hz), 5.26 (1H, m),
5.64 (1H, dd, j=5and8Hz), 5.76−6.2
(2H, m), 6.72 (1H, s), 9.44 (1H, d,
J=8Hz) Example 25 The following compound was produced by the same method as Example 24.
Built. (1) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-cephem-4
- Carboxylic acids (syn isomers). Melting point 201~213℃
(Disassembly). I.R. (Nuzhiyor): 3400-3100, 1770, 1650,
1620, 1540cm^-1 (2) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-2-methyl-3-
Cefem-4-carboxylic acid (syn isomer). I.R. (Nujiyor): 3300, 1770, 1660, 1630cm^-1 (3) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]cephalosporanic acid
(syn isomer). Melting point 141-150℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1730,
1650, 1530cm^-1 (4) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-carbamoyl
Oxymethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 182-195°C (decomposition). I.R. (Nuzhiyor): 3250, 1760, 1700, 1650,
1540cm^-1 (5) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(1,3,4-
Thiadiazol-2-yl)thiomethyl-3-
Cefem-4-carboxylic acid (syn isomer). Melt
Point 152-157℃ (decomposition). I.R. (Nujiyor): 3340, 1775, 1655cm^-1 (6) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(5-methyl-
1,3,4-thiadiazol-2-yl)thio
Methyl-3-cephem-4-carboxylic acid (syn
isomers). Melting point 148-152℃. I.R. (Nujiyor): 3260, 1770, 1650cm^-1 (7) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-methyl-
1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 147-150℃. I.R. (Nujiyor): 3300, 1770, 1660cm^-1 (8) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(1-allyl-
1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 145-153°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1620, 1520cm^-1 (9) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(1-carboxy
dimethyl-1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 164-170℃ (decomposition). I.R. (Nujiyor): 3280, 1765, 1655cm^-1 (10) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(4-carboxy
cypyridin-2-yl)thiomethyl-3-ceph
Em-4-carboxylic acid (syn isomer). Melting point 174
~205℃ (decomposition). I.R. (Nuzhiyor): 1760, 1670, 1620, 1450,
1370, 1360cm^-1 (11) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamide]-3-(1H-tetra
sol-5-yl)thiomethyl-3-cephem
-4-carboxylic acid (syn isomer). Melting point 165~
172℃ (decomposition). I.R. (Nujiyor): 3300, 1770, 1660, 1630cm^-1 (12) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(5-aminome)
Chil-1,3,4-thiadiazol-2-y
)thiomethyl-3-cephem-4-carvone
Acid (syn isomer). Melting point 145-170℃ (decomposition). I.R. (Nujiyor): 3150, 1760, 1650, 1610,
1520cm^-1 (13) 7-[2-(2-cyclohexene-1-y
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-cephem
-4-carboxylic acid (syn isomer). Melting point 220~
241℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1650,
1630, 1530cm^-1 (14) 7-[2-(2-cyclohexene-1-y
)oximino-2-(2-aminothiazole)
(l-4-yl)acetamido]-2-methyl-
3-cephem-4-carboxylic acid (syn isomer).
Melting point 159-166°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1630, 1520cm^-1 (15) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1,3,
4-thiadiazol-2-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1530cm^-1 (16) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-methy
-1H-tetrazol-5-yl)thiomethylene
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 156-160℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1520cm^-1 (17) 7-[2-(2-cyclohexene-1-y
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-aryl)
-1H-tetrazol-5-yl)thiomethylene
-3-cephem-4-carboxylic acid (syn isomer
body). Melting point 148-157°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1620, 1520cm^-1 (18) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1-cal)
boxymethyl-1H-tetrazol-5-yl)
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 166-182°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1620, 1530cm^-1 (19) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1H-te
Torazol-5-yl)thiomethyl-3-cef
Em-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1630, 1520cm^-1 (20) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-ce
Fem-4-carboxylic acid (syn isomer). melting point
145-170℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1780, 1680,
1650, 1540cm^-1 (21) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-2-meth
Chil-3-cephem-4-carboxylic acid (syn
gender body). I.R. (Nujiyor): 3260, 1780, 1680, 1660cm^-1 (22) 7-[2-(2-cyclopentene-1-i
)oximino-2-{2-(2,2,2-t)
(rifluoroacetamide) thiazole-4-y
Cephalosporanic acid (syn
isomers). I.R. (Nuzhiyor): 3400-3100, 1780, 1730,
1660, 1580, 1510cm^-1 (23) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-ka
rubamoyloxymethyl-3-cephem-4-
Carboxylic acid (syn isomer). I.R. (Nujiyor): 3450, 3260, 1770, 1700,
1660, 1640, 1610, 1550cm^-2 (24) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nujiyor): 3150, 1770, 1670cm^-1 (25) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(5
-Methyl-1,3,4-thiadiazole-2-
yl)thiomethyl-3-cephem-4-carbo
acid (syn isomer). I.R. (Nujiyor): 3240, 1765, 1660cm^-1 (26) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-Methyl-1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nujiyor): 3240, 1760, 1670cm^-1 (27) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-allyl-1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 120-139°C (decomposition). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 (28) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-carboxymethyl-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3150, 1770, 1660cm^-1 (29) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(4
-carboxypyridin-2-yl)thiomethyl
-3-cefem-4-carboxylic acid (syn isomer
body). I.R. (Nuzhiyor): 1770, 1690-1650, 1540cm^-1 (30) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-
(1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer). I.R. (Nujiyor): 1770, 1660cm^-1 (31) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-ce
Fem-4-carboxylic acid (syn isomer). melting point
155-185℃ (decomposition). I.R. (Nuzhiyor): 3400-3100, 1780, 1690,
1660, 1630, 1540cm^-1 (32) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-2-meth
Chil-3-cephem-4-carboxylic acid (syn
gender). I.R. (Nujiyor): 3275, 3175, 1780, 1690,
1660, 1620, 1570, 1530cm^-1 (33) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-
(1,3,4-thiadiazol-2-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nuzhiyor): 3300-3100, 1780, 1670,
1540cm^-1 (34) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-Methyl-1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nuzhiyor): 3400-3100, 1780, 1660,
1550cm^-1 (35) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-allyl-1H-tetrazol-5-yl)thi
Omethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 (36) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-carboxymethyl-1H-tetrazole-5
-yl)thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1670,
1540cm^-1 (37) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-
(1H-tetrazol-5-yl)thiomethyl-
3-cephem-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1660,
1540cm^-1 (38) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-hydroxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). Melting point 162-168℃ (min.
solution). I.R. (Nuzhiyor): 3400-3100, 1770, 1720,
1650, 1540cm^-1 (39) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-hydroxyethyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
- Carboxylic acids (syn isomers). I.R. (Nuzhiyor): 3400-3100, 1780, 1670,
1540cm^-1 (40) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
(4-yl)acetamide] Cephalospora
acid (syn isomer). I.R. (Nuzhiyor): 3400-3100, 1770, 1740,
1660, 1630, 1520cm^-1 (41) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-carboxyethyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
-carboxylic acids (syn isomers). I.R. (Nujiyor): 3160, 1770, 1660cm^-1 (42) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-carboxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3270, 1765, 1660, 1630cm^-1 (43) 7-[2-(2-cyclopentene-1-i
)oximino-2-2-{2-(2,2,2
-trifluoroacetamide)thiazole-4
-yl}acetamido]-3-(1H-1,2,
3-triazol-5-yl)thiomethyl-3
-Cefem-4-carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3250, 1780, 1730, 1660,
1590, 1540cm^-1 (44) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(1H-1,
2,3-triazol-5-yl)thiomethyl
-3-cefem-4-carboxylic acid (syn isomer
body). Melting point 175-185℃ (decomposition). I.R. (Nujiyor): 3420, 3250, 1760, 1650,
1530cm^-1 (45) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(1
-{3-(N-tertiary-butoxycarbonylamine
(n)propyl}1H-tetrazol-5-yl}
Thiomethyl-3-cephem-4-carboxylic acid
(syn isomer). I.R. (Nujiyor): 3180, 1780, 1680cm^-1 (46) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(3
-aminopropyl)-1H-tetrazole-5-
yl]thiomethyl-3-cephem-4-carbo
acid (syn isomer). I.R. (Nujiyor): 3180, 1760, 1660, 1620cm^-1 (47) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-(te)
Torazolo[1,5-b]pyridazine-6-y
)thiomethyl-3-cephem-4-carvone
Acid (syn isomer). I.R. (Nujiyor): 3180, 1780, 1670cm^-1 (48) 7-[2-(2-cyclopentene-1-i
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-(tetrazo
b[1,5-b]pyridazin-6-yl)thio
Methyl-3-cephem-4-carboxylic acid (syn
isomers). Melting point 178-180℃ (decomposition). I.R. (Nujiyor): 3280, 3180, 1770, 1650,
1620cm^-1 (49) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-ka
rubamoyloxymethyl-3-cephem-4-
Carboxylic acid (syn isomer). I.R. (Nuzhiyor): 3260, 1780, 1680 (Bro
), 1540cm^-1 (50) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
(l-4-yl)acetamide]-3-carbamo
yloxymethyl-3-cephem-4-carbo
acid (syn isomer). Melting point 230-235°C (decomposition). I.R. (Nujiyor): 3440, 3330, 3270, 1750,
1690, 1630, 1530cm^-1 (51) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-formamidothi)
azol-4-yl)acetamide]-3-[1
-(2-carboxyethyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4
- Carboxylic acids (syn isomers). I.R. (Nujiyor): 3180, 1770, 1660cm^-1 (52) 7-[2-(2-cyclohexene-1-y)
)oximino-2-(2-aminothiazole)
-4-yl)acetamide]-3-[1-(2
-carboxyethyl)-1H-tetrazole-5
-yl]thiomethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nuzhiyor): 3300, 3200, 1770, 1660,
1630cm^-1 Example 26 7-[2-(2-cyclopenten-1-yl)o
Kixiimino-2-(2-formamidothiazole
-4-yl)acetamide]-3-[1-{3-(N
-tertiary-butoxycarbonylamino)propyl
1H-tetrazol-5-yl]thiomethyl
-3-Cefem-4-carboxylic acid (syn isomer)
(1.75 g) in methanol (13 ml) with concentrated hydrochloric acid.
(1.0 g) with stirring, and the mixture was heated to room temperature.
The mixture was stirred for 3 hours. Distill the solvent from the resulting mixture.
Add methanol (20ml) to the residue to make a homogeneous solution.
was obtained and the solution was concentrated. Solution formation and concentration 3
After repeated cycles, the resulting reaction mixture was diluted with ethyl acetate.
and water. Add this mixture to sodium bicarbonate.
After adjusting the pH to 7.5 with
Wash with chilled water and distill off the remaining ethyl acetate.
Ta. The resulting aqueous layer was adjusted to pH 3.8 with 1N hydrochloric acid.
After that, it passed. The separated precipitate was washed with water and
Dry under vacuum over phosphorus to obtain 7-[2-(2-cyclopetrope).
(ten-1-yl)oxyimino-2-(2-a
minothiazol-4-yl)acetamide]-3
-[1-(3-aminopropyl)-1H-tetrazo
[ru-5-yl]thiomethyl-3-cephem-4-
Carboxylic acid (syn isomer) (0.31 g) was obtained. I.R. (Nujiyor): 3180, 1760, 1660, 1620cm^-1 N.M.R. (DMSO−d₆, δ): 1.68−2.60 (4H,
m), 2.96 (2H, m), 3.51 (2H, m), 4.06−
4.67 (4H, m), 5.01 (1H, d, J=5.0Hz),
5.26 (1H, m), 5.47-6.28 (3H, m), 6.70
(1H, s), 9.45 (1H, d, J = 8.0Hz) The liquid is mixed with a nonionic adsorption resin (Diaion).
HP20, manufactured by Mitsubishi Chemical Industries) column (60 ml).
After washing with water, add 15-20% isopropyl alcohol.
It was eluted with Combine the fractions containing the target compound.
The same compound (0.31
g) was obtained. Example 27 The following compound was obtained in the same manner as in Example 26. (1) 7-[2-(2-cyclopenten-1-yl)
xiimino-2-(2-aminothiazole-4
-yl)acetamide]-3-(2-aminoethyl)
)thiomethyl-3-cephem-4-carvone
Acid (syn isomer). I.R. (Nuzhiyor): 3350-3100, 1760, 1660,
1610, 1515cm^-1 (2) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-(5-aminome)
Chil-1,3,4-thiadiazol-2-y
)thiomethyl-3-cephem-4-carvone
Acid (syn isomer). Melting point 145-170℃ (decomposition). I.R. (Nujiyor): 3150, 1760, 1650, 1610,
1520cm^-1 (3) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamido]-3-carba
Moyloxymethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3450, 3260, 1770, 1700,
1660, 1640, 1610, 1550cm^-1 (4) 7-[2-(2-cyclopenten-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-carbamoyl
Oxymethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 182-195°C (decomposition). I.R. (Nuzhiyor): 3250, 1760, 1700, 1650,
1540cm^-1 (5) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-formamide thiazo
-4-yl)acetamido]-3-carba
Moyloxymethyl-3-cephem-4-cal
Bonic acid (syn isomer). I.R. (Nujiyor): 3260, 1780, 1680 (broad),
1540cm^-1 (6) 7-[2-(2-cyclohexen-1-yl)
Oximino-2-(2-aminothiazole-
4-yl)acetamido]-3-carbamoyl
Oxymethyl-3-cephem-4-carboxylic acid
(syn isomer). Melting point 230-235°C (decomposition). I.R. (Nujiyor): 3440, 3330, 3270, 1750,
1690, 1630, 1530cm^-1

Claims (1)

[Claims] 1. General formula [Wherein, R ¹ is an amino group or a protected amino group; R ² is a cyclo-lower alkenyl group; R ³ is a carboxy group or a protected carboxy group; R ⁴ is hydrogen or the formula: -CH ₂ - R ^4a ( In the formula, R ^4a is an acyloxy group; an amino lower alkylthio group; a protected amino lower alkylthio group; a pyridinium group which may have a hydroxy lower alkyl group or a carbamoyl group; or a lower alkyl group, a lower alkenyl group, or a carboxy group , carboxy lower alkyl group, hydroxy lower alkyl group,
Thiadiazolylthio group, tetrazolthio group, pyridylthio group, which may have an amino lower alkyl group or a protected amino lower alkyl group,
a triazolylthio group or a tetrazolopyridazinylthio group; R ⁵ means hydrogen or a lower alkyl group, respectively, provided that even if R ^4a has a hydroxy lower alkyl group or a carbamoyl group; When denoting a good pyridinium group, R ³ denotes a COO ^- group] and pharmaceutically acceptable salts thereof. 2 General formula [In the formula, R ³ is a carboxy group or a protected carboxy group; R ⁴ is hydrogen or the formula: -CH ₂ -R ^4a (wherein, R ^4a is an acyloxy group; an amino lower alkylthio group; a protected amino lower alkylthio group; a pyridinium group which may have a hydroxy lower alkyl group or a carbamoyl group; or a lower alkyl group, a lower alkenyl group, a carboxy group, a carboxy lower alkyl group, a hydroxy lower alkyl group,
a thiadiazolylthio group, a tetrazolylthio group, a pyridylthio group, a triazolylthio group or a tetrazolopyridazinylthio group which may have an amino lower alkyl group or a protected amino lower alkyl group; R ⁵ means hydrogen or a lower alkyl group, respectively; provided, however, that when R ^4a means a pyridinium group which may have a hydroxy lower alkyl group or a carbamoyl group, R ³ means a COO ^- group ] or a reactive derivative thereof at the amino group, or a salt thereof, with the general formula: (In the formula, R ¹ is an amino group or a protected amino group; R ² is a cyclo-lower alkenyl group) by reacting with a compound represented by the following or a reactive derivative thereof in the carboxyl group, or a salt thereof, to obtain the general formula: (In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each have the same meanings as above.) A novel method for producing a cefem compound, which is characterized by obtaining a compound or a salt thereof. 3 General formula [In the formula, R ¹ is an amino group or a protected amino group; R ² is a cyclolower alkenyl group; R ³ is a carboxy group or a protected carboxy group; Y is the formula: -R ^4c (wherein, R ^4c is Amino lower alkylthio group; protected amino lower alkylthio group; pyridinium group which may have a hydroxy lower alkyl group or carbamoyl group; or lower alkyl group, lower alkenyl group, carboxy group, carboxy lower alkyl group, hydroxy lower alkyl group group, a thiadiazolylthio group which may have an amino lower alkyl group or a protected amino lower alkyl group, a tetrazolylthio group,
pyridylthio group, triazolylthio group or tetrazolopyridazinylthio group; R ⁵ means hydrogen or lower alkyl group respectively] or its salts; Formula: R ^4b () (wherein R ^4b is amino lower alkylthiol;
Protected amino lower alkylthiol; pyridine which may have a hydroxy lower alkyl group or carbamoyl group; or lower alkyl group, lower alkenyl group, carboxy group, carboxy lower alkyl group, hydroxy lower alkyl group,
thiadiazolylthiol, tetrazolylthiol, pyridylthiol, triazolylthiol or tetrazolopyridazinylthiol which may have an amino lower alkyl group or a protected amino lower alkyl group) or a reactive derivative thereof, the general formula: (In the formula, R ¹ , R ² , R ³ , R ^4c and R ⁵ each have the same meaning as above, provided that when R ^4c means a pyridinium group which may have a hydroxy lower alkyl group or a carbamoyl group) (R ³ means COO ^- group) A novel method for producing a cefem compound, which is characterized by obtaining a compound represented by the following formula or a salt thereof.