JPH051272B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel cefem compounds and salts thereof. More specifically, the present invention relates to novel cefem compounds and salts thereof having antibacterial activity, methods for producing the same, and pharmaceutical compositions containing them. Therefore, one object of this invention is to provide novel cefem compounds and salts thereof that have high activity against many pathogenic bacteria. Another object of this invention is to provide a method for producing new cefem compounds and salts thereof. A further object of this invention is to provide pharmaceutical compositions containing the novel cefem compounds and their salts as active ingredients. The desired cefem compound is novel and has the following general formula () (In the formula, R ¹ is an amino or acylamino group, R ²
is a lower alkyl group, and Y is a CH dere). It can be shown as According to this invention, novel cefem compounds ()
can be produced by various methods shown in the scheme below. (In the formula, R ¹ , R ² and Y are each the same as above, R ¹ _a is acylamino, R ¹ _b is acylamino with protected amino, R ¹ _c is acylamino with amino, R ³ is protected carboxy,
Z is an acid residue). Among the starting compounds in this invention, compounds () and () are novel and can be produced by the production method shown in the following scheme. (In the formula, R ¹ , R ¹ _a , R ¹ _b , R ¹ _c , R ² , R ³ , Y and Z
are the same as above, R ³ _a is carboxy or protected carboxy, X is halogen,
Ph is phenyl). Target compounds (), (a) to (d) and starting compounds (), (a), (), (a), (b)
),
(c), (d), (e), (f), (), (

With regard to a), (XII) and (), it is readily understood that these target and starting compounds include cis isomers, trans isomers and mixtures thereof. For example, when it comes to the target compound (), the cis isomer has the following formula: (In the formula, R ² and Y are each the same as above), and the trans isomer is the following formula: (In the formula, R ² and Y are each the same as above) means another geometric isomer having a partial structure. Preferred pharmaceutically acceptable salts of the target compound () are usually non-toxic salts, organic acid salts such as acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate. , trifluoroacetate, etc.), inorganic acid salts (e.g., hydrochloride, hydroiodide, sulfate,
phosphate, etc.), amino acids (e.g. arginine,
Examples include salts with aspartic acid, glutamic acid, etc.). In the foregoing and following descriptions of this specification, suitable illustrations and explanations of the various definitions encompassed within the scope of this invention are set forth in detail below. "Lower" means 1 to 6 carbon atoms unless otherwise specified. Appropriate "acyl" and "acyl moiety" in the above "acylamino" are carbamoyl, aliphatic acyl group, and acyl group containing an aromatic ring (referred to as aromatic acyl), or an acyl group containing a heterocycle (heterocyclic acyl group). ). Suitable examples of said acyls are: aliphatic acyls include lower or higher alkanoyls (e.g. formyl, acetyl, succinyl, hexanoyl, heptanoyl, valeryl, stearoyl, etc.); lower or higher alkoxycarbonyls (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.); lower or higher alkanesulfonyl (e.g. methanesulfonyl, ethanesulfonyl,
etc.), etc. Aromatic acyls include aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.); al(lower)alkanoyl such as phenyl(lower)alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.); aryloxycarbonyl (e.g. , phenoxyacetyl, phenoxypropionyl, etc.); Arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.); Allensulfonyl (e.g., benzenesulfonyl, p-toluenesulfonyl, etc.) , etc. Heterocyclic acyl includes heterocyclic carbonyl (e.g., thenoyl, furoyl, nicotinoyl,
); heterocyclic (lower) alkanoyl (e.g., thienyl acetyl, thiazolyl acetyl, thiadiazolyl acetyl, tetrazolylacetyl, etc.);
Heterocyclic glyoxyloyl (e.g., thiazolylglyoxyloyl, thienylglyoxyloyl,
etc.), etc., and the above-mentioned "heterocyclic carbonyl",
More specifically, the appropriate heterocyclic moiety of "heterocyclic (lower) alkanoyl" and "heterocyclic glyoxyloyl" is a saturated or unsaturated monocyclic moiety containing at least one heteroatom such as oxygen, sulfur, or nitrogen atom. It means a cyclic or polycyclic heterocyclic group. More particularly preferred heterocyclic groups include unsaturated 3- to 8-membered, more preferably 5- or 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H
-1,2,3-triazolyl, 2H-1,2,3
-triazolyl, etc.), tetrazolyl (e.g.
1H-tetrazolyl, 2H-tetrazolyl, etc.),
etc.; saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 to 4 nitrogen atoms (e.g., pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.; containing 1 to 4 nitrogen atoms) Unsaturated fused heterocyclic groups (e.g. indolyl,
isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.); unsaturated 3- to 8-membered (more preferably 5- or 6-membered) containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms Heteromonocyclic groups [e.g. oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5
-oxadiazolyl, etc.), etc.; a saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms (e.g. morpholinyl, cydononyl, etc.); 1-2
Unsaturated fused heterocyclic groups containing oxygen atoms and 1 to 3 carbon atoms (e.g., benzoxazolyl, benzoxadiazolyl, etc.); unsaturated 3 containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms ~8-membered (more preferably 5- or 6-membered) heteromonocyclic group [e.g., thiazolyl, isothiazolyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.),
dihydrothiazinyl, etc.; saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms (e.g. thiazolidinyl, etc.); 1-2 sulfur atoms unsaturated 3- to 8-membered (more preferably 5- or 6-membered) containing
Heteromonocyclic groups (e.g., thienyl, dihydrodithienyl, dihydrodithiolyl, etc.); unsaturated fused heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e.g., benzothiazolyl, benzothiadiazolyl, etc.); , etc.); unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 oxygen atom (e.g., furyl, etc.); containing 1 oxygen atom and 1 to 2 sulfur atoms unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups (e.g., dihydroxathinyl, etc.); saturated fused heterocyclic groups containing 1 to 2 sulfur atoms (e.g.,
benzothienyl, benzodithienyl, etc.); unsaturated fused heterocyclic groups containing 1 oxygen atom and 1 to 2 sulfur atoms (e.g. benzoxathienyl,
etc.) etc. Regarding the above heterocyclic group, the following points must be kept in mind. That is, when the heterocyclic group is particularly a thiazolyl or thiadiazolyl group having an amino or protected amino group as a substituent in its molecule, the thiazolyl or thiadiazolyl group has tautomerism due to the specific behavior of the thiazole or thiadiazole ring. It includes the sexual body. That is,
For example, said amino- or protected aminothiazolyl or thiadiazolyl group has the formula

[Formula] (wherein, .R ⁸ is amino or protected amino, Ya is CH or N), and the group of formula (A) is represented by the formula

[Formula] (wherein R ⁸ and Ya are the same as above), the group of the above formula (A') also has the tautomeric formula

[Formula] (wherein Ya is the same as above and R ⁸ ' is imino or protected imino) can also be represented. That is, both groups of formulas (A′) and (A″) have the following balanced formula: (In the formula, R ⁸ , Ya and R ⁸ ' are each the same as above.) It is in a tautomer equilibrium state. This type of tautomerism between the above-mentioned 2-aminothiazole or thiadiazole compounds and 2-iminothiazoline or thiadiazole compounds is well known in the art, and both tautomers are in equilibrium and capable of converting into each other. is clear to those skilled in the art.
Therefore, it is easy to understand that such isomers are included in the same category of the compound itself.
Therefore, both tautomers are clearly included within the scope of this invention. In this specification, object and starting compounds containing such tautomeric groups are referred to by their designation, i.e. 2-amino (or protected amino) thiazolyl or thiadiazolyl and, for convenience, by the formula "

[Formula]”.The above acyl moiety is 1 to 10
suitable substituents, the same or different, {e.g.
lower alkyl (e.g. methyl, ethyl, etc.),
lower alkoxy (e.g. methoxy, ethoxy,
propoxy, etc.), lower alkylthio (e.g.
methylthio, ethylthio, etc.), lower alkylamino (e.g. methylamino, etc.), cyclo(lower)alkyl (e.g. cyclopentyl, cyclohexyl, etc.), cyclo(lower)alkenyl (e.g. cyclohexenyl, cyclohexadienyl, etc.) ), halogen, amino, protected amino,
Hydroxy; protected hydroxy, cyano, nitro, carboxy, protected carboxy, sulfo, sulfamoyl, imino, oxo, amino (lower) alkyl (e.g., aminomethyl, aminoethyl, etc.), carbamoyloxy, formula = N-
OR ⁹ [wherein R ⁹ is hydrogen, lower alkyl (e.g.
methyl, ethyl, propyl, etc.), lower alkenyl (e.g. vinyl, allyl, 2-butenyl,
etc.), lower alkynyl (e.g. ethynyl, 2-propynyl, etc.), cyclo(lower)alkyl (e.g. cyclopropyl, cyclohexyl, etc.), phenyl(lower)alkyl (e.g. benzyl, phenethyl, etc.) (lower) alkyl,
carboxy(lower)alkyl (eg, carboxymethyl, 1-carboxyethyl, etc.), protected carboxy(lower)alkyl, etc.). In this context, if the acyl moiety has as a substituent a group of the formula: =N-OR ⁹ (wherein R ⁹ is the same as above), geometric isomers (synthetic and anti-isomer). For example, the syn isomer has the formula:

It means one geometric isomer having a group represented by the formula, and the corresponding anti-isomer is the formula:

It means another geometric isomer having the group represented by the formula. Suitable "protected aminos" include acylamino (where the "acyl" moiety includes those listed above), phosphonoamino, protected phosphonoamino, al(lower) aminos such as benzylamino, phenethylamino, tritylamino. Examples include alkylamino. Suitable "protected phosphonos" include esterified phosphonos, wherein said esters include lower alkyl esters (e.g., methyl esters, ethyl esters, propyl esters, isopropyl esters, butyl esters, isobutyl esters, t-butyl esters). ester, pentyl ester, t-pentyl ester, hexyl ester,
etc.), etc.). Suitable "protected hydroxy" include acyloxy, and "acyl" moieties include those described above. Appropriate "protected carboxy moieties" and "protected carboxy" in "protected carboxy (lower) alkyl" include esterified carboxy, and examples of the "esterified carboxy" include the following: Things can be mentioned. Suitable examples of esterified carboxy ester moieties include at least one suitable substituent {e.g., lower alkanoyloxy (lower) alkyl esters [e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,
Hexanoyloxymethyl ester, 1 (or 2)-acetoxyethyl ester, 1 (or 2 or 3)-acetoxypropyl ester, 1 (or 2 or 3 or 4)-acetoxybutyl ester, 1 (or 2)-propionyloxy Ethyl ester, 1 (or 2 or 3)-propionyloxypropyl ester, 1 (or 2)-butyryloxyethyl ester, 1 (or 2)-isobutyryloxyethyl ester, 1 (or 2)-pivaloyl Oxyethyl ester, 1 (or 2)-
Hexanoyloxyethyl ester, isobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2)-pentanoyloxyethyl ester, etc.], lower alkanes Sulfonyl (lower) alkyl esters (e.g.
2-mesylethyl ester, etc.), 1 (or 2 or 3)-halo(lower) alkyl ester (e.g. 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy ( (lower) alkyl esters (e.g., methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester,
2-methoxycarbonyloxyethyl ester,
1-ethoxycarbonyloxyethyl ester,
1-isopropoxycarbonyloxyethyl ester, etc.), phthalidylidene (lower) alkyl ester or (5-lower alkyl-2-oxo-
1,3-dioxol-4-yl)(lower)alkyl ester [e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, (5-ethyl-2-oxo-1 ,3-dioxol-4-yl)methyl ester, (5-
Propyl-2-oxo-1,3-dioxole-
lower alkyl esters (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, 1-cyclo propyl ethyl ester, etc.), lower alkenyl ester (e.g.
vinyl esters, allyl esters, etc.), lower alkynyl esters (e.g. ethynyl esters,
propynyl ester, etc.), al(lower) alkyl esters having at least one suitable substituent [e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester,
phenethyl ester, trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc.], at least one Aryl esters with appropriate substituents (e.g. phenyl ester, 4-chlorophenyl ester,
tolyl ester, t-butylphenyl ester,
xylyl esters, mesityl esters, cumenyl esters, etc.), phthalidyl esters, and the like. Preferred examples of the above esterified carboxy include lower alkoxycarbonyl (e.g.
Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, isobutoxycarbonyl,
t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl, etc.) and phenyl (lower) alkoxycarbonyl which may have a nitro group (e.g. benzyloxycarbonyl) , benzhydryloxycarbonyl, etc.). Suitable "lower alkyl" includes straight or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl and the like. Suitable "halogens" include chlorine, bromine, fluorine, and iodine. Suitable "acid residues" include acyloxy, azide, halogen, etc. "acyloxy"
Examples of the acyl moiety and halogen include those exemplified above. Appropriate "acylamino" and "protected amino" in "acylamino having a protected amino" and "acylamino having an amino" include those exemplified above. The method for producing the object compound of the present invention will be explained in detail below. Production method 1 The target compound (b) or a salt thereof can be produced by reacting compound (a) or a reactive derivative thereof at an amino group or a salt thereof with an acylating agent. Suitable reactive derivatives of the amino group of compound (a) include Schiff base-type iminos or their tautomeric enamines formed by reacting compound (a) with carbonyl compounds (e.g., aldehydes, ketones, etc.); type isomers, silyl derivatives formed by reacting compound (a) with silyl compounds [e.g., bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, etc.], compound (a) with phosphorus trichloride or phosgene; Examples include derivatives formed by reaction. Suitable acylating agents may be those commonly used and can be represented by the formula: ^R4 -OH() (wherein ^R4 is acyl) or a reactive derivative thereof or a salt thereof. Suitable salts of compounds (a) and () include organic acid salts (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.) or inorganic acid salts. Acid addition salts such as salts (e.g. hydrochlorides, hydrobromides, sulfates, phosphates, etc.), metal salts (e.g. sodium salts, potassium salts, calcium salts, magnesium salts, etc.), ammonium salts , organic amine salts (eg, triethylamine salt, dicyclohexylamine salt, etc.), and the like. Suitable reactive derivatives of compound () include acid halides, acid anhydrides, activated amides, activated esters, and the like. Suitable examples thereof include acid chlorides, acid azides, acids [e.g., substituted phosphoric acids (e.g., dialkyl phosphoric acids, phenyl phosphoric acids, diphenyl phosphoric acids, dibenzyl phosphoric acids, halogenated phosphoric acids, etc.), dialkyl phosphorous acids, Sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc.) or aromatic carboxylic acid (e.g. benzoic acid, etc.)] mixed acid anhydrides with, symmetric acid anhydrides, imidazoles, 4-substituted imidazoles, dimethylpyrazoles, activated amides with triazoles or tetrazoles, or activated esters (e.g. cyanomethyl esters, methoxymethyl esters, dimethyliminomethyl [(CH ₃ ) ₂ N+ =
CH-]ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,
4-dinitrophenyl ether, trichlorophenyl ester, pentachlorophenyl ester,
mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) or N-
Esters with hydroxy compounds (e.g. N, N
-dimethylhydroxyamine, 1-hydroxy-
2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole,
etc.) etc. These reactive derivatives can be appropriately selected from them depending on the type of compound () used. The reaction usually involves water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
The reaction is carried out in conventional solvents such as N,N-dimethylformamide, pyridine, or other organic solvents that do not adversely affect the reaction. These conventional solvents may also be used in combination with water. When the compound () is used in the reaction in the form of the free acid or in the form of its salt, the reaction is preferably carried out in the presence of customary condensing agents, such as N, N' -dichlorohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, 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-cyclohexylimide, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1- Alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenyl phosphorus, 2-ethyl-7 -Hydroxybenzisoxazolium salt, hydroxide 2-
Ethyl-5-(m-sulfophenyl)isoxazolium inner salt, 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, dimethylformamide to thionyl chloride,
Examples include the so-called Wilsmeier reagent produced by reacting with phosgene, phosphorus oxychloride, and the like. The reaction may also be carried out in the presence of inorganic or organic bases, such as alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N-(lower)alkylmorpholines, N, Examples include N-di(lower)alkylbenzylamine. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature. In this reaction, the syn isomer of the target compound (b) can be obtained preferably by subjecting the corresponding syn isomer of the compound (a) and the starting compound () to this reaction. Production method 2 The target compound () or its salt can be produced by subjecting the compound () or its salt to an elimination reaction of the carboxy protecting group. Compound () as a suitable salt of compound ()
The acid addition salts exemplified in a) can be mentioned. In this elimination reaction, any conventional method used in the elimination reaction of carboxy protecting groups, such as hydrolysis, reduction, elimination using a Lewis acid, etc., can be used. When the carboxy protecting group is an ester, it can be removed by hydrolysis or removal using a Lewis acid. Hydrolysis is preferably carried out in the presence of a base or acid. Suitable bases include the aforementioned inorganic bases and organic bases. Suitable acids include organic acids (e.g. formic acid, acetic acid, propionic acid, etc.) and inorganic acids (e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). This hydrolysis is usually carried out in an organic solvent, water or a mixed solvent thereof. The reaction temperature is not critical and may be selected appropriately depending on the carboxy protecting group and the type of elimination method. Elimination using a Lewis acid is preferred for eliminating substituted or unsubstituted alkyl esters, and is carried out by reacting the compound () or a salt thereof with a Lewis acid. Such Lewis acids include boron trihalide (e.g., boron trichloride, boron trifluoride, etc.), titanium tetrahalide (e.g., titanium tetrachloride, titanium tetrabromide, etc.), tin tetrahalide (e.g.,
tin tetrachloride, tin tetrabromide, etc.), aluminum halide (eg, aluminum chloride, aluminum bromide, etc.), trihaloacetic acid (eg, trichloroacetic acid, trifluoroacetic acid, etc.), and the like.
This elimination reaction is preferably carried out in the presence of a cation scavenger (e.g., anisole, phenol, etc.) and is usually carried out in the presence of a nitroalkane (e.g., nitromethane, nitroethane, etc.), an alkylene halide (e.g., methylene chloride, ethylene chloride, etc.), etc.), diethyl ether, carbon disulfide, or other solvents that do not adversely affect the reaction. These solvents may be used as mixtures thereof. Reductive elimination can preferably be used to remove protecting groups, such as halo(lower)alkyl (e.g. 2-iodoethyl,
2,2,2-trichloroethyl, etc.) ester,
Al(lower)alkyl (e.g. benzyl, etc.)
Examples include ester, etc. Reduction methods that can be used in the elimination reaction include, for example, metal group (e.g., zinc, zinc amalgam, etc.) or salts of chromium compounds (e.g., chromous chloride, chromous acetate, etc.).
etc.) and organic or inorganic acids (e.g. acetic acid,
propionic acid, hydrochloric acid, etc.) and conventional catalytic reduction in the presence of customary metal catalysts (eg palladium on carbon, Raney nickel, etc.). The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. This elimination reaction of a carboxy protecting group also includes within its scope the following cases. That is, if another protected carboxy and/or protected amino group has been converted into the corresponding free carboxy and/or amino group during the reaction or post-processing steps of the process. Production method 3 The target compound () or its salt can be produced by reacting the compound () or its salt with a lower alkylating agent. Suitable salts of compound () or () include the salts exemplified for compound (a). The lower alkylating agent used in this alkylation reaction may be a conventional alkylating agent, such as a mono(or di)lower alkyl sulfate (e.g., dimethyl sulfate, etc.),
Examples include lower alkyl lower alkanesulfonates (eg, methyl methanesulfonate, etc.), halo(lower) alkanes (eg, bromomethane, iodomethane, iodoethane, etc.), and the like. When a lower alkyl ester of an acid is used as the lower alkylating agent, the reaction is usually carried out in a solvent such as water, acetone, tetrahydrofuran, ethanol, ether, dimethylformamide, or other solvent that does not adversely affect the reaction. This reaction is preferably carried out in the presence of a base such as the inorganic or organic bases mentioned above. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or by heating to around the boiling point of the solvent. Production method 4 The target compound (a) or its salt can be produced by subjecting compound (b) or its salt to a deacylation reaction. This deacylation reaction involves hydrolysis, reduction, deacylation using a Lewis acid, the action of an iminohalogenating agent and then an iminoetherifying agent on compound (b), and if necessary, hydration of the resulting compound. This is carried out by conventional methods such as deacylation by decomposition. Among these methods, the preferred method is "a deacylation method in which compound (b) is treated with an iminohalogenating agent and then an iminoetherifying agent, and if necessary, the resulting compound is subjected to hydrolysis." be. Suitable iminohalogenating agents include phosphorus halides (eg, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, etc.), phosphorus oxychloride, thionyl chloride, phosgene, and the like. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature. If compound (b) has a free carboxyl group in the 4-position, this reaction is preferably carried out with a silylating agent [e.g. trimethylsilyl chloride, trimethylsilylacetamide, bis(trimethylsilyl)acetamide] before carrying out the reaction. , etc.]. Suitable iminoetherifying agents to be reacted with the reaction product thus obtained include alcohols, metal alkoxides, and the like. Suitable alcohols include alkanols (e.g., methanol, ethanol, propanol, isopropanol, butanol, t-butanol, 1,3-butanediol, etc.), which include alkoxys (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.). Suitable metal alkoxides include alkali metal alkoxides (eg, sodium alkoxide, potassium alkoxide, etc.), alkaline earth metal alkoxides (eg, calcium alkoxide, barium alkoxide, etc.), and the like. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature. The product obtained is subjected to hydrolysis, if necessary. Hydrolysis can be easily carried out by placing the above reaction mixture in water, but in advance, a hydrophilic solvent (e.g. methanol, ethanol, etc.), a base (e.g. alkali metal bicarbonate, trialkylamine, etc.) Alternatively, an acid (eg diluted hydrochloric acid, acetic acid, etc.) may be added to the water. The reaction temperature is not particularly limited and may be appropriately selected depending on the protecting group of the amino group and the type of the above-mentioned elimination method, and this reaction is preferably carried out under mild conditions such as cooling, room temperature, or slightly heating. It will be held in This invention includes within its scope the case where the protected carboxy is converted to the free carboxy during or after the reaction depending on the reaction conditions and the type of protecting group. Hydrolysis includes methods using acids, bases, and the like. These methods may be selected depending on the type of acyl group to be eliminated. Suitable acids include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like. A suitable acid for the reaction can be selected depending on the type of acyl group to be eliminated. When the deacylation reaction is carried out using an acid, it can be carried out with or without the presence of a solvent. Suitable solvents include organic solvents, water, or mixed solvents thereof. When using trifluoroacetic acid,
The deacylation reaction is preferably carried out in the presence of anisole. Suitable bases include, for example, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth metal hydroxides (e.g.,
magnesium hydroxide, calcium hydroxide, etc.),
Alkali metal carbonates (e.g. sodium carbonate,
potassium carbonate, etc.), alkaline earth metal carbonates (magnesium carbonate, magnesium carbonate, etc.), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metal acetates (e.g., sodium acetate, etc.) , potassium acetate,
), alkaline earth metal phosphates (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphates (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.), and inorganic bases. and trialkylamines (e.g. trimethylamine, triethylamine, etc.), picoline, N-methylpyrrolidine, N-methylmorpholine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo [2,
Examples include organic bases such as 2,2]octane, 1,5-diazabicyclo[5,4,0]undecene-5, and the like. Hydrolysis with a base is often carried out in water or a hydrophilic organic solvent or a mixture thereof. Examples of the reduction include reduction using an alkali metal borohydride (eg, sodium borohydride, etc.), catalytic reduction, and the like. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating. The present invention also includes within its scope the case where one tautomer is converted into another isomer during the reaction and/or post-processing step of each process. Production method 5 The target compound (d) or a salt thereof can be produced by subjecting the compound (c) or a salt thereof to an amino-protecting group elimination reaction. This elimination reaction can be carried out in the same manner as the elimination reaction in Production Method 4. The target compound () may be converted into the above-mentioned pharmaceutically acceptable salt thereof by a conventional method. Details of the method for preparing the starting compounds of this invention are explained below. Production method A (i) ()→() The compound () or its reactive derivative at the amino group or its salt is prepared by reacting the compound () or its reactive derivative at the amino group or its salt with triphenylphosphine. It can be manufactured by This reaction consists of water, phosphate buffer, acetone,
In a solvent such as chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene chloride, formamide, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide, or other organic solvent that does not adversely affect the reaction, preferably with a strong polarity. It may also be carried out in a solvent containing Among these solvents, hydrophilic solvents may be used in combination with water. This reaction is preferably carried out in the presence of an alkali metal halide (eg, sodium iodide, potassium iodide, etc.), an alkali metal thiocyanate (eg, sodium thiocyanate, potassium thiocyanate, etc.), and the like. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature, with or under heating. (ii): () → () Compound () or its salt is compound ()
Alternatively, it can be produced by reacting a reactive derivative or its salt at the amino group with an acylating agent. The reaction can be carried out in the same manner as Production Method 1. (iii): (a) + () → (a) Compound (a) or a salt thereof is a compound (
It can be produced by reacting a) or a salt thereof with a compound () or a salt thereof. This reaction typically involves acetone, dioxane, acetonitrile, chloroform, methylene chloride,
dimethylformamide, tetrahydrofuran,
The reaction is carried out in a solvent such as ethyl acetate or other solvents that do not adversely affect the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. Production method B-(1) (i): () → (a) Compound (a) or its salt is compound ()
Alternatively, it can be produced by reacting a reactive derivative at the amino group or a salt thereof with an acylating agent. This reaction can be carried out in the same manner as the reaction in Production Method 1 above. (ii) :b)→(a) Compound (a) or its salt is compound (
It can be produced by reacting b) or a salt thereof with triphenylphosphine. This reaction can be carried out in accordance with the same method as the production method A-(i) above. (iii) ()→(a) Compound (a) or its salt is compound ()
Alternatively, it can be produced by reacting a reactive derivative of the hydroxymethyl group or a salt thereof with triphenylphosphine. This reaction can be carried out in accordance with the same method as the production method A-(i) above. (iv) (a)+()→(a) Compound (a) or its salt is compound (
It can be produced by reacting a) or a salt thereof with a compound () or a salt thereof. This reaction is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, dimethylformamide, ethyl acetate, or any other solvent that does not adversely affect the reaction. The reaction is preferably carried out with alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates,
It is carried out in the presence of a base such as trialkylamine or pyridine, and preferably under alkaline or neutral conditions. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, at room temperature, or under heating. Production method B-(a) (i) () → () Compound () or its salt is compound ()
Alternatively, it can be produced by oxidizing a reactive derivative at its hydroxymethyl group or a salt thereof. Suitable reactive derivatives of the hydroxymethyl group of compound () include those in which the hydroxymethyl group of compound () has a halogen (e.g., chlorine, bromine, etc.), arenesulfonyloxy (e.g.,
p-toluenesulfonyloxy, p-nitrobenzenesulfonyloxy, etc.), haloformyloxy (e.g. chloroformyloxy, etc.)
Also included are compounds that have been converted to a methyl group having an acid residue such as. A suitable oxidizing agent used in this oxidation reaction is
Included are the usual oxidizing agents capable of oxidizing hydroxymethyl or its reactive derivatives at the hydroxymethyl group to formyl. The oxidizing agent includes (1) dimethyl sulfoxide and dicyclohexylcarbodiimide, dimethyl sulfoxide and acetic anhydride, dimethyl sulfoxide and phosphorus pentoxide, dimethyl sulfoxide and sulfur trioxide-pyridine, dimethyl sulfoxide and ketene imine, dimethyl sulfoxide and chlorine,
Activated dimethyl sulfoxide formed by the reaction of dimethyl sulfoxide and mercuric acetate, dimethyl sulfide and N-chlorosuccinimide, dimethyl sulfide (or methylphenyl sulfide) and chlorine, etc., (2) Chromium trioxide-pyridine, trioxide Chromium-sulfuric acid, alkali metal dichromates (e.g., sodium dichromate, potassium dichromate, etc.), lower alkyl chromates (e.g.,
Examples include chromium compounds such as t-butylchromate, etc.). Oxidation with dimethyl sulfoxide and dicyclohexycarbodiimide is preferably performed using acids (e.g. phosphoric acid, trifluoroacetic acid, dichloroacetic acid, etc.), mixtures of acids and bases (e.g. trifluoroacetic acid-pyridine, phosphoric acid-pyridine). , etc.), etc.). This oxidation reaction is carried out in the presence or absence of an acid or a base, which is appropriately selected depending on the type of oxidizing agent used. This oxidation is carried out with or without the use of solvents such as benzene, toluene, chloroform, methylene chloride, carbon tetrachloride, diethyl ether, dimethylformamide, or other solvents that do not adversely affect the reaction. It is selected appropriately depending on the type of agent. When the starting compound for this oxidation reaction is in the form of a reactive derivative at its hydroxymethyl group, suitable oxidizing agents include dimethyl sulfoxide and the like. This oxidation is preferably carried out in the presence of a base (eg, sodium bicarbonate, triethylamine, etc.). The reaction temperature of the oxidation reaction in this production method is not particularly limited, and the reaction is carried out under cooling, at room temperature, under heating, or under heating. The reaction temperature is appropriately selected depending on the type of oxidizing agent used. (ii): () → () Compound () or its salt is compound ()
Alternatively, it can be produced by subjecting its salt to an isomerization reaction. This reaction is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, or any other solvent that does not adversely affect the reaction. The reaction is preferably carried out with alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates,
It is carried out in the presence of a base such as trialkylamine or pyridine. The reaction temperature is not particularly limited,
The reaction is preferably carried out under cooling or at room temperature. (iii): () + (XI) → (XII) Compound (XII) or its salt is compound ()
Alternatively, it can be produced by reacting a salt thereof with compound (XI) or a salt thereof. This reaction can be carried out in the same manner as in the production method B-(1)-(iv) above. (iv): (XII) → () Compound () or its salt is compound (XII)
Alternatively, it can be produced by oxidizing its salt. This oxidation reaction produces -S-

This can be carried out by conventional methods used for converting into the formula, for example, using an oxidizing agent such as m-chloroperbenzoic acid, perbenzoic acid, peracetic acid, ozone, hydrogen peroxide, periodic acid, or the like. This reaction is usually carried out in a solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, tetrahydrofuran, ethyl acetate, or any other solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, and the reaction is preferably carried out under cooling or at room temperature. (v): () → (a) Compound (a) or its salt is the compound (
) or its salts. This reduction is

Conventional methods used to convert [Formula] to -S-, such as phosphorus trichloride, a combination of stannous chloride and acetyl chloride, an alkali metal iodide (e.g., sodium iodide, etc.) and trihaloacetic anhydride (For example, trifluoroacetic anhydride, etc.). This reduction typically involves acetone, dioxane, acetonitrile, dimethylformamide, benzene, hexane, chloroform, methylene chloride,
The reaction is carried out in a solvent such as ethylene chloride, tetrahydrofuran, ethyl acetate, or any other solvent that does not adversely affect the reaction. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature. Production method B-(3) (i): (b) → (c) Compound (c) or its reactive derivative at the amino group or its salt is compound (b)
Alternatively, it can be produced by subjecting its salt to a deacylation reaction. This reaction can be carried out in the same manner as Production Method 4 above. (ii): (c) → (b) Compound (b) or a salt thereof is a compound (
c) or a reactive derivative thereof at the amino group or a salt thereof can be produced by reacting an acylating agent with an acylating agent. This reaction can be carried out in the same manner as in Production Method 1 above. Production method B-(4) (i): (d) → () Compound () or its salt is compound (d)
Alternatively, it can be produced by subjecting a salt thereof to an elimination reaction of a carboxy protecting group. This reaction can be carried out in the same manner as Production Method 2 above. Production method B-(5) The target compound (f) or a salt thereof can be produced by subjecting the compound (e) or a salt thereof to an amino-protecting group elimination reaction. Suitable salts of compound (e) include the salts exemplified for compound (). The elimination reaction is carried out according to a conventional method, which includes hydrolyzing, reducing, and treating a compound (e) whose protected amino moiety is acylamino with an iminohalogenating agent or an iminoetherifying agent;
a method for subsequent hydrolysis of the product if necessary;
etc. Hydrolysis includes methods using acids, bases, hydrazine, and the like. These methods may be selected depending on the type of protecting group to be removed. Among these methods, hydrolysis using acid is
Substituted or unsubstituted alkoxycarbonyl, such as t-pentyloxycarbonyl, lower alkanoyl (e.g. formyl, acetyl, etc.), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl, aralkyl (e.g. trityl), substituted phenylthio, This is one of the most common and preferred methods for removing protecting groups such as substituted aralkylidene, substituted alkylidene, and substituted cycloalkylidene. Suitable acids include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, etc., and the most suitable acids are easily removed from the reaction mixture by conventional methods such as distillation under reduced pressure. Acids that can be removed, 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. When the elimination reaction is carried out using an acid, it can be carried out in the presence or absence of a solvent. Suitable solvents include water, conventional 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 using a base is used when eliminating an acyl group such as trifluoroacetyl. Suitable bases include inorganic bases and organic bases. Reductive elimination generally involves protecting groups such as haloalkoxycarbonyl (e.g., trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g., benzyloxycarbonyl, etc.), 2-pyridylmethoxycarbonyl, etc. Used when detaching. Suitable reductions include, for example, alkali metal borohydrides (e.g. sodium borohydride,
etc.), metals (e.g. tin, zinc,
iron, etc.) or the metal + metal salt compound (e.g., chromium chloride, chromium acetate, etc.) and an organic or inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acid,
etc.) and catalytic reduction. Suitable catalysts are conventional ones, e.g.
Examples include runny nickel, platinum oxide, palladium on carbon, etc. Among the protecting groups, the acyl group can generally be removed by hydrolysis. In particular, halogen-substituted alkoxycarbonyl and 8-quinolyloxycarbonyl groups are usually eliminated by treatment with heavy metals such as copper and zinc. Among the protecting groups, acyl groups can also be treated with iminohalogenating agents (e.g., phosphorus oxychloride, etc.) and iminoetherifying agents such as lower alkanols (e.g., methanol, ethanol, etc.);
If necessary, it can be removed by subsequent hydrolysis. The reaction temperature is not particularly limited and may be appropriately selected depending on the type of amino protecting group and the above-mentioned elimination method, and the reaction is preferably carried out under mild conditions such as cooling or slight heating. The invention provides within its scope that further protected amino and/or protected carboxy groups are converted into corresponding free amino and/or free carboxy groups during the reaction or during the post-processing steps of the process. This includes cases where there are. The object compound () and its salt of this invention are:
It is a novel compound that exhibits high antibacterial activity and inhibits the growth of a wide range of pathogenic microorganisms, including Gram-positive and Gram-negative bacteria, making it useful as an antibacterial agent. For therapeutic purposes, the compounds according to the invention may be mixed as active ingredients with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration. It can be used in the form of conventional pharmaceutical preparations containing it. Pharmaceutical formulations may be in solid form, such as capsules, tablets, dragees, ointments or suppositories, or in liquid form, such as solutions, suspensions or emulsions. If desired, the formulations may contain auxiliaries, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives. Although the dosage of the compound will vary depending on the age and condition of the patient, the compounds according to the invention can be administered in an average single dose of about 10 mg, 50 mg, 100 mg, 250 mg, 500 mg,
It was found that 1000mg of the drug was effective in treating infectious diseases caused by pathogenic bacteria. Generally, 1
mg/individual ~ 6000mg/individual or more
May be administered daily. In order to explain the usefulness of the target compounds, the antibacterial activity of representative compounds of this invention is shown below. Minimum inhibitory concentration (A) Test method In vitro antibacterial activity was determined by the agar plate dilution method described below. Trypticase soy broth (bacteria count 10 ⁸
One loop of each test strain cultured overnight in Heart Infusion Agar (HI
- agar). This medium contained antibacterial agents at various concentrations, and the minimum inhibitory concentration (MIC) was measured after culturing at 37°C for 20 hours. (Unit: μg/ml) (B) Test compound (1) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[2- (1-methyl-
3-pyridinio)vinyl]-3-cephem-
4-carboxylate (syn isomer) (cis,
trans mixture). (2) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[2-(1-methyl-
3-pyridinio)vinyl]-3-cephem-
4-carboxylate (syn isomer) (trans isomer). (C) Results

[Table] The present invention will be described in more detail below with reference to Production Examples and Examples. Preparation Example of the Starting Material of the Invention Preparation Example 1 (1) Add John's reagent (14.5 ml) to benzhydryl 7
-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamide]-3-
Hydroxymethyl-3-cephem-4-carboxylate (syn isomer) (19.5 g) was added dropwise into an acetone suspension (300 ml) at 0-3°C with stirring, and the mixture was stirred at the same temperature for 20 min. did.
The reaction mixture was filtered and the liquid was washed with acetone. Add ethyl acetate (300ml) to the mixture of liquid and washing liquid.
was added, washed with brine, and dried over magnesium sulfate. The solution was evaporated and the residue was triturated in diethyl ether to give benzhydryl 7-[2
-(2-formamidothiazol-4-yl)-
2-methoxyiminoacetamide]-3-formyl-3-cephem-4-carboxylate (syn isomer) (13.7 g) was obtained. IR (Nujiyor): 3250, 1780, 1720, 1670,
1600, 1540cm ^-1 NMRδ (DMSO-d ₆ ): 3.67 (2H, s), 3.95
(3H, s), 5.45 (1H, d, J=5Hz), 6.15
(1H, dd, J=5, 8Hz), 7.30 (1H, s),
7.23−7.77 (11H, m), 8.57 (1H, s), 9.53
(1H, s), 9.83 (1H, d, J=8Hz), 12.70
(1H, s) (2) Benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamide]-3-formyl-3-cephem-4-carboxylate (syn isomer) ( 3g)
A solution of triethylamine (0.45 g) in tetrahydrofuran (30 ml) was stirred at room temperature for 40 minutes. Ethyl acetate (50ml) was added to the reaction mixture and washed with 3% hydrochloric acid and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated. Trituration of the residue in diisopropyl ether yields benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamide]-3-formyl-2
-Cefem-4-carboxylate (syn isomer) (2.48 g) was obtained. IR (nujiol): 1780, 1730, 1665 cm ^-1 NMRδ (DMSO-d ₆ ): 3.93 (3H, s), 5.3 (1H,
d, J=4Hz), 5.43 (1H, s), 5.73 (1H,
dd, J=4, 8Hz), 6.83 (1H, s), 7.12−
7.72 (10H, m), 7.53 (1H, s), 8.3 (1H,
s), 8.57 (1H, s), 9.40 (1H, s), 9.80
(1H, d, J=8Hz), 12.63 (1H, broad s) Production example 2 (1) Benzhydryl 7-phenylacetamido-3-formyl-2-cephem-4-carboxylate (5.1g) was converted to 2-chloride. Added to a mixture of pyridylmethylenetriphenylphosphonium (4.7 g), water (25 ml) and dichloromethane (50 ml), the resulting solution was heated at room temperature for 2 hours at 20%
The mixture was stirred while maintaining the pH at 8.8 to 9.0 with an aqueous sodium carbonate solution. The separated organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated to give the crude product. The crude product is ethyl acetate (300ml)
added to. The precipitate was collected, washed with ethyl acetate and diisopropyl ether, and dried to give benzhydryl 7-phenylacetamide-3.
-[2-(2-pyridyl)vinyl]-2-cephem-4-carboxylate (trans isomer)
(2.8g) was obtained. IR (Nujiyor): 3150, 1770, 1730, 1670,
1620, 1535cm ^-1 NMRδ (DMSO-d ₆ ): 3.60 (2H, s), 5.28
(1H, d, J=5Hz), 5.50 (1H, dd, J=
5Hz, 8Hz), 5.72 (1H, s), 7.02 (1H, d,
J=17Hz), 7.13−7.67 (16H, m), 7.90
(1H, d, J = 17Hz), 7.7-8.50 (3H, m),
8.72 (1H, d, J = 4Hz), 9.30 (1H, d, J
= 8 Hz) (2) A solution of m-chloroperbenzoic acid (9.73 g) in dichloromethane (60 ml) was mixed with benzhydryl 7-phenylacetamide-3-[2-(2-pyridyl)
The mixture was added dropwise to a solution of vinyl]-2-cephem-4-carboxylic acid (trans isomer) (2.76 g) in dichloromethane (280 ml) at -30°C to -25°C, and stirred at the same temperature for 10 minutes. Pour the reaction mixture into water (100ml)
I put it in. The separated organic layer was washed with 2% aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and the solvent was evaporated to produce benzhydryl 7-phenylacetamide-3-
[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate-oxide (trans isomer) (24.5 g) was obtained. IR (Nujiyor): 3270, 1780, 1700, 1640,
1580, 1560, 1530 cm ^-1 NMRδ (DMSO-d ₆ ): 3.67 (2H, s),
3.72and4.55 (2H, ABq, J=18Hz), 5.05
(1H, d, J=5Hz), 5.93 (1H, dd, J=
5Hz, 8Hz), 7.02 (1H, s), 7.05 (1H, d,
J=17Hz), 8.12 (1H, d, J=17Hz), 7.05
-8.67 (19H, m) (3) Phosphorus trichloride (15.2g) is converted into benzhydryl 7-
Phenylacetamido-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate-1-oxide (trans isomer)
(22.2 g) in dimethylformamide (220 ml) at -30°C, the resulting solution was -30 to -25
Stirred at ℃ for 10 minutes. The reaction mixture was soaked in cold water (1
) and collected the resulting precipitate. The precipitate was dissolved in ethyl acetate (300 ml), the ethyl acetate layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated to give benzhydryl 7.
-Phenylacetamido-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (15.9 g) was obtained. IR (Nujiyor): 3300, 1770, 1695, 1645,
1575, 1555, 1520 cm ^-1 NMRδ (DMSO-d ₆ ): 3.60 (2H, s), 3.95
(2H, ABq, J = 18Hz), 5.27 (1H, d, J
= 5Hz), 5.83 (1H, dd, J = 5Hz, 8Hz),
7.07 (1H, s), 7.15 (1H, d, J=17Hz),
7.92 (1H, d, J = 17Hz), 7.17−8.0 (18H,
m), 8.60 (1H, d, J=5Hz), 9.20 (1H,
d, J = 8 Hz) (4) Benzhydryl 7-phenylacetamide-3 was added to a methylene chloride (120 ml) suspension of a pyridine-phosphorus pentachloride complex prepared from pyridine (48 g) and phosphorus pentachloride (12.7 g). -[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (12 g) was added with stirring under ice cooling. The mixture was stirred at the same temperature for 30 min and then dissolved in methanol (90 ml).
Pour at 25°C. This mixed solution was further heated at -5°C.
Stirred for 10 minutes at ˜-15° C. then evaporated under reduced pressure. Tetrahydrofuran (200ml) to the residue,
Add a mixture of ethyl acetate (200 ml) and water (200 ml) and dilute with a saturated aqueous solution of sodium bicarbonate.
Adjusted to PH6.5. The separated organic layer was washed with brine, dried over magnesium sulfate, and the solvent was evaporated to produce benzhydryl 7-amino-3-
[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer)
(6.6g) was obtained. IR (Nujiyor): 3300, 1770, 1720, 1615,
1580cm ^-1 NMRδ (DMSO-d ₆ ): 3.93 (2H, ABq, J = 18
Hz), 4.92 (1H, d, J=5Hz), 5.20 (1H,
d, J=5Hz), 7.05 (1H, s), 7.15 (1H,
d, J=17Hz), 7.92 (1H, d, J=17Hz),
7.17-8.10 (15H, m), 8.50-8.75 (1H, m) (5) Dissolve phosphorus oxychloride (1.29g) and dimethylformamide (0.62g) in ethyl acetate (30ml) using the Vilsmeyer reagent in a conventional manner. ). 2-(2-formamidothiazole-4-
yl)-2-methoxyiminoacetic acid (syn isomer)
(1.6 g), ethyl acetate (2 ml) and tetrahydrofuran (10 ml) of Willsmeier's reagent.
It was added to a medium stirred suspension under ice cooling and stirred at the same temperature for 0.5 hours to obtain an activated acid solution. N-
(Trimethylsilyl)acetamide (5.0 g) in benzhydryl 7-amino-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (3 g) in ethyl acetate (30 ml). Add to the stirred suspension at 40-43℃
The mixture was stirred for 30 minutes. The above activated acid solution was added to the resulting clear solution at -20°C, and the mixture was stirred at the same temperature for 30 minutes. Water (30 ml) was added to this solution and the separated organic layer was washed with 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give a benzhydryl 7-[2-methoxyimino-2-(2 -formamidothiazol-4-yl)acetamide]-3-[2-
(2-pyridyl)vinyl]-3-cephem-4-
Carboxylate (syn isomer) (trans isomer) (4.1 g) was obtained. IR (Nujiyor): 3150, 1770, 1710, 1670,
1610, 1540cm ^-1 NMRδ (DMSO-d ₆ ): 3.58 (2H, m), 3.92
(3H, s), 5.38 (1H, d, J=5Hz), 6.0
(1H, dd, J=5Hz, 8Hz), 7.07 (1H,
s), 7.13-8.28 (14H, m), 8.55 (1H, s),
8.50−8.77 (1H, m), 9.82 (1H, d, J=8
Hz) (6) Benzhydryl 7-amino-3-[2-(2-
pyridyl)vinyl]-3-cephem-4-carboxylate (trans isomer) (25 g) and N-(trimethylsilyl)acetamide (4.2
A mixture of g) in ethyl acetate (20ml) and tetrahydrofuran (10ml) was stirred at room temperature for 20 minutes to give a clear solution. Add 2-
Ethoxyimino-2-(5-amino-1,2,
4-thiadiazol-3-yl)acetyl chloride (syn isomer) (1.4 g) was added at -15 to -20°C, and the mixture was stirred at the same temperature for 30 minutes. Water (20 ml) was added to the obtained solution, and the separated organic layer was diluted to 5%.
Washing with aqueous sodium bicarbonate and brine, drying over magnesium sulfate and evaporation gives the benzhydryl 7-(2-ethoxyimino-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-cephem-4-carboxylate (syn isomer) (trans isomer) (3.6 g) was obtained. IR (Nujiyor): 3250, 1775, 1710, 1670,
1610, 1520cm ^-1 NMRδ (DMSO-d ₆ ): 1.23 (3H, t, J = 7
Hz), 3.83 (2H, m), 4.15 (2H, q, J=7
Hz), 5.28 (1H, d, J=5Hz), 5.92 (1H,
dd, J=5Hz, 8Hz), 6.98 (1H, s), 7.08
(1H, d, J=17Hz), 7.60 (1H, d, J=
17Hz), 7.10-8.33 (13H, m), 8.55 (1H,
d, J=5Hz), 9.58 (1H, d, J=8Hz) Production Example 3 (1) The following compound was obtained by the same method as Production Example 2-(1). (1) Benzhydryl 7-phenylacetamide-3-[2-(4-pyridyl)-vinyl]-2-
Cefem-4-carboxylate (trans isomer). IR (Nujiyor): 3770, 1767, 1725, 1645
cm ^-1 NMRδ (DMSO-d ₆ ): 3.57 (2H, s), 5.23
(1H, d, J = 4Hz), 5.50 (1H, dd, J
=4Hz, 8Hz), 5.83 (1H, s), 6.85 (1H,
s), 7.53 (1H, s), 6.6-7.8 (19H, m),
8.52 (2H, d, J=6Hz), 9.16 (1H, d,
J=8Hz) (2) Benzhydryl 7-phenylacetamide-3-[2-(3-pyridyl)-vinyl]-2-
Cefem-4-carboxylate (cis isomer). IR (Nujiyor): 3250, 1760, 1720(s),
1650, 1520cm ^-1 NMRδ (DMSO-d ₆ ): 3.60 (2H, s), 5.20
(1H, d, J=5Hz), 5.43 (1H, m),
5.80 (1H, s), 6.53 (2H, s), 6.80−8.50
(19H, m), 8.68 (2H, m), 9.27 (1H,
d, J=8Hz) (2) The following compound was obtained in the same manner as in Production Example 2-(2). (1) Benzhydryl 7-phenylacetamide-3-[2-(4-pyridyl)vinyl]-3-
Cefem-4-carboxylate-1-oxide (trans isomer). IR (Nujiyor): 1770, 1718, 1698, 1647
cm ^-1 NMRδ (DMSO-d ₆ ): 3.66 (2H, s), 3.8
(2H, m), 5.07 (1H, d, J=4Hz),
5.97 (1H, dd, J=4Hz, 8Hz), 6.9−8.2
(20H, m), 8.53 (2H, brs), 8.60 (1H,
d, J=8Hz) (2) Benzhydryl 7-phenylacetamido-3-[2-(3-pyridyl)vinyl]-3-
Cefem-4-carboxylate-1-oxide (cis isomer). IR (Nujiyor): 3200, 1780, 1720, 1670
cm ^-1 NMRδ (DMSO-d ₆ ): 3.50 (2H, m), 3.67
(2H, s), 5.03 (1H, d, J=5Hz),
5.92 (1H, dd, J=5Hz, 8Hz), 6.52
(2H, s), 6.85 (1H, s), 7.0−8.0 (17H,
m), 8.47 (3H, m) (3) The following compound was obtained in the same manner as in Production Example 2-(3). (1) Benzhydryl 7-phenylacetamide-3-[2-(4-pyridyl)vinyl]-3-
Cefem-4-carboxylate (trans isomer). IR (Nujiyor): 3270−3170, 1772, 1710,
1670cm ^-1 NMRδ (DMSO-d ₆ ): 3.60 (2H, s), 3.70,
4.13 (2H, ABq, J=17Hz), 5.23 (1H,
d, J=5Hz), 5.82 (1H, dd, J=5Hz,
8Hz), 6.9-7.7 (20H, m), 8.50 (2H, broad s), 9.23 (1H, d, J = 8Hz) (2) Benzhydryl 7-phenylacetamide-3-[2-(3-pyridyl) Vinyl]-3-
Cefem-4-carboxylate (cis isomer). IR (Nujiyor): 3150, 1770, 1710, 1660,
1530cm ^-1 NMRδ (DMSO−d ₆ ): 3.47 (2H, ABq, J=
18Hz), 3.57 (2H, s), 5.27 (1H, d, J
= 5Hz), 5.83 (1H, dd, J = 5Hz, 8
Hz), 6.52 (2H, s), 6.85 (1H, s), 7.17
-8.0 (17H, m), 8.57 (1H, d, J=8
Hz) (4) The following compound was obtained in the same manner as in Production Example 2-(4). (1) Benzhydryl 7-amino-3-[2-small(4-pyridyl)vinyl]-3-cephem-4
-carboxylate (trans isomer). IR (nujiol): 1770, 1719, 1583cm ^-1 NMRδ (DMSO-d ₆ ): 3.83 (2H, m), 4.87,
5.13 (2H, ABq, J=5Hz), 6.9−7.6
(17H, m), 8.45 (2H, d, J=5Hz) (2) Benzhydryl 7-amino-3-[2-(3
-pyridyl)vinyl]-3-cephem-4-
Carboxylate (cis isomer). IR (nujiol): 3300, 1760, 1720 cm ^-1 NMRδ (DMSO−d ₆ ): 3.42 (2H, ABq, J=
18Hz), 4.87 (1H, d, J = 5Hz), 5.12
(1H, d, J=5Hz), 6.45 (2H, s),
6.77 (1H, s), 7.05−7.67 (12H, m),
8.38 (2H, m) (3) Benzhydryl 7-amino-3-[2-(3
-pyridyl)vinyl]-3-cephem-4-
Carboxylate (cis, trans isomers). IR (nujiol): 3300, 1760, 1710 cm ^-1 NMRδ (DMSO-d ₆ ): 3.87 (2H, m), 4.90
(1H, d, J = 5Hz), 5.15 (1H, d, J
=5Hz), 7.0-7.80 (15H, m), 8.43 (2H,
m) (5) The following compound was obtained in the same manner as in Production Example 2-(5). Benzhydryl 7-[2-(t-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamide]-3
-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (trans isomer). IR (Nujiyor): 3250, 1780, 1720, 1680,
1540cm ^-1 NMRδ (DMSO-d ₆ ): 1.43 (9H, s), 3.95
(2H, ABq, J=18Hz), 4.67 (2H, s),
5.38 (1H, d, J = 5Hz), 6.0 (1H, dd, J
=5Hz, 8Hz), 7.05 (1H, s), 7.18 (1H,
d, J=17Hz), 7.68 (1H, d, J=17Hz),
7.19−8.15 (13H, m), 8.57 (1H, s), 8.50
-8.75 (1H, m), 9.75 (1H, d, J = 8Hz) (6)(1) Benzhydryl 7-[2-(t-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl ) acetamide]-3-[2-(2-pyridyl)vinyl]-3
- To a methanol solution of cefem-4-carboxylate (syn isomer) (trans isomer) (4.4 g) was added concentrated hydrochloric acid (1.8 g), and the mixture was stirred at room temperature for 4.5 hours. The precipitate was collected by filtration, washed with tetrahydrofuran and diisopropyl ether, and dried over phosphorus pentoxide to give benzhydryl 7-[2-(t-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl). -acetamide]-3-[2-(2
-pyridyl)vinyl]-3-cephem-4-
Carboxylate dihydrochloride (syn isomer)
(trans isomer) (3.9 g) is obtained. IR (Nujiyor): 3200, 1780, 1720, 1680,
1610, 1570cm ^-1 NMRδ (DMSO-d ₆ ): 1.47 (9H, s), 3.93
(2H, broad s), 4.72 (2H, s),
5.42 (1H, d, J=5Hz), 6.05 (1H, dd,
J=5Hz, 8Hz), 7.05 (1H, s), 7.18
(1H, d, J=17Hz), 7.80 (1H, J=17
Hz), 7.17−8.50 (13H, m), 8.72 (1H,
d, J = 5 Hz), 9.92 (1H, d, J = 8 Hz) The following compound was obtained in the same manner as in Production Example 3-(6)-(1). (2) Benzhydryl 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)
Acetamide]-3-[2-(2-pyridyl)
vinyl)-3-cephem-4-carboxylate (syn isomer) (trans isomer). IR (Nujiyor): 3250, 1780, 1720, 1680,
1610, 1580, 1530 cm ^-1 NMRδ (DMSO-d ₆ ): 3.63 (2H, m), 3.88
(3H, s), 5.30 (1H, d, J=5Hz),
5.92 (1H, dd, J=5Hz, 8Hz), 6.97
(1H, d, J=17Hz), 7.03 (1H, s),
7.97 (1H, d, J = 17Hz), 7.08−7.70
(14H, m), 8.45−8.67 (1H, m), 9.67
(1H, d, J=8Hz) (7) The following compound was obtained in the same manner as in Production Example 2-(6). (1) Benzhydryl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[2
-(4-pyridyl)vinyl]-3-cephem-
4-carboxylate (syn isomer) (trans isomer). IR (Nujiyor): 3260, 1777, 1710, 1672,
1610cm ^-1 NMRδ (DMSO-d ₆ ): 1.20 (3H, t, J=7
Hz), 3.85 (2H, m), 4.15 (2H, q, J=7
Hz), 5.25 (1H, d, J=5Hz), 5.92 (1H, dd,
J=5Hz, 8Hz), 6.99 (1H, s), 6.9−7.8
(16H, m), 8.70 (2H, d, J=5Hz), 9.60
(1H, d, J=8Hz) (2) Benzhydryl 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[2
-(3-pyridyl)vinyl]-3-cephem-
4-carboxylate (syn isomer) (cis isomer). IR (Nujiyor): 3250, 1770, 1720, 1670,
1610, 1520cm ^-1 NMRδ (DMSO-d ₆ ): 1.10 (3H, t, J = 7
Hz), 3.47 (2H, ABq, J=18Hz), 4.22
(2H, q, J = 7Hz), 5.33 (1H, d, J
= 5Hz), 5.97 (1H, dd, J = 5Hz, 8
Hz), 6.50 (2H, s), 6.83 (1H, s), 7.10
-7.88 (12H, m), 8.40 (1H, m), 9.67
(1H, d, J=8Hz) (8) The following compound was obtained by the same method as in Production Example 12-(1) below. (1) 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamide]-
3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (trans isomer). IR (Nujiyor): 3330, 1770, 1670, 1625,
1570, 1520cm ^-1 NMRδ (DMSO-d ₆ ): 3.62 (2H, m), 3.88
(3H, s), 5.28 (1H, d, J=5Hz),
4.83 (1H, dd, J=5Hz, 8Hz), 6.78
(1H, s), 7.05 (1H, d, J=17Hz),
7.95 (1H, d, J = 17Hz), 7.0−8.18 (5H,
m), 8.57 (1H, d, J=5Hz), 9.65 (1H,
d, J=8Hz) (2) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-(2-pyridyl)vinyl ]-3-Cefem-4-carboxylic acid (syn isomer) (trans isomer). IR (Nujiyor): 3250, 1770, 1670, 1620,
1575, 1520 cm ^-1 NMRδ (DMSO-d ₆ ): 1.12 (3H, t, J = 7
Hz), 3.90 (2H, ABq, J=18Hz), 4.22
(2H, q, J = 7Hz), 5.27 (1H, d, J
= 5Hz), 5.87 (1H, dd, J = 5Hz, 8
Hz), 7.03 (1H, d, J = 17Hz), 7.93 (1H,
d, J=17Hz), 7.17−8.38 (3H, m),
8.58 (1H, d, J=5Hz), 9.62 (1H, d,
J=8Hz) (3) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[2-(4-pyridyl)vinyl]- 3-Cefem-4-carboxylic acid (syn isomer) (trans isomer). IR (Nujiyor): 3200, 1770, 1665, 1630,
1608cm ^-1 NMRδ (DMSO-d ₆ ): 1.28 (3H, t, J=7
Hz), 3.93 (2H, m), 4.22 (2H, q, J=
7Hz), 5.28 (1H, d, J = 5Hz), 5.87
(1H, dd, J=5Hz, 8Hz), 7.07 (1H,
d, J = 16Hz), 7.62 (2H, d, J = 5
Hz), 7.73 (1H, d, J = 16Hz), 8.17 (2H,
Broad s), 8.65 (2H, d, J=5
Hz), 9.60 (1H, d, J = 8Hz) (4) 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido-3-[2- (3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis isomer). IR (Nujiyor): 3250, 1770, 1680, 1610,
1520cm ^-1 NMRδ (DMSO-d ₆ ): 1.18 (3H, t, J = 7
Hz), 3.67 (2H, m), 4.17 (2H, q, J=
7Hz), 5.22 (1H, d, J=5Hz), 5.82
(1H, dd, J=5Hz, 8Hz), 6.57 (2H,
s), 7.10−7.88 (2H, m), 8.47 (2H,
m), 9.58 (1H, d, J = 8Hz) (5) 7-[2-carboxymethoxyimino-2
-(2-aminothiazol)-4-yl)acetamido]-3-[2-(2-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (trans isomer). IR (Nujiyor): 3250, 1770, 1670, 1620,
1565, 1530 cm ^-1 NMRδ (DMSO−d ₆ ): 3.93 (2H, ABq, J=
18Hz), 4.67 (2H, s), 5.33 (1H, d, J
= 5Hz), 5.90 (1H, dd, J = 5Hz, 8
Hz), 6.87 (1H, s), 7.05 (1H, d, J=
17Hz), 8.0 (1H, d, J = 17Hz), 7.0−
8.08 (3H, m), 8.62 (1H, d, J=5Hz),
9.62 (1H, d, J = 8Hz) Production Example 4 (1) Sodium iodide (1.8g) was mixed with benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate (5.0g) and triphenylphosph. The mixture was added to a solution of Yin (3.2 g) in dimethylformamide (15 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. The resulting solution was added dropwise to ethyl acetate (250 ml) with vigorous stirring.
The precipitate was collected and washed with ethyl acetate (4-
Benzhydryloxycarbonyl-7-amino-3-cephem-3ylmethyl)triphenylphosphonium iodide hydrochloride (9.6 g) was obtained. IR (nujiyor): 3330, 1780, 1700, 1645cm
^-1 (2) (4-benzhydryloxycarbonyl-7
-Amino-3-cephem-3-ylmethyl)triphenylphosphonium iodide hydrochloride (5 g) was dissolved in a mixed solution of tetrahydrofuran (35 ml) and 35 ml of an aqueous solution of sodium hydrogen carbonate (1.6 g). 2-(5-
Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetyl chloride.
A solution of hydrochloride (syn isomer) (2.6 g) in tetrahydrofuran was added at -3°C to 3°C and incubated for 30 minutes at 20
% potassium carbonate aqueous solution while maintaining the pH at 6.5 to 7.5. Add ethyl acetate to the reaction mixture;
The pH was adjusted to 10. with a 20% aqueous potassium carbonate solution.
The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was evaporated.
2-Ethoxyiminoacetamide]-3-(triphenylphosphoranediylmethyl)-3-cephem-4-carboxylate (syn isomer)
(4.5g) was obtained. IR (nujiol): 1740, 1640 (br) cm ^-1 NMRδ (DMSO-d ₆ ): 1.25 (3H, t, J = 7.0
Hz), 3.11−3.77 (2H, m, overlapping _H2O ), 4.10
(2H, q, J = 7.0Hz), 5.19 (1H, d, J =
4.0Hz), 5.63 (1H, m), 6.70−8.27 (26H,
m), 9.20 (1H, d, J=8.0Hz) (3) The following compound was obtained in the same manner as in Production Example 8-(2). Benzhydryl 7-[2-(5-amino-1,
2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[2-(1-
Methyl-3-pyridinio)vinyl]-3-cephem-4-carboxylate iodide (syn isomer) (cis, trans mixture). IR (nujiyor): 1780, 1720, 1660, 1610cm
^-1 NMRδ (DMSO-d ₆ ): 1.27 (3H, t, J = 7.0
Hz), 3.53 (2H, m), 4.20 (2H, q, J=7.0
Hz, 4.31 (2H, s), 5.37 (1H, d, J=4.0
Hz), 5.90 (1H, m), 6.58-8.30 (15H, m),
8.73 (1H, m), 9.54 (1H, d, J = 8.0Hz) Production example 5 (1) 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic acid ( syn isomer) (14.4g) to phosphorus pentachloride (13.8g)
Added to a stirred suspension of g) in dichloromethane (150ml) at -5°C and stirred for 20 minutes at -10°C to 0°C. Isopropyl ether was added to the reaction mixture at the same temperature, and the mixture was stirred at room temperature for 10 minutes. The precipitate was separated and washed with isopropyl ether. N-(trimethylsilyl)acetamide (43.6g) was converted into benzhydryl 7-amino-3-
Chloromethyl-3-cephem-4-carboxylate hydrochloride (25g) in ethyl acetate (250ml)
Add to medium stirring suspension. The above precipitate was added to the obtained solution at -10°C, and the mixture was stirred at -10°C to -5°C for 30 minutes. Water was added to the reaction mixture. The separated organic layer was washed with a saturated aqueous sodium bicarbonate solution and water. The organic layer was dried with magnesium sulfate and the solvent was evaporated to give benzhydryl 7.
-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-chloromethyl-3-cephem-
4-carboxylate (syn isomer) (36.8g)
was gotten. IR (Nujiyor): 3270, 3140, 1775, 1720,
1670, 1620cm ^-1 NMRδ (DMSO−d ₆ ): 1.25 (3H, tJ=7.0Hz),
3.61 (2H, m), 4.19 (2H, q, J = 7.0Hz),
4.43 (2H, s), 5.24 (1H, d, J=5.0Hz),
5.95 (1H, dd, J=5.0Hz, 8.0Hz), 6.95
(1H, s), 7.36 (10H, m), 8.12 (2H, broad s), 9.59 (1H, d, J = 8.0Hz) (2) Benzhydryl 7-[2-(5-amino-1,
A solution of 2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-chloromethyl-3-cephem-4-carboxylate (syn isomer) (36.7 g) in ethyl acetate (600 ml), triphenyl A mixture of phosphine (18.8 g) and sodium iodide (1 g) was brought under reflux.
Boiled for 100 minutes. The precipitate was collected and washed with ethyl acetate to give [4-benzhydryloxycarbonyl-7-[2-(5-amino-1,2,4-
Thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-cephem-3-ylmethyl]triphenylphosphonium chloride (syn isomer) (31.1 g) was obtained. IR (nujiol): 1770, 1670, 1600 cm ^-1 NMR δ (DMSO-d ₆ ): 1.23 (3H, t, J = 7.0
Hz), 3.62 (2H, m), 4.19 (2H, q, J=7.0
Hz), 5.03−5.56 (2H, m), 5.38 (1H, d,
J = 5.0Hz), 5.95 (1H, dd, J = 5.0Hz, 8.0
Hz), 6.30 (1H, s), 7.10−8.07 (25H, m),
8.36 (2H, broad s), 9.64 (1H, d, J
=8.0Hz) (3) Nicotinaldehyde (1.1g) was converted into {4-benzhydryloxycarbonyl-7-[2-(5-
Amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-
A solution of triphenylphosphonium chloride (syn isomer) (3.0 g) in tetrahydrofuran (30 ml) and water (15 ml) was added to a solution of 20% sodium carbonate aqueous solution to pH 9.0.
Adjusted to. This solution was heated to 20% at room temperature for 2 hours.
The mixture was stirred while maintaining the pH at 8.8 to 9.2 with an aqueous potassium carbonate solution. Ethyl acetate and water were added to the resulting solution. The separated organic layer was washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The crude product obtained by concentration was subjected to silica gel column chromatography, and an acetone-dichloromethane mixture (1:1) was used as the eluent.
It was purified using Evaporation of the solvent in the eluted fraction yields benzhydryl 7-[2-(5-amino-1,
2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[2-(3-
pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans mixture) (1.1 g) was obtained. IR (nujiyor): 1770, 1710, 1670, 1610cm
^-1 NMRδ (DMSO−d ₆ ): 1.26and1.30 (total 3H,
each t, J=7.0Hz), 3.48(2H, q, J=
18.0Hz), 4.21 (2H, q, J = 7.0Hz), 5.33
(1H, d, J = 5.0Hz), 5.97 (1H, dd,
J=5.0Hz, 8.0Hz), 6.51 (1H, s), 6.83
(1H, s), 7.07−7.76 (13H, m), 8.17 (2H,
s), 8.35-8.60 (2H, m), 9.74 (1H, d,
J=8.0Hz) (4) Trifluoroacetic acid (1.2ml) was added to benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[ 2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans mixture) (1.0
The mixture was added to a suspension of g) in dichloromethane (10 ml) and anisole (0.65 ml) at room temperature, and stirred at the same temperature for 2 hours. Isopropyl ether (50 ml) was added to the resulting solution and stirred. The precipitate was collected and washed with diisopropyl ether. Add this precipitate to an ethyl acetate-water mixture,
The pH was adjusted to 7.5 with a 20% aqueous potassium carbonate solution.
The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid while cooling on ice. The resulting precipitate was separated, washed with ice water, and vacuum dried over phosphorus pentoxide to give 7-[2-
(5-amino-1,2,4-thiadiazole-
3-yl)-2-ethoxyiminoacetamide]
-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis-trans mixture) (0.4 g) was obtained. IR (Nujiyor): 3240, 3140, 1765, 1665,
1610 cm ^-1 NMRδ (DMSO−d ₆ ): 1.25 and 1.29 (total
3H, each, t, J = 7.0Hz), 3.40 (2H,
q, J = 18.0Hz), 4.18 and 4.22 (total
2H, each q, J=7.0Hz), 5.26 (1H,
d, J = 5.0Hz), 5.85 (1H, dd, J = 5.0
Hz, 8.0Hz), 6.58 (1H, s), 7.04 (0.5H, d,
J = 17.0Hz), 7.23-8.24 (3.5H, m), 8.28
(2H, broad s), 8.39−8.72 (2H, m),
9.58 (1H, d, J=8.0Hz) Production Example 6 (1) The following compound was obtained by the same method as Production Example 5-(3). Benzhydryl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamide]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans mixture). IR (nujiol): 1765, 1670, 1640cm ^-1 NMRδ (DMSO-d ₆ ): 3.48 (2H, m), 3.91
(3H, s), 5.35 (1H, d, J=5.0Hz), 5.98
(1H, dd, J=5.0Hz, 8.0Hz), 6.52
(1H, s), 6.83 (1H, s), 6.85−7.71 (14H,
m), 8.37-8.66 (3H, m), 9.80 (1H, d,
J=8.0Hz) (2) The following compound was obtained by the same method as Production Method 5-(4). 7-[2-(2-formamidothiazole-4
-yl)-2-methoxyiminoacetamide-
3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis-
trans mixture). IR (nujiol): 1760, 1665 cm ^-1 NMRδ (DMSO-d ₆ ): 3.43 (2H, q, J = 18.0
Hz), 3.92 (3H, s), 5.29 (1H, d, J=5.0
Hz), 5.87 (1H, dd, J=5.0Hz, 8.0Hz),
6.61 (1H, s), 6.85-8.31 (3H, m), 7.43 and 7.46 (total 1H, each s), 8.38-
8.77 (3H, m), 9.74 (1H, d, J = 8.0Hz) (3) 7-[2-(2-formamidothiazole-4
-yl)-2-methoxyiminoacetamide]-
3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis-
trans mixture) (0.8 g) of methanol (6
ml) solution, tetrahydrofuran (3 ml) and concentrated hydrochloric acid (0.5 g) was stirred at room temperature for 3 hours. The resulting solution was added to an ethyl acetate-water mixture, and the pH was adjusted to 7.5 with a 20% aqueous potassium carbonate solution. The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid under ice cooling. 7-
[2-(2-aminothiazol-4-yl)-2
-Methoxyiminoacetamide]-3-[2-
(3-pyridyl)vinyl]-3-cephem-4-
Carboxylic acid (syn isomer) (cis-trans mixture) (0.3 g) was obtained. IR (nujiyor): 3280, 1770, 1660, 1620cm
^-1 NMRδ (DMSO-d ₆ ): 3.39 (2H, q, J = 18.0
Hz), 3.85 (3H, s), 5.23 (1H, d, J=5.0
Hz), 5.80 (1H, dd, J=5.0Hz, 8.0Hz),
6.56 (1H, s), 6.77 (1H, s), 6.80−8.00
(3H, m), 8.35-8.68 (2H, m), 9.65 (1H,
d, J = 8.0 Hz) Production Example 7 (1) A solution of phosphorus tribromide (5.0 g) in tetrahydrofuran (10 ml) was mixed with benzhydryl 7-phenylacetamido-3-hydroxymethyl-3-cephem-4-carboxylate (25.7 g) in tetrahydrofuran (200 ml) at -10 to -5°C.
and stirred at the same temperature for 15 minutes. The resulting mixture was water (250ml) - ethyl acetate (300ml).
into the mixture. The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporation of the solvent gave an oily product. This crude oil product was dissolved in ethyl acetate (250 ml) and
Triphenylphosphine (21 g) was added. The mixture was stirred at room temperature for 3 hours. The precipitate was collected and washed with ethyl acetate to obtain (4-benzhydryloxycarbonyl-7-phenylacetamido-3-cephem-3-ylmethyl)triphenylphosphonium bromide (22.8 g). IR (Nudiyol): 1780, 1710, 1665 cm ^-1 (2) Nicotinaldehyde (32.1 g) was converted into [4-benzhydryloxycarbonyl-7-(2-phenylacetamido)-3-cephem-3-ylmethyl] trifle. Enylphosphonium bromide (84.0 g) was added to an aqueous solution of a mixture of tetrahydrofuran (800 ml) and water (400 ml), and the pH was adjusted to 9.0 with a 20% aqueous sodium carbonate solution. This solution was diluted with 20% potassium carbonate aqueous solution for 2 hours at room temperature.
The mixture was stirred while maintaining the temperature between 8.8 and 9.2. Ethyl acetate (800ml) and water (800ml) were added to the resulting solution. The separated organic layer was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The crude product obtained by concentration was subjected to silica gel column chromatography using acetone-dichloromethane (1:1 V/V) as the eluent.
The mixture was used for purification. Evaporation of the solvent of the eluted fractions yielded benzhydryl 7-(2-phenylacetamide)-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (cis-trans mixture) (28.5 g) was obtained. IR (Nujiyor): 3250, 1770, 1710, 1660,
1530cm ^-1 NMRδ (DMSO-d ₆ ): 3.50 (2H, ABq, J = 18
Hz), 3.58 (2H, s), 5.27 (1H, d, J=5
Hz), 5.80 (1H, dd, J=5Hz, 8Hz), 6.55
(1.5H, s), 6.82 (1H, s), 7.17−7.93
(17.5H, m), 8.50 (2H, m), 9.22 (1H, d,
J=8Hz) (3) Benzhydryl 7-phenylacetamide-
A mixture of 3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (cis-trans mixture) (5.9 g), anisole (6 ml) and trifluoroacetic acid (20 ml) was prepared at room temperature.
Stir for 30 minutes. The reaction mixture was added to diisopropyl ether (300ml). Take the precipitate,
Washing with diisopropyl ether gives 7-phenylacetamide-3-[2-(3-pyridyl)
vinyl]-3-cephem-4-carboxylic acid trifluoroacetate (cis-trans mixture) (2.5
g) was obtained. IR (nujiyor): 3200, 1760, 1660, 1520cm
^-1 NMRδ (DMSO-d ₆ ): 3.58 (2H, s), 3.45
(2H, ABq, J = 18Hz), 5.20 (1H, d, J
= 5Hz), 5.70 (1H, dd, J = 5Hz, 8Hz),
6.65 (1H, s), 7.17-8.33 (8H, m), 8.65
(2H, m), 9.15 (1H, d, J=8Hz) Production example 8 (1) (4-benzhydryloxycarbonyl-7
-phenylacetamide-3-cephem-3-
(methyl) triphenylphosphonium bromide (8.4 g) in tetrahydrofuran (50 ml)
The solution in water (50 ml) was adjusted to pH 11.0 with an aqueous sodium hydroxide solution, and the resulting solution was extracted with ethyl acetate and tetrahydrofuran. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was washed with ether to give benzhydryl 7-phenylacetamido-3-triphenylphosphoranediylmethyl)-3-cephem-4-carboxylate (4.5 g). IR (nujiyor): 3370, 1760, 1680, 1650cm
^-1 (2) Benzhydryl 7-phenylacetamide-
3-(triphenylphosphoranediylmethyl)-
3-cephem-4-carboxylate (3.8g)
and 1-methyl-3-formylpyridinium iodide (3.74 g) in dimethylformamide (50
ml) The solution was stirred at room temperature for 5 hours. The mixture was poured into a diethyl ether-ethyl acetate (2:1) mixture and decanted. Add water to the residue,
The pH was adjusted to 8.0 with a 20% aqueous potassium carbonate solution.
This solution was extracted with an ethyl acetate-tetrahydrofuran mixture, and the extracted solution was dried over magnesium sulfate. Vacuum distillation of the solvent and trituration of the residue in diethyl ether yielded benzhydryl 7.
-Phenylacetamido-3-[2-(1-methyl-3-pyridinio)vinyl]-3-cephem-4-carboxylate iodide (cis-trans mixture) (2.1 g) was obtained. IR (nujiol): 1770, 1720, 1660 cm ^-1 NMRδ (DMSO-d ₆ ): 3.6 (2H, s), 3.6 (2H,
m), 4.33 (3H, s), 5.28 (1H, m), 5.78
(1H, m), 6.57-8.23 (19H, m), 8.6-9.4
(3H, m) Production example 9 Benzhydryl 7-[2-(5-amino-1,
Trans and cis isomers of 2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) A mixture of (8 g) was subjected to medium pressure column chromatography on silica gel [Merck Kieselgel 60 (230-400 mesh, 160 g)] using chloroform-acetic acid (ratio 20:1-10:1) as the eluent. there was. The fractions containing the cis isomer were washed with saturated sodium bicarbonate solution and brine and dried over magnesium sulfate. The solvent of the solution was evaporated and the residue was triturated with diethyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-
The cis isomer (4.1 g) of thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) was Obtained. The second fraction containing the trans isomer was then washed with saturated sodium bicarbonate solution and brine and dried over magnesium sulfate. The solvent of the solution was evaporated and the residue was triturated with diethyl ether to give benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2
-ethoxyiminoacetamide]-3-[2-(3
-Pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) trans isomer (1.72 g) was obtained. Trans isomer IR (Nudiyol): 1765, 1670cm ^-1 NMRδ (DMSO-d ₆ ): 1.29 (3H, t, J = 7.0
Hz), 3.93 (2H, q, J = 18.0Hz, 4.20 (2H,
q, J = 7.0Hz), 5.29 (1H, d, J = 5.0Hz),
5.92 (1H, dd, J=5.0Hz, 8.0Hz), 6.98 (1H,
d, J=17.0Hz, 7.00−7.58 (13H, m), 7.03
(1H, s), 8.33−8.51 (2H, m), 9.51 (1H,
d, J = 8 Hz) Cis isomer IR (Nujiol): 1765, 1670 cm ^-1 NMR δ (DMSO-d ₆ ): 1.24 (3H, t, J = 7.0
Hz), 3.45 (2H, q, J = 18.0Hz), 4.19 (2H,
q, J = 7.0Hz), 5.32 (1H, d, J = 5.0Hz),
5.97 (1H, dd, J=5.0Hz, 8.0Hz), 6.50 (2H,
s), 6.81 (1H, s), 7.14−7.70 (12H, m),
8.34−8.53 (2H, m), 9.66 (1H, d, J = 8.0
Hz) Production Example 10 The following compound was obtained in the same manner as in Production Example 12-(1) below. 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3-[2-(3-pyridyl)vinyl]-3
-Cefem-4-carboxylic acid (syn isomer) (trans isomer). IR (Nujiyor: 3400, 3250, 1760, 1670,
1655, 1620 cm ^-1 NMRδ (DMSO-d ₆ ): 1.28 (3H, t, J = 7.0
Hz), 3.88 (2H, q, J = 18.0Hz), 4.20 (2H,
q, J = 7.0Hz), 5.25 (1H, d, J = 4.0Hz),
5.85 (1H, dd, J=4.0Hz, 8.0Hz), 7.01 (1H,
d, J=17.0Hz), 7.21−8.24 (3H, m), 8.32−
8.75 (2H, m), 9.57 (1H, d, J = 8.0Hz) Production example 11 (1) Nicotinaldehyde (1.28g) was converted into {4-benzhydryloxycarbonyl-7-[(5-benzhydryloxy N,N-dimethylformamide (48
ml)-ethanol (4.8 ml) mixture. The mixture was stirred at room temperature for 3.5 hours. Water (300ml) and ethyl acetate (300ml) were added to the reaction mixture. The separated organic layer was washed with brine and dried over magnesium sulfate. The crude product obtained by concentration was subjected to silica gel column chromatography using acetone as the eluent.
A dichloromethane (1:1 V/V) mixture was used. Evaporation of the solvent of the fractions containing the desired compound yields benzhydryl 7-(5-benzhydryloxycarbonyl-5-benzamidovaleramide)-3-[2-(3-pyridyl)vinyl]
-3-cephem-4-carboxylate (cis-trans mixture) (1.25 g) was obtained. NMR (DMSO- _d6 , δ): 1.83 (4H, m), 2.33
(2H, m), 4.63 (1H, m), 5.25 (1H, d,
J=5Hz), 5.83(1H, dd, J=5Hz, 8
Hz), 6.33-8.17 (36H, m), 8.45 (2H, m),
8.82 (1H, d, J = 8Hz), 8.95 (1H, d, J
=8Hz) (2) Pyridine (4.7g) and phosphorus pentachloride (12.5
Add benzhydryl 7-(5-benzhydryloxycarbonyl-5-benzamidevaleramide)-3-[to a suspension of the pyridine-phosphorus pentachloride complex prepared from g) in dichloromethane (90 ml) with stirring under ice cooling. 2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (cis-trans isomer) (17.7 g) was added.
The mixture was stirred at the same temperature for 30 minutes. Methanol (5.7 ml) was added to the resulting solution at -15 to -10°C, and the mixture was poured into water (300 ml). The separated aqueous layer was washed sequentially with methylene chloride and diisopropyl ether, and then with 20% aqueous sodium hydroxide solution.
Adjusted to PH5.5. Take the precipitate, wash it with water,
Drying over phosphorus pentoxide under reduced pressure gave benzhydryl 7-amino-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (cis-trans mixture) (6.9 g). . IR (nujiol): 3300, 1760, 1710 cm ^-1 NMR (DMSO-d ₆ , δ): 3.87 (2H, m), 4.90
(1H, d, J=5Hz), 5.15 (1H, d, J=
5Hz), 7.0-7.80 (15H, m), 8.43 (2H, m) Production example 12 (1) Benzhydryl 7-[2-propargyloxyimino-2-(2-aminothiazole-4-
yl)acetamido]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans isomer)
To a methylene chloride solution of (1.2 g) and anisole (1.2 ml) was added trifluoroacetic acid (5 ml) under stirring and cooling, and the mixture was stirred at room temperature for 1 hour. The solution was added dropwise to a diisopropyl ether (150 ml) solution, and the resulting precipitate was collected by filtration and dissolved in an aqueous sodium bicarbonate solution. PH the aqueous layer with 10% hydrochloric acid
3.5, and subjected to column chromatography using Macco porous nonionic adsorption resin "Diaion HP-20" and eluted with 20% isopropyl alcohol aqueous solution. The fractions containing the target compound were concentrated and lyophilized to give 7-[2-propargyloxyimino-2-(2-aminothiazole-4
-yl)acetamide]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis-trans mixture)
(0.56g) was obtained. IR (Nujiyor): 3250, 1765, 1670, 1610,
1330cm ^-1 NMRδ (DMSO-d ₆ ): 3.35 (2H, ABq, J = 18
Hz), 3.35 (1H, m), 4.70 (2H, m), 5.23
(1H, d, J=5Hz), 5.80 (1H, dd, J=
5Hz, 8Hz), 6.50-7.80 (5H, m), 8.47
(2H, m), 9.67 (1H, d, J=8Hz) The following compound was obtained in the same manner as in Production Example 12-(1). (2) 7-[2-methoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[2-(3-pyridyl)vinyl]-3-cephem- 4-carboxylic acid (syn isomer) (cis-trans mixture). IR (Nujiyor): 3270, 3150, 1765, 1670,
1610, 1530cm ^-1 NMR (DMOS-d ₆ , δ): 3.37 (2H, ABq, J
= 18Hz), 3.90 (3H, s), 5.22 (1H, d, J
= 5Hz), 5.83 (1H, dd, J = 5Hz, 8Hz),
6.35−7.85 (4H, m), 8.47 (2H, m), 9.57
(1H, d, J=8Hz) (3) 7-[2-ethoxyimino-2-(2-aminothiazol-4-yl)acetamide]-3-
[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (syn isomer) (cis-trans mixture). IR (Nujiyor): 3300, 1770, 1670, 1610,
1530cm ^-1 NMR (DMSO-d ₆ , δ): 1.20 (3H, t, J
=7Hz), 3.37 (2H, ABq, J = 18Hz), 4.10
(2H, q, J = 7Hz), 5.23 (1H, d, J =
8Hz), 5.80 (1H, dd, J=5Hz, 8Hz),
6.37−7.87 (4H, m), 6.70 (1H, s), 8.43
(2H, m), 9.60 (1H, d, J = 8Hz) (4) 7-formamide-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylic acid (cis-trans mixture ). IR (nujiol): 1760, 1665, 1600cm ^-1 NMR (DMSO−d ₆ , δ): ^3.41 _3.93 }2H, each
q, J = 18.0Hz, 5.22 (1H, d, J = 5.0Hz),
5.82 (1H, dd, J=5.0Hz, 8.0Hz), 6.61
(0.5H, s), 7.02 (0.75H, d, J=17.0Hz),
7.27−7.60 (1H, m), 7.60 (0.75H, d, J=
17.0Hz, 7.68-8.07 (1H, m), 8.37-8.80
(2H, m), 9.11 (1H, d, J = 8.0Hz) (5) 7-(2-m-hydroxyphenyl-2-methoxyiminoacetamide)-3-[2-(3-
(pyridyl)vinyl]-3-cephem-4-carboxylic acid (cis-trans mixture). IR (nujiol): 3150, 1770, 1678 cm ^-1 NMR (DMSO-d ₆ , δ): 3.8 (2H, m), 4.0
(3H, s), 5.26 (1H, d, J=4Hz), 5.90
(1H, dd, J=4Hz, 8Hz), 6.7−8.0 (8H,
m), 8.50 (2H, m), 9.77 (1H, d, J=8
Hz) (6) 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamide]-3-[2-(3-pyridyl)vinyl]-3 -Cefem-4-carboxylic acid (syn isomer) (cis-trans mixture). IR (nujiyor): 3300, 1770, 1674, 1620cm
^-1 NMR (D ₂ O−NaHCO ₃ , δ): 3.70 (2H, m),
4.75 (2H, s), 5.30 (1H, d, J=5Hz,
5.90 (1H, d, J = 5Hz, 6.5-7.8 (4H,
m), 8.40 (2H, m) Production Example 13 The following compound was obtained by the same method as Production Example 3-(6)-(1). (1) Benzhydryl 7-[2-propargyloxyimino-2-(2-aminothiazole-4-
yl)acetamido]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans mixture). IR (Nujiyor): 3250, 1780, 1710, 1670,
1610, 1540cm ^-1 NMR (DMSO-d ₆ , δ): 3.50 (2H, ABq, J
=18Hz, 3.50 (1H, m), 4.73 (2H, m),
5.35 (1H, d, J = 5Hz), 5.87 (1H, dd, J
=5Hz, 8Hz), 6.40−7.73 (15H, m), 8.43
(2H, m), 9.77 (1H, d, J=8Hz) (2) Benzhydryl 7-[2-ethoxyimino-
2-(2-aminothiazol-4-yl)acetamide]-3-[2-(3-pyridyl)vinyl]
-3-Cefem-4-carboxylate (syn isomer) (cis-trans mixture). IR (Nujiyor): 3200, 1770, 1720, 1670,
1610, 1520cm ^-1 NMR (DMSO-d ₆ , δ): 1.23 (3H, s), 3.43
(2H, AB9, J = 18Hz), 4.13 (2H, q, J
= 7Hz), 5.33 (1H, d, J = 5Hz), 5.88
(1H, dd, J=5Hz, 8Hz), 6.37−7.87
(5H, m), 8.38 (1H, m), 9.62 (1H, d,
J=8Hz) Production Example 14 The following compound was obtained by the same method as Production Example 2-(5). (1) Benzhydryl 7-[2-alkyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[2
-(3-pyridyl)vinyl]-3-cephem-4
-carboxylate (syn isomer) (cis-trans mixture). IR (Nudiyol): 1770, 1720, 1670 cm ^-1 (2) Benzhydryl 7-[2-propargyloxyimino-2-(2-formamidothiazol-4-yl)acetamide]-3-[2-(3-
pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans mixture) IR (nudyl): 3200, 1770, 1710, 1670,
1535cm ^-1 NMR (DMSO−d ₆ , δ): 3.17−4.17 (3H,
m), 5.08 (2H, m), 5.13and5.32 (1H, d,
J=5Hz), 5.80and6.0(1H, dd, J=5Hz,
8Hz), 6.4-7.77 (15H, m), 8.37 (1H,
s), 8.47 (2H, m), 9.80 (1H, d, J=8
Hz) (3) Benzhydryl 7-[2-methoxyimino-
2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide]-3-[2-(3
-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans mixture). IR (Nujiyor): 1350, 1760, 1720, 1660,
1520cm ^-1 NMR (DMSO-d ₆ , δ): 3.90 (2H, ABq, J
= 18Hz), 5.28 (1H, d, J = 5Hz), 5.92
(1H, dd, J=5Hz, 8Hz), 6.37−7.90
(15H, m), 8.37 (2H, m), 9.62 (1H, d,
J=8Hz) (4) Benzhydryl 7-[2-ethoxyimino-
2-(2-formamidothiazol-4-yl)
Acetamide]-3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer) (cis-trans mixture). IR (Nujiyor): 3150, 1780, 1720, 1660,
1550cm ^-1 NMR (DMSO-d ₆ , δ): 1.2 (3H, t, J=7
Hz), 3.40 (2H, ABq, J=18Hz), 4.12 (2H,
q, J=7Hz), 5.30 (1H, d, J=5Hz),
5.92 (1H, dd, J=5Hz, 8Hz), 6.37−7.87
(17H, m), 8.40 (2H, m), 9.70 (1H, d,
J=8Hz) (5) Benzhydryl 7-{2-(m-hydroxyphenyl)-2-methoxyiminoacetamide}-
3-[2-(3-pyridyl)vinyl]-3-cephem-4-carboxylate (syn isomer)
(cis-trans mixture). IR (nujiol): 1780, 1720, 1670cm ^-1 NMR (DMSO-d ₆ , δ): 3.7 (2H, m), 3.95
(3H, s), 5.03 (1H, d, J=5Hz), 6.0
(1H, dd, J=5Hz, 8Hz), 6.6−7.6 (19H,
m), 8.45 (2H, m), 9.80 (1H, d, J=8
Hz) (6) Benzhydryl 7-[2-(5-amino-1,
2,4-thiadiazol-3-yl)-2-t
-butoxycarbonylmethoxyiminoacetamide]-3-[2-(3-pyridyl)vinyl]-3
-Cefem-4-carboxylate (syn isomer) (cis-trans mixture) IR (Nudiyol): 3350, 1780, 1720, 1683cm
^-1 NMR (DMSO-d ₆ , δ): 1.43 (9H, s), 3.67
(2H, m), 4.70 (2H, s), 5.37 (1H, d,
J=5Hz), 6.00 (1H, dd, J=5Hz, 8
Hz), 6.6-7.6 (7H, m), 8.45 (2H, m),
9.70 (1H, d, J = 8Hz) Production example 15 Trifluoroacetic acid (2.6ml) was converted into benzhydryl 7-[2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl) Acetamide]-3-[2-(3-pyridyl)vinyl]-
Added to a suspension of 3-cephem-4-carboxylate (syn isomer) (cis-trans mixture) (2.3 g) and anisole (1.5 ml) in dichloromethane (11 ml) at room temperature, and stirred at the same temperature for 1.5 hours. Stirred. Diisopropyl ether (50%
ml) and stirred. The precipitate was collected, washed with isopropyl ether, and added to an ethyl acetate-water mixture. The mixture was adjusted to pH 8 with 20% potassium carbonate. The separated aqueous layer is diluted with 10% hydrochloric acid under cooling to pH 3.5.
Adjusted to. The precipitate was filtered and washed with water. Water was added to the precipitate, and the mixture was adjusted to pH 5.0 with a saturated aqueous solution of sodium hydrogen carbonate. Insoluble substances were separated.
The liquid was subjected to column chromatography using a macroporous nonionic adsorption resin "Diaion HP-20" (trademark: manufactured by Mitsubishi Chemical Industries, Ltd.) and eluted with a 15% isopropyl alcohol aqueous solution. The fractions containing the target compound are concentrated and lyophilized to yield 7-[2-allyloxyimino-2-(5-amino-1,2,4
-thiazol-3-yl)acetamide]-3-
[2-(3-pyridyl)vinyl]-3-cephem-
4-carboxylate sodium salt (syn isomer) (trans isomer) (0.5 g) was obtained. IR (nujiol): 3250, 1760, 1660, 1610 cm ^-1 NMR (DMSO-d ₆ , δ): 3.73 (2H, broad s),
4.66 (4H, m), 5.06−5.56 (3H, m), 5.63−
6.60 (2H, m), 7.06 (1H, d, J = 17.0Hz),
7.29−8.06 (3H, m), 8.40−8.79 (2H, m),
9.61 (1H, d, J = 8.0Hz) Production example 16 Trifluoroacetic acid (15.2ml) was converted into benzhydryl 7-amino-3-[2-(3-pyridyl)vinyl]
-3-Cefem-4-carboxylate (cis-
The mixture was added to a suspension of trans mixture (8.0 g) and anisole (7.4 ml) in dichloromethane (40 ml) at room temperature, and the mixture was stirred at the same temperature for 1.5 hours. Diisopropyl ether (200 ml) was added to the resulting solution and stirred. The precipitate was collected and washed with diisopropyl ether. This precipitate was added to a water-ethyl acetate mixture, and the pH was adjusted to 7 with 20% potassium carbonate. The separated aqueous layer was purified using 10% hydrochloric acid under ice cooling.
Adjusted to 4.5. The resulting precipitate was primarily the desired trans isomer, which was separated and added to water. This mixture was adjusted to pH 7.0 with a saturated aqueous solution of sodium hydrogen carbonate. After removing insoluble substances, the aqueous solution was adjusted to pH 4.5 with 10% hydrochloric acid under ice cooling. The resulting precipitate was filtered, washed with ice-cold water, and dried under vacuum over phosphorus pentoxide to yield 7-amino-3-[2-(3-
pyridyl)vinyl]-3-cephem-4-carboxylic acid (trans isomer) (1.9 g) was obtained. IR (nujiol): 3150, 1790, 1670, 1610 cm ^-1 NMR (D ₂ O + DCl, δ): 4.03 (2H, s), 5.28
(1H, d, J=5.0Hz), 5.45 (1H, d, J=5.0
Hz), 7.17 (1H, d, J = 17.0Hz), 7.85 (1H,
d, J=17.0Hz), 7.94−8.25 (1H, m), 8.65−
9.00 (3H, m) Production example 17 Trifluoroacetic acid (18.3 ml) was converted into benzhydryl 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide]-3- [2-(3-pyridyl)vinyl]-3-
Cefem-4-carboxylate (syn isomer)
(cis-trans mixture) (16.4 g) and anisole (10.7 ml) in dichloromethane (65 ml) at room temperature, and stirred at the same temperature for 1.5 hours.
Diisopropyl ether (300ml) to the reaction mixture
was added under stirring. The resulting precipitate was collected and washed with diisopropyl ether. Add this precipitate to a mixture of ethyl acetate (100 ml) and water (300 ml) and add 20%
The pH was adjusted to 8 with potassium carbonate. The separated aqueous layer was adjusted to pH 3.5 with 10% hydrochloric acid while cooling on ice. The precipitate that formed was mainly the desired trans isomer, which was separated and added to water (300ml). The resulting solution was adjusted to pH 7.5 with a saturated aqueous solution of sodium hydrogen carbonate. After excessively removing insoluble substances, cool the solution on ice.
The pH was adjusted to 3.5 with 2N hydrochloric acid. The resulting precipitate was filtered, washed with ice-cold water, and dried under vacuum over phosphorus pentoxide to yield 7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetamide.

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is an amino or acylamino group; R ²
is a lower alkyl group, Y means CH) and salts thereof. 2 R ¹ is amino, lower alkanoylamino, al(lower)alkanoylamino, hydroxy-substituted al(lower)alkanoylamino with lower alkoxyimino, amino- or acylamino-thiazolyl(lower)alkanoylamino with lower alkoxyimino, lower alkynyl Amino- or acylamino-thiazolylalkanoylamino with oxyimino, aminothiadiazolyl(lower)alkanoylamino with lower alkoxyimino, aminothiadiazolyl(lower)alkanoylamino with lower alkenyloxyimino, or carboxy(lower) 2.) The compound according to claim 1, which is aminothiadiazolyl(lower)alkanoylamino having alkoxyimino. 3 R ¹ is 2-methoxyimino-2-(2-aminothiazol-4-yl)acetamide, 2-propargyloxyimino-2-(2-aminothiazol-4-yl)acetamide, 2-ethoxyimino-2- (5-amino-1,2,4-thiadiazol-3-yl)acetamide, 2-allyloxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamide, 2-carboxymethoxy imino-2-(5-amino-1,
2,4-thiadiazol-3-yl)acetamide, or 2-methoxyimino-2-(m-hydroxyphenyl)acetamide, and ^R2 is methyl or ethyl. Isomers.