JPH06179684A - New cephem compound - Google Patents

Abstract

PURPOSE:To obtain a new cephen compound useful as an antimicrobial agent, preventing pathogenic microbes in a wide range. CONSTITUTION:The compound of formula I [R<1> is amino or acylamino: R<2> is (protected) carboxyl; R<3> is (protected) hydroxy, lower alkoxy, lower alkylamino, etc.] such as diphenylmethyl 7beta-tert-butoxycarbonylamino-3-[(Z)-4- hydroxy-1-buten-1-yl]-3-cephem-4-carboxylate. The compound of formula I is obtained by reacting a compound of formula II (R<4> is lower alkyl or aryl; X is acid residue) with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel cephem compound having high antibacterial activity and is used in the medical field.

[0002]

BACKGROUND OF THE INVENTION Many cephem compounds are known, but the cephem compound represented by the following general formula (I) of the present invention is not known.

[0003]

Although many cephem compounds having antibacterial activity and useful as medicines are known,
This invention was made with the intention of developing a further excellent drug product.

[0004]

DETAILED DESCRIPTION OF THE INVENTION The object of the present invention, the cephem compound is novel and can be represented by the following general formula (I).

[Chemical 2] [Wherein R ¹ is amino or acylamino, R ² is carboxy or protected carboxy, R ³ is hydroxy, protected hydroxy, lower alkoxy, lower alkylamino, protected (lower) alkylamino, acyl Or each represents a heterocyclethio] The object compound (I) of the present invention can be produced by the following methods.

Method (1)

[Chemical 3]

Method (2)

[Chemical 4]

Method (3)

[Chemical 5]

Method (4)

[Chemical 6]

Method (5)

[Chemical 7]

Method (6)

[Chemical 8]

Method (7)

[Chemical 9]

Method (8)

[Chemical 10]

Method (9)

[Chemical 11]

Method (10)

[Chemical 12] In the above formula, R ¹ , R ² and R ³ are each as defined above, R ⁴ is lower alkyl or aryl, R ⁵
Is lower alkyl, R ¹ _a is acylamino, R ¹ _b is acylamino having a protected hydroxy group, R ¹ _c is acylamino having a hydroxy group, R ² _a is a protected carboxy, R ³ _a Represents protected hydroxy, R ³ _b represents acyloxy, R ³ _c represents protected carbamoyloxy, X represents an acid residue, and Y represents a leaving group. The starting compound (V) of the present invention can be produced by the following methods.

Method (A)

[Chemical 13]

Method (B)

[Chemical 14]

Method (C)

[Chemical 15] In the above formula, R ³ , R ³ _b and R ⁵ are each as defined above. In the above and subsequent description of the present specification, suitable examples and specific examples of various definitions included in the scope of the present invention are explained in detail below. The term "lower" shall mean 1 to 6 carbon atoms unless otherwise specified. The term "higher" shall mean 7 to 20 carbon atoms unless otherwise specified. Suitable "lower alkyl" and "lower alkylamino" and "protected (lower) alkylamino" in the expressions "lower alkyl moiety" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, Secondary butyl, t-butyl, pentyl, t-pentyl, hexyl and the like, which may be straight-chain or branched-chain having 1 to 6 carbon atoms, and preferably have 1 to 4 carbon atoms Is. Suitable "lower alkoxy" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, t-butoxy, pentoxy, t-pentoxy, hexyloxy and the like, which is a straight chain having 1 to 6 carbon atoms. And branched ones are preferable, and those having 1 to 4 carbon atoms are preferable.

Suitable "aryl" includes phenyl,
Examples include naphthyl. Suitable "acyl" in the expressions "acyl" and "acylamino", "acyloxy", "acylamino having a protected hydroxy group" and "acylamino having a hydroxy group" include organic carboxylic acid, organic carbonic acid, Carbamoyl derived from organic sulfonic acid, organic carbamic acid, etc., protected carbamoyl, aliphatic acyl group, acyl group containing aromatic ring (referred to as aromatic acyl) or acyl containing heterocycle (heterocyclic acyl and And the like). Suitable examples of the acyl include the following: carbamoyl; protected carbamoyl; lower or higher alkanoyl (eg formyl, acetyl, succinyl, hexanoyl, heptanoyl, valeryl, stearoyl etc.); lower or higher alkoxycarbonyl. (Eg methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl etc.); lower or higher alkylsulfonyl (eg methylsulfonyl,
Ethylsulfonyl etc.); aliphatic acyl such as lower or higher alkoxysulfonyl (eg methoxysulfonyl, ethoxysulfonyl etc.); aroyl (eg benzoyl, naphthoyl etc.); phenyl (lower) alkanoyl (eg phenylacetyl, phenylpropionyl etc.) etc. Ar (lower) alkanoyl; aryloxycarbonyl (eg, phenoxycarbonyl,
Naphthyloxycarbonyl etc.); aryloxy (lower) alkanoyl (eg phenoxyacetyl, phenoxypropionyl etc.); arylglyoxyloyl (eg phenylglyoxyloyl, naphthylglyoxyloyl etc.); arenesulfonyl (eg benzenesulfonyl, p-toluene) Aromatic acyl such as sulfonyl);

Heterocyclic carbonyl (eg, thenoyl, furoyl, nicotinoyl, etc.); Heterocyclic (lower) alkanoyl (eg, thienylacetyl, thiazolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc.); Heterocyclic glyoxyloyl ( Heterocyclic acyl such as thiazolyl glyoxyloyl, thienyl glyoxyroyl, etc .; the above "heterocyclic carbonyl", "heterocyclic lower alkanoyl" and "heterocyclic glyoxyloyl"
A preferred heterocyclic moiety in the expression is more specifically a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as an oxygen atom, a sulfur atom or a nitrogen atom. means. Particularly preferred heterocyclic groups are unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and the like. N-oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4-triazolyl, 1H-1,2,
3-triazolyl, 2H-1,2,3-triazolyl, etc., tetrazolyl (for example, 1H-tetrazolyl, 2
H-tetrazolyl and the like); saturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl,
Piperidino, piperazinyl and the like; unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atoms, for example, indolyl, isoindolyl, indoridinyl, benzimidazolyl,
Quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc .;

Unsaturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,
2,5-oxadiazolyl and the like); a saturated 3 to 8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl, Cydnonyl and the like; unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms,
For example, benzoxazolyl, benzooxadiazolyl and the like; unsaturated 3-8 member (more preferably 5 or 6 member) containing 1-2 sulfur atoms and 1-3 nitrogen atoms.
Heteromonocyclic groups such as thiazolyl, isothiazolyl, thiadiazolyl (eg 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc .; non-containing one to two sulfur atoms and one to three nitrogen atoms A saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group such as thiazolidinyl;

Unsaturation containing 1-2 sulfur atoms 3-
8-membered (more preferably 5- or 6-membered) heteromonocyclic group, for example, thienyl, dihydrothiynyl, dihydrodithionyl, etc .; unsaturated condensed heterocycle containing 1-2 sulfur atoms and 1-3 nitrogen atoms Groups such as benzothiazolyl,
Benzothiadiazolyl, etc .; unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1 oxygen atom, such as furyl; 1 oxygen atom and 1-2 sulfur. An unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing an atom, such as dihydrooxathinyl; an unsaturated fused heterocyclic group containing 1 to 2 sulfur atoms, such as Examples thereof include benzothienyl, benzodithynyl, and the like; unsaturated condensed heterocyclic groups containing one oxygen atom and 1 to 2 sulfur atoms, for example, a heterocyclic group such as benzoxatiynyl.

Regarding the above heterocyclic group, the following points should be noted. That is, especially when the heterocyclic group is a thiazolyl or thiadiazolyl group having amino or protected amino as a substituent in the molecule, the thiazolyl or thiadiazolyl group is attributable to the specific behavior of the thiazole or thiadiazole ring. Includes tautomers. For example, the amino- or protected amino-thiazolyl or thiadiazolyl group is
formula

[Chemical 16] Wherein R ⁶ represents amino or protected amino, Z represents CH or N, and the group of formula (Q) is represented by the formula

[Chemical 17] Where R ⁶ and Z are as defined above, the group of formula (Q ′) is of its tautomeric formula

[Chemical 18] (Wherein Z is as defined above and R ^{6 ′} represents imino or protected imino). That is, the groups of both formulas (Q ′) and (Q ″) are in a tautomeric equilibrium state that can be represented by the following equilibrium formula:

[Chemical 19] Where R ⁶ , Z and R ^{6 ′} are as defined above.

These types of tautomerism between the 2-aminothiazole or 5-aminothiadiazole compounds and the 2-iminothiazoline or 5-iminothiadiazoline compounds are well known in the art and It is obvious to a person skilled in the art that both tautomers are in equilibrium and are in a state where they can be converted alternately, and therefore such isomers are included in the same category of the compound itself. I want to be done. Therefore, both tautomeric forms are clearly included in the scope of the present invention. As used herein, a target compound and a starting compound containing such a tautomeric group are represented by only one of their expression forms.
That is, for convenience only, the expression and formula 2-amino (or protected amino) thiazolyl or 5-amino (or protected amino) thiadiazolyl

[Chemical 20] Will be represented by. The above-mentioned acyl moiety is lower alkyl, lower alkoxy (eg methoxy, ethoxy, propoxy etc.), lower alkylthio (eg methylthio, ethylthio etc.), lower alkylamino (eg methylamino etc.), cyclolower alkyl (eg cyclopentyl, cyclohexyl etc.). ), Cyclo lower alkenyl (eg cyclohexenyl, cyclohexadienyl, etc.), halogen, amino, protected amino, hydroxy, protected hydroxy, cyano, nitro, carboxy, protected carboxy, sulfo, sulfamoyl, imino, oxo , Amino (lower) alkyl (eg aminomethyl, aminoethyl etc.), carbamoyloxy, hydroxy (lower) alkyl (eg hydroxymethyl, 1- or 2-hydroxyethyl). Le, 1
Or 2 or 3-hydroxypropyl, etc.), cyano (lower) alkenylthio (eg, cyanovinylthio, etc.), a group of the formula ═N—OR ⁷ [wherein, R ⁷ represents hydrogen or an organic group exemplified below], etc. 1 to 10 may be the same or different.

In this connection, the acyl group has the formula ═N—O
When it has a radical R ⁷ (R ⁷ as defined above) as a substituent, geometric isomers (syn and anti isomers) are present due to the presence of the double bond. And, for example, the syn isomer has the formula

[Chemical 21] Means one geometric isomer having a group of

[Chemical formula 22] Means the other geometric isomer having the group Suitable "protected amino" includes acylamino (the acyl moiety may include those exemplified above) and optionally substituted ar (lower) alkyl (eg, benzyl, trityl). And the like) and amino groups substituted with a conventional protecting group. Suitable "organic group" includes lower alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, neopentyl, tertiary pentyl, hexyl, etc.), mono (or di or tri). Halo (lower) alkyl (for example, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, chloroethyl, dichloroethyl, trichloroethyl, fluoroethyl, trifluoroethyl, etc.),

Lower alkenyl (eg vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.) , Lower alkynyl (eg ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1
Or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc., a hydroxy protecting group such as acyl as exemplified above, aryl (eg, phenyl, naphthyl, etc.), Phenyl (lower) alkyl (eg benzyl,
Such as phenethyl, phenylpropyl, etc.), carboxy (lower) alkyl (the lower alkyl moiety may include those exemplified above), protected carboxy (lower) alkyl (as the lower alkyl moiety). Are those exemplified above, and as the protected carboxy moiety, those exemplified below can be mentioned respectively) and the like.

Suitable examples of "protected carboxy" in the expression "protected carboxy" as well as "protected carboxy (lower) alkyl" include esterified carboxy and the like. Suitable examples of the ester include a lower alkyl ester (eg, methyl ester, ethyl ester, propyl ester,
Isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-
Pentyl ester, hexyl ester etc.), lower alkenyl ester (eg vinyl ester, allyl ester etc.), lower alkynyl ester (eg ethynyl ester, propargyl ester etc.), lower alkoxyalkyl ester (eg methoxymethyl ester, ethoxymethyl ester, isopropoxy) Methyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.), lower alkylthioalkyl ester (eg, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.), mono (or di or tri or ) Halo (lower) alkyl ester (eg, 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.), lower Lucanoyloxy (lower) alkyl ester (for example, acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.), lower alkanesulfonyl (lower) alkyl ester (eg, mesylmethyl ester, 2-mesylethyl ester, etc.), al (lower)
Alkyl esters, such as phenyl (lower) alkyl esters optionally having one or more suitable substituents (eg, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydrido). Ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-t-butylbenzyl ester, etc., a substituted or unsubstituted phenyl ester (eg phenyl ester, tolyl ester, aryl ester which may have one or more suitable substituents such as t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester) , Tri (lower) alkylsilyl ester, lower alkyl thioester (e.g. methylthio ester, such as ethyl thio ester), and the like.

Suitable "protecting groups" in the expressions "protected carbamoyl" and "protected carbamoyloxy" include the aforementioned acyl or mono (or di or tri) phenyl (lower) alkyl (eg benzyl, Trityl etc.) and the like. Suitable “protecting group” in “protected hydroxy” is the aforementioned acyl, phenyl (lower) alkyl optionally having one or more appropriate substituents (eg benzyl, 4-methoxybenzyl etc.) , Tetrahydropyranyl, tri (lower) alkylsilyl (eg trimethylsilyl,
Tertiary butyldimethylsilyl etc.) and the like.
Suitable “leaving group” includes lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy etc.), aryloxy (eg phenoxy, naphthoxy etc.), acid residue and the like. Can be mentioned. Suitable "acid residue"
Examples thereof include halogen (eg chlorine, bromine, iodine etc.), sulfonyloxy (eg methylsulfonyloxy, phenylsulfonyloxy, tolylsulfonyloxy etc.) and the like. Suitable "protecting group" in "protected (lower) alkylamino" includes the aforementioned acyl and the like. As the preferable "heterocyclic moiety" in "heterocyclic thio", those exemplified above can be mentioned. Suitable pharmaceutically acceptable salts of the target compound (I) are conventional non-toxic salts such as alkali metal salts [eg sodium salt, potassium salt etc.], alkaline earth metal salts [eg calcium salt, magnesium salt etc. ], Such as metal salts, ammonium salts, organic base salts [eg, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,
N'-dibenzylethylenediamine salt, etc.], organic acid salt [eg formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], Inorganic acid salts [eg hydrochloride, hydrobromide, sulfate, phosphate, etc.], salts with amino acids [eg arginine salt, aspartate, glutamate, etc.] and the like are included.

Preferred embodiments of the target compound (I) are as follows:
It is the next one. R ¹ is amino, lower alkanoylamino, lower alkoxycarbonylamino or a formula

[Chemical formula 23] (Wherein R ⁶ is amino or protected amino [more preferably acylamino], and R ⁷ is hydrogen or an organic group [more preferably lower alkyl, lower alkenyl, lower alkynyl, carboxy (lower) alkyl, protected Carboxy (lower) alkyl or acyl, more preferably lower alkyl or lower alkanoyl], Z is CH or N), and R ² is carboxy or esterified carboxy [more preferably 1 Phenyl (lower) alkoxycarbonyl optionally having the above suitable substituents, or lower alkanoyloxy (lower) alkoxycarbonyl, more preferably benzhydryloxycarbonyl, or lower alkanoyloxy (lower) alkoxycarbonyl] Yes, R ³ is hydro Ci, tri (lower) alkylsilyloxy, acyloxy [more preferably lower alkanoyloxy, carbamoyloxy or protected carbamoyloxy [more preferably mono (or di or tri) halo (lower) alkanoylcarbamoyloxy)], lower Alkoxy, lower alkylamino, N-acyl-N- (lower) alkylamino [more preferably N
-(Lower) alkoxycarbonyl-N- (lower) alkylamino], carbamoyl, protected carbamoyl [more preferably mono (or di or tri) phenyl (lower) alkylcarbamoyl; more preferably tritylcarbamoyl], or What is thiadiazolylthio.

The method for producing the object compound and starting compound of the present invention will be explained in detail below. Method (1) Compound (I) or a salt thereof can be produced by reacting compound (II) or a salt thereof with compound (III) or a salt thereof. The reaction is usually water, alcohol (eg, methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride, N, N-dimethylacetamide,
It is carried out in a conventional solvent such as N, N-dimethylformamide, other organic solvents that do not adversely influence the reaction.
Of these solvents, the hydrophilic solvent may be used as a mixture with water. The reaction includes alkali metal, its hydroxide, carbonate or bicarbonate, tri (lower) alkylamine, pyridine, alkali metal lower alkanoate, N-
It may be carried out in the presence of an inorganic or organic base such as (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine. When the above bases are liquid, they can be used as a solvent.
The reaction temperature is not particularly limited, but usually,
The reaction is carried out under cooling or heating.

Method (2) Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to a reaction for eliminating a hydroxy protecting group. Suitable methods for this reaction include conventional methods such as hydrolysis and reduction. (I) Hydrolysis Hydrolysis is preferably carried out in the presence of a base or an acid including a Lewis acid. Suitable bases include alkali metals [eg sodium, potassium etc.], alkaline earth metals [eg magnesium, calcium etc.], their hydroxides or carbonates or bicarbonates,
Such as trialkylamine [eg trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, etc. Inorganic bases and organic bases are mentioned. Suitable acids include organic acids [eg formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid etc.] and inorganic acids [eg hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide etc.]. . The elimination with a Lewis acid such as trihaloacetic acid [eg trichloroacetic acid, trifluoroacetic acid etc.] is preferably carried out in the presence of a cation scavenger [eg anisole, phenol etc.]. The reaction is usually performed in a solvent such as water, alcohol [eg, methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof, or another solvent which does not adversely influence the reaction. A liquid base or acid can also be used as a solvent. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

(Ii) In the case of reduction The reduction is carried out by a conventional method including chemical reduction and catalytic reduction. Suitable reducing agents to be used for the chemical reduction include metals (eg tin, zinc, iron etc.) or metal compounds (eg chromium chloride, chromium acetate etc.) and organic or inorganic acids (eg formic acid, acetic acid, propionic acid, tri-acid). Fluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.). Suitable catalysts to be used for catalytic reduction include platinum catalysts (for example, platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example, spongy palladium, palladium black,
Palladium oxide, palladium charcoal, colloidal palladium, palladium / barium sulfate, palladium / barium carbonate, etc.), nickel catalyst (eg, reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (eg, reduced cobalt, Raney cobalt, etc.), iron catalyst (Eg, reduced iron, Raney iron, etc.), copper catalysts (eg, reduced copper, Raney copper, Ullmann copper, etc.) and the like. The reduction is usually performed with water, methanol, ethanol,
It is carried out in conventional solvents such as propanol, N, N-dimethylformamide, mixtures thereof and the like. When the above acids used for chemical reduction are liquid, they can also be used as a solvent. Suitable solvents for catalytic reduction include the above-mentioned solvents and other conventional solvents such as diethyl ether, dioxane and tetrahibitofuran, or a mixture thereof. The reaction temperature of this reaction is not particularly limited, but usually the reaction is carried out under cooling or heating.

Method (3) Compound (Id) or a salt thereof can be produced by subjecting compound (Ic) or a salt thereof to a deacylation reaction. This deacylation can be carried out in analogy to method (2) above, so that for the reagents to be used and the reaction conditions (eg solvent, reaction temperature, etc.), those of method (2) can be cited.

Method (4) Compound (If) or a salt thereof can be produced by subjecting compound (Ie) or a salt thereof to a reaction for eliminating a carboxy protecting group. This reaction can be carried out in the same manner as in the above method (2), and therefore, regarding the reagents to be used and the reaction conditions (for example, solvent, reaction temperature, etc.), those in the method (2) can be referred to.

Method (5) Compound (I) or a salt thereof can be produced by reacting compound (IV) or a salt thereof with compound (V) or a salt thereof. This reaction is usually carried out with water, alcohol (eg methanol, ethanol, etc.), benzene, N,
N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform,
It is carried out in a solvent such as diethyl ether or any other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating. The reaction is preferably carried out in the presence of a catalyst such as bis (acetonitrile) palladium (II) halide [eg bis (acetonitrile) palladium (II) chloride].

Method (6) Compound (Ic) or a salt thereof can be produced by subjecting compound (Id) or its reactive derivative at the amino group or a salt thereof to an acylation reaction. As a suitable reactive derivative at the amino group of compound (Id), a Schiff base type imino compound formed by the reaction of compound (Id) with a carbonyl compound such as aldehyde or ketone or an enamine type tautomer thereof; (I
d) a silyl derivative formed by the reaction of a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea; formed by the reaction of compound (Id) with phosphorus trichloride or phosgene And derivatives. Suitable acylating agents to be used in the present acylation reaction include those conventionally used, and are represented by the formula R ⁸ —OH (IX)
(Wherein R ⁸ represents acyl) or a reactive derivative thereof or a salt thereof.

Suitable reactive derivatives of the compound (IX) include acid halides, acid anhydrides, isocyanates, active amides, active esters and the like. Suitable examples of these reactive derivatives include acid chlorides; acid azides; substituted phosphoric acids [eg dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.],
Dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [eg methanesulfonic acid], aliphatic carboxylic acid [eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid , Trichloroacetic acid, etc.], mixed acid anhydrides with acids such as aromatic carboxylic acids [eg benzoic acid]; symmetrical acid anhydrides; imidazole, 4-substituted imidazole, 1-hydroxy-1H-benzotriazole, dimethylpyrazole, Active amides with triazoles or tetrazoles;
Active esters [eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂
N ⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p- Nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, benzothiazolyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.] or N-hydroxy compound [eg N, N-dimethylhydroxylamine] , 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-
1H-benzotriazole and the like] and the like. These reactive derivatives can be appropriately selected from them according to the type of compound (IX) used. The reaction is usually water, alcohol [eg methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine, and does not adversely affect the reaction. It is carried out in a conventional solvent, such as any other solvent.
These conventional solvents may be used as a mixture with water.

In this reaction, when compound (IX) is used in the form of a free acid or a salt thereof, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-
Cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N
-Ethyl-N '-(3-dimethylaminopropyl) carbodiimide, N, N'-carbonylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1 -Alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, lower alkyl haloformates [eg ethyl chloroformate, chloroformate Isopropyl formate, etc.], triphenylphosphine, 2
-Ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium inner salt, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H -The reaction is carried out in the presence of a conventional condensing agent such as so-called Vilsmeier reagent prepared by the reaction of benzotriazole, N, N-dimethylformamide with thionyl chloride, trichloromethyl chloroformate, phosphorus oxychloride and the like. preferable. Alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N,
The reaction may be carried out in the presence of an inorganic base or organic base such as N-di (lower) alkylbenzylamine. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Method (7) Compound (Ih) or a salt thereof can be produced by subjecting compound (Ig) or a salt thereof to a reaction for eliminating a hydroxy protecting group. This reaction can be carried out in the same manner as that of the above-mentioned method (2), and therefore, regarding the reagents to be used and the reaction conditions (for example, solvent, reaction temperature, etc.), those of the method (2) can be referred to.

Method (8) Compound (Ie) or a salt thereof can be produced by subjecting compound (If) or a salt thereof to a reaction for introducing a carboxy protecting group. Examples of the carboxy-protecting group-introducing agent to be used in this reaction include conventional esterifying agents such as alcohols or reactive equivalents thereof (for example, halides, sulfonates, sulfates, diazo compounds, etc.). This reaction is usually performed in the presence of a base. Suitable bases include, for example, alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide, cesium hydroxide etc.), alkaline earth metal hydroxides (eg magnesium hydroxide, calcium hydroxide etc.), alkali metal Carbonates (eg sodium carbonate, potassium carbonate, cesium carbonate etc.), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.),
Alkali metal bicarbonate (eg sodium bicarbonate, potassium bicarbonate, cesium bicarbonate etc.), alkali metal acetate (eg sodium acetate, potassium acetate etc.),
Alkaline earth metal phosphates (eg magnesium phosphate,
Calcium phosphate), alkali metal hydrogen phosphate (eg disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.)
Inorganic bases and trialkylamines (eg trimethylamine, triethylamine etc.), picoline,
N-methylpyrrolidine, N-methylmorpholine, 1,5
-Diazabicyclo [4.3.0] non-5-ene, 1,
4-diazabicyclo [2.2.2] octane, 1,5-
Organic bases such as diazabicyclo [5.4.0] undecene-5 are mentioned. This reaction is usually
N, N-dimethylformamide, tetrahydrofuran,
It is carried out in a solvent such as toluene, methylene chloride, ethylene dichloride, chloroform or any other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Method (9) Compound (Ii) or a salt thereof can be produced by subjecting compound (Ib) or a salt thereof to an acylation reaction. Suitable acylating agents to be used in this acylation reaction include:
The conventional ones include the formula R ⁹ --OH (X) (in the formula,
R ⁹ represents acyl), a reactive derivative thereof or a salt thereof. Suitable reactive derivatives of compound (X) include acid halides, acid anhydrides, isocyanates, active amides, active esters and the like. Preferable examples of the reactive derivative include acid azide; substituted phosphoric acid [for example, dialkyl phosphoric acid,
Phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.], dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid [eg methanesulfonic acid etc.], aliphatic carboxylic acid [eg acetic acid, propionic acid, butyric acid, iso Butyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or a mixed acid anhydride with an aromatic carboxylic acid [for example, benzoic acid]; symmetrical acid anhydride; imidazole, 4-substituted imidazole, 1-hydroxy-1H-benzotriazole,
Active amides with dimethylpyrazole, triazole or tetrazole; active esters [eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N ⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl Ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, benzothiazolyl Thioester, pyranyl ester, pyridyl ester, piperidyl ester,
8-quinolyl thioester etc.] or N-hydroxy compound [eg N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-
Hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.]
And ester and the like. These reactive derivatives can be appropriately selected from among them according to the kind of the compound (X) used.

The reaction is usually water, alcohol [eg methanol, ethanol etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N.
Carried out in a conventional solvent, such as dimethylformamide, pyridine, or any other solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water. In this reaction, when the compound (X) is used in the form of a free acid or a salt thereof, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N '
-Morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N,
N'-diisopropylcarbodiimide, N-ethyl-
N '-(3-dimethylaminopropyl) carbodiimide, N, N'-carbonylbis (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, ethoxyacetylene, 1-alkoxy- 1-chloroethylene, trialkyl phosphite, ethyl pyrophosphate, isopropyl pyrophosphate, phosphorus oxychloride (phosphoryl chloride), phosphorus trichloride, thionyl chloride, oxalyl chloride, haloformic acid (lower)
Alkyl [eg ethyl chloroformate, isopropyl chloroformate, etc.], triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide molecule Inner salt, 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole,
The reaction is preferably carried out in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent formed by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride and the like. The reaction is carried out in the presence of an inorganic or organic base such as alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine. You can also The reaction temperature is not particularly limited, but usually the reaction is carried out under cooling or heating.

Method (10) Compound (Ik) or a salt thereof can be produced by subjecting compound (Ij) or a salt thereof to elimination reaction of a carbamoyl protecting group. This reaction can be carried out in analogy to that of method (2) above, so that for the reagents to be used and the reaction conditions (eg solvent, reaction temperature, etc.), those of method (2) can be cited.

Method (A) Compound (VIIa) or a salt thereof can be produced by subjecting compound (VI) or a salt thereof to an acylation reaction. This acylation can be carried out in analogy to that of method (9) above, therefore reference can be made to method (9) regarding the reagents to be used and the reaction conditions (eg solvent, reaction temperature, etc.).

Method (B) Compound (VIIb) or a salt thereof can be prepared by reacting compound (VIIb)
It can be prepared by subjecting a) or a salt thereof to elimination reaction of a carbamoyl protecting group. This reaction is the above method (2).
Can be carried out in the same manner as that of Method (2), and thus, regarding the reagents to be used and the reaction conditions (for example, solvent, reaction temperature, etc.), those of Method (2) can be referred to.

Method (C) Compound (V) or a salt thereof can be produced by reacting compound (VII) or a salt thereof with compound (VIII). This reaction is usually carried out using water, alcohol (eg methanol, ethanol, etc.), benzene, N, N-.
It is carried out in a solvent such as dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, diethyl ether, or any other solvent that does not adversely influence the reaction. The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating. The reaction is usually carried out by bis (triphenylphosphine) palladium (II) halide [for example, bis (triphenylphosphine) palladium (II) chloride.
Etc.] and the like in the presence of a catalyst. Method (1)-
Suitable salts of the objective compound, starting compound and reactive derivative thereof in (10) and (A) to (C) include those exemplified for the compound (I). The object compound (I) and its pharmaceutically acceptable salts are novel and have high antibacterial activity, inhibit growth of a wide range of pathogens including Gram-positive and Gram-negative bacteria, and are useful as antibacterial agents, It is particularly useful as an oral preparation. Now, in order to show the usefulness of the target compound (I), the minimum inhibitory concentration (MIC) test data of a representative compound belonging to the compound (I) is shown below.

Test method In vitro antibacterial activity was measured by the following agar plate multiple dilution method. Each test strain was cultivated overnight in tryptocase-soy-broth, and 1 platinum loop (viable cell count: 10 ⁸ cells / ml) was
Heart infusion agar (HI-agar) containing representative test compounds at each concentration step was inoculated and incubated at 37 ° C. for 20 hours, after which the minimum inhibitory concentration (MIC) was expressed in μg / ml. Test compound 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -4-
Carbamoyloxy-1-buten-1-yl] -3-cephem-4-carboxylic acid (syn isomer) test results

[Table 1] When the object compound (I) of the present invention and a pharmaceutically acceptable salt thereof are used for therapeutic purposes, an organic or inorganic solid or liquid suitable for oral administration, parenteral administration or external use is used as the active ingredient. It is administered as a usual preparation mixed with a pharmaceutically acceptable carrier such as an excipient. These formulations may be solid dosage forms such as tablets, granules, powders and capsules, or a solvent,
It may be a liquid dosage form such as a suspension, syrup, emulsion or lemonade. If necessary, various auxiliaries, stabilizers, wetting agents, and other commonly used additives for the above-mentioned preparations such as lactose, citric acid, tartaric acid, stearic acid,
Magnesium stearate, white clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil,
Olive oil, cocoa butter, ethylene glycol and the like can be added. The dose of compound (I) will vary depending on the age and other conditions of the patient, the type of disease, the type of compound used, etc., but generally, about 1 mg to about 4,000 mg or more per day is administered to each patient. be able to. For the treatment of infectious diseases caused by pathogenic bacteria, the target compound (I) has an average dose of about 50 mg,
100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg can be administered. The following Production Examples and Examples are provided to describe the present invention in more detail.

Production Example 1 A solution of 3-butyn-1-ol (35.0 g) in dichloromethane (300 ml) was added at 5 ° C. to trichloroacetyl isocyanate (94.23 g) in dichloromethane (30 ml).
ml) solution was added dropwise over 1 hour and the mixture was stirred at the same temperature for 3 hours.
Stir for 0 minutes. The mixture is evaporated to dryness and dissolved in a mixture of chloroform (250 ml) and methanol (50 ml). To this solution is added silica gel (50 g) and the mixture is stirred at room temperature for 2 days. The mixture is filtered to remove silica gel and the filtrate is evaporated under reduced pressure. The residue is chromatographed on silica gel to give 4-carbamoyloxy-1-butyne (43.1 g) as a crystalline solid. IR (nujol): 3420, 3270, 1640 cm ^-1 NMR (CDCl ₃ , δ): 2.05 (1H, t, J = 2.6Hz), 2.53 (2H, td,
J = 6.7 and 2.6Hz), 4.16 (2H, t, J = 6.7Hz), 5.30 (2H,
br s)

Production Example 2 4-carbamoyloxy-1-butyne (11.31 g)
In tetrahydrofuran (100 ml) at room temperature,
Bis (triphenylphosphine) palladium chloride (I
I) (702 mg) and tri (n-butyl) tin hydride (2)
7.11 g) is added dropwise over 25 minutes. The mixture is stirred at room temperature for 1 hour and evaporated under reduced pressure. The residue is subjected to silica gel chromatography to give (E) -1-tri (n-butyl) stannyl-4-carbamoyloxy-
1-butene and 2-tri (n-butyl) stannyl-
4-carbamoyloxy-1-butene (30.87 g)
As an oil. IR (nujol): 3300, 2900, 1700, 1585 cm ^-1 NMR (DMSO-d ₆ , δ): 0.8-1.7 (27H, m), 2.4-2.5 (2H,
m), 4.1-4.2 (2H, m), 4.71 (2H, br s), 5.89 (1H, dt, J = 1
8.3 and 5.6Hz), 6.14 (1H, d, J = 18.3Hz)

Example 1 7β-tertiary butoxycarbonylamino-3-triphenylphosphoniomethyl-3-cephem-4-carboxylic acid diphenylmethyl iodide (130.31 g) suspension in dichloromethane (1.3 l) And saline (225m
1) and 1N sodium hydroxide solution are added at room temperature and the mixture is stirred at the same temperature for 1 hour. The separated organic layer is washed twice with brine and dried over magnesium sulfate. To the filtrate is added 3-tert-butyldimethylsilyloxypropanal (38.0 g) and the mixture is stirred at room temperature for 72 hours. The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel to give 7β-tertiary butoxycarbonylamino-3-[(Z) -4-tert-butyldimethylsilyloxy-1-butene-1. -Yl] -3-cephem-4-carboxylate diphenylmethyl (13.56 g)
To get IR (nujol): 1760, 1700 cm ^-1 NMR (DMSO-d ₆ , δ): 0.02 (6H, s), 0.84 (9H, s), 1.43
(9H, s), 1.9-2.3 (2H, m), 3.46 (2H, t, J = 6.4Hz), 3.6-3.
7 (2H, m), 5.16 (1H, d, J = 4.7Hz), 5.51 (1H, dd, J = 9.0 and 4.7Hz), 5.35-5.5 (1H, m), 6.23 (1H, d, J = 11.9H
z), 6.88 (1H, s), 7.2-7.6 (10H, m), 8.03 (1H, d, J = 9.0
Hz)

Example 2 7β-tertiary butoxycarbonylamino-3-[(Z)
-4-tert-Butyldimethylsilyloxy-1-buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl (13.20 g) in methanol (106 ml)
To the solution is added concentrated hydrochloric acid (8.45 ml) and the mixture is stirred at room temperature for 1.5 hours. The mixture is poured into a mixture of ethyl acetate and cold water and the pH is adjusted to about 6 by adding saturated aqueous sodium hydrogen carbonate solution. The separated organic layer is washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 7β-tertiary butoxycarbonylamino-3-
[(Z) -4-Hydroxy-1-buten-1-yl]-
Diphenylmethyl 3-cephem-4-carboxylate (7.
60 g) are obtained. IR (nujor): 1765, 1700, 1695 cm ^-1 NMR (DMSO-d ₆ , δ): 1.41 (9H, s), 1.8-2.25 (2H, m),
3.3-3.7 (4H, m), 4.53 (1H, t, J = 5.2Hz), 5.15 (1H, d, J =
4.7Hz), 5.53 (1H, dd, J = 9.0 and 4.7Hz), 5.4-5.6 (1
H, m), 6.18 (1H, d, J = 11.7Hz), 6.86 (1H, s), 7.3-7.6 (1
0H, m), 8.03 (1H, d, J = 9.0Hz)

Example 3 7β-tertiary butoxycarbonylamino-3-[(Z)
-4-Hydroxy-1-buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl (5.62g)
In dichloromethane (56 ml) at 5 ° C. under a stream of nitrogen, trichloroacetyl isocyanate (2.368).
A solution of g) in dichloromethane (8 ml) is added dropwise and stirring is continued for 1 hour at 5 ° C. The mixture is evaporated to dryness and dissolved in a mixture of chloroform (50 ml) and methanol (10 ml). To this solution silica gel (20 g) is added and the mixture is stirred at room temperature for 24 hours. The mixture is filtered to remove silica gel and the filtrate is evaporated under reduced pressure. The residue was subjected to silica gel chromatography to give 7β-tertiary butoxycarbonylamino-3-[(Z) -4-carbamoyloxy-1-buten-1-yl] -3-cephem-.
Diphenylmethyl 4-carboxylate (2.91 g) is obtained as a crystalline solid. IR (nujor): 1765, 1695 cm ^-1 NMR (DMSO-d ₆ , δ): 1.41 (9H, s), 1.75-2.3 (2H, m),
3.5-3.6 (2H, br s), 3.75 (2H, t, J = 6.6Hz), 5.15 (1H, d,
J = 4.8Hz), 5.35-5.5 (1H, m), 5.52 (1H, dd, J = 8.9 and
4.8Hz), 6.17 (1H, d, J = 11.5Hz), 6.46 (2H, br s), 6.87
(1H, s), 7.3-7.5 (10H, m), 8.03 (1H, d, J = 8.9Hz)

Example 4- (1) 7β-tertiary butoxycarbonylamino-3-[(Z)
-4-carbamoyloxy-1-buten-1-yl]-
Diphenylmethyl 3-cephem-4-carboxylate (1.
To a mixed solution of 79 g) of dichloromethane (9 ml) -anisole (1.8 ml) at 5 ° C, trifluoroacetic acid (3.6 ml) is added. The mixture is stirred at room temperature for 2.5 hours. The mixture is concentrated under reduced pressure and triturated with diisopropyl ether. The powder is collected by filtration, washed with diisopropyl ether, dried under reduced pressure and treated with 7β-amino-3-
[(Z) -4-carbamoyloxy-1-butene-1-
Ill] -3-Cephem-4-carboxylic acid / trifluoroacetic acid salt (1.38 g) is obtained. NMR (DMSO-d ₆ , δ): 2.2-2.5 (2H, m), 3.63 (2H, br s),
3.92 (2H, t, J = 6.7Hz), 5.11 (1H, d, J = 4.9Hz), 5.22 (1
H, d, J = 4.9Hz), 5.5-5.7 (1H, m), 6.32 (1H, d, J = 11.5Hz),
6.49 (2H, br s) In the same manner as in Example 4- (1), the following compound was obtained. (2) 7β-amino-3-[(Z) -4-hydroxy-
1-buten-1-yl] -3-cephem-4-carboxylic acid / trifluoroacetate NMR (DMSO-d ₆ , δ): 2.3-2.6 (2H, m), 3.4-3.7 (4H, m),
4.82 (1H, d, J = 4.8Hz), 5.03 (1H, d, J = 4.8Hz), 5.5-5.6
(1H, m), 6.1-6.2 (1H, m)

Example 5- (1) 7β-formamido-3-methylsulfonyloxy-3
-Cephem-4-carboxylate diphenylmethyl (63.
22 g) of N, N-dimethylformamide (630 m
l) To the solution at 5 ° C., crude (E) -1-tri (n-butyl) stannyl-4-carbamoyloxy-1-butene (about 52.30 g) and anhydrous lithium bromide (22.41).
g) is added and the mixture is degassed with nitrogen for 5 minutes. Bis (acetonitrile) palladium (II) chloride was added to the mixture.
(669 mg) is added and the mixture is stirred at 5 ° C. for 1 hour and at room temperature for 14 hours under a stream of nitrogen. Mix the mixture with ice water (3.
5l), the precipitate is filtered off and washed with cold water. This precipitate was added to tetrahydrofuran (400 ml) and ethyl acetate (8
Dissolve in a mixture with 00 ml) and add water (400 m
l) is added. The separated organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to silica gel chromatography to give 7β-formamide-3-[(E) -4-carbamoyloxy-1-.
Buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl (14.23 g) is obtained as a white solid. IR (Nujor): 3400, 3250, 1760, 1710, 1670 cm
^-1 NMR (DMSO-d ₆ , δ): 2.2-2.4 (2H, m), 3.62 and 3.8
5 (2H, ABq, J = 17.5Hz), 3.90 (2H, t, J = 6.6Hz), 5.21 (1H,
d, J = 4.8Hz), 5.82 (1H, dd, J = 9.3 and 4.8Hz), 6.12
(1H, dt, J = 15.9 and 6.7Hz), 6.47 (2H, br s), 6.57
(1H, d, J = 15.9Hz), 6.98 (1H, s), 7.3-7.6 (10H, m), 8.1
6 (1H, s), 9.13 (1H, d, J = 9.3Hz) In the same manner as in Example 5- (1), the following compound was obtained. (2) 7β-formamido-3-[(E) -4-hydroxy-1-buten-1-yl] -3-cephem-4-carboxylic acid diphenylmethyl IR (nujol): 3600-3100 (br), 1755 , 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 2.17 (2H, q like), 3.41 (2H, q, J = 6H
z), 3.62 and 3.85 (2H, ABq, J = 17Hz), 4.56 (1H, t, J =
5Hz), 5.21 (1H, d, J = 5Hz), 5.80 (1H, dd, J = 5.9Hz), 6.17
(1H, dt, J = 16 and 7Hz), 6.55 (1H, s), 6.57 (1H, d, J
= 16Hz), 6.96 (1H, s), 7.2-7.5 (10H, m), 8.16 (1H, s),
9.12 (1H, d, J = 9Hz)

Example 6- (1) 7β-formamido-3-[(E) -4-carbamoyloxy-1-buten-1-yl] -3-cephem-4-
A suspension of diphenylmethyl carboxylate (14.12 g) in methanol (140 ml) was added with concentrated hydrochloric acid (2
3.2 ml) is added and the mixture is stirred at room temperature for 4 hours.
The resulting solution is poured into a mixture of ethyl acetate and ice water and saturated aqueous sodium hydrogen carbonate solution is added to adjust pH to 6.
The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 7β-amino-
3-[(E) -4-carbamoyloxy-1-butene-
1-yl] -3-cephem-4-carboxylate diphenylmethyl (12.02 g) is obtained as an amorphous solid. NMR (DMSO-d ₆ , δ): 2.2-2.4 (2H, m), 2.34 (2H, br s),
3.54 and 3.80 (2H, ABq, J = 17.7Hz), 3.89 (2H, t, J =
6.7Hz), 4.82 (1H, d, J = 5.0Hz), 5.05 (1H, d, J = 5.0Hz),
6.04 (1H, dt, J = 15.8 and 6.9Hz), 6.47 (1H, d, J = 15.
8 Hz), 6.47 (2H, br s), 6.96 (1H, s), 7.3-7.6 (10H, m) In the same manner as in Example 6- (1), the following compound is obtained. (2) 7β-amino-3-[(E) -4-hydroxy-
1-buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl IR (nujol): 3300, 1745, 1690 cm ^-1 NMR (DMSO-d ₆ , δ): 2.15 (2H, q, J = 7Hz), 2.32 (2H, br
s), 3.39 (1H, dt, J = 6.7Hz), 3.54 and 3.81 (2H, AB
q, J = 18Hz), 4.56 (1H, t, J = 5Hz), 4.81 (1H, br s), 5.05
(1H, d, J = 5Hz), 6.09 (1H, dt, J = 16.7Hz), 6.47 (1H, d, J = 1
6Hz), 6.95 (1H, s), 7.2-7.6 (10H, m)

Example 7 7β-Amino-3-[(Z) -4-carbamoyloxy-1-buten-1-yl] -3-cephem-4-carboxylic acid.trifluoroacetic acid salt (1.37 g) was added. Dissolve in dichloromethane (40 ml) by adding N- (trimethylsilyl) acetamide (4.21 g). 2- (2-Aminothiazol-4-yl) -2-acetoxyiminoacetyl hydrochloride (syn isomer) (1.09 g) was added to this solution at 5 ° C, and the mixture was added to 5
Stir at 20 ° C. for 20 minutes and at room temperature for 3.5 hours. The mixture is poured into diisopropyl ether (600 ml), the precipitate formed is filtered off, washed with diisopropyl ether and dried under reduced pressure. Dissolve this powder in water (150 ml) and
Cool to. Ammonium chloride (1.72) was added to this solution.
g) is added and the mixture is stirred at 5 ° C. During this period, 28%
Aqueous ammonia is added to maintain the pH at 10.5. 6N
Hydrochloric acid was added to adjust the mixture to pH 4.8, and the mixture was subjected to chromatography using Diaion HP-20 (trademark: Mitsubishi Kasei) (80 ml), eluted with 10% isopropyl alcohol, freeze-dried, and 7β-. [2- (2-Aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(Z) -4-carbamoyloxy-1
-Buten-1-yl] -3-cephem-4-carboxylic acid (syn isomer) (355 mg) is obtained. IR (nujol): 1750, 1640 cm ^-1 NMR (DMSO-d ₆ , δ): 2.2-2.5 (2H, m), 3.46 and 3.6
2 (2H, ABq, J = 17.7Hz), 3.90 (2H, t, J = 6.6Hz), 5.17 (1H,
d, J = 4.8Hz), 5.52 (1H, dd, J = 11.6 and 7.0Hz), 5.76
(1H, d, J = 8.2 and 4.8Hz), 6.24 (1H, d, J = 11.6Hz),
6.47 (2H, br s), 6.66 (1H, s), 7.13 (2H, br s), 9.47
(1H, d, J = 8.2Hz), 11.32 (1H, s)

Example 8 7β-Amino-3-[(Z) -4-hydroxy-1-buten-1-yl] -3-cephem-4-carboxylic acid trifluoroacetic acid salt (1.41 g) in dichloromethane (3
0 ml) solution, bis (trimethylsilyl) acetamide (2.24 g) is added and the mixture is stirred at room temperature for 20 minutes. The resulting solution was cooled to 5 ° C., added to 2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetyl hydrochloride hydrochloride (syn isomer) (1.25 g), and the mixture at 5 ° C. Stir for 1.8 hours and room temperature for 1 hour. Pour the mixture into cold diisopropyl ether (600 ml),
The precipitate is filtered off, washed with diisopropyl ether and dried under reduced pressure. The powder is suspended in a mixture of water (100 ml) and methanol (5 ml) to which ammonium chloride (588 mg) is added. The mixture is stirred at room temperature for 2.5 hours, keeping the pH at 8.0 by addition of saturated aqueous sodium hydrogen carbonate solution. The mixture is adjusted to pH 6 by adding 1N hydrochloric acid and the methanol is removed under reduced pressure. The mixture is adjusted to pH 4.7 by adding 1N hydrochloric acid, and the insoluble matter is filtered off. The filtrate was added to Diaion HP-20 (50
ml), elute with 5% aqueous isopropyl alcohol and lyophilize. The crude product was purified by preparative HPLC to give 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamido] -3-[(Z) -4-hydroxy-1-butene-1. -Yl] -3-Cephem-4-carboxylic acid (syn isomer) (195 mg) is obtained. IR (nujol): 1750 cm ^-1 NMR (DMSO-d ₆ , δ): 2.1-2.4 (2H, m), 3.41 (2H, t, J = 6.
6Hz), 3.49 and 3.61 (2H, ABq, J = 17.6Hz), 5.18 (1H,
d, J = 4.7Hz), 5.58 (1H, dt, J = 11.6 and 7.2Hz), 5.76
(1H, dd, J = 8.2 and 4.7Hz), 6.21 (1H, d, J = 11.6Hz),
6.67 (1H, s), 7.13 (2H, br s), 9.46 (1H, d, J = 8.2Hz), 1
1.31 (1H, s)

Example 9- (1) 7β-Amino-3-[(E) -4-carbamoyloxy-1-buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl (8.02 g) To bis (trimethylsilyl) acetamide (7.01 g) is added and the mixture is stirred at room temperature for 25 minutes. The mixture was cooled to 5 ° C and 2- (2-aminothiazol-4-yl) -2 chloride
-Acetoxyiminoacetyl hydrochloride (syn isomer)
(5.90 g). The mixture is stirred at 5 ° C. for 3.5 hours, poured into a mixture of ethyl acetate and ice water, and saturated aqueous sodium hydrogen carbonate solution is added to adjust the pH to about 6. The separated organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure to give 7β- [2- (2-
Aminothiazol-4-yl) -2-acetoxyiminoacetamido] -3-[(E) -4-carbamoyloxy-1-buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer ) (10.71
g) is obtained as an amorphous solid. IR (Nujor): 3400, 1750, 1700, 1650, 1520 cm
^-1 NMR (DMSO-d ₆ , δ): 2.17 (3H, s), 2.2-2.4 (2H, m), 3.
59 and 3.83 (2H, ABq, J = 17.8Hz), 3.89 (2H, t, J = 6.6
Hz), 5.28 (1H, d, J = 4.7Hz), 5.87 (1H, dd, J = 8.1 and
4.7Hz), 6.11 (1H, dt, J = 16.0 and 6.7Hz), 6.46 (2H,
br s), 6.56 (1H, d, J = 16.0Hz), 6.96 (1H, s), 7.11 (1
H, s), 7.3-7.6 (12H, m), 9.93 (1H, d, J = 8.1Hz) In the same manner as in Example 9- (1), the following compound was obtained. (2) 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3-
[(E) -4-carbamoyloxy-1-butene-1-
Il] -3-cephem-4-carboxylic acid diphenylmethyl (syn isomer) IR (nujol): 3200, 1750, 1715, 1660 cm ^-1 NMR (DMSO-d ₆ , δ): 2.2-2.4 (2H, m ), 3.59 and 3.8
3 (2H, ABq, J = 17.6Hz), 3.83 (3H, s), 3.85 (2H, t, J = 6.6
Hz), 5.21 (1H, d, J = 4.7Hz), 5.83 (1H, dd, J = 8.7 and
4.7Hz), 6.45 (2H, br s), 6.58 (1H, d, J = 16.0Hz), 6.70
(1H, s), 6.96 (1H, s), 7.3-7.6 (12H, m), 9.50 (1H, d, J
= 8.7 Hz) (3) 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3-
[(E) -4-Hydroxy-1-buten-1-yl]-
3-Cephem-4-carboxylic acid diphenylmethyl (syn isomer) IR (nujol): 3500-3000, 1750, 1680, 1620, 151
0 cm ^-1 NMR (DMSO-d ₆ ,, δ): 2.0-2.1 (2H, m), 2.13 (3H, s), 3.
35 (2H, t, J = 6Hz), 3.59 and 3.81 (2H, ABq, J = 17Hz),
5.23 (1H, d, J = 5Hz), 5.81 (1H, dd, J = 5 and 8Hz), 6.
13 (1H, dt, J = 16 and 7Hz), 6.52 (1H, d, J = 16Hz), 6.9
1 (1H, s), 7.07 (1H, s), 7.2-7.5 (12H, m), 9.89 (1H,
(d, J = 8Hz)

Example 10 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3-[(E) -4
-Carbamoyloxy-1-buten-1-yl] -3-
Triphenylacetic acid (20 ml) was added dropwise at 5 ° C. to a suspension of a mixture of diphenylmethyl cephem-4-carboxylate (syn isomer) (0.71 g) in dichloromethane (50 ml) -anisole (10 ml) at 5 ° C. The solution is stirred at the same temperature for 2.2 hours. The solution is poured into cold diisopropyl ether (800 ml), the precipitate is filtered off, washed with diisopropyl ether and dried under reduced pressure. The powder obtained is suspended in a mixture of water (700 ml) and methanol (35 ml), to which ammonium chloride (2.54 g) is added. The mixture is stirred at room temperature, keeping the pH at 8.0 by addition of saturated aqueous sodium hydrogen carbonate solution.
The mixture is adjusted to pH 6 by adding 1N hydrochloric acid and the methanol is removed under reduced pressure. The mixture is adjusted to pH 4.8 by adding 1N hydrochloric acid and the insoluble matter is filtered off. The filtrate is chromatographed on Diaion HP-20 (500 ml), eluted with 5% aqueous isopropyl alcohol and freeze dried. The crude product was purified by preparative HPLC to give 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-.
[(E) -4-carbamoyloxy-1-butene-1-
Il] -3-cephem-4-carboxylic acid (syn isomer)
(727 mg) is obtained. IR (nujol): 1740, 1620 cm ^-1 NMR (DMSO-d ₆ ,, δ): 2.4-2.55 (2H, m), 3.55 and 3.
75 (2H, ABq, J = 17.4Hz), 3.96 (2H, t, J = 6.6Hz), 5.16 (1
H, d, J = 4.8Hz), 5.74 (1H, dd, J = 8.1 and 4.8Hz), 6.0
1 (1H, dt, J = 15.9 and 6.9Hz), 6.46 (2H, br s), 6.6
7 (1H, s), 6.75 (1H, d, J = 15.9Hz), 7.12 (2H, br s), 9.
47 (1H, d, J = 8.1Hz), 11.3 (1H, s)

Example 11- (1) 7β- [2- (2-aminothiazol-4-yl) -2
-Methoxyiminoacetamide] -3-[(E) -4-
Carbamoyloxy-1-buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) (5.15 g) in dichloromethane (25 ml) -anisole (5 ml) mixture suspension at 5 ° C. At this point, trifluoroacetic acid (10 ml) is added dropwise, and the resulting solution is stirred at the same temperature for 1.8 hours. The solution is poured into cold diisopropyl ether (300 ml), the precipitate is filtered off, washed with diisopropyl ether and dried under reduced pressure. The pH of the obtained powder was adjusted to 7 by adding saturated aqueous sodium hydrogen carbonate solution to water.
Dissolve in 1 and add 1N hydrochloric acid to adjust pH to 4.5.
The solution is chromatographed on Diaion HP-20 (250 ml), eluted with 5% aqueous isopropyl alcohol and lyophilized. Preparative HPLC of crude products
And purified by 7β- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamide] -3.
-[(E) -4-carbamoyloxy-1-butene-1
-Yl] -3-cephem-4-carboxylic acid (syn isomer) (302 mg) is obtained. IR (nujor): 3250, 1740, 1640 cm ^-1 NMR (DMSO-d ₆ , δ): 2.4-2.6 (2H, m), 3.56 and 3.7
6 (2H, ABq, J = 17.5Hz), 3.84 (3H, s), 3.96 (2H, t, J = 6.6H
z), 5.17 (1H, d, J = 4.7Hz), 5.73 (1H, dd, J = 8.1 and
4.7Hz), 6.01 (1H, dt, J = 16.0 and 7.0Hz), 6.46 (2H,
br s), 6.75 (1H, s), 6.75 (1H, d, J = 16.0Hz), 7.22 (2
H, br s), 9.61 (1H, d, J = 8.1 Hz) In the same manner as in Example 11- (1), the following compound was obtained. (2) 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3-
[(E) -4-Hydroxy-1-buten-1-yl]-
3-Cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer) NMR (DMSO-d ₆ , δ): 2.19 (3H, s), 2.2-2.3 (2H, m), 3.
46 (2H, t, J = 6Hz), 3.61 and 3.83 (2H, ABq, J = 17Hz),
5.22 (1H, d, J = 5Hz), 5.79 (1H, dd, J = 5 and 8Hz), 6.
0-6.2 (1H, m), 6.74 (1H, d, J = 16Hz), 7.11 (1H, s), 9.92
(1H, d, J = 8Hz)

Example 12 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3-[(E) -4
-Hydroxy-1-buten-1-yl] -3-cephem-4-carboxylic acid / trifluoroacetic acid salt (syn isomer)
(2.02 g) water (60 ml) -methanol (6 m
l) Ammonium chloride (544 mg) is added to the suspension. The mixture is stirred at room temperature, keeping the pH at 8.0 by addition of aqueous sodium hydrogen carbonate solution. The mixture is adjusted to pH 6 by adding 1N hydrochloric acid and the methanol is evaporated off under reduced pressure. Add 1N hydrochloric acid and p
Adjusted to H4.3, Diaion HP-20 (60m
Chromatography on l), eluting with 5% aqueous isopropyl alcohol. Lyophilize the eluate. The crude product was purified by preparative HPLC and Diaion HP-20 to give 7β- [2- (2-aminothiazole-4
-Yl) -2-hydroxyiminoacetamide] -3-
[(E) -4-Hydroxy-1-buten-1-yl]-
3-Cephem-4-carboxylic acid (syn isomer) (515
mg) is obtained. IR (nujol): 3300-3000, 1740, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 2.28 (2H, q, J = 7Hz), 3.46 (2H, t, J
= 7Hz), 3.55 and 3.75 (2H, ABq, J = 17Hz), 5.15 (1H,
d, J = 5Hz), 5.73 (1H, dd, J = 5 and 8Hz), 6.07 (1H, dt,
J = 16 and 7Hz), 6.67 (1H, s), 6.74 (1H, d, J = 16Hz),
7.13 (2H, br s), 9.47 (1H, d, J = 8Hz), 11.3 (1H, br s)

Example 13 7β- [2- (2-aminothiazol-4-yl) -2
-Hydroxyiminoacetamide] -3-[(E) -4
-Carbamoyloxy-1-buten-1-yl] -3-
Cephem-4-carboxylic acid (syn isomer) (300 m
To a solution of g) in N, N-dimethylformamide (3 ml) is added cesium carbonate (111 mg) at 5 ° C. The mixture is stirred at 5 ° C. for 1.5 hours. To this solution is added iodomethyl pivalate (160 mg). The mixture is stirred at 5 ° C. for 3 hours. The reaction mixture is poured into a mixture of ethyl acetate and water. The organic layer is separated, washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue is triturated with diisopropyl ether. The precipitate was collected by filtration to give 7β- [2- (2-aminothiazole-4
-Yl) -2-hydroxyiminoacetamide] -3-
[(E) -4-carbamoyloxy-1-butene-1-
Yyl] -3-cephem-4-carboxylate pivaloyloxymethyl (syn isomer) (206 mg) is obtained. IR (nujor): 3500-3100, 1730, 1720-1650 cm ^-1 NMR (DMSO-d ₆ , δ): 1.16 (9H, s), 2.42 (2H, q-like), 3.6
0 and 3.86 (2H, ABq, J = 18Hz), 3.96 (2H, t, J = 7Hz),
5.22 (1H, d, J = 5Hz), 5.8-5.9 (1H, m), 5.81 and 5.91
(2H, ABq, J = 6Hz), 6.17 (1H, dt, J = 16 and 7Hz), 6.46
(2H, br s), 6.66 (1H, d, J = 16Hz), 6.67 (1H, s), 7.12
(2H, br s), 9.48 (1H, d, J = 8Hz), 11.3 (1H, s)

Production Example 3 To a solution of 2-chloroacetamide (93.51 g) in acetic acid was added triphenylmethanol (273.36 g) at room temperature, followed by acetic anhydride (107.2 g) and concentrated sulfuric acid (9.8).
1 g) is added. The mixture is stirred at 50 ° C. for 4.5 hours. After cooling to 5 ° C, the precipitate was collected by filtration, washed with acetic acid and diisopropyl ether, dried under reduced pressure, and 2-chloro-N-tritylacetamide (284.35).
g) is obtained. IR (nujor): 3200, 1640, 1530 cm ^-1 NMR (DMSO-d ₆ ,, δ): 4.23 (2H, s), 7.15-7.4 (15H, m),
8.96 (1H, s)

Preparation Example 4 To a solution of 4,4-dimethoxybutanoic acid (27.60 g) in dichloromethane (200 ml) was added triethylamine (37.70 g) at 5 ° C., followed by isobutyl chloroformate (5 minutes at 50 ° C.). 50.94 g) are added dropwise. 5
After stirring at ℃ for 1 hour, triphenylmethylamine (48.24 g) in dichloromethane (250 m) was added to the solution.
l) The solution is added dropwise at 5 ° C. over 40 minutes and stirred for 20 minutes at room temperature. The mixture is poured into cold water, the organic layer is separated off, washed with water and brine, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- (N-tritylcarbamoyl) propionaldehyde dimethyl acetal (9.2.
6 g) are obtained. IR (nujor): 3210, 1630, 1580, 1520 cm ^-1 NMR (CDCl ₃ , δ): 1.93 (2H, td, J = 7.2 and 5.4Hz),
2.35 (2H, t, J = 7.2Hz), 4.34 (1H, t, J = 5.4Hz), 6.84 (1H,
s), 7.15-7.4 (15H, m)

Production Example 5 Bis (trimethylsilyl) acetamide (148.1 g) was added to a solution of 4-methylamino-1-butyne (60.50 g) in dichloromethane (600 ml) at room temperature, and the mixture was stirred at the same temperature for 15 minutes. To do. Di (tertiary butyl) dicarbonate (190.7 g) was added to the mixture,
Reflux for 8 hours. The mixture is poured into ice water (200 ml), the organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- (N-tertiary butoxycarbonyl-N-methylamino) -1-butyne (4
0.68 g) is obtained. NMR (CDCl ₃ , δ): 1.46 (9H, s), 1.97 (1H, t, J = 2.7Hz),
2.41 (2H, td, J = 7.0 and 2.7Hz), 2.92 (3H, s), 3.38
(2H, t, J = 7.0Hz)

Production Example 6 To a benzene solution (170 ml) of 4-methoxy-1-butyne (17.5 g) was added 2,2'-azobisisobutyronitrile (683 mg) under reflux. A solution of tri (n-butyl) tin hydride (56.0 ml) in benzene (50 ml) was added dropwise to the solution over 50 minutes. The solution is refluxed for 1 hour. The reaction mixture is cooled to room temperature and concentrated under reduced pressure to obtain a crude product of (E) -4-methoxy-1-tri (n-butyl) stannyl-1-butene (82.7 g). NMR (CDCl ₃ , δ): 0.8-1.0 (15H, m), 1.2-1.6 (12H.m),
2.3-2.5 (2H, m), 3.33 (3H, s), 3.44 (2H, t, J = 7Hz), 5.
96 (2H, m)

Production Example 7 In the same manner as in Production Example 6, the following compound was obtained. (E) -1-Tri (n-butyl) stannyl-4- (N
-Tertiary butoxycarbonyl-N-methylamino) -1
-Butene IR (film): 2870, 1670, 1590 cm ^-1 NMR (CDCl ₃ , δ): 0.8-1.6 (27H, m), 1.46 (9H, s), 2.2
-2.4 (2H, m), 2.84 (3H, s), 3.26 (2H, t, J = 6.8Hz), 5.8-
6.1 (2H, m)

Production Example 8 3-Chloropropionaldehyde diethyl acetal (66.7 g) in N, N-dimethylformamide (40
Sodium = 1,2,3-thiadiazole-5-thiolate (76.1 g) is added to the solution at 5 ° C. The mixture is stirred for 6 hours at 50 ° C. Pour the reaction mixture into ethyl acetate and cold water. The organic layer is separated, washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3-[(1,2,3-thiadiazol-5-yl).
Thio] propionaldehyde diethyl acetal (6
8.7 g) are obtained. NMR (CDCl ₃ , δ): 1.22 (6H, t, J = 7Hz), 2.04 (2H, m),
3.15 (2H, t, J = 7Hz), 3.4-3.8 (4H, m), 4.61 (1H, t, J = 5H
z), 8.46 (1H, s)

Production Example 9 3-[(1,2,3-thiadiazol-5-yl) thio] propionaldehyde diethyl acetal (68.
3 g) of acetonitrile (600 ml) and water (67 m)
l) In solution, 2,3-dichloro-5,6-dicyano-1,
4-Benzoquinone (6.24 g) is added. The mixture is stirred for 18 hours at room temperature. Acetonitrile is removed by vacuum concentration. The aqueous solution is poured into ethyl acetate and water, the organic layer is washed with water and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3-[(1,2,3-thiadiazol-5-yl) thio] propionaldehyde (18.
5 g) are obtained. IR (film): 1690 cm ^-1 NMR (CDCl ₃ , δ): 2.96 (2H, t, J = 7Hz), 3.33 (2H, t, J = 7)
Hz), 8.47 (1H, s), 9.81 (1H, s)

Production Example 10 In the same manner as in Production Example 9, the following compound was obtained. 3- (N-Tritylcarbamoyl) propionaldehyde NMR (CDCl ₃ , δ): 2.55 (2H, t, J = 6.0Hz), 2.79 (2H, t, J)
= 6.0Hz), 6.81 (1H, s), 7.15-7.4 (15H, m), 9.77 (1H,
s)

Example 14 The following compound was obtained in the same manner as in Example 5- (1). (1) 7β-formamido-3-{(E) -4-methoxy-1-buten-1-yl} -3-cephem-4-carboxylic acid diphenylmethyl NMR (DMSO-d ₆ , δ): 2.24 (2H , q, J = 6Hz), 3.18 (3H, s),
3.62 and 3.85 (2H, ABq, J = 17Hz), 5.21 (1H, d, J = 5H
z), 5.82 (1H, dd, J = 9 and 5Hz), 6.1-6.2 (1H, m), 6.
55 (1H, d, J = 16Hz), 6.98 (1H, s), 7.2-7.5 (10H, m), 8.1
7 (1H, s), 9.13 (1H, d, J = 9Hz) (2) 7β-formamide-3-{(E) -4- (N-
Tertiary butoxycarbonyl-N-methyl) amino-1-
Buten-1-yl} -3-cephem-4-carboxylate diphenylmethyl IR (nujol): 1760, 1710, 1655 cm ^-1 NMR (DMSO-d ₆ , δ): 1.35 (9H, s), 2.1-2.3 (2H, m), 2.
71 (3H, s), 3.16 (2H, t, J = 6.1Hz), 3.60 and 3.84
(2H, ABq, J = 17.7Hz), 5.19 (1H, d, J = 4.7Hz), 5.81 (1H, d
d, J = 8.8 and 4.7Hz), 6.10 (1H, dt, J = 15.9 and 5.
5Hz), 6.54 (1H, d, J = 15.9Hz), 6.98 (1H, s), 7.2-7.5
(10H, m), 8.16 (1H, s), 9.13 (1H, d, J = 8.8Hz)

Example 15 In the same manner as in Example 1, the following compound is obtained. (1) 7β-tertiary butoxycarbonylamino-3-
{(Z) -4- (1,2,3-thiadiazol-5-yl) thio-1-buten-1-yl} -3-cephem-4
-Diphenylmethyl carboxylate NMR (DMSO-d ₆ , δ): 1.41 (9H, s), 2.2-2.5 (2H, m), 3.
06 (2H, t, J = 7Hz), 3.48 (2H, s), 5.06 (1H, d, J = 5Hz), 5.
5-5.6 (2H, m), 6.20 (1H, d, J = 12Hz), 6.87 (1H, s), 7.2
-7.5 (10H, m), 8.01 (1H, d, J = 8Hz), 8.79 (1H, s) (2) 7β-tertiary butoxycarbonylamino-3-
{(Z) -4-Methoxy-1-buten-1-yl) -3
-Cephem-4-carboxylate diphenylmethyl IR (nujol): 1760, 1680 cm ^-1 NMR (DMSO-d ₆ , δ): 1.41 (9H, s), 1.8-2.3 (2H, m), 3.
12 (3H, s), 3.13 (2H, t, J = 6.5Hz), 3.58 and 3.80
(2H, ABq, J = 17.4Hz), 5.17 (1H, d, J = 4.8Hz), 5.4-5.6 (2
H, m), 6.17 (1H, d, J = 11.5Hz), 6.88 (1H, s), 7.2-7.5
(10H, m), 8.03 (1H, d, J = 8.9Hz) (3) 7β-tertiary butoxycarbonylamino-3-
{(Z) -4-Tritylcarbamoyl-1-butene-1
-Yl) -3-cephem-4-carboxylic acid diphenylmethyl IR (nujol): 3250, 1760, 1580 cm ^-1 NMR (DMSO-d ₆ , δ): 1.41 (9H, s), 2.1-2.4 (4H, m), 3.
44 (2H, br s), 5.09 (1H, d, J = 4.7Hz), 5.35-5.45 (1H, d
d, J = 9.1 and 4.7Hz), 5.50 (1H, dd, J = 9.1 and 4.
7Hz), 6.11 (1H, d, J = 11.6Hz), 6.85 (1H, s), 7.15-7.5
(10H, m), 8.02 (1H, d, J = 9.1Hz), 8.56 (1H, s)

Example 16 7β-Amino-3-{(E) -4-hydroxy-1-buten-1-yl} -3-cephem-4-carboxylate diphenylmethyl hydrochloride (8.45 g) was added to tetrahydrofuran. Dissolve in (100 ml) and add mono (trimethylsilyl) acetamide (11.72 g) at 45 ° C.
Di (tertiary butyl) dicarbonate (5.
86 g) are added and the mixture is stirred for 7 hours at 45 ° C. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 7β-tertiary butoxycarbonylamino-3-{(E) -4-hydroxy-1-.
Diphenylmethyl buten-1-yl) -3-cephem-4-carboxylate (6.95 g) is obtained. IR (Nujor): 3510, 3320, 1740, 1705, 1670 cm
^-1 NMR (DMSO-d ₆ , δ): 1.41 (9H, s), 2.18 (2H, td, J = 4.4
And 6.6Hz), 3.42 (2H, td, J = 4.4 and 5.3Hz), 3.5
8 and 3.79 (2H, ABq, J = 17.2Hz), 4.57 (1H, t, J = 5.3H
z), 5.14 (1H, d, J = 4.7Hz), 5.48 (1H, dd, J = 8.9 and
4.7Hz), 6.19 (1H, dd, J = 15.9 and 7.0Hz), 6.63 (1
H, d, J = 15.9Hz), 6.94 (1H, s), 7.3-7.6 (10H, m), 8.04
(1H, d, J = 8.9Hz)

Example 17 7β-tertiary butoxycarbonylamino-3-{(E)
-4-Hydroxy-1-buten-1-yl} -3-cephem-4-carboxylate diphenylmethyl (6.94 g)
Solution of triethylamine (1.31
g) is added at -20 ° C, followed by dropwise addition of a solution of acetyl chloride (1.22g) in dichloromethane (10ml) at -20 ° C. The mixture is stirred for 2.5 hours at −20 ° C., poured into cold water, the organic layer is separated off, washed with 1N hydrochloric acid and brine, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7β-tertiary butoxycarbonylamino-3-.
{(E) -4-acetoxy-1-buten-1-yl}-
Diphenylmethyl 3-cephem-4-carboxylate (4.
04g) is obtained. NMR (DMSO-d ₆ , δ): 1.41 (1H, s), 1.95 (3H, s), 2.25-
2.4 (2H, m), 3.58 and 3.81 (2H, ABq, J = 17.4Hz), 3.
99 (2H, t, J = 6.4Hz), 5.14 (1H, t, J = 4.7Hz), 5.51 (1H, d
d, J = 9.1 and 4.7Hz), 6.14 (1H, dt, J = 15.9 and
6.8Hz), 6.59 (1H, d, J = 15.9Hz), 6.95 (1H, s), 7.3-7.5
(10H, m), 8.05 (1H, d, J = 9.1Hz)

Example 18 The following compound was obtained in the same manner as in Example 6- (1). (1) 7β-amino-3-{(E) -4-methoxy-1
-Buten-1-yl} -3-cephem-4-carboxylate diphenylmethyl NMR (DMSO-d ₆ , δ): 2.21 (1H, q, J = 7Hz), 2.41 (2H, br
s), 3.18 (3H, s), 3.54 and 3.81 (2H, ABq, J = 18Hz),
4.82 (1H, d, J = 5Hz), 5.05 (1H, d, J = 5Hz), 6.0-6.2 (1H,
m), 6.45 (1H, d, J = 16Hz), 6.56 (1H, s), 7.2-7.5 (10H,
m) (2) 7β-amino-3-[(E) -4- (N-tertiary butoxycarbonyl-N-methylamino) -1-buten-1-yl] -3-cephem-4-carboxylic acid Diphenylmethyl IR (nujol): 1750, 1660, 1550 cm ^-1 NMR (DMSO-d ₆ , δ): 1.35 (9H, s), 2.17 (2H, td, J = 7.5
And 7.4Hz), 2.42 (2H, br s), 3.15 (2H, t, J = 7.5Hz),
3.53 and 3.78 (2H, ABq, J = 17.6Hz), 4.81 (1H, d, J =
5.0Hz), 5.04 (1H, d, J = 5.0Hz), 6.02 (1H, dt, J = 15.9 and 7.4Hz), 6.45 (1H, d, J = 15.9Hz), 6.95 (1H, s), 7 .
3-7.5 (10H, m)

Example 19 The following compound was obtained as in Example 4- (1). (1) 7β-amino-3-[(Z) -4- (1,2,3
-Thiadiazol-5-yl) thio-1-buten-1-
Il] -3-cephem-4-carboxylic acid / trifluoroacetate NMR (DMSO-d ₆ , δ): 2.4-2.7 (2H, m), 3.29 (2H, t, J = 7H
z), 3.6-3.8 (2H, m), 5.0-5.2 (2H, m), 5.66 (1H, dt, J = 1
1.8Hz), 6.34 (1H, d, J = 11Hz), 8.87 (1H, s) (2) 7β-amino-3-[(Z) -4-methoxy-1
-Buten-1-yl] -3-cephem-4-carboxylic acid / trifluoroacetate NMR (DMSO-d ₆ , δ): 2.1-2.4 (2H, m), 3.21 (3H, s), 3.
32 (2H, t, J = 6.5Hz), 3.45 and 3.60 (2H, ABq, J = 17.4
Hz), 4.80 (1H, d, J = 5.0Hz), 5.05 (1H, d, J = 5.0Hz), 5.52
(1H, d, J = 11.6 and 7.1Hz), 6.18 (1H, d, J = 11.6Hz) (3) 7β-amino-3-[(E) -4-acetoxy-
1-buten-1-yl] -3-cephem-4-carboxylic acid / trifluoroacetate NMR (DMSO-d ₆ , δ): 2.00 (3H, s), 2.43 (2H, td, J = 6.5)
And 6.9Hz), 3.59 and 3.79 (2H, ABq, J = 17.4Hz),
4.06 (2H, t, J = 6.5Hz), 4.89 (1H, d, J = 5.0Hz), 5.08 (1
H, d, J = 5.0Hz), 6.07 (1H, dt, J = 16.0 and 6.9Hz), 6.7
6 (1H, d, J = 16.0Hz) (4) 7β-amino-3-[(Z) -4-carbamoyl-1-buten-1-yl] -3-cephem-4-carboxylic acid / trifluoroacetic acid Salt IR (nujol): 1750, 1645 cm ^-1 NMR (DMSO-d ₆ , δ): 2.1-2.45 (4H, m), 3.65 (2H, m),
5.08 (1H, d, J = 4.9Hz), 5.22 (1H, d, J = 4.9Hz), 5.54 (1H,
dt, J = 11.6 and 7.4Hz), 6.23 (1H, d, J = 11.6Hz), 6.5
6 (2H, br s)

Example 20 The following compound was obtained in the same manner as in Examples 7 and 8. (1) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
{(Z) -4-Methoxy-1-buten-1-yl} -3
-Cephem-4-carboxylic acid (syn isomer) IR (nujol): 1750, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 2.15-2.45 (2H, m), 3.21 (3H, s),
3.33 (2H, t, J = 6.5Hz), 3.46 and 3.60 (2H, ABq, J = 17.
7Hz), 5.18 (1H, d, J = 4.8Hz), 5.53 (1H, dt, J = 11.6 and 7.5Hz), 5.75 (1H, dd, J = 8.2 and 4.8Hz), 6.23 (1
H, d, J = 11.6Hz), 6.66 (1H, s), 7.12 (2H, br s), 9.45
(1H, d, J = 8.2Hz), 11.30 (1H, s) (2) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -4-acetoxy-1-buten-1-yl]-
3-Cephem-4-carboxylic acid (syn isomer) IR (nujol): 1760, 1710 cm ^-1 NMR (DMSO-d ₆ , δ): 2.00 (3H, s), 2.45 (2H, td, J = 6.6)
And 7.0Hz), 3.55 and 3.78 (2H, ABq, J = 17.6Hz),
4.06 (2H, t, J = 6.6Hz), 5.17 (1H, d, J = 4.8Hz), 5.76 (1
H, dd, J = 8.1 and 4.8Hz), 6.04 (1H, dd, J = 16.0 and 7.0Hz), 6.67 (1H, s), 6.74 (1H, d, J = 16.0Hz), 7.12
(2H, br s), 9.47 (1H, d, J = 8.1Hz), 11.30 (1H, s) (3) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -4-carbamoyl-1-buten-1-yl]
-3-Cephem-4-carboxylic acid (syn isomer) IR (nujol): 1740, 1630 cm ^-1 NMR (DMSO-d ₆ , δ): 2.0-2.4 (4H, m), 3.48 and 3.6
1 (2H, ABq, J = 17.7Hz), 5.18 (1H, d, J = 4.8Hz), 5.47 (1H,
dd, J = 11.5 and 7.8Hz), 5.76 (1H, dd, J = 8.2 and
4.8Hz), 6.14 (1H, d, J = 11.5Hz), 6.67 (1H, s), 6.77 and 7.27 (total 2H, br s), 7.13 (2H, br s), 9.46 (1
H, d, J = 8.2Hz), 11.31 (1H, s)

Example 21 The following compound is obtained in the same manner as in Example 9- (1). (1) 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3-
[(E) -4-Methoxy-1-buten-1-yl] -3
- cephem-4-carboxylic acid diphenylmethyl (syn _{isomer) NMR (DMSO-d 6,} δ): 2.17 (3H, s), 2.2-2.4 (2H, m), 3.
16 (3H, s), 3.3-3.4 (2H, m), 3.62 and 3.79 (2H, AB
q, J = 18Hz), 5.27 (1H, d, J = 5Hz), 5.87 (1H, dd, J = 8 and 5Hz), 6.0-6.2 (1H, m), 6.54 (1H, d, J = 16Hz) , 7.10
(1H, s), 7.2-7.6 (12H, m), 9.93 (1H, d, J = 8Hz) (2) 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyiminoacetamide] -3-
[(Z) -4- (1,2,3-thiadiazol-5-yl) thio-1-buten-1-yl] -3-cephem-4
-Carboxylic acid (syn isomer) NMR (DMSO-d ₆ , δ): 2.15 (3H, s), 2.3-2.6 (2H, m), 3.
21 (2H, t, J = 7Hz), 3.4-3.6 (2H, m), 5.12 (1H, d, J = 5Hz),
5.4-5.6 (1H, m), 5.7-5.8 (1H, m), 6.17 (1H, d, J = 11H
z), 7.11 (1H, s), 8.81 (1H, s), 9.90 (1H, d, J = 8Hz) (3) 7β- [2- (2-aminothiazol-4-yl) -2-acetoxyimino Acetamide] -3-
[(E) -4- (N-tertiary butoxycarbonyl-N-
Methylamino) -1-buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) IR (nujol): 1760, 1720, 1650 cm ⁻¹ NMR (DMSO-d ₆ , δ) : 1.33 (9H, s), 2.1-2.3 (2H, m), 2.
17 (3H, s), 2.69 (3H, s), 3.1-3.2 (2H, m), 3.51 and
3.72 (2H, ABq, J = 17.6Hz), 5.29 (1H, d, J = 5.0Hz), 5.87
(1H, dd, J = 8.0 and 5.0Hz), 6.0-6.2 (1H, m), 6.54 (1
H, d, J = 15.9Hz), 6.94 (1H, s), 7.10 (1H, s), 7.2-7.5
(10H, m), 9.92 (1H, d, J = 8.0Hz)

Example 22 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3-[(E) -4
-(N-tertiary butoxycarbonyl-N-methylamino) -1-buten-1-yl] -3-cephem-4-carboxylate diphenylmethyl (syn isomer) (10.63)
g) dichloromethane (50 ml) and anisole (40
ml) mixed solution with trifluoroacetic acid (20
ml) is added and the mixture is stirred for 3.5 hours at 5 ° C. The mixture is poured into diisopropyl ether (600 ml), the precipitate is filtered off, washed with diisopropyl ether and evaporated to dryness under reduced pressure. The powder is mixed with water (300 ml)
Suspended in a mixture of and methanol (15 ml) and added ammonium chloride (2.25 g). The mixture is stirred at room temperature for 2 hours while keeping the pH at 8 by adding aqueous sodium hydrogen carbonate solution. The mixture is adjusted to pH about 6 with 6N hydrochloric acid and the methanol is removed by vacuum concentration. The residue was adjusted to pH 2. by adding 6N hydrochloric acid.
Adjust to 9, subject to column chromatography with HP-20 (400 ml) and elute with 5% isopropyl alcohol solution. The eluate was lyophilized and the crude product was purified by preparative HPLC to give 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-[(E)-. 4-Methylamino-1-buten-1-yl] -3-cephem-4-carboxylic acid (syn isomer) (668 mg) is obtained. IR (nujor): 1740, 1660, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 2.50 (3H, s), 2.4-2.55 (2H, m),
2.8-3.0 (2H, m), 3.43 and 3.55 (2H, ABq, J = 17.2Hz),
5.05 (1H, d, J = 4.8Hz), 5.64 (1H, dd, J = 8.0 and 4.8
Hz), 5.5-5.7 (1H, m), 6.65 (1H, s), 6.79 (1H, d, J = 15.
6Hz), 7.14 (2H, br s), 9.43 (1H, d, J = 8.0Hz)

Example 23 The following compound was obtained in the same manner as in Example 11- (1). 7β- [2- (2-aminothiazol-4-yl) -2
-Acetoxyiminoacetamide] -3-[(E) -4
-Methoxy-1-buten-1-yl] -3-cephem-
4-carboxylic acid / trifluoroacetic acid salt (syn isomer) NMR (DMSO-d ₆ , δ): 2.19 (3H, s), 2.37 (2H, q, J = 6Hz),
3.23 (3H, s), 3.39 (2H, t, J = 6Hz), 3.61 and 3.76
(2H, ABq, J = 17Hz), 5.23 (1H, d, J = 5Hz), 5.79 (1H, dd, J = 8)
And 5Hz), 6.0-6.2 (1H, m), 6.75 (1H, d, J = 16Hz),
7.11 (1H, s), 9.92 (1H, d, J = 8Hz)

Example 24 The following compound was obtained in the same manner as in Example 12. (1) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(E) -4-Methoxy-1-buten-1-yl] -3
-Cephem-4-carboxylic acid (syn isomer) IR (nujol): 3300-3100, 1750, 1620-1500 cm ^-1 NMR (DMSO-d ₆ , δ): 2.37 (2H, q, J = 6Hz), 3.23 (3H, s),
3.39 (2H, t, J = 6Hz), 3.55 and 3.77 (2H, ABq, J = 18H
z), 5.16 (1H, d, J = 5Hz), 5.74 (1H, d, J = 8 and 5Hz),
6.06 (1H, dt, J = 16 and 7Hz), 6.67 (1H, s), 6.73 (1
H, d, J = 16Hz), 7.12 (2H, br s), 9.47 (1H, d, J = 8Hz), 1
1.3 (1H, s) (2) 7β- [2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetamide] -3-
[(Z) -4- (1,2,3-thiadiazol-5-yl) thio-1-buten-1-yl] -3-cephem-4
-Carboxylic acid (syn isomer) IR (nujol): 3300, 1740, 1650, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 2.3-2.6 (2H, m), 3.26 (2H, t, J = 7H
z), 3.43 and 3.53 (2H, ABq, J = 18Hz), 5.10 (1H, d, J =
5Hz), 5.57 (1H, dt, J = 11, 8Hz), 5.76 (1H, dd, J = 5, 8H
z), 6.25 (1H, d, J = 11Hz), 6.66 (1H, s), 7.12 (2H, br
s), 8.87 (1H, s), 9.45 (1H, d, J = 8Hz), 11.3 (1H, br s)

Claims (1)

[Claims] 1. A general formula: [Wherein R ¹ is amino or acylamino, R ² is carboxy or protected carboxy, R ³ is hydroxy, protected hydroxy, lower alkoxy, lower alkylamino, protected (lower) alkylamino, acyl Or represents heterocyclethio]
A novel cephem compound represented by and a pharmaceutically acceptable salt thereof.