JPH1149778A - Production of intermediate for synthesizing cephalosporin derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject intermediate by reaction of a cephalosporin derivative bearing methyl group on the 3-site with a specific compound to effect slight formation of byproduct Δ<2> -form on the cephem ring and also transform the methyl group on the 3-site to enaminomethyl group in high yield. SOLUTION: This intermediate of formula II is obtained by reaction of a compound of formula I (R<1> is an amino-protective group interposed with a carbon, sulfur or silicon atom, or an acyl; R<2> is a carboxyl-protective group) or a salt thereof with tris(dimethylamino)methane, wherein the amount of the tris(dimethylamino)methane to be used is pref. 2-3 equivalents per mol of the compound of formula. The above reaction is carried out using N- methylpyrrolidone as reaction solvent pref. at 10-20 wt. times based on the compound of formula I at 30-40 deg.C for 2-4 h. After hydrolyzing this compound of formula II, reaction of the reaction product with a disulfide compound in the presence of a phosphorus compound affords a raw material compound for antimicrobial agents.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a synthetic intermediate for producing a cephalosporin derivative having an antibacterial action.

[0002]

2. Description of the Related Art JP-A-55-154981 discloses that
A method is disclosed in which a methyl group at the 3-position of a cephalosporin derivative is converted to an enaminomethyl group by a reactive formamide derivative. A method for producing a derivative having a thiovinyl group at the 3-position by subjecting the obtained enaminomethyl derivative to a hydrolysis reaction to convert the resulting enaminomethyl derivative into a sulfonic acid enol ester derivative or an acyl enolate derivative, and reacting the resulting product with a thiol compound is shown. I have. JP-A-58-439
No. 898 discloses that a methyl group at the 3-position of a cephalosporin derivative is a methyl group and an amino group at the 7-position protected by a group via a phosphorus atom is a methyl group at the 3-position with enaminomethyl by tris (dimethylamino) methane. Reactions to convert to groups are shown.

[0003]

Problems to be Solved by the Invention
In the method specifically described in the example in Japanese Patent Publication No. 81, △ ²
Isomer, that is, the formula

Embedded image With an isomer having a partial structure represented by Therefore, the target △ ³ body, that is, the formula

Embedded image In order to obtain the isomer having the partial structure represented, △ ²
It is necessary to convert the sulfur atom at the 1-position of the isomer cephem ring to a sulfoxide group, which is then subjected to a reduction reaction, and therefore the number of steps is increased, which is inconvenient for industrial production. In the case of a compound in which the amino group at the 7-position in JP-A-58-439898 is protected by a group via a phosphorus atom, the product is not a single product, and therefore requires a purification step by recrystallization, so that the yield is low. Low. To industrially advantageously producing a cephalosporin derivative having antibacterial activity, fewer steps, less preparation of secondary raw △ ² body in the cephem ring it is desired.

[0004]

Means for Solving the Problems In view of the above circumstances, the present inventors have conducted intensive studies and found that the general formula

Embedded image [Wherein, R ¹ represents a protecting group for an amino group or an acyl group via a carbon atom, a sulfur atom or a silicon atom, and R ² represents a protecting group for a carboxyl group], or a salt thereof and tris (dimethyl). By reacting with (amino) methane, it was found that the methyl group at the 3-position of the cephalosporin derivative can be converted into an enaminomethyl group with little by-product of the △ ² form in the cephem ring, and with high yield, As a result of further research based on this, the present invention was completed.

[0005] The present invention provides:

Embedded image [Wherein, R ¹ represents a protecting group for an amino group or an acyl group via a carbon atom, a sulfur atom or a silicon atom, and R ² represents a protecting group for a carboxyl group], or a salt thereof and tris (dimethyl). General formula characterized by reacting with (amino) methane

Embedded image [The symbols in the formula are as defined above] or a method for producing a salt thereof.

(2) R ¹ is t-butoxycarbonyl,
The production method according to the above (1), wherein R ² represents Benzhydryl. (3) The production method according to the above (1), wherein the reaction is carried out in the presence of an amide solvent. (4) The method according to the above (3), wherein the amide solvent is N-methylpyrrolidone. (5) General formula

Embedded image [Wherein R ¹ represents a protecting group for an amino group or an acyl group via a carbon atom, a sulfur atom or a silicon atom, and R ² represents a protecting group for a carboxyl group, respectively]. Reaction with amino) methane

Embedded image Wherein each symbol in the formula is as defined above, or a salt thereof, and the obtained compound is subjected to a hydrolysis reaction to obtain a compound represented by the general formula

Embedded image Wherein each symbol in the formula is as defined above, or a salt thereof, and then reacting the obtained compound or a salt thereof with a disulfide compound in the presence of a phosphorus compound. General formula

Embedded image [In the formula, R ⁴ represents a group via a sulfur atom. The other symbols have the same meaning as described above. ] Or a salt thereof.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, examples of the amino-protecting group via a carbon atom represented by R ¹ include an optionally substituted C _1-6 alkanoyl group and an optionally substituted C _1-6 alkanoyl group. C _3-5 alkenoyl group, optionally substituted C _6-10 aryl-carbonyl group, heterocyclic carbonyl group, substituted oxycarbonyl group, optionally substituted carbamoyl group, optionally substituted C _{6- 10} aryl-
A methyl group, an optionally substituted di C _6-10 aryl-methyl group, an _optionally substituted tri C _6-10 aryl-methyl group, an _optionally substituted C _6-10 aryl-methylene group, 2-C _1-10 alkoxy - carbonyl-1-methyl-1-ethenyl group, wherein M'OCO- [wherein, M 'represents an alkali metal. And the like. Examples of the “optionally substituted C _1-6 alkanoyl group” include halogen, oxo, C _1-6 alkoxy,
1-3 selected from _1-6 alkanoyl, C _6-10 aryl, halogeno C _6-10 aryl, C _6-10 aryloxy, halogeno C _6-10 aryloxy, C _6-10 arylthio and the like.
C _1-6 alkanoyl groups which may be substituted by two substituents are used. Specifically, for example, formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl,
Succinyl, glutaryl, monochloroacetyl, dichloroacetyl, trichloroacetyl, monobromoacetyl, monofluoroacetyl, difluoroacetyl, trifluoroacetyl, monoiodoacetyl, acetoacetyl, 3-oxobutyryl, 4-chloro-3-oxobutyryl, phenylacetyl, p-Chlorophenylacetyl, phenoxyacetyl, p-chlorophenoxyacetyl and the like are used. The “optionally substituted C _3-5
Examples of the "alkenoyl group" include, for example, halogen, C _6-10
A C _3-5 alkenoyl group which may be substituted with 1 to 3 substituents selected from aryl and the like is used. Specifically, for example, acryloyl, crotonoyl, maleoyl, cinnamoyl, p-chlorocinnamoyl, β-phenylcinnamoyl and the like are used. Examples of the “optionally substituted C _6-10 aryl-carbonyl group” include 1 to 3 substituents selected from halogen, nitro, hydroxy, C _1-6 alkyl, C _1-6 alkoxy and the like. A C _6-10 aryl-carbonyl group which may be substituted with, for example, benzoyl, naphthoyl, phthaloyl, p-toluoyl, p-tert-butylbenzoyl, p-hydroxybenzoyl, p-methoxy Benzoyl, p-tert-butoxybenzoyl, p-chlorobenzoyl, p-nitrobenzoyl and the like are used.

The "heterocyclic group" in the "heterocyclic carbonyl group" is a hydrogen atom bonded to a carbon atom of the heterocyclic ring by 1
A heterocyclic ring is, for example, one to several hetero atoms such as a nitrogen atom (which may be oxidized), an oxygen atom and a sulfur atom, preferably one to four hetero atoms. And a condensed ring thereof.
As such a heterocyclic group, specifically, 2- or 3-
Pyrrolyl; 3-, 4- or 5-pyrazolyl; 2-, 4
-Or 5-imidazolyl; 1,2,3- or 1,2,4
-Triazolyl; 1H- or 2H-tetrazolyl; 2
-Or 3-furyl; 2- or 3-thienyl; 2-,
4- or 5-oxazolyl; 3-, 4- or 5-isoxazolyl; 1,2,3-oxadiazol-4-yl or 1,2,3-oxadiazol-5-yl; 1,2,
4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl; 1,2,5- or 1,3,4-
Oxadiazolyl; 2-, 4- or 5-thiazolyl;
1,3,4- or 5-isothiazolyl; 1,2,3-thiadiazol-4-yl or 1,2,3-thiadiazol-5-yl; 1,2,4-thiadiazol-3-yl or 1,2, 4-thiadiazol-5-yl; 1,2,5- or 1,3,4-thiadiazolyl; 4- or 5- (1,
2,3-thiadiazolyl), 3- or 5- (1,2,4)
-Thiadiazolyl); 2- or 3-pyrrolidinyl; 2
-, 3- or 4-pyridyl; 2-, 3- or 4-pyridyl-N-oxide; 3- or 4-pyridazinyl;
3- or 4-pyridazinyl-N-oxide; 2-, 4
2- or 4- or 5-pyrimidinyl-N-oxide; pyrazinyl; 2-, 3- or 4-piperidinyl; piperazinyl; 3H-indol-2-yl or 3H-indol-3-yl; 2-,
3- or 4-pyranyl; 2-, 3- or 4-thiopyranyl; benzopyranyl; quinolyl; pyrido [2,3-
d] Pyrimidyl; 1,5-, 1,6-, 1,7-, 1,8
-, 2,6- or 2,7-naphthyridyl; thieno [2,
3-d] pyridyl; pyrimidopyridyl; pyrazinoquinolyl; benzopyranyl and the like.

The "substituted oxycarbonyl group" includes, for example, C _1-10 alkoxy-carbonyl group, C _3-10 cycloalkyloxycarbonyl group, C _5-10 bridged cyclic hydrocarbon oxycarbonyl group, C _2-10 In addition to an alkenoyloxy-carbonyl group, a C _6-10 aryloxy-carbonyl group or a C _7-19 aralkyloxy-carbonyl group, they further include a C _1-6 alkoxy group, a C _1-6 alkanoyl group,
A substituent selected from a substituted silyl group (substituted silyl group described later, eg, trimethylsilyl, tert-butyldimethylsilyl, etc.), C _1-6 alkylsulfonyl group, halogen, cyano, C _1-6 alkyl group, nitro, etc. Those having up to three are also included. Specifically, for example, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, 2-
Trimethylsilylethoxycarbonyl, 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-cyanoethoxycarbonyl, allyloxycarbonyl, p-methylphenoxycarbonyl, p-methoxyphenoxycarbonyl, p-chlorof Enoxycarbonyl, m-nitrophenoxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
o-Nitrobenzyloxycarbonyl, 3,4-dimethoxy-6-nitrobenzyloxycarbonyl and the like are used. Examples of the “optionally substituted carbamoyl group” include a C _1-6 alkyl group, a C _6-10 aryl group, a C _1-6 alkanoyl group, a C _6-10 aryl-carbonyl group, and a C _1-6 alkoxy group. And a carbamoyl group which may be substituted with one or two substituents selected from -phenyl group and the like. Specifically, for example, N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl , N, N-diethylcarbamoyl, N-
Phenylcarbamoyl, N-acetylcarbamoyl, N
-Benzoylcarbamoyl, N- (p-methoxyphenyl) carbamoyl and the like are used.

The “optionally substituted C _6-10 aryl-methyl group” includes, for example, halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
A C _6-10 aryl-methyl group which may be substituted with two substituents is used. Specifically, for example, benzyl, naphthylmethyl, p-methylbenzyl, p-methoxybenzyl, p-chlorobenzyl, p-chlorobenzyl -Nitrobenzyl and the like are used. Examples of the “optionally substituted di C _6-10 aryl-methyl group” include, for example, halogen, nitro,
1 selected from C _1-6 alkyl, C _1-6 alkoxy, etc.
A di C _6-10 aryl-methyl group which may be substituted with three substituents is used, and specific examples include benzhydryl and di (p-tolyl) methyl. The “optionally substituted tri-C _6-10 aryl-methyl group” is, for example, one to three substituents selected from halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy and the like. An optionally substituted tri-C _6-10 aryl-methyl group is used, and specific examples include trityl and tri (p-tolyl) methyl. Examples of the “optionally substituted C _6-10 aryl-methylene group” include, for example, 1 to 3 substituents selected from halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy and the like. An _{optionally substituted} C _6-10 aryl-methylene group is used, for example, benzylidene, p-methylbenzylidene, p-chlorobenzylidene and the like. The “2-C _1-10 alkoxy-carbonyl-1-methyl-1”
As the "-ethenyl group", specifically, for example, 2-methoxycarbonyl-1-methyl-1-ethenyl, 2-ethoxycarbonyl-1-methyl-1-ethenyl, 2-te
rt-butoxycarbonyl-1-methyl-1-ethenyl,
2-cyclohexyloxycarbonyl-1-methyl-1
-Ethenyl, 2-norbornyloxycarbonyl-1-
Methyl-1-ethenyl and the like. As the “alkali metal” represented by M ′, for example, sodium, potassium and the like are preferable, and sodium and the like are particularly preferable.

In the above general formula, examples of the protective group for the amino group via the sulfur atom represented by R ¹ include, for example, an optionally substituted C _1-10 alkylsulfonyl group, a camphorsulfonyl group and an optionally substituted A good C _6-10 arylsulfonyl group, an _optionally substituted thiocarbamoyl group,
And an _optionally substituted C _6-10 arylthio group. The “optionally substituted C _1-10 alkylsulfonyl group” is, for example, substituted with 1 to 3 substituents selected from halogen, C _6-10 aryl, C _6-10 aryloxy and the like. A C _1-10 alkylsulfonyl group which may be used, for example, methanesulfonyl, ethanesulfonyl and the like are specifically used. The “optionally substituted C _6-10 arylsulfonyl group” includes, for example, 1 to 3 substituents selected from halogen, nitro, C _1-6 alkyl, C _1-6 alkoxy and the like. A C _6-10 arylsulfonyl group which may be used, for example, benzenesulfonyl, naphthalenesulfonyl, p-toluenesulfonyl, p-tert-butylbenzenesulfonyl, p-methoxybenzenesulfonyl, p-chlorobenzenesulfonyl , P-nitrobenzenesulfonyl and the like. As the “optionally substituted thiocarbamoyl group”, for example, thiocarbamoyl optionally substituted by one or two substituents selected from a C _1-6 alkyl group and a C _6-10 aryl group Groups, for example, thiocarbamoyl, N-methylthiocarbamoyl, N-phenylthiocarbamoyl and the like. As the “ _optionally substituted C _6-10 arylthio group”, for example, halogen, nitro, C
1-3 selected from _1-6 alkyl, C _1-6 alkoxy, etc.
A C _6-10 arylthio group which may be substituted with a plurality of substituents is used, and specifically, for example, o-nitrophenylthio and the like are used.

In the above general formula, examples of the amino-protecting group via a silicon atom represented by R ¹ include a substituted silyl group. Said "substituted silyl group", together with the amino group to be protected, has the formula R ⁸ R ⁹ R ¹⁰ SiNH—,
(R ⁸ R ⁹ R ¹⁰ Si) ₂ N- or

Embedded image [Wherein R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ^11a and R ^12a each represent a C _1-6 alkyl group or a C _6-10 aryl group,
Z represents a C _1-3 alkylene group (eg, methylene, ethylene, propylene)]. Preferable examples of the "substituted silyl group", for example, trimethylsilyl, tert- Bed Chirushi Bu _{methylsilyl, -Si (CH 3) 2 CH} 2 CH 2 Si
(CH ₃ ) ₂ — and the like.

R ¹ is a C such as tert-butoxycarbonyl.
C- ₁₀ which may be substituted with a _C6-10 aryl group such as a _1-10 alkoxy-carbonyl group, formyl, phenylacetyl, etc.
_{A 1-6} alkanoyl group is preferred.

Examples of the acyl group represented by R ¹ include an acyl group substituted on the 6-position amino group of a conventionally known penicillin derivative and an acyl group substituted on the 7-position amino group of a cephalosporin derivative. Is used. Examples of acyl groups include, for example,

Embedded image Wherein R ²⁰ represents an alkyl or heterocyclic group *;

Embedded image Wherein, R ²¹ represents hydrogen, an amino acid residue, the amino protecting group, or a group of the formula _{^{R 23 - (CH 2) n}} 1 -CO- ( wherein, R ²³ is a heterocyclic group *, n1 is 0-2 R ²² represents an alkyl, phenyl * or a heterocyclic group * respectively), a group represented by

Expression

Embedded image [Wherein R ²⁴ is a formula

Embedded image (Wherein R ²⁶ is alkyl *, heterocyclic group * or phenyl *, R ²⁷ is hydrogen, alkyl *, cycloalkyl, alkenyl *, alkanoyl * or formula -R ²⁸ -R ²⁹ (where R ²⁸ is An alkylene or alkenylene, R ²⁹ represents a group represented by phenyl *, carboxy or an ester thereof or mono- or dialkylamino, respectively)), a group represented by a), and R ²⁵ represents a mere bond or a formula

Embedded image (Wherein, R ³⁰ represents alkyl, phenyl * or thiazolyl group *). A group represented by the formula:

Formula

Embedded image Wherein R ³¹ is hydroxy, hydroxysulfonyloxy, carboxy, carbamoyl *, sulfamoyl *,
R ³² represents hydrogen, alkyl, alkoxy, halogen, sulfo or phenoxy * -carbonyl, formyloxy,
Nitro and hydroxy represent respectively. A group represented by the formula:

Embedded image Wherein R ³³ represents cyano, phenyl *, phenoxy *, alkyl *, alkenylene * or heterocyclic group *, and R ³⁴ represents a bond or —S—. Formula for R ²⁴ above

Embedded image Is the expression

Embedded image Syn isomer represented by

Embedded image Or a mixture thereof.

In the above formula, a group represented by the formula [B] is preferably a group represented by the formula:

Embedded image [Wherein, R ²¹ ′ is an amino-protecting group or a compound represented by the formula R ^23- (CH
₂ ) n ₁ -CO- (wherein R ²³ represents a heterocyclic group *, n 1 represents 0
Represents an integer of 2 to 2),
R ²² ′ represents phenyl * or heterocyclic group *, respectively]
And the group represented by In the above formula, a preferable group represented by the formula [C] is a group represented by the formula:

Embedded image Wherein, R ²⁶ 'is a heterocyclic group * or phenyl *, R ^27'
Is hydrogen, alkyl * or a formula —R ²⁸ —R ²⁹ ′ (wherein R
²⁸ is as defined above, and R ²⁹ ′ is carboxy or an ester thereof. ) Represents each group. ] The group represented by this is mentioned.

In the above formula, a group represented by the formula [E] is preferably a group represented by the formula:

Embedded image [Wherein, R ³³ ′ represents a heterocyclic group *, and R ³⁴ has the same meaning as described above]. In particular, regarding the antibacterial action, the formula

Embedded image Wherein Q ⁷ represents an amino or a protected amino group, Q ⁸
Is an alkyl *, alkenyl, a group represented by the formula —CH ₂ COOQ ⁹ or a formula

Embedded image Represents a group represented by In the formula, COOQ ⁹ represents carboxyl or an ester thereof, and X represents CH or N, respectively. ] Is more preferable as the acyl of the acylated amino group of R ¹ .

In the above groups R ^{20 to} R ³⁴ , in the case of a “optionally substituted” group, an asterisk is added to the right of the group. For example, "alkyl which may have a substituent" is represented as "alkyl *". In this case, the number of substituents is not limited to one, and depending on the group to be substituted, two to several (preferably 2 to 4) identical or different substituents may be present. In the above groups, the alkyl group is preferably a C _1-6 alkyl group, and examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and ter.
t-butyl, n-pentyl, isopentyl, neopentyl, 2,2-dimethylpropyl, n-hexyl, isohexyl and the like. In the above groups, examples of the heterocyclic group in the optionally substituted heterocyclic group include the same as the above-mentioned heterocyclic group in the heterocyclic carbonyl group. In the above group, as the amino acid residue, for example, glycyl, alanyl, valyl, leucyl,
Isoleucyl, seryl, threonyl, cysteyl, cystyl, methionyl, α- or β-asparagyl, α-
Or γ-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl,
Tryptophanyl, prolyl and the like. In the above groups, examples of the amino-protecting group include the same as those described above. In the above groups, the alkenyl group is preferably a C _2-6 alkenyl group, and examples thereof include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, butadienyl, Methyl-1-propenyl, 2-methallyl, 3-methallyl, 2-methylallyl, 1,1-dimethylallyl, hexatrienyl, 1-pentenyl, 1-hexenyl and the like can be mentioned. In the above groups, the alkylene group is preferably a C _1-6 alkylene group, and examples thereof include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, and n.
-Pentylene, n-hexylene and the like. In the above groups, the alkenylene group is preferably a C _2-6 alkenylene group, and examples thereof include vinylene, propenylene, and butenylene.

In the above groups, the ester in the carboxyl group may be a C _1-6 alkyl ester (eg, methyl ester, ethyl ester, propyl ester, n-
Butyl ester, isobutyl ester, sec-butyl ester, tert-butyl ester, etc.). In the above groups, the alkoxy group is preferably a C _1-6 alkoxy group, and examples thereof include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy,
Examples include pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 2,2-dimethylpropyloxy, n-hexyloxy, and isohexyloxy. In the above groups, the alkanoyl group is preferably a C _1-6 alkanoyl group, and examples thereof include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, and hexanoyl. In the above group, a substituent in a heterocyclic group which may have a substituent, a substituent in a phenyl group which may have a substituent, a substituent in a thiazolyl group which may have a substituent, Examples of the substituent in the phenoxycarbonyl group which may have a substituent and the substituent in the phenoxy group which may have a substituent include, for example, (1) C _1-6 alkyl, (2) C _{1- 6} alkoxy, (3) C _2-6 alkenyl,
(4) C _6-10 aryl, (5) C _7-20 aralkyl, (6) mercapto, (7) C _1-6 alkylthio, (8) C _6-14 arylthio, (9) C _7-19 aralkylthio , (10) C _1-6 alkylsulfonyl, (11) C _6-10 arylsulfonyl, (12) C _7-20 aralkylsulfonyl, (13) trihalogeno C _1-6 alkyl, (14) hydroxy, (15) oxo , (16) Thioxo, (17)
Halogen, (18) nitro, (19) amino, (20) cyano, (21)
Carbamoyl, (22) carboxy, (23) C _1-6 alkanoyloxy, (24) C _1-6 alkanoyloxy, (25) C _1-6 alkanoylamino, (26) hydroxy C _1-6 alkyl, (27) carboxy -C _1-6 alkyl, (28) halogeno C _1-6 alkyl,
(29) Mono- or di-C _1-6 alkylamino C _1-6 alkyl, (30) pyridyl, (31) thienyl, (32) thiadiazolyl, (33) phenyl and the like. The substituent of the thiazolyl group which may have a substituent, in addition to those described above, include C _2-6 acylamino, said C _2-6
Acylamino has, as a substituent, 1-2 C _1-4 alkyl (eg, methyl, ethyl, propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, etc., C _1-4 alkoxy (eg, methoxy, ethoxy, n
-Propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), halogen, hydroxy, amino and the like. As the substituent in the heterocyclic group which may have a substituent,
The above-mentioned C _6-14 aryl has, as a substituent, 1-2 C _1-4 alkyl (examples are as described above), C _1-4 alkoxy (examples are as described above), halogen, nitro, amino and the like. May be provided.

In the above, examples of the substituent in the optionally substituted carbamoyl include, for example, sulfo, carbamoyl, sulfamoyl, amidino, C _1-4 alkyl (for example, salts formed with sodium or potassium). And the like). In the above,
Examples of the substituent in the sulfamoyl which may have a substituent include, for example, C _1-4 alkyl (the examples are the same as described above), amidino and the like. In the above, examples of the substituent in the alkyl which may have a substituent include halogen, hydroxy, cyano, trifluoromethyl and the like. In the above, as the substituent in the alkenyl optionally having a substituent,
For example, carboxy, cyano and the like can be mentioned. In the above, examples of the substituent in the alkanoyl which may have a substituent include halogen, hydroxy, cyano, trifluoromethyl and the like.

In the above acyl group, specific examples of the acyl group represented by the formula [A] include, for example, 3- (2,6
-Dichlorophenyl) -5-methylisoxazole-4
-Yl-carbonyl, 4-ethyl-2,3-dioxo-
1-piperazinocarbonyl and the like. In the acyl group described above, specific examples of the acyl group represented by the formula [B], for example, D- alanyl, benzyl N ^alpha - carbobenzoxy-gamma-D-glutamyl -D- alanyl,
D-phenylglycyl-D-alanyl, N-carbobenzoxy-D-alanyl, N-carbobenzoxy-D-phenylglycyl, D-alanyl-D-phenylglycyl, γ-D-glutamyl-D- Alanyl, 2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamide) -2-phenylacetyl, 2- (4-ethyl-2,3
-Dioxo-1-piperazinocarboxamide) -2- (4
-Sulfoxyphenyl) acetyl, N- (4-ethyl-
2,3-dioxo-1-piperazinocarbonyl) -D-alanyl, N- (4-ethyl-2,3-dithioxo-1-piperazinocarbonyl) -D-phenylglycyl, 2,2-
Bis- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) acetyl, 2- (2-amino-4-thiazolyl) -2- (4-ethyl-2,3-dioxo-1-pipe (Radinocarboxamido) acetyl, 2- (4-hydroxy-6-methylnicotinamide) -2-phenylacetyl, 2- (4-hydroxy-6-methylnicotinamide)
-2- (4-hydroxyphenyl) acetyl, 2- {5,
8-dihydro-2- (4-formyl-1-piperazinyl)
-5-oxopyrido [2,3-d] pyrimidine-6-carboxamide} -2-phenylacetyl, 2- (3,5-dioxo-1,2,4-triazine-6-carboxamide)
-2- (4-hydroxyphenyl) acetyl, 2- (3-
Furfuridenamino-2-oxoimidazolidin-1-
Carboxamide) -2-phenylacetyl, 2- (coumarin-3-carboxamide) -2-phenylacetyl, 2
-(4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxamide) -2-phenylacetyl, 2
-(4-hydroxy-7-trifluoromethylquinoline-3-carboxamide) -2-phenylacetyl, N-
[2- (2-amino-4-thiazolyl) acetyl] -D-
Phenylglycyl, 2- (6-bromo-1-ethyl-1,4-dihydro-4-oxothieno [2,3-b] pyridine-3-carboxamide) -2-phenylacetyl,
2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamide) -2-thienylacetyl, 2- (4-n-
Pentyl-2,3-dioxo-1-piperazinocarboxamide) -2-thienylacetyl, 2- (4-n-octyl-2,3-dioxo-1-piperazinocarboxamide)
-2-thienylacetyl, 2- (4-cyclohexyl-
2,3-dioxo-1-piperazinocarboxamide) -2
-Thienylacetyl, 2- [4- (2-phenylethyl)
-2,3-dioxo-1-piperazinocarboxamide]-
2-thienylacetyl, 2- (3-methylsulfonyl-
2-oxoimidazolidin-1-carboxamide) -2
-Phenylacetyl, 2- (3-furfuridenamino-
2-oxoimidazolidin-1-carboxamide) -2
-(4-hydroxyphenyl) acetyl, 2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamide) -2- (4-benzyloxyphenyl) acetyl,
-(4-ethyl-2,3-dioxo-1-piperazinocarboxamide) -2- (4-methoxyphenyl) acetyl,
2- (8-hydroxy1,5 naphthyridine-7-carboxamide) -2-phenylacetyl, 2- (2-amino-4
-Thiazolyl) -2-formamidoacetyl, 2- (2-
Amino-4-thiazolyl) -2-acetamidoacetyl and the like.

Specific examples of the acyl group represented by the formula [C] include, for example, N- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl] -D-alanyl,
-[2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl] -D-phenylglycyl, 2- (2-
Amino-4-thiazolyl) -2- [2- (2-amino-4
-Thiazolyl) -2-methoxyiminoacetamide] -acetyl, 2- (2-chloroacetamido-4-thiazolyl)-
2-methoxyiminoacetyl, 2- (2-amino-4-
Thiazolyl) -2-methoxyiminoacetyl, 2- (2-
Amino-4-thiazolyl) -2-ethoxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-propoxyiminoacetyl, 2- (2-amino-4-thiazolyl)
-2-butoxyiminoacetyl, 2- (2-amino-4
-Thiazolyl) -2-benzyloxyiminoacetyl,
2- (2-amino-4-thiazolyl) -2-allyloxyiminoacetyl, 2- (2-amino-4-thiazolyl)-
2-[(1-methyl-1-carbonylethyl) oxyimino] acetyl, 2- (2-amino-4-thiazolyl) -2
-[(1-methyl-1-methoxycarboxyethyl) oxyimino] acetyl, 2- (2-amino-4-thiazolyl) -2-carboxymethyloxyiminoacetyl,
-(2-amino-4-thiazolyl) -2-carboxyvinyloxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-carboxyethyloxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-methoxycarbonylethyloxyiminoacetyl, 2- (2-amino-5-chloro-4-thiazolyl) -2-methoxyiminoacetyl, 2- (2-amino-5-bromo-4-thiazolyl) -2- Methoxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-oxyiminoacetyl,
2-thienyl-2-methoxyiminoacetyl, 2-furyl-2-methoxyiminoacetyl, 2- (1,2,4-thiadiazol-3-yl) -2-methoxyiminoacetyl, 2- (5-amino-1 , 2,4-thiadiazole-3
-Yl) -2-methoxyiminoacetyl, 2- (5-amino-1,2,4-thiadiazol-3-yl) -2-fluoromethoxyiminoacetyl, 2- (5-amino-1,
2,4-thiadiazol-3-yl) -2-fluoroethoxyiminoacetyl, 2- (1,2,4-thiadiazol-5-yl) -2-methoxyiminoacetyl, 2- (1,
3,4-thiadiazolyl) -2-methoxyiminoacetyl, 2- (4-hydroxyphenyl) -2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl, 2-phenyl-2-oxyiminoacetyl, 2-
[4- (γ-D-glutamyloxy) phenyl] -2-oxyiminoacetyl, 2- [4- (3-amino-3-carboxypropoxy) phenyl] -2-oxyiminoacetyl and the like.

Specific examples of the acyl group represented by the formula [D] include, for example, α-sulfophenylacetyl, α-hydroxyphenylacetyl, α-ureidophenylacetyl, α-sulfoureidophenylacetyl, α-sulfamoyl Phenylacetyl, α-phenoxycarbonylphenylacetyl, α- (p-tolyloxycarbonyl) phenylacetyl, α-formyloxyphenylacetyl and the like. Specific examples of the acyl group represented by the formula [E] include, for example, cyanoacetyl, phenylacetyl, phenoxyacetyl, trifluoromethylthioacetyl, cyanomethylthioacetyl, 1H-tetrazolyl-1-acetyl, thienylacetyl,
(2-amino-4-thiazolyl) acetyl, 4-pyridylthioacetyl, 2-thienylthioacetyl, 3,5-dichloro-1,4-dihydro-4-oxopyridine-1-
Acetyl, β-carboxyvinylthioacetyl, 2-
(2-aminomethylphenyl) acetyl and the like. The amino group and / or the carboxyl group and / or the hydroxyl group in the above acyl group include those having a protecting group. Examples of the amino-protecting group include those similar to the aforementioned “amino-protecting group”.
As the protective group of the carboxyl group and hydroxyl group, and those described in the R ^2.

As the carboxyl-protecting group represented by R ² , the carboxyl-protecting group usually used in the field of synthetic organic chemistry, particularly used in the field of β-lactam antibiotics such as cephalosporin Is used. Examples of such a protecting group include an optionally substituted C _1-6 alkyl group, C _2-6 alkenyl group, C _6-10 aryl group and C _7-20 aralkyl group. Examples of such a substituent of the C _1-6 alkyl group, C _2-6 alkenyl group, C _6-10 aryl group or C _7-20 aralkyl group include hydroxyl group, nitro group, halogen, C _1-6 alkoxy group. Group, C _1-10 alkanoyloxy group, C _3-10 cycloalkyl-carbonyloxy group, C _6-10 aryl-carbonyloxy group, C _1-10 alkoxy-carbonyloxy group, C _3-10 cycloalkyloxy-carbonyl An oxy group, a C _6-10 aryl-carbonyloxy group, a tri (C
_1-6 alkyl) silyl group (eg, trimethylsilyl, tert
-Butyldimethylsilyl), a C _1-6 alkylthio group and the like. The number of such substituents is preferably 1 to 3, and in the case of a plurality of substituents, they may be the same or different. R ² is preferably an optionally substituted C _7-20 aralkyl group, particularly preferably benzhydryl, methoxybenzyl and the like.

In the above formula, examples of the group via a sulfur atom represented by R ⁴ include a group represented by the formula —S (O) n—R ⁵ (wherein
n is an integer of 0 to 2, and R ⁵ is a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent. Groups.
Examples of the hydrocarbon group in the optionally substituted hydrocarbon group represented by R ⁵ include (1) C _1-15
Alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pendadecyl, etc., (2) C _3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl) , Cyclooctyl, cyclononyl, etc.), (3) _C2-10 alkenyl group (eg, vinyl, allyl, 1-butenyl, 2-butenyl,
Butadienyl, isopropenyl, 2-methylallyl, hexatrienyl, 3-octenyl, etc., (4) C _2-10 alkynyl group (eg, ethynyl, propargyl, 2-propynyl, isopropynyl, 2-butynyl, 3-hexynyl, etc.) ), (5) _C3-10 cycloalkenyl groups (eg, cyclopropenyl, cyclopentenyl, cyclohexenyl),
(6) C _6-14 aryl group (eg, phenyl, naphthyl, anthryl, phenanthryl, acenaphthyl, anthracenyl, etc.), (7) C _7-19 aralkyl group (eg, benzyl, phenethyl, benzhydryl, trityl) and the like. .

The number of the hydrocarbon groups is 1 to 6, preferably 1
May have up to 3 substituents, and examples of the substituent include, for example, (1) halogen (eg, fluorine, chlorine, bromine, iodine), (2) nitro, (3) nitroso, (4) hydroxy, (5) oxo, (6) thioxo, (7) sulfo, (8) cyano,
(9) azide, (10) carbamoyl, (11) N-monosubstituted carbamoyl group (eg, C _1-6 alkylcarbamoyl group such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl and the like), (12) N, N
-Disubstituted carbamoyl groups (eg, dimethylcarbamoyl,
An N, N-disubstituted carbamoyl group substituted with a C _1-6 alkyl group such as diethylcarbamoyl), (13) a sulfamoyl group, and (14) an N-monosubstituted sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl) N-alkylsulfamoyl groups having a C _1-6 alkyl group such as famoyl and propylsulfamoyl groups, and (15) N, N-disubstituted sulfamoyl groups (eg, dimethylsulfamoyl, diethylsulfamoyl) N substituted with a C _1-6 alkyl group such as moyl,
N-disubstituted sulfamoyl group, etc.), (16) carboxyl group, (17) C _1-4 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, etc.), (18) C _1-6 alkoxy Groups (eg, methoxy, ethoxy, n-propoxy, isopropoxy, n-
Butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., (19) C _6-16 aryloxy group (eg, phenyloxy, naphthyloxy, etc.), (20) C _2-4 alkenyloxy group (eg, vinyloxy, Allyloxy),
(21) cycloalkyloxy group (eg, C _3-7 aralkyloxy group such as cyclopropyloxy, _{cycloethyloxy} ), (22) aralkyloxy group (eg, C _7-13 aralkyloxy group such as benzyloxy) , (23) C _1-3 alkylenedioxy (e.g., methylenedioxy, ethylenedioxy, propylenedioxy, etc.), (24) mercapto group, (25) C _1-6 alkylthio group (e.g., methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, etc.), (26) aralkylthio group (eg, C _7-13 aralkylthio group such as benzylthio), (27) arylthio group (eg, phenylthio, naphthylthio) etc.), (28) C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, propyl-sulfinyl, a butylsulfinyl ), (29) C
_1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), (30) Formula -S (O) t-R (where t is 0 to 2)
And R 1 represents amino. ), A group represented by (31)
Amino, (32) C _1-6 acylamino (eg, formylamino, acetylamino, propionylamino, etc.), (33)
Mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, dimethylamino, diethylamino, etc.), (34) _C1-6 acyl (eg, , Formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, etc.), (35) C _6-12 aryl-carbonyl (eg, benzoyl etc.), (36) heterocyclic group [eg, from nitrogen atom, oxygen atom and sulfur atom 5 to 10 membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected (eg, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,
Triazolyl, tetrazolyl, pyrazolyl, pyridyl,
Pyrimidyl, pyridazinyl, quinolyl, isoquinolyl,
A 3- to 9-membered non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur (eg, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydro Furyl, thiolanyl, piperidyl, tetrahydropyranyl, oxazolidino, morpholinyl, thiomorpholinyl, thiazolidino, piperazinyl, hexamethylimino, etc.)]. In addition, when a carbon atom is substituted by an oxo group, it becomes a group represented by -CO-.

The above-mentioned substituents of the hydrocarbon group may further have 1 to 3 substituents, more preferably 1 to 2 substituents. (1) hydroxy, (2) amino, (3) C _1-4 alkyl group (eg, methyl, ethyl, n-propyl, isopropyl,
Butyl, isobutyl, sec-butyl, tert-butyl),
(4) halogen (eg, fluorine, chlorine, bromine, iodine), (5)
C _1-4 alkylthio (eg, methylthio, ethylthio, n
-Propylthio, isopropylthio, n-butylthio,
tert-butylthio, etc.), (6) C _1-4 alkoxy (eg, methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, sec-butoxy, tert-
Butoxy).

The heterocyclic group in the optionally substituted heterocyclic group is, for example, a 5- to 8-membered heterocyclic group containing 1 to 4 heteroatoms of oxygen, sulfur or nitrogen, or a condensation thereof. And heterocyclic groups. Examples of such a heterocyclic group include (1) 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-oxazolyl, 2-, 4- Or 5-thiazolyl, 3-, 4- or 5-pyrazolyl,
2-, 4- or 5-imidazolyl, 3-, 4- or 5
-Isoxazolyl, 3-, 4- or 5-isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl),
1,3,4-oxadiazolyl, 3- or 5- (1,2,
4-thiadiazolyl), 1,3,4-thiadiazolyl, 4
-Or 5- (1,2,3-thiadiazolyl), 1,2,5-
Thiadiazolyl, 1,2,3-triazolyl, 1,2,4-
A 5-membered heterocyclic group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon such as triazolyl, 1H- or 2H-tetrazolyl, (2)
For example, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, oxoimidazinyl, triazinyl, pyrrolidinyl, piperidinyl, pyranyl, Thiopyranyl, 1,4-oxazinyl, 1,4-
Selected from oxygen, sulfur, nitrogen and the like in addition to carbon atoms such as thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, 3- or 4-pyridazinyl, etc. 6-membered heterocyclic group containing 1 to 4 heteroatoms,
(3) For example, benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-b] pyridazinyl,
Triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl,
Acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, formula

Embedded image [In the formula, ring B represents a 6-membered aromatic heterocyclic ring in which a hetero atom is one or two nitrogen atoms. 2) containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to the carbon atom of the imidazolyl condensed ring group represented by
And a cyclic or tricyclic fused heterocyclic group.

Preferred examples of the heterocyclic group in the optionally substituted heterocyclic group include, for example, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
1,4-thiazinyl, imidazolinyl, formula

Embedded image

[0031]

Embedded image [The symbols in the formula are as defined above].

When the heterocyclic group has a substituent, examples of the substituent include (1) C _1-6 alkyl (eg, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), (2) C _2-6 alkenyl (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, etc.), (3) C _2-6 alkynyl (eg, ethynyl, 1-propynyl, propargyl, etc.), (4) C _3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (5) C _5-7 cycloalkenyl ( Eg, cyclopentenyl, cyclohexenyl, etc.), (6)
C _7-11 aralkyl (eg, benzyl, α-methylbenzyl, phenethyl, etc.), (7) C _6-14 aryl (eg, phenyl, naphthyl, etc.), (8) C _1-6 alkoxy (eg, methoxy, ethoxy) , Propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, etc.), (9) C _6-14 aryloxy (eg, phenoxy etc.), (10) C _1-6 alkanoyl ( For example, formyl, acetyl, propionyl, n-butyryl, iso-butyryl, etc.), (1
1) C _6-14 aryl-carbonyl (eg, benzoyl etc.),
(12) C _1-6 alkanoyloxy (eg, formyloxy,
Acetyloxy, propionyloxy, n-butyryloxy, iso-butyryloxy, etc.), (13) C _6-14 aryl-carbonyloxy (eg, benzoyloxy etc.), (14) carboxyl, (15) C _1-6 alkoxy-carbonyl (Eg, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, etc.), (16) carbamoyl group, (17) N-mono-C
_1-4 alkylcarbamoyl (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl,
N-isopropylcarbamoyl, N-butylcarbamoyl, etc.), (18) N, N-di-C _1-4 alkylcarbamoyl (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-di) Propylcarbamoyl, N, N-dibutylcarbamoyl, etc.), (19) cyclic aminocarbonyl (eg, 1-
Aziridinylcarbonyl, 1-azetidinylcarbonyl,
1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, morpholinocarbonyl, etc.), (20) halogen (eg, fluorine, chlorine, bromine,
Iodine), (21) mono-, di- or tri-halogeno-C
_1-4 alkyl (eg, chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl, etc.), (22) oxo group, (23) amidino, (24) imino group, (25) amino, (26)
Mono- or di-C _1-4 alkylamino (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino,
Dipropylamino, diisopropylamino, dibutylamino, etc.),

(27) A 3- to 6-membered cyclic amino group which may contain 1 to 3 hetero atoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to a carbon atom and one nitrogen atom ( Examples: aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, vilazolyl, imidazolidinyl, piperidino, morpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, etc.), (28) _C1-6 Alkanoylamino (eg, formamide, acetamide, trifluoroacetamide, propionamide, n-butylamide, isobutylamide, etc.), (29) benzamide, (30) carbamoylamino, (31) NC _1-4 alkylcarbamoylamino (Example: N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylua Bruno, N- isopropylcarbamoyl amino, N- butylcarbamoyl amino etc.), (32) N, N- di -C _1-4 alkylcarbamoyl amino (e.g., N, N- dimethylcarbamoyl-amino, N, N- diethylcarbamoyl amino , N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, etc.), (33)
C _1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), (34) hydroxyl, (35) epoxy (—O—), (36) nitro, (37) cyano, (38) mercapto, (39) sulfo, (40) sulfino, (41) phosphono, (42)
Dihydroxyboryl, (43) Sulfamoyl, (44) C
_1-6 alkylsulfamoyl (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.), (45) Di C _1-6 alkylsulfamoyl (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.), (46) C _1-6 alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, n- butylthio, sec- butylthio, tert- butylthio, etc.), (47) phenylthio, (48) C _1-6 alkylsulfinyl (e.g. , methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl etc.), (49) phenylsulfinyl, (50) C _1-6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, Ropirusuruhoniru, butylsulfonyl, etc.), (51)
Phenylsulfonyl and the like. The number of substitutions is 1 to 6, preferably 1 to 3, more preferably 1
Or two. The substituent further has a substituent of 1 to
It may have three, more preferably one or two. Examples of the further substituted group include (1) C _1-4 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, etc.), (2) trifluoromethyl, (3) C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butyl) Butoxy, tert-
Butoxy), (4) halogen (eg, fluorine, chlorine, bromine, iodine), (5) nitro, (5) sulfamoyl, (6) C
_1-4 alkoxy-carbonyl, (7) C _1-4 alkylthio (eg, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio, sec-butylthio, tert-butylthio, etc.) and the like.

The imidazole ring and / or ring B in the above imidazolyl fused ring group is preferably 1 or 2
May have one or more substituents. Such substituents include, for example, hydroxyl, hydroxy C _1-6 alkyl, C _1-6
Alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group,
A C _3-10 cycloalkyl group, a C _5-6 cycloalkenyl group,
C _3-10 cycloalkyl C _1-6 alkyl group, C _6-10 aryl group, C _7-12 aralkyl group, heterocyclic group, C _1-6 alkoxy group, C _1-6 alkoxy-C _1-6 alkyl group , Amino C
_1-6 alkoxy group, C _3-10 cycloalkyloxy group, C
_6-10 aryloxy group, C _7-19 aralkyloxy group, mercapto group, mercapto C _1-6 alkyl group, sulfo group,
Sulfo C _1-6 alkyl group, C _1-6 alkylthio group, C _{1-6
Alkylthio} C _1-6 alkyl group, C _3-10 cycloalkylthio group, C _6-10 arylthio group, C _7-19 aralkylthio group, amino C _1-6 alkylthio group, amino group, amino C
_1-6 alkyl group, mono C _1-6 alkylamino group, di C _1-6
Alkylamino group, mono C _1-6 alkylamino C _1-6 alkyl group, di C _1-6 alkylamino C _1-6 alkyl group, C
_{3-1 0} cycloalkyl group, C _6-10 arylamino group, C _7-19 aralkylamino group, cyclic amino group, cyclic amino C _1-6 alkyl group, cyclic amino C _1-6 alkylamino group, a carbamoyl group , A C _1-6 alkylcarbamoyl group,
Azide group, nitro group, halogen atom, halogeno C _1-6 alkyl group, cyano group, cyano C _1-6 alkyl group, carboxyl group, carboxy C _1-6 alkyl group, C _1-10 alkoxy-carbonyl group, C _{1 -10} alkoxy-carbonyl C
_1-6 alkyl group, C _6-10 aryloxy-carbonyl group, C _7-19 aralkyloxy-carbonyl group, C _6-10 aryl-acyl group, C _1-6 alkanoyl group, C _2-6 alkanoyl C _{1- 6} alkyl group, C _3-5 alkenoyl group, C _6-10
Aryl-acyloxy group, C _2-6 alkanoyloxy group, C _2-6 alkanoyloxy C _1-6 alkyl group, C _3-5
Alkenoyloxy group, carbamoyl C _1-6 alkyl group, thiocarbamoyl group, carbamoyloxy group, carbamoyloxy C _1-6 alkyl group, C _1-6 alkanoylamino group, C _6-10 aryl-acylamino group, sulfonamide group Carboxyamino group, _C1-10 alkoxy-carboxamide group, _C6-10 aryloxy-carboxamide group, _C7-19 aralkyloxy-carboxamide group and the like. The group represented by R ^5, 4-pyridyl, imidazo [1,2-b] pyridazin-6-yl group, and the like are particularly preferred.

Specific examples of each group unless otherwise specified in the present specification are shown below. Halogen atom: fluorine, chlorine, bromine, iodine, etc .; C _1-6 alkyl group: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, 2,2-dimethylpropyl, n- hexyl, isohexyl; C _2-6 alkenyl group: vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3
-Butenyl, 2-methallyl, 1,1-dimethylallyl and the like; C _2-6 alkynyl group: ethynyl, 1-propynyl, 2-
C _3-10 cycloalkyl group: adamantyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl; C _5-6 cycloalkenyl group : Cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc .; C _6-10 aryl group: phenyl, naphthyl, etc .; C _7-20 aralkyl group: benzyl, 1-phenylethyl,
2-phenylethyl, phenylpropyl, naphthylmethyl, benzhydryl and the like;

Halogeno C _1-6 alkyl group: fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoro Ethyl, 2-chloroethyl, 2,2-dichloroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl and the like; cyano C _1-6 alkyl group: cyanomethyl, 2-cyanoethyl and the like; carboxy C _{1- 6} alkyl groups: carboxymethyl, 1-
Carboxyethyl, 2-carboxyethyl, etc .; sulfo C _1-6 alkyl group: sulfomethyl, 2-sulfoethyl, etc .; hydroxy C _1-6 alkyl group: hydroxymethyl, 1-
Hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like; mercapto C _1-6 alkyl group: mercaptomethyl, 1-
Mercaptoethyl, 2-mercaptoethyl, etc .; amino C _1-6 alkyl group: aminomethyl, 2-aminoethyl, 3-aminopropyl, etc .; mono C _1-6 alkylamino C _1-6 alkyl group: methylaminomethyl, ethyl Aminomethyl, 2- (N-methylamino) ethyl, 3- (N-methylamino) propyl and the like; di C _1-6 alkylamino C _1-6 alkyl group: N, N-dimethylaminomethyl, N, N- Diethylaminomethyl, 2
-(N, N-dimethylamino) ethyl, 2- (N, N-diethylamino) ethyl, 3- (N, N-dimethylamino) propyl and the like; Cyclic amino C _1-6 alkyl group: pyrrolidinomethyl, piperidinomethyl, Piperazinomethyl, morpholinomethyl,
2- (morpholino) ethyl and the like; C _1-6 alkoxy C _1-6 alkyl group: methoxymethyl, ethoxymethyl, 2-methoxyethyl and the like; C _1-6 alkylthio C _1-6 alkyl group: methylthiomethyl, 2-methylthio Ethyl and the like; C _3-10 cycloalkyl C _1-6 alkyl group: cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclodecylmethyl and the like; C _2-6 alkanoyl C _{1 -6} alkyl group: acetylmethyl,
1-acetylethyl, 2-acetylethyl, etc .; C _2-6 alkanoyloxy C _1-6 alkyl group: acetoxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, etc .; C _1-10 alkoxy-carbonyl C _1-6 alkyl Groups: methoxycarbonylmethyl, ethoxycarbonylmethyl, te
rt-butoxycarbonylmethyl and the like; carbamoyl C _1-6 alkyl group: carbamoylmethyl,
2-carbamoylethyl and the like; carbamoyloxy C _1-6 alkyl group: carbamoyloxymethyl, 1-carbamoyloxyethyl and the like;

C _1-10 alkoxy group: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, 2,2-dimethylpropyloxy, hexyloxy, octyloxy, decyloxy like; C _1-6 alkoxy group: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-
Butoxy, pentyloxy, 2,2-dimethylpropyloxy, hexyloxy, etc .; C _3-10 cycloalkyloxy group: cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclodecyl C _6-10 aryloxy group: phenoxy, naphthyloxy, etc .; C _7-19 aralkyloxy group: benzyloxy, 1-phenylethyloxy, 2-phenylethyloxy, benzhydryloxy, etc .; amino C _{1- 6} alkoxy groups: aminomethoxy, 2-aminoethoxy, 3-aminopropoxy, etc .; C _1-6 alkylthio groups: methylthio, ethylthio, propylthio, butylthio, isobutylthio, tert-butylthio, pentylthio, 2,2-dimethylpropylthio Oh,
Hexylthio, etc.; C _3-10 cycloalkylthio group: cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, cyclooctyl thio, such as cyclo decyl thio; C _6-10 arylthio group: phenylthio, etc. naphthylthio; C _7-19 aralkylthio group: benzylthio, phenylethylthio, Benz hydride Lucio, such as tritylthio; amino C _1-6 alkylthio group: amino methylthio, 2-
Aminoethylthio, 3-aminopropylthio, etc .; C _1-6 alkylsulfonyl group: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, te
rt-butylsulfonyl, pentylsulfonyl, 2,2-
Dimethylpropylsulfonyl, hexylsulfonyl and the like;

Mono C _1-6 alkylamino group: methylamino, ethylamino, n-propylamino, n-butylamino, etc .; _diC1-6 alkylamino group: dimethylamino, diethylamino, methylethylamino, di- ( tri-C _1-6 alkylammonium group: trimethylammonium, etc .; C _3-10 cycloalkylamino group: cyclopropylamino, cyclopentylamino, cyclohexylamino, etc .; C _6-10 arylamino group: anilino, N-methylanilino, etc .; _C7-19 aralkylamino group: benzylamino, 1-phenylethylamino, 2-phenylethylamino, benzhydrylamino, etc .; cyclic amino group: pyrrolidino, piperidino , Piperazino,
Morpholino, 1-pyrrolyl, etc .; cyclic amino C _1-6 alkylamino group: pyrrolidinoethylamino, piperidinoethylamino, piperazinoethylamino, morpholinoethylamino, etc .; C _1-6 alkanoylamino group: acetamide, propion Amide, butyroamide, valeroamide, pivaloamide and the like; C _6-10 aryl-carbonylamino group: benzamide,
Naphthoylamide, phthalimide and the like; C _6-10 aryl-C _1-6 alkanoylamino group: phenylacetylamino and the like;

C _1-10 alkanoyl group: formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, succinyl, glutaryl, hexanoyl, etc .; C _1-6 alkanoyl group: formyl, acetyl, propionyl, butyryl, valeryl , Pivaloyl, succinyl,
Glutaryl and the like; C _2-6 alkanoyloxy group: acetoxy, propionyloxy, butyryloxy, valeryloxy, pivaloyloxy and the like; C _3-5 alkenoyl group: acryloyl, crotonoyl,
C _3-5 alkenoyloxy group: acryloyloxy, crotonoyloxy, maleoyloxy, etc .; C _6-10 aryl-carbonyl group: benzoyl, naphthoyl, phthaloyl, phenylacetyl, etc .; C _6-10 aryl-carbonyl Oxy group: benzoyloxy, naphthoyloxy, phenylacetoxy, etc .;

C _3-10 cycloalkyl-carbonyl group: cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
_C5-6 cycloalkenyl-carbonyl group: cyclopentenylcarbonyl, cyclopentadienylcarbonyl, cyclohexenylcarbonyl, cyclohexadienylcarbonyl, etc .; _C7-19 aralkyl-carbonyl; cycloheptylcarbonyl, cyclooctylcarbonyl, cyclodecylcarbonyl, etc. Group: phenylacetyl,
Phenylpropionyl, α, α-diphenylacetyl,
α, α, α-triphenylacetyl, etc .; C _6-10 aryl-C _1-6 alkanoyl group: phenylacetyl, etc .; C _6-10 aryl-C _1-6 alkanoyloxy group: phenylacetyloxy, etc .; C _{1- 6} alkylsulfonyl groups: methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, t
_C6-10 arylsulfonyl group: phenylsulfonyl and the like;

C _1-10 alkoxy-carbonyl group: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, 2,2-dimethylpropyloxycarbonyl, Hexyloxycarbonyl, heptyloxycarbonyl, decyloxycarbonyl and the like; C _1-10 alkoxy-carbonyloxy group: methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy,
Butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxycarbonyloxy, 2,2-dimethylpropyloxycarbonyloxy, hexyloxycarbonyloxy,
Heptyloxycarbonyloxy, decyloxycarbonyloxy and the like; C _3-10 cycloalkyloxy-carbonyl group: cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, cycloheptyloxycarbonyl,
Cyclooctyloxycarbonyl, cyclodecyloxycarbonyl, etc .; _C3-10 cycloalkyloxy-carbonyloxy group: cyclopropyloxycarbonyloxy, cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy, cyclohexyloxycarbonyloxy, cycloheptyloxycarbonyloxy , Cyclooctyloxycarbonyloxy, cyclodecyloxycarbonyloxy, etc .; _C3-10 cycloalkyloxy-carbonyloxy group: cyclopropyloxycarbonyloxy, cyclobutyloxycarbonyloxy, cyclopentyloxycarbonyloxy, cyclohexyloxycarbonyloxy, cycloheptyl Oxycarbonyloxy, cyclooctyloxycarbonyloxy, cyclodecyl Such alkoxycarbonyloxy; C _5-10 bridged cyclic hydrocarbon-oxy - group: norbornyloxy oxycarbonyl, such as adamantyloxycarbonyl; C _2-10 alkenyloxy - group: such as allyloxycarbonyl; C _6-10 aryl Oxy-carbonyl group: phenoxycarbonyl, naphthyloxycarbonyl, etc.

C _7-19 aralkyloxy-carbonyl group:
Benzyloxycarbonyl, benzhydryloxycarbonyl, etc .; amino C _1-6 alkyl-carbonyl group: 2-aminoethylcarbonyl, 3-aminopropylcarbonyl, etc .; mono C _1-6 alkylamino C _1-6 alkyl-carbonyl group: Methylaminomethylcarbonyl, 2-ethylaminoethylcarbonyl and the like; di C _1-6 alkylamino C _1-6 alkyl-carbonyl group:
Dimethylaminomethylcarbonyl, diethylaminomethylcarbonyl, etc .; cyclic aminoalkylcarbonyl group: imidazolinomethyl, pyrazolinoethyl, etc .; C _1-10 alkoxy-carboxamide group: methoxycarboxamide (CH ₃ OCONH-), ethoxycarboxamide, tert-butoxycarboxamide; C _6-10 aryloxy - carboxamide group: phenoxy carboxamide (C ₆ H ₅ OCONH-), etc.; C _7-10 aralkyloxy - carboxamide group: benzyloxy carboxamide _{(OCONH- C 6 H 5 CH 2} ),
Such Benz benzhydryl oxy carboxamide; C _1-6 alkyl ureido group: methylureido, ethylureido, n- propyl ureido like; sulfonamido group: methanesulfonyl, etc. ethanesulfonyl.

Hereinafter, the method of the present invention will be described in detail. 1. Compound (II) or a salt thereof and Tris which are the method of the present invention
In the method for producing compound (I) or a salt thereof by reacting with (dimethylamino) methane, tris (dimethylamino) methane is used in an amount of about 1 to 5 equivalents, preferably about 2 to 1 mol of compound (II). React ~ 3 equivalents. In the reaction, a solvent usually used in the production of a cephalosporin derivative is used, and examples thereof include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.) and halogenated hydrocarbons (eg, Carbon chloride, 1,2-dichloroethane, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane, etc.),
Ethers (eg, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.), amide solvents (N, N-dimethylformamide, N, N-dimethylacetamide, N-
Examples thereof include methylpyrrolidone, hexamethylphosphortriamide, etc.), esters (eg, ethyl acetate, etc.), and basic solvents (eg, pyridine, etc.). Among them, amide solvents are preferable, and N-methyl is particularly preferable. Pyrrolidone is preferred. The amount of the solvent used is about 5 to 30 times, preferably about 10 to 20 times the amount of the compound (II).
This reaction is carried out at a reaction temperature of about 0 to 80 ° C, preferably about 20 to 80 ° C.
The reaction is carried out at 50 ° C. for about 1 to 12 hours, preferably for about 4 to 5 hours. After completion of the reaction, the obtained compound (I) is subjected to the next reaction without isolation, or
If necessary, isolation and purification can be performed by known means, for example, concentration, concentration under reduced pressure, distillation, fractionation, solvent extraction, liquid conversion, transfer, chromatography, crystallization, recrystallization, and the like. .

2. The obtained compound (I) is subjected to hydrolysis to produce a compound (III). The hydrolysis reaction is performed by reacting compound (I) with an acid. The acid generally includes an organic acid (eg, formic acid, acetic acid, etc.) or a mineral acid (eg, sulfuric acid, hydrochloric acid, phosphoric acid, etc.). In the reaction, a solvent usually used in the production of a cephalosporin derivative is used. Examples of the solvent include alcohols (eg, methanol, ethanol, n-propanol, isopropanol, n-butanol, 3-pentanol, etc.). , Aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, carbon tetrachloride, 1,2-dichloroethane, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, Heptane, cyclohexane, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), ketones (eg, acetone, methyl ethyl ketone, etc.), nitriles (eg, acetonitrile, etc.), sulfoxides (eg, dimethyl sulfoxide) Amide solvents (N, N-di) Examples thereof include tylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphortriamide, etc., esters (eg, ethyl acetate, etc.), and basic solvents (eg, pyridine, etc.). , Nitriles, especially acetonitrile are preferred. This reaction is carried out at a reaction temperature of about 20 to 50 ° C., preferably about 30 to 40 ° C., for about 1 to 10 hours, preferably about 2 to 10 hours.
The reaction is carried out for up to 4 hours. After the reaction,
The obtained compound (III) is subjected to the next reaction without isolation, or, if necessary, a known means, for example, concentration, concentration under reduced pressure, distillation, fractionation, solvent extraction, liquid conversion, By phase transfer, chromatography, crystallization, recrystallization, etc.
It can be isolated and purified.

3. Compound (III) thus obtained
Alternatively, a compound (IV) or a salt thereof is produced by reacting a disulfide compound with a salt thereof in the presence of a phosphorus compound.
The disulfide compound has the formula R ⁵ —S—S—R ⁵ (wherein
R ⁵ is as defined above). As the phosphorus compound used in this reaction, 3
Monovalent phosphorus compounds are preferred. Examples of the phosphorus compound include compounds represented by the formula (R ³ ) ₃ P (wherein R ³ represents a hydrocarbon group which may have a substituent).
Examples of the hydrocarbon group which may have a substituent include the same as the above-mentioned hydrocarbon group which may have a substituent represented by R ⁵ . The hydrocarbon group represented by R ⁵ is preferably an alkyl group, especially a C _1-10 alkyl group, and a C _1-4 alkyl group (eg, methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl) are more preferred, especially n-
Butyl is preferred. Examples of phosphorus compounds represented by the formula (R ^{₃₎ 3} P, for example, trimethyl phosphine, triethyl phosphine, tri -n- propyl phosphine, triisopropyl phosphine, tri -n- butyl phosphine, tri - n-hexylphosphine, tri-n-octylphosphine and the like.

In the production method of the present invention, the compound (II
About 1 to 5 equivalents, preferably about 1.5 to 2 equivalents, of a disulfide compound is used per 1 mol of I) or a salt thereof. The phosphorus compound is used in an amount of about 1 to 1.5 equivalents, preferably about 1.0 equivalent, per 1 mol of compound (III) or a salt thereof.
1-1.2 equivalents are used. The reaction is generally performed in a solvent, and a solvent that does not inhibit the reaction is appropriately selected.
Examples of such a solvent include ethers (eg, dioxane, tetrahydrofuran, diethyl ether, te
rt-butyl methyl ether, diisopropyl ether,
Ethylene glycol-dimethyl ether, etc.), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride, trichlene, 1,2-dichloroethane, etc.) , Hydrocarbons (eg, n-hexane, benzene, toluene, etc.), amides (eg, formamide,
N, N-dimethylformamide, N, N-dimethylacetamide, etc.), ketones (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), nitriles (eg, acetonitrile, propionitrile, etc.), dimethyl sulfoxide, Sulfolane, hexamethylphosphoramide and the like are used alone or as a mixed solvent. Among these solvents, amides are preferable, and among them, N-methylpyrrolidone is most preferable.
In order to make this reaction proceed efficiently, a small amount of water is preferably present. The amount of water added is 0.5 to 1
Equivalent is preferable, and 0.3 to 0.4 equivalent is more preferable. The reaction is preferably performed under light shielding and under a nitrogen stream. The reaction temperature is about -40C to -10C, preferably about -2C.
It is preferable to carry out the reaction for about 30 minutes to 2 hours, preferably 1 to 1.5 hours, while maintaining the temperature at 5 ° C to -15 ° C. After completion of the reaction, the obtained compound (IV) is subjected to the next reaction without isolation, or if necessary, a known means, for example,
Concentration, vacuum concentration, distillation, fractionation, solvent extraction, liquid conversion,
It can be isolated and purified by phase transfer, chromatography, crystallization, recrystallization and the like.

The salts of the compounds in the production method of the present invention include inorganic base salts, ammonium salts, organic base salts, inorganic acid addition salts, organic acid addition salts and the like. Inorganic base salts include alkali metal salts (eg, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, calcium salt, etc.), and organic base salts include, for example, trimethylamine salt, triethylamine salt, tert-butyldimethylamine salt. , Dibenzylmethylamine salt, benzyldimethylamine salt, N, N-dimethylaniline salt, pyridine salt, quinoline salt and the like, and examples of inorganic acid addition salts include hydrochloride, hydrobromide, sulfate, nitrate, phosphorus Acid salts and the like, and organic acid addition salts include formate, acetate, trifluoroacetate, methanesulfonate and p-toluenesulfonate.

The starting compound (II) used in the method of the present invention can be produced, for example, by the method described in JP-A-55-154981, or a method analogous thereto.

In the compound (IV) thus obtained, a compound or a salt thereof in which R ¹ is a protected amino group can be produced, for example, by preparing a cephalosporin derivative described in JP-A-55-154981. And can also be used as a starting compound for PCT International Publication WO96 / 237.
No. 98, PCT International Publication WO96 / 38451, and can be used as a synthetic raw material for producing a cephalosporin derivative useful as an antibacterial agent.

That is, for example, the compound (IV) or a salt thereof, wherein R ¹ is a protected amino group, obtained by the production method of the present invention,

Embedded image [Wherein, R ¹³ represents an optionally substituted hydrocarbon group;
¹⁴ represents an amino group which may be protected, R ¹⁵ represents a hydrocarbon group which may be substituted, and other symbols have the same meanings as described above. ], The compound (V) or a salt thereof can be derived. In the formula, examples of the optionally substituted hydrocarbon group represented by R ¹³ and R ¹⁵ include the above R ³ ,
Examples include the same groups as the optionally substituted hydrocarbon group represented by R ⁴ . Examples of the protecting group for the optionally protected amino group represented by R ¹⁴ include the same groups as those described above for R ¹ .

In the compound (V) obtained by the method of the present invention, the compound wherein R ¹ is an acylated amino group,

Embedded image (Each symbol in the formula is as defined above) or a salt thereof, has a broad antibacterial spectrum and excellent antibacterial activity against Gram-negative bacteria including Pseudomonas and Gram-positive bacteria including Staphylococcus and MRSA. It has an action and is useful as an antibacterial agent against infectious diseases based on these bacteria (PCT International Publication WO96 / 2379).
No. 8, PCT International Publication WO96 / 38451).

[0052]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. Example 1 Preparation of 7β-tert-butoxycarbonylamino-3- (2-dimethylamino) vinyl-3-cephem-4-carboxylic acid benzhydryl ester: JP-A-55-1549
81β-tert-butoxycarbonylamino-3-methyl-3-cephem-4-carboxylic acid benzhydryl ester (4.78 g) prepared in a similar manner to that described in Example 1 of JP-A-81-81, -Methylpyrrolidone (90m
1) and heated to 45 ° C. under a stream of argon. While stirring, tris (dimethylamino) methane (3.4m
1) was added dropwise over 3.5 hours, and the mixture was reacted at the same temperature for another 20 minutes. The reaction solution was cooled on ice, and ethyl acetate (100 m
1) and saturated saline (300 ml) were added to carry out liquid separation, and the aqueous layer was extracted three times with ethyl acetate (70 ml) each. The ethyl acetate layers were combined, and a saturated aqueous ammonium chloride solution (100 ml)
Each was washed three times. Quantification of the ethyl acetate extract by high performance liquid chromatography (HPLC) confirmed the formation of 5.10 g (yield: 95.7%) of the title compound. Further, NMR of a light brown foam obtained by drying a part of the ethyl acetate extract to dryness was confirmed, and it was confirmed that the product was only 体³ . ¹ H-NMR (CDCl ₃ , δ): 1.49 (9H, s), 2.89 (6H, s),
3.18 (2H, m), 5.07 (1H, d, J = 4Hz), 5.29 (1H, dd, J = 4Hz, 8H
z), 5.66 (1H, d, J = 8Hz), 6.50 (1H, d, J = 13.5Hz), 6.75 (1
(H, d, J = 13.5Hz), 6,87 (1H, s), 7.2-7.6 (10H, m)

Example 2 Preparation of 7β-tert-butoxycarbonylamino-3-formylmethyl-3-cephem-4-carboxylic acid benzhydryl ester: 7β-tert-butoxycarbonylamino-3- prepared in Example 1 (2-Dimethylamino) vinyl-3-cephem-4-carboxylic acid benzhydryl ester (198 mg) was dissolved in acetonitrile (10 ml), 1 mol of phosphoric acid (2 ml) was added, and 35 ° C.
And stirred for 3.5 hours. Ethyl acetate (30m
l) and saturated saline (30 ml) were added, and the mixture was stirred and then separated to remove the aqueous layer.
0 ml), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a candy-like residue. Use ethyl acetate (10m
l) and ice-cooled isopropyl ether (50 m
l) It was dripped slowly while stirring. The obtained slurry was stirred for 1 hour, heated to room temperature, and then filtered. Wash the obtained cake with isopropyl ether,
After air-drying, the residue was dried under reduced pressure on silica gel to obtain the title compound (190 mg) as a pale brown powder. This product is subjected to silica gel column chromatography (ethyl acetate-hexane =
1: 1) to give the title compound (16) as a pale brown powder.
1 mg, yield 85.8%). ¹ H-NMR (CDCl ₃ , δ): 1.47 (9H, s), 2,85-3.7
3 (2H, m), 3.24 & 3.58 (2H, ABq, J = 18.2Hz), 4.99 (1H, d, J =
4.8Hz), 5.30 (1H, d, J = 9.7), 5.66 (1H, dd, J = 4.8Hz, 9.7H
z), 6.88 (1H, s), 7.22-7.48 (10H, m), 9.55 (1H, s).

Example 3 7β-tert-butoxycarbonylamino-3-[(E)-
2- (4-pyridyl) thiovinyl] -3-cephem-4-
Preparation of carboxylic acid benzhydryl ester: 7β-tert-butoxycarbonylamino-3-formylmethyl-3-cephem-4-carboxylic acid benzhydryl ester (998 mg) obtained by the method described in Example 2 was N-methyl. Dissolve in pyrrolidone (15 ml) and add water
(17.5 μL) and stirred for 10 minutes. Then 4
-Pyridyl disulfide (810 mg) was added and dissolved, and then cooled to -23 ° C. Tri-n-butylphosphine (0.95 ml) was added to the solution, and the mixture was added at -23 to -15 ° C.
Stir for hours. Ice chips (150 g), ethyl acetate
(150 ml) and a saturated saline solution (50 ml), and the mixture was stirred and separated. The aqueous layer was further treated with ethyl acetate (50
ml). Combine the ethyl acetate layers and add saturated saline
(50 ml) twice. H of ethyl acetate extract
By quantification by PLC, 891.4 mg of the title compound (7
5.5%). ¹ H-NMR (CDCl ₃ , δ): 1.47 (9H, s), 3.59 & 3.71 (2H, A
Bq, J = 18Hz), 5.02 (1H, d, J = 4.8Hz), 5.32 (1H, d, J = 9.6H
z), 5.65 (1H, dd, J = 4.8Hz, 9.6Hz), 6.66 (1H, d, J = 15.6H
z), 6.99 (1H, s), 7.17 (2H, dd, J = 1.6Hz, 4.6Hz), 7.3-7.5
(10H, m), 8.47 (2H, dd, J = 1.6Hz, 4.6Hz).

Example 4 7β-tert-butoxycarbonylamino-3-[(E)-
Preparation of 2- (imidazo [1,2-b] pyridazin-6-yl) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester: 7β-tert-butoxy obtained by the method described in Example 2. Carbonylamino-3-formylmethyl-3-cephem-4-carboxylic acid benzhydryl ester (225 mg) was dissolved in N, N-dimethylformamide, and the mixture was dissolved in a stream of argon at 0 ° C. with 6-imidazo [1,2-
b] Pyridazinyl disulfide (300 mg) and then tri-n-butylphosphine (0.27 ml) were added and reacted at the same temperature for 1 hour. Ethyl acetate (30 ml) was added to the reaction solution,
Ice chips (20 g) and saturated saline (20 ml) were added to carry out liquid separation. The ethyl acetate layer was washed twice with saturated saline (20 ml) each. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. The oily residue was dissolved in isopropyl ether (20 ml), cooled on ice, and hexane (30 ml) was added. The precipitated precipitate was filtered and dried to give 240 mg of the title compound (8
(4.5%) as a yellow powder. ¹ H-NMR (CDCl ₃ , δ): 1.48 (9H, s), 3.68 & 3.81 (2H, A
Bq, J = 18Hz), 5.04 (1H, d = 4.8Hz), 5.37 (1H, d, J = 9.6Hz),
5.67 (1H, dd, J = 4.8Hz, 9.6Hz), 6.85 (1H, d, J = 9.4Hz), 6.9
9 (1H, s), 7.2-7.6 (10H, m), 7.72 (1H, s), 7.82 (1H, d, J =
9.4Hz), 7.93 (1H, s).

Example 5 7β-tert-butoxycarbonylamino-3-[(E)
Production of (4-pyridyl) thiovinyl] -3-cephem-4-carboxylic acid benzhydryl ester:
7β-tert-butoxycarbonylamino-3-methyl-3-cephem-4-carboxylic acid benzhydryl ester (4.78 g) prepared in a manner similar to that described in Example 1 of US Pat. -Methylpyrrolidone (0.90 L), tris (dimethylamino) methane (3.2 ml) was added under a nitrogen stream at 44 to 46 ° C over 4 hours, and the mixture was stirred at the same temperature for 30 minutes. . The reaction solution was added to ice water (1.25 kg) with stirring.
A saturated ammonium chloride solution (0.2 L) was added, and ethyl acetate was added 5 times (0.7 L, 0.5 L, 0.3 L, respectively).
0.2L, 0.2L). The extract was washed three times with a mixture of water (0.3 L each) and a saturated ammonium chloride solution (0.05 L each), the washing was extracted with ethyl acetate (0.2 L), and the extract was washed with water (0.2 L). ) And a saturated ammonium chloride solution (0.05 L). The ethyl acetate extracts were combined, evaporated to dryness, dissolved in ethyl acetate (1.5 L) and filtered. 10% phosphoric acid (0.35 L) was added to the filtrate and reacted at 35 ° C. for 2 hours. The aqueous layer was separated and the organic layer was combined with water (0.2 L each) and saturated ammonium chloride solution (0.2 L).
(0.4 L each), the washing solution and the above aqueous layer were combined, extracted with ethyl acetate (0.1 L), and the extract was washed with water (0.1 L).
2L) and a saturated ammonium chloride solution (0.04L). The organic layers were combined, washed with a saturated ammonium chloride solution (0.05 L), and then dried over anhydrous sodium sulfate (40 L).
g) and then evaporated to dryness. The dried product was dissolved in N-methylpyrrolidone (0.46 L), and 4-mercaptopyridine disulfide (26.9 g) was added in a dark place.
After adding water (0.3 ml) under a nitrogen stream, tri-n-butylphosphine (28 ml) was added dropwise over 5 minutes while cooling and stirring at -25 ° C, and then -16 to -25 ° C.
For 1 hour. The reaction solution was added to 1 kg of ice water with stirring, water (0.5 L) and a saturated ammonium chloride solution (0.2 L) were added, and the mixture was added four times with ethyl acetate (0.5 L, 0.3 L, 0. .2L, 0.2L).
The extract was washed three times with a mixture of water (0.2 L) and a saturated ammonium chloride solution (0.4 L), dried over anhydrous sodium sulfate and evaporated to dryness to give the crude title compound (47) as a pale brown foam. .26 g). This product (178 mg) was purified by silica gel column chromatography (ethyl acetate-hexane = 3: 2) to give the title compound (172 mg) as a pale brown foam. This product is compatible with NMR and HPLC
As a result of measurement, the product contained 91.3% of the title compound (total yield: 63.1%). ¹ H-NMR (CDCl ₃ , δ): 1.47 (9H, s), 3.59 & 3.70 (2H, A
Bq, J = 18.0Hz), 5.02 (1H, d, J = 4.8Hz), 5.36 (1H, d, J = 9.6H
z), 5.60 (1H, dd, J = 4.8Hz, 9.6Hz), 6.66 & 7.35 (2H, ABq, J =
15.4Hz), 6.98 (1H, s), 7.15-8.48 (14H, m).

[0057]

According to the preparation of the present invention, fewer steps, by-product is extremely small in △ ² body in the cephem ring.
Therefore, the method of the present invention has a specific configuration,
This is an advantageous method for industrially producing a cephalosporin derivative having an excellent antibacterial action.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 501/36 109 C07D 501/36 109 501/40 501/40 // A61K 31/545 ADZ A61K 31/545 ADZ

Claims (5)

[Claims] 1. A compound of the general formula [Wherein R ¹ represents a protecting group for an amino group or an acyl group via a carbon atom, a sulfur atom or a silicon atom, and R ² represents a protecting group for a carboxyl group, respectively]. General formula characterized by reacting with amino) methane [The symbols in the formula are as defined above] or a method for producing a salt thereof. 2. The process according to claim 1, wherein R ¹ represents t-butoxycarbonyl and R ² represents benzhydryl. 3. The process according to claim 1, wherein the reaction is carried out in the presence of an amide solvent. 4. The method according to claim 3, wherein the amide solvent is N-methylpyrrolidone. 5. A compound of the general formula Wherein R ¹ represents a protecting group for an amino group or an acyl group via a carbon atom, a sulfur atom or a silicon atom, and R ² represents a protecting group for a carboxyl group. Reaction with amino) methane [The symbols in the formula have the same meanings as described above] or a salt thereof, and the obtained compound is subjected to a hydrolysis reaction to give a compound represented by the general formula: Wherein each symbol in the formula is as defined above, or a salt thereof, and then reacting the obtained compound or a salt thereof with a disulfide compound in the presence of a phosphorus compound. General formula [In the formula, R ⁴ represents a group via a sulfur atom. The other symbols have the same meaning as described above. ] Or a salt thereof.